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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

 

    ENVIRONMENTAL HEALTH CRITERIA 89




    FORMALDEHYDE









    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1989


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    WHO Library Cataloguing in Publication Data

    Formaldehyde.

        (Environmental health criteria ; 89)

        1.Formaldehyde
        I.Series

        ISBN 92 4 154289 6        (NLM Classification: QV 225)
        ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR FORMALDEHYDE

1. SUMMARY AND CONCLUSIONS

    1.1. Physical and chemical properties, and analytical methods
    1.2. Sources of human and environmental exposure
    1.3. Environmental transport, distribution, and transformation
    1.4. Environmental levels and human exposure          
    1.5. Kinetics and metabolism          
    1.6. Effects on organisms in the environment          
    1.7. Effects on experimental animals          
    1.8. Effects on man                   

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1. Identity                         
    2.2. Physical and chemical properties                 
    2.3. Conversion factors               
    2.4. Analytical methods               

3. SOURCES IN THE ENVIRONMENT               

    3.1. Natural occurrence               
    3.2. Man-made sources                 
         3.2.1. Production levels and processes          
                3.2.1.1  World production figures                 
                3.2.1.2  Manufacturing processes          
         3.2.2. Uses                     
                3.2.2.1  Aminoplastics (urea-formaldehyde resins and 
                         melamine formaldehyde resins           
                3.2.2.2  Phenolic plastics (phenol formaldehyde resins)
                3.2.2.3  Polyoxymethylene (polyacetal plastics)                
                3.2.2.4  Processing formaldehyde to other compounds
                3.2.2.5  Medical and other uses           
         3.2.3. Sources of indoor environmental exposure                 

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION                   

    4.1. Transport, and distribution              
    4.2. Transformation                   
         4.2.1. Special products of degradation under specific conditions
         4.2.2. Microbial degradation            

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE          

    5.1. Environmental levels             
         5.1.1. Air                      
                5.1.1.1  Air in the vicinity of industrial sources and 
                         in urban communities                 
                5.1.1.2  Emissions from industrial plants                 
                5.1.1.3  Emissions from furnaces          
                5.1.1.4  Emissions from motor vehicles            

         5.1.2. Water     
         5.1.3. Soil      
         5.1.4. Food      
    5.2. Indoor air levels
         5.2.1. Indoor exposure from particle boards             
         5.2.2. Indoor air pollution from urea-formaldehyde foam 
                insulation (UFFI)           
         5.2.3. Indoor air pollution from phenol-formaldehyde plastics
         5.2.4. Exposure to indoor air containing cigarette smoke          
    5.3. General population exposure              
         5.3.1. Air             
                5.3.1.1  Smoking
         5.3.2. Drinking-water  
         5.3.3. Food            
         5.3.4. Other routes of exposure                 
    5.4. Occupational exposure            

6. KINETICS AND METABOLISM          

    6.1. Absorption                       
         6.1.1. Inhalation               
                6.1.1.1  Animal data              
                6.1.1.2  Human data               
         6.1.2. Dermal                   
         6.1.3. Oral                     
    6.2. Distribution                     
    6.3. Metabolic transformation                 
    6.4. Elimination and excretion                
    6.5. Retention and turnover           

7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT          

    7.1. Microorganisms       
    7.2. Aquatic organisms    
    7.3. Terrestrial organisms
    7.4. Plants               

8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

    8.1. Skin and eye irritation; sensitization
    8.2. Single exposures         
    8.3. Short-term exposures     
         8.3.1. Inhalation studies
         8.3.2. Oral studies      
    8.4. Long-term exposure and carcinogenicity
         8.4.1. Inhalation    
         8.4.2. Dermal studies
         8.4.3. Oral studies  
    8.5. Mutagenicity and related end-points   
    8.6. Reproduction, embryotoxicity, and teratogenicity
    8.7. Mechanisms of carcinogenicity           
         8.7.1. Reactions with macromolecules    
         8.7.2. Cytotoxicity and cell proliferation      

9. EFFECTS ON MAN                  

    9.1. Sources of exposure        
    9.2. General population exposure
         9.2.1. Sensory effects     
         9.2.2. Toxic effects       
         9.2.3. Respiratory effects 
         9.2.4. Dermal, respiratory tract, and systemic sensitization
                9.2.4.1  Mucosal effects
                9.2.4.2  Skin effects   
                9.2.4.3  Respiratory tract sensitization
                9.2.4.4  Systemic sensitization         
                         9.2.4.4.1  Allergic reaction following the
                                    dental use of paraformaldehyde
         9.2.5. Skin irritation         
         9.2.6. Genotoxic effects       
         9.2.7. Effects on reproduction 
         9.2.8. Other observations in exposed populations
         9.2.9. Carcinogenic effects            

10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

    10.1. Evaluation of human health risks         
    10.2. Evaluation of effects on the environment 
    10.3. Conclusions                     

11. RECOMMENDATIONS                 

    11.1. Recommendations for future research      
    11.2. Recommendations for preventive measures  

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES   

REFERENCES                                         

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR FORMALDEHYDE

 Members 

Professor  O. Axelson, Department of  Occupational Medicine, University
   Hospital, Linköping, Sweden
Dr Birgitta   Berglund,   Department   of  Psychology,   University  of
   Stockholm, Stockholm, Sweden
Professor  D. Calamari, Institute  of  Agricultural Entomology, Faculty
   of Agriculture, Milan, Italy ( Vice-Chairman )
Dr Ildiko Farkas, National Institute of Hygiene, Budapest, Hungary
Dr V.J. Feron, TNO-CIVO Toxicology and Nutrition Institute,  AJ  Zeist,
   Netherlands
Dr O.J. Grundler, BASF AG, Ludwigshafen, Federal Republic of Germany
Professor J.M. Harrington, Institute of Occupational Health, University
   of Birmingham, Birmingham, United Kingdom
Dr H.D.  Heck,  Chemical  Industry Institute   of  Toxicology, Research
   Triangle Park, USA
Dr R.F.  Hertel,  Fraunhofer  Institute  for  Toxicology  and   Aerosol
   Research, Hanover, Federal Republic of Germany ( Rapporteur )
Professor F. Klaschka, Department of Dermatology, Clinic and Polyclinic
   in  the  Steglitz Clinic  of the Free  University of Berlin,  Berlin
   (West)
Dr Y.  Kurokawa, Division of Toxicology, National Institute of Hygienic
   Sciences, Tokyo, Japan
Dr Mathuros Ruchirawat, Department of Pharmacology, Faculty of Science,
   Mahidol University, Bangkok, Thailand
Dr A.  Schaich Freis, Danish National Institute of Occupational Health,
   Copenhagen, Denmark
Dr A. Shaker, Environmental and Occupational Health Center, Ministry of
   Health, Cairo, Egypt
Dr J.A.J.  Stolwijk, Department of Epidemiology and Public Health, Yale
   University School of Medicine, New Haven, USA ( Chairman )
Dr U.  Thielebeule, Bezirks Hygiene  Inspection, Rostock, German  Demo-
   cratic Republic

 Observers 

Dr J.C.  Aubrun, (representing the  European Council of  Chemical Manu-
   facturers) Courbevoie, France
Dr A. Basler, Federal Health Office, Berlin (West)
Dr J.-C.  Berger,  Health and  Safety  Directorate, Commission  of  the
   European Communities, Luxembourg
Dr M.A. Cooke, University of Aston, Birmingham, United Kingdom
Mr W.R.  Gaffey  (representing  Formaldehyde Institute),  Department of
   Medicine and Environmental Health, Monsanto Company, St. Louis, USA
Dr P. Messerer, BASF AG, Occupational Medicine and  Health  Protection,
   Ludwigshafen, Federal Republic of Germany
Dr M.G.  Penman  (representing  the European  Chemical Industry Ecology
   and   Toxicology   Centre),  ICI,   Central  Toxicology  Laboratory,
   Macclesfield, United Kingdom
Dr N. Petri, BASF AG, Ludwigshafen, Federal Republic of Germany
Mr V.  Quarg, Federal Ministry for Environment, Nature Conservation and
   Nuclear Safety, Bonn, Federal Republic of Germany

Dr A.G.  Smith (representing the European Chemical Industry Ecology and
   Toxicology Centre), Ciba Geigy (UK), Macclesfield, United Kingdom
Dr K.  Ulm, Institute for  Medical Statistics and  Epidemiology of  the
   Technical University of Munich, Munich, Federal Republic of Germany
Dr G.  Vollmer, Federal Ministry  for Environment, Nature  Conservation
   and Nuclear Safety, Bonn, Federal Republic of Germany

 Secretariat 

Dr D.  Kello, Environmental Health Division, World Health Organization,
   Regional Office for Europe, Copenhagen, Denmark
Dr E. Smith, International Programme on Chemical Safety,  World  Health
   Organization, Geneva, Switzerland
Dr Linda  Shuker,  Division  on  Environmental  Carcinogenesis,  Inter-
   national Agency for Research on Cancer, Lyons, France

NOTE TO READERS OF THE CRITERIA DOCUMENTS

    Every effort has been made to present information in  the  criteria
documents  as accurately as possible without unduly delaying their pub-
lication. In the interest of all users of the environmental health cri-
teria documents, readers are kindly requested to communicate any errors
that may have occurred to the Manager of the International Programme on
Chemical  Safety,  World  Health Organization,  Geneva, Switzerland, in
order  that they may  be included in  corrigenda, which will  appear in
subsequent volumes.



                              *    *    *



    A detailed data profile and a legal file can be obtained  from  the
International  Register  of  Potentially Toxic  Chemicals,  Palais  des
Nations,  1211  Geneva  10,  Switzerland  (Telephone  no.   7988400   -
7985850).


ENVIRONMENTAL HEALTH CRITERIA FOR FORMALDEHYDE

    A  WHO Task Group on Environmental Health Criteria for Formaldehyde
met  at the Fraunhofer Institute  for Toxicology and Aerosol  Research,
Hanover,  Federal  Republic of  Germany, from 9  to 13 November,  1987.
Professor U. Mohr opened the meeting and welcomed the members on behalf
of the host Institute, and Dr G. Vollmer spoke on behalf of the Federal
Government,  which sponsored the meeting. Dr D. Kello, opened the meet-
ing  on behalf of the Director-General, World Health  Organization  and
Dr  E. Smith addressed the  meeting on behalf of  the three cooperating
organizations  of the IPCS (UNEP/ILO/WHO).  The Task Group reviewed and
revised the draft criteria document and made an evaluation of the risks
for human health and the environment of exposure to formaldehyde.

    The  drafts of this  document were prepared  by DR R.F.  HERTEL and
DR  G. ROSNER of  the Fraunhofer Institute  for Toxicology and  Aerosol
Research, Hanover, Federal Republic of Germany. Available international
and   national  reviews  of  formaldehyde  were  consulted  during  the
preparation  of the criteria document  and are listed in  the Appendix.
Dr E.  Smith of the IPCS  Central Unit was responsible  for the overall
scientific contents of the document and Mrs M.O. Head of Oxford for the
editing.

    The efforts of all who helped in the preparation  and  finalization
of the document are gratefully acknowledged.


                                 * * *


    Partial  financial  support for  the  publication of  this criteria
document  was kindly provided by the United States Department of Health
and Human Services, through a contract from the National  Institute  of
Environmental  Health Sciences, Research Triangle Park, North Carolina,
USA  - a WHO Collaborating Centre for Environmental Health Effects. The
United Kingdom Department of Health and Social Security also generously
contributed to the costs of printing.

1. SUMMARY AND CONCLUSIONS

1.1  Physical and Chemical Properties, and Analytical Methods

    Formaldehyde is a flammable, colourless and readily polymerized gas
at ambient temperatures. The most common commercially available form is
a 30-50% aqueous solution.  Formaldehyde is readily soluble  in  water,
alcohols,  and other polar solvents, but has a low degree of solubility
in non-polar fluids.

    Methanol  or other substances are usually added to the solutions as
stabilizers to reduce intrinsic polymerization.

    Formaldehyde decomposes at 150 °C into methanol and  carbon  monox-
ide;  in general it  is highly reactive  with other chemicals.  In sun-
light, it is readily photo-oxidized to carbon dioxide.  It has  a  very
low  n -octanol/water   partition  coefficient as  well  as a  low  soil-
absorption   coefficient.  The  Henry  constant is relatively  high  at
0.02 Pa x m3/mol.

    Chemical  analysis for formaldehyde involves direct extraction from
solid and liquid samples while absorption and/or concentration  by  ac-
tive  (filtration) or passive (diffusion) sampling is necessary for air
samples.  A variety of absorbants is available.  The most  widely  used
methods of analysis are based on photometric determination. Low concen-
trations in air can be detected, after appropriate absorption, by means
of high performance liquid chromatography.

1.2  Sources of Human and Environmental Exposure

    Formaldehyde is present in the environment as a result  of  natural
processes  and from man-made sources.  It is formed in large quantities
in  the troposphere by  the oxidation of  hydrocarbons.  Minor  natural
sources  include the decomposition of plant residues and the transform-
ation of various chemicals emitted by foliage.

    Formaldehyde  is produced industrially in large quantities and used
in  many applications. Two other important man-made sources are automo-
tive exhaust from engines without catalytic converters,  and  residues,
emissions, or wastes produced during the manufacture of formaldehyde or
by materials derived from, or treated with it.

    It has been calculated that the average rate of  global  production
from methane in the troposphere is of the order  of  4 x 1011 kg/year,
while  the total industrial production  in recent years has  been about
3.5 x 109 kg/year;    the emission from automotive engines has not been
quantifiable on a global basis.

    Formaldehyde has a variety of uses in many industries, it has medi-
cal applications as a sterilant and is used as a preservative  in  con-
sumer  products,  such  as  food,  cosmetics,  and  household  cleaning
agents.

    One of the most common uses is in urea-formaldehyde  and  melamine-
formaldehyde  resins.   Urea-formaldehyde  foam  is  used  to  insulate

buildings  (UFFI); it can continue  to emit formaldehyde after  instal-
lation  or constituting a source of persistent emission. Phenolic plas-
tics  and polyacetal plastics are also important fields of application,
but are not expected to release formaldehyde.

    There are several indoor environmental sources that can  result  in
human  exposure  including  cigarettes and  tobacco products, furniture
containing  formaldehyde-based  resins,  building materials  containing
urea-formaldehyde  resins,  adhesives containing  formaldehyde used for
plastic  surfaces  and  parquet, carpets,  paints,  disinfectants,  gas
cookers, and open fireplaces.

    Indoor  areas of special  importance are hospitals  and  scientific
facilities where formaldehyde is used as a sterilizing  and  preserving
agent,  and living spaces, such  as schools, kindergartens, and  mobile
homes  or  apartments  where there  may  be  uncontrolled emissions  of
formaldehyde from tobacco smoking, building materials, and furniture.

1.3  Environmental Transport, Distribution, and Transformation

    Air  is the most  relevant compartment in  the formaldehyde  cycle,
most  of  the production  and/or  emissions, and  degradation processes
occurring in the atmosphere.

    Photolysis  and  reaction  with hydroxyl  radicals  rapidly  remove
formaldehyde  from the atmosphere.   The calculated half-life  of  each
process  is a matter of  hours, according to environmental  conditions.
Transport  of formaldehyde  over distances  is probably  not  of  great
importance,  nevertheless  some  organic compounds  (air  pollutants or
natural) from which formaldehyde can be derived are more stable and can
contribute  to  the formation  of  formaldehyde over  considerable dis-
tances.  The compound can be dissolved in the atmosphere in  cloud  and
rainwater and can be adsorbed as an atmospheric aerosol.

    The  value of  the Henry  constant suggests  that  formaldehyde  in
aqueous  solution is less volatile  than water and that  volatilization
from  an aquatic environment is not expected under normal environmental
conditions. The high water solubility and the low  n -octanol/water  par-
tition  coefficient  suggest that  adsorption  on suspended  solids and
partition in sediments is not significant.  In water,  formaldehyde  is
rapidly (days) biodegraded by several species of  microorganisms,  pro-
vided the concentration is not too high. Formaldehyde is  also  readily
biodegradable in the soil. Because the soil adsorption  coefficient  is
very low, leaching occurs easily and mobility in soil is very high.

    As it has a low  n -octanol-water  partition coefficient  (log  Pow),
formaldehyde  is not be expected to bioaccumulate in aquatic organisms.
Furthermore,  aquatic organisms are able to metabolize and transform it
through various metabolic pathways.

1.4  Environmental Levels and Human Exposure

    Air  concentrations of formaldehyde,  near the ground  in  coastal,
mountain, or oceanic areas, ranged from 0.05 to 14.7 µg/m3,     and the
majority  of concentrations were within the range 0.1-2.7 µg/m3.     In

the   presence   of   man-made inputs,  but  away  from any  industrial
plants, mean values ranged from 7 to 12 µg/m3 with    a few peaks up to
60-90 µg/m3.      Data from different parts  of the world were  in good
agreement.

    Rain   water  contains  110-174 µg/litre     with peaks as  high as
310-1380 µg/litre.

    Emissions  of  formaldehyde  from industrial  processes vary widely
according  to the types of industry. A considerable amount of formalde-
hyde  comes from  the exhaust  emissions of  motor vehicles,  but  this
varies greatly according to country and the grade of fuel.

    There is some natural formaldehyde in raw food, levels ranging from
1  mg/kg up to 90 mg/kg, and accidental contamination of food may occur
through  fumigation, the  use of  formaldehyde as  a  preservative,  or
through cooking.

    Tobacco  smoke  as well  as  urea-formaldehyde foam  insulation and
formaldehyde-containing  disinfectants  are  all important  sources  of
indoor formaldehyde.

    Indoor  air levels (non-workplace), measured  in various countries,
depended  on several factors, but mainly on the age of the building and
the  building materials, the type of construction, and the ventilation.
They  varied widely with different  situations, but most ranged  from a
minimum of 10 µg/m3 up   to a maximum of 4000 µg/m3.     In some cases,
low values were found in rooms with substantial sources of formaldehyde
emission.   Disinfection  of areas  of  hospitals produced  the highest
levels, up to 20 000 µg/m3,     but the personnel carrying  out  disin-
fection  wear protective equipment and the areas are not occupied until
formaldehyde levels have fallen to 1.2 mg/m3 (1 ppm)  and below. Levels
in rooms in which there is tobacco smoking can exceed 100 µg/m3.

    The  contributions of various atmospheric environments to the aver-
age human daily intake has been calculated to be 0.02 mg/day  for  out-
door air, 0.5-2 mg/day for indoor conventional buildings, < 1-10 mg/day
for  buildings with sources  of formaldehyde, 0.2-0.8 mg/day  for  work
places  without  occupational use  of  formaldehyde, 4 mg/day  for work
places  using  formaldehyde,  and 0-1 mg/day  for environmental tobacco
smoke.   Smoking 20  cigarettes per  day corresponds  to an  intake  of
1 mg/day through inhalation.

    The  formaldehyde  concentration  in  drinking-water  is  generally
about 0.1 mg/litre resulting in a mean daily intake of 0.2 mg/day.  The
quantity of formaldehyde ingested in food depends on the composition of
the meal and, for an average adult, may range from 1.5 to 14 mg/day.

1.5  Kinetics and Metabolism

    Formaldehyde  is readily absorbed  in the respiratory  and  gastro-
intestinal tracts. Dermal absorption of formaldehyde appears to be very
slight.  Increases in blood concentrations of formaldehyde were not de-
tected  in rats or human  beings exposed to formaldehyde  through inha-
lation, because of rapid metabolism.

    The  metabolites  of  formaldehyde are  incorporated into macromol-
ecules  via one-carbon pathways  or are eliminated  in the expired  air
(CO2)   and urine.  Formaldehyde that escapes metabolism can react with
macromolecules at the site of entry.  DNA-protein cross-links have been
detected  in  tissues  exposed directly  to  formaldehyde,  but not  in
tissues remote from the absorption site.

1.6  Effects on Organisms in the Environment

    Formaldehyde is used as a disinfectant to kill  viruses,  bacteria,
fungi,  and parasites,  but it  is only  effective at  relatively  high
concentrations.

    Algae,  protozoa,  and  other unicellular  organisms are relatively
sensitive  to  formaldehyde  with  acute  lethal concentrations ranging
from 0.3 to 22 mg/litre. Aquatic invertebrates showed a wide  range  of
responses; some crustaceans are the most sensitive with  median  effec-
tive  concentration (EC50)   values ranging from 0.4 to 20 mg/litre. In
96-h  tests on  several fish  species, the  LC50 of   formaldehyde  for
adults  ranged from a minimum of about 10 mg/litre to a maximum of sev-
eral hundred mg/litre; most species showed LC50 values  in the range of
50-100 mg/litre.   The responses of  various species of  amphibians are
similar  to  those  of fish  with  median  acute lethal  concentrations
(LC50) ranging from 10 to 20 mg/litre for a 72-h exposure.

    No data are available on long-term aquatic studies.

    Eggs  and larvae of  some cattle parasites  were killed by  formal-
dehyde  solution (1-5%) and some  nematodes by a 37%  solution, whereas
other  nematodes  were  unaffected.  In  ruminant mammals, formaldehyde
protects  dietary protein from microbial  proteolysis in the rumen  and
increases the efficiency of utilization of amino acids.

    Few  data are available on  the effects of formaldehyde  on plants.
However, from the agricultural use of urea-formaldehyde fertilizers, it
appears  that,  at  recommended concentrations,  formaldehyde  does not
alter  nitrogen and carbohydrate  metabolism in plants,  but that  high
doses have negative effects on soil metabolism.   Formaldehyde  impairs
pollen germination.

1.7  Effects on Experimental Animals

    Acute  inhalation exposure of rats and mice to formaldehyde at very
high   concentrations  (120 mg/m3)    produced   salivation,  dyspnoea,
vomiting,  spasms, and death.  At  a concentration of 1.2 mg/m3,    eye
irritation,  decreased  respiratory rate,  increased airway resistance,
and  decreased  compliance appeared.   Mice  were more  sensitive  than
rats.

    Short-term,  repeated  exposures  (7-25 mg/m3)   of  rats  produced
histological  changes in the  nasal epithelium, such  as cell  degener-
ation,  inflammation, necrosis, squamous metaplasia, and increased cell
proliferation.

    There is growing evidence that it is concentration rather than dose
that  determines the  cytotoxic effects  of formaldehyde  on the  nasal
mucosa  of rats;  concentrations below  1 mg/m3 do  not  lead  to  cell
damage and hyperplasia.

    Dose-related  lesions  observed  in long-term,  repeated inhalation
exposure  (2.4, 6.7, or 17.2 mg/m3)   were dysplasia and squamous meta-
plasia of the respiratory and olfactory epithelia, which  regressed  to
some extent after cessation of exposure.

    Formaldehyde  produced  nasal  squamous  cell  carcinomas  in  rats
exposed to high concentrations (17.2 mg/m3),   which also caused severe
tissue  damage.  The concentration - response curve  was extremely non-
linear with a disproportionate increase in tumour incidence  at  higher
concentrations.  A low, but not statistically significant, incidence of
nasal  tumours occurred at 6.7 mg/m3.    No tumours were found at other
sites. Mice developed squamous cell carcinomas of the nasal cavity with
long-term  exposure to 17.2 mg/m3,   but this finding was not statisti-
cally significant.  No tumours were found at other sites.   No  tumours
were found in hamsters.

    Long-term  oral  administration  of formaldehyde  (0.02-5%  in  the
drinking-water)  to rats was  found to induce  papillomas in the  fore-
stomach.

    Several skin initiation/promotion studies with formaldehyde did not
produce  evidence of  skin carcinogenicity  in mice;  the results  with
respect to promotion were either negative or inconclusive.

1.8  Effects on Man

    Formaldehyde  has a pungent odour detectable at low concentrations,
and  its vapour and solutions are known skin and eye irritants in human
beings.   The common effects of formaldehyde exposure are various symp-
toms  caused by irritation of the mucosa in the eyes and upper airways.
In the non-industrial indoor environment, sensory reactions are typical
effects, but there are large individual differences in the normal popu-
lation and between hyperreactive and sensitized people.

    There  are  a few  case reports of  asthma-like symptoms caused  by
formaldehyde,  but none of  these demonstrated a  sensitization  effect
(neither Type I nor Type IV) and the symptoms were considered to be due
to  irritation.  Skin  sensitization is  induced only  by  direct  skin
contact  with  formaldehyde  solutions in  concentrations  higher  than
20 g/litre (2%).  The lowest patch test challenge concentration  in  an
aqueous solution reported to produce a reaction in  sensitized  persons
was 0.05% formaldehyde.

    The available human evidence indicates that formaldehyde  does  not
have  a high carcinogenic potential.  While some studies have indicated
an excess of cancer in exposed individuals or populations,  only  nasal
or  nasopharyngeal tumours are likely to be causally related to formal-
dehyde exposure.

    Formaldehyde  does not have any adverse effects on reproduction and
is not teratogenic.

    Formaldehyde  in  vitro interferes with DNA  repair in human  cells,
but there are no data relating to mutagenic outcomes.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1  Identity

Chemical formula:       CH2O  [HCHO]

Chemical structure:     H
                        |
                        C = O
                        |
                        H

CAS registry number:    50-00-0

RTECS registry number:  LP 8925000

UN number:              1198, 2209, 2213

EC numbers:             605-001-01 (solution 5% to < 25%)
                        605-001-02 (solution 1% to < 5%)
                        605-001-005 (solution > 25%)

IUPAC name:             Methanal

Common synonyms:        formaldehyde,  methanal,  methylene  oxide,
                        oxymethylene, methylaldehyde, oxomethane

Common names for solutions
of formaldehyde:        Formalin, Formol

    Formaldehyde is a colourless gas at normal temperature  and  press-
ure, with a relative molecular mass of 30.03.

    The  most common commercially  available form is  a 30-50%  aqueous
solution.  Methanol or other substances  are usually added to  the sol-
ution  as stabilizers to  reduce intrinsic polymerization.  The concen-
tration  of methanol  can be  up to  15%.  The  concentration of  other
stabilizers  is  of the  order  of several  100 mg/litre.  Concentrated
liquid formaldehyde-water systems containing up to 95% formaldehyde are
obtainable,  but  the temperature  necessary  to maintain  solution and
prevent separation of polymer increases from around room temperature to
120 °C as the solution concentration increases.

    In  solid  form, formaldehyde  is  marketed as  trioxane (CH2O)3,
and  its polymer, paraformaldehyde,  with 8-100 units of  formaldehyde.
Paraformaldehyde has become technologically important.

2.2  Physical and Chemical Properties

    Formaldehyde  is  a  flammable, colourless,  reactive,  and readily
polymerized  gas at  normal temperature.   The heat  of combustion  for
formaldehyde  gas is 4.47 Kcal per  gram.  It forms explosive  mixtures
with  air and oxygen at atmospheric pressure.  Flammability is reported
to  range from 12.5 to  80 volume %, a  65-70% formaldehyde-air mixture
being the most readily flammable.

    Formaldehyde is present in aqueous solutions as a hydrate and tends
to polymerize.  At room temperature and a formaldehyde content  of  30%
and more, the polymers precipitate and render the solution turbid.

    Formaldehyde  decomposes  into  methanol  and  carbon  monoxide  at
temperatures  above 150 °C, although uncatalysed  decomposition is slow
below 300 °C.

    Under   atmospheric  conditions,  formaldehyde  is  readily  photo-
oxidized in sunlight to carbon dioxide.  It reacts  relatively  quickly
with trace substances and pollutants in the air so that  its  half-life
in urban air, under the influence of sunlight, is short. In the absence
of  nitrogen  dioxide, the half-life of formaldehyde  is  approximately
50 min  during the daytime; in  the presence of nitrogen  dioxide, this
drops to about 35 min (Bufalini et al., 1972).

    Some physical and chemical properties of formaldehyde are presented
in Table 1.

Table 1.  Physical and chemical properties of formaldehydea 
------------------------------------------------------------
 
Relative molecular mass              30.03 
 
Relative gas density (air = 1)       1.04 
 
Melting point (°C)                   -118b
 
Boiling point (°C)                   -19.2b
 
Explosivity range in air (vol %)     7-73 
(g/m3)                             87-910 
 
 n -octanol/water partition           -1 
  coefficient) (log Pow) 

Specific reaction rate (k) with      15.10-18 m3/mol x s 
  OH radical (k OH ) 
 
Distribution water/air: Henry        0.02 Pa. m3/mol 
  constant (H) 
 
Vapour pressure                      101.3 kPa at -19 °C 
                                     52.6 kPa at -33 °C 
------------------------------------------------------------
a       Modified from: BGA (1985). 
b       From: Diem & Hilt (1976) and IARC (1982). 
        From: Neumüller (1981) and Windholz (1983). 

2.3  Conversion Factors

        1 ppm formaldehyde      = 1.2 mg/m3 at 25 °C, 1066 mbar
        1 mg formaldehyde/m3    = 0.83 ppm

    A  number of other conversion factors have been cited but, for this
draft, 0.83 has been used.

2.4  Analytical Methods

    The  most widely used methods for the determination of formaldehyde
are  based on photometric measurements.   Methods for the sampling  and
determination  are summarized in Table 2.  The type of sampling depends
on the medium in which the formaldehyde is to be determined.

    Direct and indirect methods can be used for  sampling  formaldehyde
in  air.  Indirect sampling (by  means of a grab  sample) is used  when
formaldehyde is present in extremely low concentrations or  where  sam-
pling sites are removed from analytical laboratories.  However, lack of
preconcentration  means that a  very sensitive analytical  technique is
needed and there may also be absorption on the wall of  the  collecting
container.  Alternatively, the sample may be preconcentrated by passing
air  (active sampling) through an absorbing liquid.  The collection ef-
ficiency of some liquids is reported in NRC (1981):

Water                           80-85% (85% with ice bath)

1% aqueous bisulfite            94-100% (with ice bath)

3-methyl-2-benzothiazolene
hydrazine (MBTH)                84-92%

Chromotropic acid in concen-
trated sulfuric acid            99%

Concentrated sulfuric acid      99%

    Formaldehyde in air may be collected in an absorbing medium by dif-
fusion (passive sampling). Aqueous or 50% 1-propanol solutions are used
for formaldehyde sampling. For active sampling, aqueous  solutions  and
solutions   containing   sulfite,   3-methyl-2-benzothiazolonehydrazone
(MBTH),  chromotropic  acid,  or 2,4-dinitrophenylhydrazine  (DNPH) are
generally  used as the absorbing  solution (Stern, 1976).  For  passive
sampling,  sodium  bisulfite  (Kennedy &  Hull,  1986), triethanolamine
(Prescher & Schönbude, 1983), and DNPH (Geisling et al., 1982) are used
and sorbents such as silica gel, aluminium oxide, and activated carbon,
sometimes specially pretreated, may be useful for taking samples at the
work place (DFG, 1982).


Table 2.  Sampling and analytical methods for formaldehydea                                           
--------------------------------------------------------------------------------------------------------
Method                Sampling    Analysis           Sensitivity mg/litre (ppm)       Interferences 
 
                                                     15-min          long-term 
--------------------------------------------------------------------------------------------------------
Chromotropic acid:    midget      spectrophotometry  0.19 (0.16)     0.05 (0.04)      phenol, other 
NIOSH 3500            impinger                                       (1 h)            organic substances 
 
Paraosaniline         midget      spectrophotometry  0.02 (0.02)     0.0006 (0.0005)  sulfur dioxide 
(original)            impinger                                       (8 h) 
 
Paraosaniline         midget      spectrophotometry  0.05 (0.045)    0.0012 (0.001)   sulfur dioxide 
(modified)            impinger                                       (8 h) 
 
Paraosaniline         continuous  colorimetric       0.06 (0.05)     NA               sulfur dioxide 
(TGM-555)

MBTH                  absorber    spectrophotometry  0.12 (0.10)     0.0036 (0.003) 
                                                                     (8 h) 
 
Acetylacetone         midget      spectrophotometry  0.12 (0.10)     ---              other aldehydes, 
spectrophotometric    impinger                                                        amines, Sulfur 
                                                                                      dioxide 
 
Acetylacetone         midget      fluorimetry        0.05 (0.04)     ---              other aldehydes, 
fluorimetric          impinger                                                        amines, Sulfur 
                                                                                      dioxide 
 
2.4-DNPH aqueous      midget      HPLC               0.00007         0.000018 (0.000015) 
ethanol               impinger                       (0.00006)       (1 h) 
 
2.4-DNPH coated       adsorbent   HPLC               1.58 (1.32)     0.12 (0.10) 
adsorbent             tube                                           (3 h) 
 
NIOSH 3501            midget      polarography       1.94 (1.62)     0.32 (0.27)      other aldehydes 
                      impinger                                       (1.5 h) 
 
OSHA acidic           midget      polarography       0.12 (0.10)     0.012 (0.01)     acetaldehyde 
hydrazine             impinger                                       (2.5 h) 
-------------------------------------------------------------------------------------------------------


                                   
Table 2 (contd). 
-------------------------------------------------------------------------------------------------------
Method                Sampling    Analysis           Sensitivity mg/litre (ppm)       Interferences 
                                        
                                                     15-min          long-term 
-------------------------------------------------------------------------------------------------------
NIOSH 2502            reactive    gas chromatography 9.38 (7.82)     0.6 (0.5) 
                      adsorbent                                      (4 h) 
 
MIRAN                 continuous  infrared           0.5 (0.4)       NA               multiple 
 
Draeger               reactive    visual             0.6 (0.5)       NA 
                      adsorbent 
 
Passive               reactive    spectrophotometry  3.84 (3.2)      0.12 (0.1) 
monitor 3M            adsorbent     (CA)                             (8 h) 
 
DuPont                reactive    spectrophotometry  9.6 (8)         0.3 (0.25) 
                      adsorbent     (CA)                             (8 h) 
 
Air Quality           reactive    spectrophotometry  8.04 (6.7)      0.25 (0.21) 
Research              adsorbent     (CA)                             (8 h) 
 
Envirotech            moist       spectrophotometry  0.86 (0.72)     0.07 (0.06)      other aldehydes 
                      adsorbent     (PUR)                            (8 h) 
-------------------------------------------------------------------------------------------------------
 
a Modified from: Consensus Workshop on Formaldehyde (1984). 
    In  1981, the  US National  Institute of  Occupational  Safety  and
Health  (NIOSH)  developed a  solid-sorbent  sampling method  in  which
samples  collected can be stored for at least 14 days, at room tempera-
ture, before analysis, without loss of the analyte (Blade, 1983).

    A  method for the specific  and sensitive determination of  formal-
dehyde  and other aldehydes  and ketones in  air has been  described by
Binding et al. (1986). The specificity is based on subsequent high per-
formance liquid chromatographic separation. In air samples of 5 litres,
the  detection limit is 0.05 ml/m3.   The method is suitable for deter-
mining 5-min short-term values, as well as for continuous sampling over
a whole work shift.

    A sensitive method for the determination of formaldehyde  is  based
on  the Hantzsch reaction between  acetylacetone (2,4-pentanedione) am-
monia  and formaldehyde to form 3,5-diacetyl-1,4-dihydrolutidine.  For-
maldehyde concentration can be determined colorimetrically (Nash, 1953)
or, more sensitively, by fluorimetry (Belman, 1963). The method is sub-
ject  to interference by oxides  of nitrogen, sulfur dioxide  and ozone
but  is less subject  to interference by  phenol than the  chromotropic
acid method.

    Photometric  assay, using the sulfite-pararosaniline or the chromo-
tropic  acid method, is  usually applied to  determine formaldehyde  in
air.  Automated analytical equipment has been developed.

    Suitable  analytical methods for  monitoring air in  the work-place
environment  have been developed and recommended by the German Research
Society, DFG (1982) and by NIOSH (1984).

    Menzel  et  al.  (1981) described  a special continuously-operating
measuring  device, developed for  determining formaldehyde in  particle
boards  for classification purposes; equipment  for continuous measure-
ments  using the  pararosaniline method  is available  (Lyles  et  al.,
1965).

    A simple colour reaction for the identification of  urea  formalde-
hyde resins and diisocyanates, carried out on the surface of wood-based
panels, has been described by Schriever (1981).  This is based  on  the
reaction  with  p -dimethyl-aminocinnamaldehyde   (DACA), resulting  in a
red  colour  for both  the resins and  diisocyanates.  The reaction  of
purpald with formaldehyde is used to distinguish between urea formalde-
hyde  resins and diisocyanates  and it is  possible to identify  diiso-
cyanates when mixed with urea formaldehyde resins.

    Water  sampling may be  by means of  grab samples.  Where  water or
individual  effluents  are not  homogeneous  several subsamples  may be
collected  at  different times  from  different sampling  locations and
combined  for analysis.  If  sample storage is  necessary it should  be
frozen  or at  least kept  at 4 °C  to prevent  biological or  chemical
degradation of formaldehyde.  An organic solvent is used for extraction
of formaldehyde prior to analysis.

    Concentrations  of  formaldehyde  in  the  air  in  the  range   of
0.05-40 mg/m3 can  be determined by the use of gas-detector tubes which

contain  a colour reagent (Leichnitz, 1985). They cannot be relied upon
in  the presence of  other substances, e.g.,  tobacco smoke or  below a
concentration of 0.05 mg/m3.

    Formaldehyde can be extracted from foods using a solvent,  such  as
isopetane,  or by steam distillation and extraction with ether.  Before
extraction foodstuffs may be pulverized or homogenized.

    The  Association  of  Official  Analytical  Chemists  (AOAC,  1984)
recommends  the Helmer-Fulton Test  (registration No. 20.081)  for  the
determination of formaldehyde in food and a  spectrophotometric  method
(Nash's reagent B; registry no. 31203) for the determination of formal-
dehyde in maple syrup.

3.  SOURCES IN THE ENVIRONMENT

3.1  Natural Occurrence

    Formaldehyde  is  naturally formed  in  the troposphere  during the
oxidation of hydrocarbons.  These react with OH radicals and  ozone  to
form formaldehyde and/or other aldehydes as intermediates in  a  series
of reactions that ultimately lead to the formation of  carbon  monoxide
and  dioxide, hydrogen, and  water (Zimmermann et  al., 1978;  Calvert,
1980).

    Of the hydrocarbons found in the troposphere, methane occurs in the
highest concentration (1.18 mg/m3)   in the northern hemisphere.  Thus,
it provides the single most important source of formaldehyde  (Lowe  et
al., 1981).

    Terpenes  and isoprene, emitted by foliage, react with the OH radi-
cals,  forming formaldehyde as  an intermediate product  (Zimmermann et
al., 1978).  Because of their short life-times, this potentially impor-
tant  source of formaldehyde is only important in the vicinity of vege-
tation (Lowe et al., 1981). The processes of formaldehyde formation and
degradation are discussed in section 4.

    Formaldehyde is one of the volatile compounds formed in  the  early
stages  of decomposition of plant residues in the soil (Berestetskii et
al., 1981).

3.2.  Man-Made Sources

    The  most important man-made  source of formaldehyde  is automotive
exhaust  from engines not fitted with catalytic converters (Berglund et
al., 1984; Guicherit & Schulting, 1985).

3.2.1  Production levels and processes

Table 3. World production figures for formaldehyde 
--------------------------------------------------------
Year   Area                                Quantity 
                                           (million kg) 
--------------------------------------------------------
 
1978   USA, 16 companies                   1073 
1978   Canada, 4 companies                 88 
1979   USA, 16 companies                   1003 
1983   USA                                 905 
1983   Germany, Federal Republic of, 
        11 companies                       534 
1983   Japan, 24 companies                 403 
1983   Major producing countries  total    3200 
1984   Major producing countries  total    5780 
1985   USA, 13 companies                   941 
--------------------------------------------------------

3.2.1.1  World production figures

    The total production figures for formaldehyde are calculated  on  a
100% formaldehyde basis, though a variety of concentrations  and  forms

are  produced. In 1984, the overall production capacity of major indus-
trial  countries was approximately 5780 million kg/year  (European Eco-
nomic Community 1700 kg/year, other Western European countries 530, USA
1440,   Japan 640,  other Asian  countries and  Australia  1240,  Latin
America  230). Formaldehyde is also produced in Africa and the USSR. No
production figures for formaldehyde are available for eastern industri-
alized  countries (Izmerov, 1982). Table 3 shows actual production fig-
ures for some western industrialized countries.

3.2.1.2  Manufacturing processes

    Formaldehyde  is  produced by  oxidizing  methanol using  two  dif-
ferent   procedures:  (a)  oxidation   with silver crystals  or  silver
nets  at 600-720 °C; and (b)  oxidation with iron molybdenum  oxides at
270-380 °C. Formaldehyde can be produced as a by-product of hydrocarbon
oxidation processes (Walker, 1975), but this method is not used commer-
cially.

    Formaldehyde  is an inexpensive starting  material for a number  of
chemical  reactions, and a large number of products are made using for-
maldehyde as a base. Thus, it is important in the chemical industry.

3.2.2  Uses

    Products manufactured using formaldehyde as an intermediate product
are listed in Table 4.

    In animal nutrition, formaldehyde is used to protect  dietary  pro-
tein  in ruminants (section 7.3). In the USA, formaldehyde is used as a
food additive to improve the handling characteristics of animal fat and
oilseed  cattle food mixtures by  producing a dry free-flowing  product
(US  FDA, 1980). Urea formaldehyde  fertilizer is used in  farming as a
source  of nitrogen  to improve  the biological  activity of  the  soil
(section 7.1).

3.2.2.1  Aminoplastics (urea formaldehyde resins and melamine formalde-
         hyde resins)

    Reaction  of formaldehyde with urea or melamine yields urea formal-
dehyde (UF) or melamine formaldehyde (MF) (condensation process). These
synthetic resins are then delivered in solution or powder form at vari-
ous concentrations for further processing.

Table 4.  Products produced with formaldehyde as a compounda
-----------------------------------------------------------------------------                                                                 
Intermediate product              Product 
-----------------------------------------------------------------------------                                                                  
 
urea formaldehyde resins          particleboard, fibreboard, plywood, 
                                  paper treatment, textile treatment, 
                                  moulding compounds, surface coatings, 
                                  foam 
 
phenolic resins                   plywood adhesives, insulation, 
                                  foundry binders 
 
melamine resins                   surface coatings, moulding compounds, 
                                  laminates, wood adhesives 
 
hexamethylenetetramine            phenolic thermosetting, resin curing 
                                  agents, explosives 
 
trimethylolpropane                urethanes, lubricants, alkyd resins, 
                                  multifunctional acrylates 
 
1,4-butanediol                    tetrahydrofuran, butyrolactone, 
                                  polybutylene terephthalate 
 
polyacetal resins                 auto applications, plumbing components 
 
pentaerythritol                   alkyd resins, synthetic lubricants, 
                                  tall oil esters, foundry resins, 
                                  explosives 
 
urea formaldehyde concentrates    controlled release fertilizers 
-----------------------------------------------------------------------------                                                                  
 
a       From: Archibald (1982). 
 
    In the Federal Republic of Germany, about 70% of the  total  amount
of  aminoplastics produced, i.e.,  170 000 tonnes of  formaldehyde  per
annum,  is used as glue  in the manufacture of  particle boards.  These
boards  are  mostly manufactured  from  urea formaldehyde  resins,  the
water  resistance of which is  less than that of  other resins, but  is
sufficient  for use in enclosed  areas.  About 10% of  the aminoplastic
glues  used are melamine-urea-formaldehyde resins, i.e., products where
melamine  and urea are co-condensed with formaldehyde.  Melamine resins
are  more damp-proof than urea  resins, but they are  also more expens-
ive.

    Formaldehyde  can be released from  such wood products over  a long
period, even years, at a continuously declining rate. This  occurs  es-
pecially  if the particle board material has become wet due to careless
handling,  e.g., in construction work.  The emission is composed of the
excess  of formaldehyde used during actual production of the wood prod-
ucts  and that produced  by hydrolytic cleavage  of unreacted  methylol
groups  in the resins.  Melamine formaldehyde resins are generally more
stable and the amounts of formaldehyde emitted from them are much lower
(Deppe, 1982).

    Aminoplastics are also used as glue for plywood and in the manufac-
ture  of furniture.  Paper saturated with aminoplastics and with a high
melamine-formaldehyde-resin  content is used  to coat surfaces  of par-
ticle boards.  Aminoplastics are used to increase the wet  strength  of
certain products in the paper industry.

    Urea formaldehyde resins are used as urea formaldehyde  foam  insu-
lation (UFFI), or as reinforcing foams in the insulation  of  buildings
and  in  mining,  where hollow areas are filled with foam. UFFI is pro-
duced  by  the  aeration of a mixture of urea formaldehyde resin and an
aqueous surfactant solution containing a phosphoric acid  curing  cata-
lyst (Meek et al., 1985). This type of foam can emit formaldehyde, even
after  completion  of work,  depending on factors  such as process  and
installation, age of building materials, temperature, and humidity.

    Condensed aminoplastics of very low relative molecular  mass  serve
as textile treatments to make cotton and fabrics  containing  synthetic
fibres creaseproof and permanently pressed. In the USA, it is estimated
(CPSC, 1979) that approximately 85% of all fabrics used in the clothing
industry have been treated in this way.  Extremely stable aminoplastics
are used in order to ensure that they will not degrade during the life-
time  of the articles.  Formaldehyde  concentrations ranging from 1  to
3000 mg/kg were found in such fabrics in the early years of  this  type
of use (Schorr et al., 1974).  However, residues of  free  formaldehyde
from the manufacturing process can largely be removed by heat treatment
with  washing during  the textile  finishing process.  In the  last  10
years, the processing of finishing agents in the textile  industry  has
improved  and  textiles treated  with formaldehyde-containing finishing
agents  contain very little free formaldehyde and cannot cause allergic
contact dermatitis (Bille, 1981).

    Compounds similar to those used in finishing textiles are  used  in
the  tanning of leather.   Another field of  application is for  amino-
plastics  mixed with rock  or wood dust,  fibres, or synthetic  pulp in
hard  materials manufactured by hot moulding. They are used in electri-
cal  engineering,  e.g., in  light switches, sockets,  and in parts  of
electrical  motors;  in  mechanical engineering;  in  the motor-vehicle
industry;  and for household articles,  e.g., camping dishes, parts  of
electrical household appliances, lamps, and plumbing components.

    Aminoplastics   are  used  in the  paint  industry  as carriers  in
binders  for special types  of lacquer and  paint, e.g., for  cars.  In
agriculture,  they are used  as preservatives.  They  are also used  in
carpet-cleaning agents in the form of foam resin.

    The  fields of application of aminoplastics in the Federal Republic
of Germany are given in Tables 5 and 6.

3.2.2.2  Phenolic plastics (phenol formaldehyde resins)

    Phenolic  plastics are synthetic  resins in which  formaldehyde  is
condensed  with phenols.  Phenol, resorcinol, and cresols are among the
phenolic  components. Owing to the stable binding of phenol and formal-
dehyde, formaldehyde should not be emitted from the final products made
of  phenolic  plastics,  as  long  as  there  is no  free  formaldehyde
present.

    As  in the case  of aminoplastics, the  wood-working industry is  a
major consumer.

Table 5.  Uses of melamine formaldehyde resins in the Federal Republic of 
Germany during 1981-82a
------------------------------------------------------------------
Area of use                       Proportion as   Consumption 
                                  % of resin      of formaldehyde 
                                  consumption     (tonnes) 
------------------------------------------------------------------
 
Adhesive resins for timber        30              12 000 
products, especially particle 
boards (adhesives) 
 
Resin varnishes                   36              14 500 
 
Hardenable moulding material      10              4 000 
for plastic products 
 
Raw materials for paints          8               3 000 
 
Paper and textile finishing       5               2 000 
 
Other                             11              4 500 
------------------------------------------------------------------
a       From: BASF (1984). 

    Other  major  areas  of application  are  the  production  of  hard
materials,  similar to those produced from aminoplastics, as a moulding
material, and as a binder in enamel, paints, and lacquers.

    Phenolic  plastics are used as  binders in the production  of insu-
lating  materials  from rock  wool or glass  fibres, in brake  linings,
abrasive materials, and moulded laminated plastics.  They also serve as
binding agents for moulding sand in foundries. Fields of application of
phenolic  plastics  in the  Federal Republic of  Germany are listed  in
Table 7.

    Emissions  of  formaldehyde  are produced  when processing phenolic
plastics at high temperatures. Phenol and formaldehyde emissions during
moulding led to complaints in previous decades about  annoying  smells.
Now, resins have been improved to meet work-place environment standards
and emissions should not cause annoyance.

3.2.2.3  Polyoxymethylene (polyacetal plastics)

    Polyoxymethylenes  (POM) are another  type of plastics  produced by
polymerizing  formaldehyde. Like the final products from phenolic plas-
tics,  articles  made  of polyoxymethylene  are  not  expected to  emit
formaldehyde.

    Polyoxymethylenes  are  harder,  tougher, and  longer-lasting  than
other  plastics and are used in many areas of application in which met-
allic materials were previously used. They are used in producing motor-

vehicle and machine parts that are subjected to mechanical  or  thermal
stress,  parts for precision  and communication engineering,  parts for
household appliances, and plumbing fixtures.

Table 6. Uses of urea formaldehyde resins in the Federal Republic of 
Germany during 1981-82a
------------------------------------------------------------------
Area of use                        Proportion as   Consumption of 
                                   % of resin      formaldehyde 
                                   consumption     (tonnes) 
------------------------------------------------------------------
 
Adhesive resins for timber         80              160 000 
products, especially particle 
boards (adhesives) 
 
Paper finishing                    4               8 000 
 
Hardenable moulding material       4               8 000 
for plastic products 
 
Textile finishing                  3               6 000 
 
Resin varnishes for impregnating,  2               4 000 
e.g., moulded, laminated plastics 
 
Foam resins                        2               4 000 
for: building insulation           0.2 
     mining                        1.0 
     amelioration                  0.4 
     carpet-cleaning products      0.3 
     other purposes                0.1 
 
Raw materials for paints           2               4 000 
 
Binding agents for fibre           1               2 000 
mats, etc.

Foundry resins                     1               2 000 
 
Other                              1               2 000 
------------------------------------------------------------------
a       From: BASF (1984). 

3.2.2.4  Processing formaldehyde to other compounds

    Formaldehyde  is an important raw  material in the industrial  syn-
thesis of a number of organic compounds.

    In  the Federal Republic  of Germany during  1981-82, the  chemical
industry  processed 34% of all  formaldehyde products to the  following
derivative substances (BASF, 1984):

    -   1,4 butane diol                         10%
    -   pentaerythritol                          6%

    -   methylenediphenyldiisocyanate            5%
    -   trimethylolpropane and neopentylglycol   4%
    -   hexamethylenetetramine                   2%
    -   chelating agents (NTA, EDTA)             2%
    -   miscellaneous (e.g., dyes, dispersion,   5%
        pesticides, perfumes, vitamins)

Table 7. Uses of phenolic plastic resins in the 
         Federal Republic of Germany during 1981-82a
------------------------------------------------------------------
Area of use                        Proportion as   Consumption of 
                                   % of resin      formaldehyde 
                                   consumption     (tonnes)  
------------------------------------------------------------------
 
Hardenable moulding material       23              9000 
for plastic products 
 
Adhesive resins for timber         20              8000 
products, especially particle 
boards (adhesives) 
 
Binding agents for rock wool,      17              7000 
glass wool, etc. 
 
Raw materials for paints           14              5500 
 
Foundry resins                     7               3000 
 
Resin varnishes for impregnating,  4               1500 
e.g., moulded, laminated plastics 
 
Abradant binders, e.g., for        3               1000 
sandpaper 
 
Binding agents for friction        3               1000 
surfaces, e.g., brake linings 
 
Rubber chemicals                   2               1000 
 
Other                              7               3000 
------------------------------------------------------------------
a       From: BASF (1984). 
 
3.2.2.5  Medical and other uses

    The use of formaldehyde in medical and other fields  is  relatively
small (1.5% of the total production) compared with its use in the manu-
facture of synthetic resins and chemical compounds. However, its use in
these  areas is of great significance for human beings, since it occurs
either as free formaldehyde and can therefore be easily  liberated  and
affect  people (e.g., when used as a disinfectant) or it may reach many
people via various consumer goods, such as preservatives and cosmetics.
The  use of formaldehyde for the preservation of organic material is of
historical importance.

    Examples of fields of application are listed in Table 8.

Table 8.  Use of products containing formaldehyde in medicinal 
         and other technical areasa
-------------------------------------------------------------------------
Area                      Use 
-------------------------------------------------------------------------
 
Detergents and cleaning   Preservative in soaps, detergents, cleaning 
agents industry           agents 
 
Cosmetics industry        Preservative in soaps, deodorants, shampoos, 
                          etc; additive in nail hardeners and products 
                          for oral hygiene 
 
Sugar industry            Infection inhibitor in producing juices 
 
Medicine                  Disinfection, sterilization, preservation of 
                          preparations 
 
Petroleum industry        Biocide in oil well-drilling fluids; auxiliary 
                          agent in refining 
 
Agriculture               Preservation of grain, seed dressing, soil 
                          disinfection, rot protection of feed, nitrogen 
                          fertilizer in soils, protection of dietary 
                          protein in ruminants (animal nutrition) 
 
Rubber industry           Biocide for latex; adhesive additive; anti-
                          oxidizer additive also for synthetic rubber 
 
Metal industry            Anti-corrosive agent; vehicle in vapour 
                          depositing and electroplating processes 
 
Leather industry          Additive to tanning agents 
 
Food industry             Preservation of dried foods; disinfection of 
                          containers; preservation of fish and certain 
                          oils and fats; modifying starch for cold 
                          swelling 
 
Wood industry             Preservative 
 
Photographic industry     Developing accelerator; hardener for gelatin 
                          layers 
-------------------------------------------------------------------------
a       Modified from: BASF (1984). 

    (a)  Disinfectants and sterilizing agents

    At  present, formaldehyde is the disinfectant with the broadest ef-
ficiency; its virucidal property makes it indispensable  for  disinfec-
tion in the clinical field. It is an important active substance in dis-
infectants  that kill and inactivate microorganisms and are used in the
prevention and control of communicable diseases and hospital infections

(BGA,  1982). Agents containing  formaldehyde are marketed  as  concen-
trated  solutions and must be diluted appropriately by the user.  These
concentrates  usually  contain  6-10% formaldehyde,  occasionally up to
30%.  The formaldehyde contents of the diluted mixtures lie between 0.3
and 0.5% and, in exceptional cases, 0.9%.  Application of the solutions
is  supposed to kill pathogenic  organisms on the surfaces  of objects.
The  ensuing effect  is proportional  to the  concentration of  formal-
dehyde,  length  of application,  and  temperature (Spicher  &  Peters,
1981).   The objects to be disinfected are either placed in the formal-
dehyde solution (e.g., disinfecting linen in washing machines) or wiped
and/or sprayed with the solutions.  When disinfecting a room, a formal-
dehyde  solution is either  vaporized or atomized.   Disinfecting in  a
formaldehyde  chamber and  gas sterilization  both work  on  a  similar
principle, that is a mixture of formaldehyde and water vapour is pumped
into a special air-tight chamber in which the objects to be disinfected
or  sterilized have been placed.  This method is also used to disinfect
incubators for premature babies and haemodialysis equipment.
 
    (b)  Medicines

    Pharmaceutical products containing formaldehyde are rarely used for
disinfecting the skin and mucous membranes, but formaldehyde  is  added
to pharmaceutical products as a preservative.

    Root canal filling sealants containing paraformaldehyde are used in
dental surgery.

    (c)  Cosmetics

    Formaldehyde  is used as a  preservative in cosmetics and  in nail-
hardening  agents.  Traces can be found in cosmetics resulting from the
disinfecting  of apparatus used in their manufacture. Furthermore, pro-
ducts  containing formaldehyde are used for other purposes, e.g., anti-
perspirants and skin-hardening agents. The formaldehyde content of some
cosmetics  has been reported to be up to 0.6% and is as high as 4.5% in
nail hardeners (Marzulli & Maibach, 1973; Consensus Workshop on Formal-
dehyde,  1984).  Concentrations in  dry-skin lotion, creme  rinse,  and
bubble bath oil are in the range of 0.4-0.6%. Present regulatory values
are given in section 11.

    Formaldehyde  is  considered technically  superior  to a  number of
other  preservatives, especially in products with a high water content,
e.g.,  shampoos.  As a preservative, formaldehyde also assures that the
product  is  germ-free,  prevents microbial  contamination  during pro-
duction  and  packaging,  multiplication of  residual  organisms during
storage, and re-contamination during use.

    (d)  Consumer goods and other products

    The  use of formaldehyde in  consumer goods is intended  to protect
the products from spoilage by microbial contamination.

    It  is used as a  preservative in household cleaning  agents, dish-
washing liquids, fabric softeners, shoe-care agents, car  shampoos  and

waxes, carpet cleaning agents, etc. As a rule, the formaldehyde concen-
tration is less than 1%.  Disinfecting cleaning agents  contain  higher
concentrations (up to 7.5%) and are diluted before use.

    Flooring  adhesives contain formaldehyde.   It is added  to  paper,
leather, dyes, wood preservatives, sealing agents for  parquet  floors,
as a preservative with fungicidal and bactericidal properties (see also
Table 4).

    Formaldehyde is a component of reactive resins  (urea  formaldehyde
resins,  melamine  formaldehyde  resins,  phenol  formaldehyde  resins,
benzoguanomine  formaldehyde, and polymers on a methyloacylamide and/or
methylomethacrylamide basis), which control the hardening properties of
lacquers  and varnishes and are essential for the surface properties of
the  treated products.  The resins used for these purposes contain free
formaldehyde  at  concentrations  of up to 3%, this means up to 0.3% in
ready-to-use varnishes (BASF, 1983).  This free formaldehyde is emitted
during application.  Thermal degradation of resins during the baking of
paints may cause additional emissions of formaldehyde.

3.2.3  Sources of indoor environmental exposure

    The major man-made sources affecting human beings are in the indoor
environment.   Primary sources include cigarette  smoke, particle board
and plywood, furniture and fabrics, gases given off by heating systems,
and cooking.

    Thus,  the indoor levels  of formaldehyde differ  clearly from  the
concentrations in the outdoor air. Indoor concentrations are influenced
by  temperature, humidity, ventilation rate, age of the building, prod-
uct  usage, presence of combustion  sources, and the smoking  habits of
occupants.  When considering the indoor presence of formaldehyde, it is
necessary to differentiate between:

-   Hospitals or other scientific facilities, where formaldehyde has to
    be used as a disinfectant or preservative; and
-   All  other indoor areas, especially living spaces, schools, kinder-
    gartens, and mobile homes where there may be uncontrolled emissions
    of formaldehyde from sources such as smoking,  building  materials,
    and furniture. This sector presents the specific problems in indoor
    areas.

Possible sources of indoor formaldehyde emissions are:

    -   cigarettes and other tobacco products;
    -   particle boards;
    -   furniture; urea formaldehyde foam insulation (UFFI);
    -   gas cookers;
    -   open fireplaces;
    -   other   building  materials  made  with  adhesives  containing
        formaldehyde,  such  as  plastic surfaces  and certain parquet
        varnishes;
    -   carpeting, drapes, and curtains;
    -   paints, coatings, and wood preservatives; and
    -   disinfectants and sterilizing agents.

    Other products containing formaldehyde do not noticeably contribute
to  indoor exposure because of their stable formaldehyde binding, e.g.,
plastic  articles  made by  moulding, or because  of their low  rate of
emission,  e.g., cosmetics.  Data  are summarized in  Tables 15 and  16
(section 5.2).

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1  Transport and Distribution

    The degradation of methane is a major source of the  natural  back-
ground  concentration of formaldehyde in the atmosphere.  Since methane
is widely distributed naturally and has a half-life of  several  years,
formaldehyde is formed on a global scale.

    Fig. 1 provides a survey of processes that may contribute  to  for-
maldehyde concentrations in ambient air.

    Formaldehyde  is a highly reactive compound with a half-life in the
atmosphere of about 1-3 h in the sunlit troposphere at 30° N at mid-day
(Bufalini  et al., 1972;  Lowe & Schmidt,  1983). Therefore,  transpor-
tation  of formaldehyde over distances is probably not of great import-
ance.

    The organic compounds from which formaldehyde is derived are usual-
ly much more stable. Thus, emissions of organic air pollutants can con-
tribute to the formation of formaldehyde over considerable distances.

    Various photochemical models have also been used to predict formal-
dehyde  distribution in the  troposphere, but the  computed values  are
difficult  to compare,  because of  the different  assumptions used  to
generate the models.

    Lowe  et al. (1981) estimated a chemical life-time for formaldehyde
using  the following reactions for formaldehyde formation (Levy, 1971):

        CH4     +   OH      -> CH3     +   H2O     (1)
        CH3     +   O2 + M  -> CH3O2   +   M       (2)
        CH3O2   +   NO      -> NO2     +   CH3O    (3)
        CH3O    +   O2      -> HCHO    +   HO2     (4)

    Wofsy et al. (1972) considered that reaction (3) was  unlikely  and
suggested that methyl hydroperoxide (CH3OOH)   could be an intermediate
in the reaction series producing formaldehyde.

        CH3O2   +   HO2     -> CH3OOH  +   O2      (5)
        CH3OOH  +   hv      -> CH3O    +   OH      (6)
        CH3O    +   O2      -> HCHO    +   HO2     (7)

    For  the purposes of  estimating a chemical  life-time for  formal-
dehyde in the troposphere, reactions (1)-(4) are assumed, with reaction
(1)  as the rate-limiting  step. Hence, the  rate of formaldehyde  pro-
duction (P) from methane can be written as:

                P = K1 [OH] x [CH4]     (8)

FIGURE 1

    Using  K1 = 2.4 x 10-12     e-1710/T (Lowe   et al., 1981), OH pro-
files for latitude 45 °N (Logan, 1980), and a mean tropospheric methane
mixing  ratio of 1.18 mg/m3,    equation (5) can  be numerically  inte-
grated over a 10-km high troposphere to yield an average column formal-
dehyde  production rate, due to methane oxidation, of 9 x 10-5 g/cm2
per year.

    Similar results are obtained using a mean tropospheric  OH  concen-
tration  of 6.5 x 105 molecules/cm3 (Volz   et  al., 1981) with  a mean
methane mixing ratio of 1.18 mg/m3 giving  a column  formaldehyde  pro-
duction  in a 10-km high troposphere of 8 x 10-5g/cm2 per    year. This
is  equivalent to an average world production rate of formaldehyde from
methane  of 4 x 1011 kg/year,  which  greatly exceeds the  total indus-
trial formaldehyde production rate (6 x 109 kg/year).

    Various  processes contribute to  the removal of  formaldehyde from
tropospheric  air. The action of solar ultraviolet radiation on formal-
dehyde  results in its  photolysis via two  channels (Moortgat et  al.,
1978; Calvert, 1980).

        HCHO    +   h v      -> H2      +   CO      (9)
                            -> H       +   HCO     (10)

    Formaldehyde  is also removed from the troposphere by reaction with
the OH radical (Stief et al., 1980).

        HCHO    +   OH      -> HCO     +   H20     (11)
        HCO     +   O2      -> HO2     +   CO      (12)

    Through  the reaction series (1)-(4) and reactions (9)-(12), CO and
H2 are   produced in the atmosphere via formaldehyde as an intermediate
product.  The  destruction of  one methane molecule  leads to the  pro-
duction of approximately one formaldehyde  molecule and  ultimately  to
the  production of a CO molecule.  The series of reactions also results
in  a net production of HO2 radicals,  resulting in an overall increase
in the chemical reactivity of the atmosphere.

    From  equations (9), (10), and  (11), it follows that  the chemical
destruction of formaldehyde (D) is given by:

    D = [HCHO][K11[OH] + J9 + J10] = [HCHO] (13)
                                      tau

where  K11 is  the rate constant of equation (11), J9 and  J10 are  the
photodissociation coefficients for equations (9) and (10) and tau [s]-1 
is the chemical life-time of formaldehyde in the lower troposphere.

    Substituting J9+J10 = 4.5 x 10-5 s -1 (mean estimated from Calvert,
1980),  K11 = 1.05 x 10-11 (Stief    et al., 1979),  and [OH] = 5 x 106
molecules/cm3 (Logan    et  al., 1981)  into  equation (13)   yields an
average  chemical life-time for  formaldehyde in the  lower troposphere
during  daylight, of 3 h.  Under atmospheric conditions in the presence
of nitrogen dioxide (NO2),   the half-life of formaldehyde was found to
be 35 min (Bufalini et al., 1972).

    At  ground level in the atmosphere, reaction with the OH radical is
the dominant removal process for formaldehyde.  However, in  the  first
few  kilometres of the troposphere, the importance of the OH radical as
a  removal process decreases  with altitude and  the  photodissociation
coefficients J9 and J10 increase in importance.

    Formaldehyde  is  also  removed  from  the  troposphere  by rainout
(gaseous  constituents of the atmosphere are absorbed during the forma-
tion  of cloud droplets),  washout (falling raindrops  scavenge  gases,
particles,  and aerosols from the atmosphere), and by deposition at the
surface.   However, these processes are only of minor importance in the
free  troposphere.  For example, from formaldehyde measurements made in
rainwater collected at an equatorial site in the Pacific,  Zafiriou  et
al.  (1980) estimated that rainout was responsible for removing only 1%
of  the  formaldehyde produced  in the atmosphere  by the oxidation  of
methane.   In addition, Warneck et al. (1978) showed that washout, as a
removal process for gaseous formaldehyde in the troposphere, is import-
ant only in polluted regions and may be ignored in unpolluted air.

    Dry  deposition at the surface  is usually defined by  a deposition
velocity,  (vo (cm/second)),  and the flux (fo)   to the surface may be
estimated by:

                fo = vo x [HCHO]o       (14)

where  [HCHO]o is   the  mean  formaldehyde  concentration  above   the
surface.

    The  deposition velocity depends on the surface.  For example, from
measurements  made at  an equatorial  Pacific atoll,  Zafiriou  et  al.
(1980), deduced a value for vo of 0.4 cm/second at the ocean surface.

    The   mean  formaldehyde  mixing ratio,  [HCHO]o,   measured during
an   oceanographic  expedition  in  the north and  south Atlantic,  was
0.29 x 10-3 mg/m3, corresponding to  a concentration  of 5.9 x 109 mol-
ecules/cm3    (Lowe  et  al., 1981).   With  a  deposition velocity  of
0.4 cm/second, equation (14) suggests a loss due to deposition  at  the
ocean  surface of 2.4 x 109 molecules/cm2 per    second or about  4% of
the  column formaldehyde production  from methane oxidation  calculated
above. Although vo for  formaldehyde is expected to vary with wind vel-
ocity,  it is unlikely to  exceed 1 cm/second.  Hence, loss  of formal-
dehyde  from the troposphere due  to deposition will only  be important
near the surface itself.

    More recently, consideration has been given to the  possibility  of
how  much formaldehyde indirectly contributes  to the overacidification
of  precipitation (Richards et  al., 1983).  Formaldehyde  reacts  with
sulfur dioxide (SO2)   and gives off relatively  concentrated  hydroxy-
methanesulfonic acid, whereby SO2 may  contribute to the  acid  content
of precipitation without preceding oxidation to sulfuric acid, which is
a  relatively slow process.   More in-depth investigations  have to  be
carried  out, in  order to  ascertain to  what extent  this process  is
important for acid formation.

4.2  Transformation

4.2.1  Special products of degradation under specific conditions

    Highly  carcinogenic  bis(chloromethyl)ether  can be  produced by a
condensation   reaction  between  formaldehyde  and  hydrogen  chloride
(Thiess  et al., 1973; Nelson, 1977; Albert et al., 1982; Sellakumar et
al.,  1985).   The  maximum equilibrium  concentration  of  bis(chloro-
methyl)ether  generated  from  atmospheric  formaldehyde  and  hydrogen
chloride was estimated to reach 4 x 10-16 ppb;  it was  concluded  that
this  represented little impact on human health (NRC, 1981).  According
to  Keefer  & Roller  (1973), formaldehyde is  able to catalyze  nitro-
sation  of a series of secondary amines to carcinogenic nitrosamines or
 N -nitroso-compounds.

4.2.2  Microbial degradation

    Formaldehyde  released  into  the aquatic  environment  appears  to
undergo  relatively  rapid  biodegradation. Kamata  (1966) examined the
biodegradation of formaldehyde in natural water obtained from  a  stag-
nant lake in Japan. Under aerobic conditions, known quantities of added

formaldehyde  were  decomposed  in ca. 30 h at  20 °C, anaerobic decompo-
sition  required ca. 48 h.  No  decomposition  was  noted  in  sterilized
water.

    Various  activated sludges and  microorganisms isolated from  acti-
vated sludges have been shown to be very efficient in degrading formal-
dehyde  in aqueous effluents, providing  the formaldehyde concentration
does not exceed 100 mg/litre (Verschueren, 1983).  Essentially complete
degradation is achieved in 48-72 h, if the proper temperature  and  nu-
trient conditions are maintained (Kitchens et al.,  1976).   Grabinska-
Loniewska  (1974) isolated 44 bacteria strains from an industrial acti-
vated  sludge  and found  that formaldehyde was  used as a  sole carbon
source   by   various Pseudomonas strains   but  not   by   strains  of
 Achromobacter ,  Flavobacterium ,  Mycobacterium , or  Xanthomonas . Several
studies  have revealed significant degradation of formaldehyde by mixed
cultures  obtained from sludges and settled sewage (Heukelekian & Rand,
1955;  Hatfield, 1957; Sakagami & Yokoyama, 1980; Speece, 1983; Behrens
& Hannes, 1984), while in other studies, little or no  degradation  has
been found (Placak & Ruchhoft, 1947; Gerhold & Malaney, 1966;  Belly  &
Goodhue, 1976; Kalmykova & Rogovskaya, 1978; Chou et al., 1979).

    A  number of pure culture  studies have shown that  formaldehyde is
biologically  degradable.  Cell extracts  of  Pseudomonas methanica and
 Methylosinus  trichosporium  (Patel et al., 1979) and cell-free extracts
of  yeast strains of the Candida sp.  are able to oxidize  formaldehyde
(Fujii & Tonomura, 1972, 1974, 1975; Sahm, 1975; Pilat & Prokop, 1976).
Cell  extracts  of  Pseudomonas oleovorans  (Sokolov  & Trotsenko, 1977),
 Pseudomonas   putida  Cl (Hohnloser et al.,  1980),  Hansenula polymorpha 
(Van   Dijken et al.,  1975),  Methylococcus capsulatus  (Patel &  Hoare,
1971),  Methanobacterium   thermoautotrophicum ,    M.   voltae and    M.
 jannaschii  (Escalante-Semerena  & Wolfe, 1984) and  Alcaligenes faecalis 
(Marion & Malaney, 1963) can also oxidize formaldehyde.

    Yamamoto  et al. (1978)  isolated 65 strains  of methanol-utilizing
bacteria from seawater, sand, mud, and weeds of marine origin and found
that  all  were able  to use formaldehyde  as a sole  carbon source for
growth.  In contrast, Kimura et  al. (1977)  found that  336 strains of
bacteria, isolated from coastal seawater and mud, could not use formal-
dehyde as a sole carbon source for growth.

5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1  Environmental Levels

5.1.1  Air

    Measurements  in maritime air yielded  average formaldehyde concen-
trations of < 1-14 µg/m3 (Table  9).

Table 9.  Measurements of aldehyde mixing ratios in the air 
          near the grounda
-----------------------------------------------------------------------------
Location              RCHO      HCHO      Number   Reference 
                                          of
                                          measure- 
                           (µg/m3)        ments
-----------------------------------------------------------------------------
 
Baltic sea coast         -      0.7-2.7   5        Hadamczik (1947) 
 
Panama                1.2-4.8      -      ?        Lodge & Pate (1966) 
 
Antarctica            <0.6-12       -    ?        Breeding et al. (1973) 
 
Panama                <0.3-3.7      -    ?        Breeding et al. (1973) 
 
Amazon Basin          1.2-7.4      -      ?        Breeding et al. (1973) 
 
Irish west coast         -      0.1-0.5   5        Platt et al. (1979) 
 
Eastern Indian Ocean     -      < 1-14   63       Fushimi & Miyake (1980) 
 
Central Pacific          -      0.1-0.8   7        Zafiriou et al. (1980) 
 
South Africa             -      0.3-1.0   5        Neitzert & Seiler 
                                                   (1981) 
 
Irish west coast         -      0.1-0.6   36       Lowe et al. (1981) 
 
Bürserberg, Austria      -      0.05-2.3  55       Seiler (1982) 
-----------------------------------------------------------------------------
a   Modified from: Lowe et al. (1981). 

    Higher  values were generally obtained  in the equatorial zone  and
the  Pacific (Fushimi &  Miyake, 1980; Guderian,  1981; Seiler,  1982).
Measurements of the Nuclear Research Centre (Jülich,  Federal  Republic
of Germany), carried out with different measurement procedures  in  the
North  and South Atlantic, yielded values of 0.1 µg/m3 and   less (Lowe
et al., 1981).  In the vicinity of the Pacific islands, values of up to
14 µg/m3 were    reported (Fushimi & Miyake, 1980).  However, it should
be  borne in mind that considerable technical difficulties are involved
in measuring such low concentrations, with ensuing uncertainties.

    The values measured in continental air are  higher  (0-16 µg/m3).
Measurements in Bürserberg, Austria, at 1250 m above sea level (Seiler,

1982),  showed a mean  value of 0.6 µg/m3 with   a  variation range  of
0.05-2.3 µg/m3.

    Measurements   made   by   the  Federal   Environmental  Agency  at
Deuselbach,  Hunsrück, Federal Republic of  Germany, have proved to  be
representative  for  the  air in  the  rural  areas of  Central  Europe
(Seiler,  1982).  The mean  value was about 1.5 µg/m3,     ranging from
0.1 to 4.5 µg/m3 (Seiler,   1982). The lowest values were measured when
there  was a rapid inflow  of maritime air over  extended periods.  The
elevated  values were probably due  to man-made organic compounds  that
had been transported long distances.  Values of 6 µg/m3 generally   ap-
pear  together  with increased  concentrations  of carbon  monoxide and
sulfur  dioxide, indicating man-made air pollution.  Man-made emissions
dominate  in the highly industrialized areas of Central Europe (Ehhalt,
1974).

    Pronounced diurnal concentrations of formaldehyde are recognizable.
A  typical example is given in Fig. 2.  The resulting values are higher
in summer than in winter.  They vary from season to season  because  of
the variation in intensity of the ultraviolet radiation.

FIGURE 2

5.1.1.1  Air in the vicinity of industrial sources and in urban communities

    Estimated  formaldehyde  concentrations  in emissions  from various
sources are summarized in Table 10.

Table 10.  Estimated formaldehyde concentrations in emissions 
           from various sourcesa
-------------------------------------------------------------
Emission source                Formaldehyde level 
-------------------------------------------------------------
 
Natural gas combustion 
 
    Home appliances and        2400-58 800 µg/m3 
     industrial equipment 
    Power plants               15 000 µg/m3 
    Industrial plants          30 000 µg/m3 
 
Fuel-oil combustion            0-1.2 kg/barrel oil 
 
    Coal combustion 
    Bituminous                 < 0.005-1 g/kg coal 
    Anthracite                 0.5 g/kg coal 
 
Power plant, industrial and 
  commercial combustion 
 
Incinerators 
 
    Municipal                  0.3-0.4 g/kg refuse 
    Small domestic             0.03-64 g/kg refuse 
    Backyard                   11.6 g/kg (max) refuse 
 
Oil refineries 
 
    Catalytic cracking units   4.27 kg/barrel oil 
    Thermofor units            2.7 kg/barrel oil 
 
Mobile sources 
 
    Automobiles                0.2-1.6 g/litre fuel 
    Diesel engines             0.6-1.3 g/litre fuel 
    Aircraft                   approximately 0.3-0.5 g/litre 
                               fuel 
-------------------------------------------------------------
a       From: Kitchens et al. (1976). 

    Motor vehicle exhaust from automobiles not equipped with catalyzers
is the major source of formaldehyde in ambient outdoor air (Kitchens et
al., 1976).

    Only a few highly industrialized areas, which are also  areas  with
heavy traffic, have been covered completely by measurements of the for-
maldehyde burden. In one such area in the Federal Republic  of  Germany
(Ludwigshafen-Frankenthal),  annual  mean values  of 7-12 µg  formalde-
hyde/m3 were   measured during 1979-84. The  annual mean value was  the
arithmetic  average of  all half-hour  values measured  within  a  year
(long-term value).  Peak concentrations in certain subareas, one square
km  in size, ranged from 16 to 69 mg/m3.    These were based on the 95-
percentile,  i.e., 5%  of the  measured values  were allowed  to be  in

excess of the prescribed parameters for concentrations in  ambient  air
(MSGU  RP, 1984).  The majority of subareas showed 95-percentile values
of about 25 µg/m3.

    A  mean value  of 7 µg/m3 was   determined  in 1971-73  for the  43
measurement  points in  the Lower  Main District,  Federal Republic  of
Germany,   which   is  a   radial   measuring  network   with  downtown
Frankfurt/Main (Federal Republic of Germany) as its centre.   This  was
based on 1-h measurements (n = 862).  The 95% value of  the  cumulative
frequency distribution was 18 µg/m3,    and the 4 highest single values
were 69, 65, 59, and 52 µg/m3 (Lahmann, 1977).

    In another area at Mainz-Budenheim (Federal Republic  of  Germany),
continuous  exposure  to 8-20 µg/m3 was    measured,  with   short-term
values  of 23-99 µg/m3.     Analysis of the causes of these high levels
showed that they were not only caused by industrial emissions. Individ-
ual measurements showed a correlation with carbon monoxide  levels  and
were not season-dependent. Hence, it can be assumed that motor vehicles
not equipped with catalyzers are responsible, to a considerable extent,
for  the concentrations in ambient air (section 5.1.1.2). Usually, con-
centrations in ambient air are below 1 µg/m3.    Data on concentrations
of formaldehyde in ambient air are presented in Table 11.

    Formaldehyde  concentrations in ambient  air in areas  with a  high
level  of air pollution, away  from the vicinity of  industrial plants,
are presented in Table 12.

    Ambient  air  concentrations  of  formaldehyde,  measured  in   Los
Angeles,   California,  during   the  autumn  in 1961  and  1966,  were
0.006-0.197 mg/m3 (Kitchens   et  al., 1976)   and  a daily  average of
0.06-0.148 mg/m3 (Patterson   et  al.,  1976),  respectively.   Concen-
trations of formaldehyde in the Los Angeles area ranged from  0.003  to
0.167 mg/m3 in  1969 (Kitchens et al., 1976).  More recent air measure-
ments  taken during 1979 in  Los Angeles indicated levels  of less than
18.5 µg  formaldehyde/m3 (Versar  Inc., 1980).

    The  results of continuous analyses  of formaldehyde concentrations
in  ambient  air  at the  National  Autoexhaust  Monitoring Station  at
Kasumigaseki  in Tokyo were  studied by Matsumura  et al. (1979).   The
hourly,  daily, monthly, and yearly average concentrations  were  1-88,
1-34,  3.7-23,  and 5.5-12.6 µg/m3 (1-73,   1-28.4,  3.1-19.1, and 4.6-
10.5 ppb),  respectively,  with a  9-year  average value  of 8.5 µg/m3
(7.1 ppb).   Daily  average  concentrations showed  logarithmic  normal
distribution.   Ratios of the  daily to hourly  average  concentrations
were about 1 to 2.  The daily maximum value was observed at around noon
and the yearly maximum was found during June and August.

    Richards  et al. (1983)  collected cloud water  samples in the  Los
Angeles  Basin during 5  aircraft flights (altitude  not reported)  and
found a median of 2 mg formaldehyde/litre (68 µmol/litre)   (range, 11-
142 µmol/litre).

    Measurements  taken in 4 cities  in New Jersey showed  median daily
concentrations  in  the  range of  4.67-8.12 µg/m3 (Cleveland   et al.,
1977).

    A   study   in   Switzerland showed  formaldehyde concentrations of
11.4-12.3 µg/m3 in   street air (Wanner et al., 1977).  Maritime air in
the  northern part of the Federal Republic of Germany has been reported
to  contain  formaldehyde at  levels  of 0.12-8 µg/m3 (Platt    et al.,
1979).

    Tanner  & Meng (1984)  observed strong seasonal  variations in  the
levels  of formaldehyde, maximum levels  being observed in the  summer.
The  formaldehyde samples were  collected at an  unidentified northeast
coastal  site in the USA, using an impinger containing acetonitrile and
DNPH;  they  were  analysed using  high-pressure liquid chromatography.
The concentrations ranged from 1 to 58 µg/m3 (0.9   to 48 ppbv) with an
overall  mean  of  9 µg/m3 (7.5 ppbv).    The  monthly  average ambient
levels were:
                                                       equivalent to:

    July/August:     1982:  15.8 ppbv, 16 samples        16 µg/m3
    October/November:1982:   4.4 ppbv, 24 samples         4 µg/m3
    March:           1983:   3.8 ppbv, 59 samples         4 µg/m3
    April:           1983:  11.2 ppbv, 11 samples; and   11 µg/m3
    May:             1983:  12.2 ppbv, 25 samples        12 µg/m3


Table 11.  Levels of formaldehyde in ambient aira                                                     
---------------------------------------------------------------------------------------------------------
Country   Sampling area    % of        Analytical       Source       HCHOb    Comment          Reference 
                           samples     method                        (µg/m3) 
---------------------------------------------------------------------------------------------------------
Federal   Eifel Region     -           2,4 dinitrophe-  easterly     5.0-     Within boundary  Schmidt & 
Republic  (51°N, 6°E)                  nylhydrazine     winds        6.1      layer            Lowe  
of                                                      from indus-  0.37     above boundary   (1981)
Germany                                                 trial area;           layer 
                                                        westerly     0.12     5-7 km altitude 
                                                        maritime 
                                                        winds 
 
Federal   Mainz-outskirts  8           glass fibre      automobiles  0.063    formaldehyde     Klippel & 
Republic  of city;         54          filters          some auto-   0.037-   aerosol only     Warneck 
of        Deuselbach-rural                              mobile       0.39                      (1978) 
Germany                                                 industry 
 
France    Paris roadside               2,4-dinitrophe-  automobiles  41-      total aldehydes  Favart et 
                                       nylhydrazine                  120                       al. (1984) 
 
Ireland   Mace Head and    28          glass fibre      maritime air 0.049-   formaldehyde     Klippel & 
          Loop Head                    filters                       0.082    aerosol only     Warneck 
          located on                                                                           (1978) 
          shoreline

Italy     Northern - near  15          2,4-dinitrophe-               7.06                      De Bortoli 
          Swiss border                 nylhydrazine                                            et al. 
                                                                                               (1985) 
Nether-   Terschelling     350         chromatropic acid             7.4                       Guicherit & 
lands     Island - small   at each     method                                                  Schulting 
          population;      site                                                                (1985) 
          Delft - small 
          city; Rotterdam - 
          heavily industrialized 
---------------------------------------------------------------------------------------------------------
 

                                   
Table 11 (contd). 
---------------------------------------------------------------------------------------------------------
Country   Sampling area    % of        Analytical       Source       HCHOb    Comment          Reference 
                           samples     method                        (µg/m3) 
---------------------------------------------------------------------------------------------------------
USA       Rural Illinois   30          3-methyl-2-      -            <1.2-   total            Breeding 
          and Missouri;                benzothiazolone               5.0      aldehydes        et al. 
          3 samples                    hydrazone                                               (1973) 
          1 m above ground,
          1 sample 20-15 m 
          above tree tops  
                                                        
USA       Los Angeles-     31          30 or 60 litres     -         49.1     July-November,   Altshuller 
          downtown                     of air at 1 litre             55.3     1960             & McPherson, 
                                       per min through                        Sept-Nov. 1961   (1963) 
                                       20 ml of 0.1% 
                                       chromotropic acid 
                                       in conc. H2SO4 
 
USA       Riverside,       32          Fournier-transform            < 5-                     Tuazon et 
          California                   infrared system               12                        al. (1978) 
 
USA       Lennox, Calif.,  36          Microimpinger    industrial   0.6-     levels between   Grosjean & 
          roof top                     method with      emissions    48.6     07h30 and 20h00  Swanson, 
          Azusa, Calif.,   36          2,4-dinitro-     photo-       0.9-     during air pol-  (1983) 
          roof top                     phenylhydra-     chemical     43       lution episode 
                                       zine             pollutants 
 
          Los Angeles      20                                        4.5-     between 9h30 and 
          Area                                                       70.1     16h20 during air 
                                                                              pollution episode
 
USA       Bayonne,         hourly      dichlorosulfit-  automobiles  17.2-    range of max.    Cleveland 
          Camden,          samples     omercurate                    20.0     levels from 4    et al.  
          Elizabeth        between     complex and acid                       sites            (1977)
          and Newark,      May 1 and   bleached pararo-              4.7-     range of average 
          New Jersey       Sept. 30,   saniline hydro-               8.1      levels from 
                           1974        chloride                               4 sites 
---------------------------------------------------------------------------------------------------------
 a      Modified from: Meek et al. (1985). 
 b      Unless other specified, mean or ranges. 


 
Table 12.  Measurements of formaldehyde in ambient air in areas remote 
           from industrial emission sourcesa
--------------------------------------------------------------------------------------------------------
Location                     Period     Mean value   Maximum    Remarks             Reference 
                                        or range     value 
                                        (ug/m3)    (ug/m3) 
--------------------------------------------------------------------------------------------------------
Federal Republic of Germany 
 
Berlin                     1973-74        0.6          18       118-h mean          Lahmann & 
                                          2.1          32       119-h mean          Prescher 
Berlin - Airport                          2.2          29        72-h mean          (1979) 
Berlin - Steglitz          1966-67                     39       243-h mean          Lahmann & Prescher 
Berlin - Tempelhof         1973-74        0.5          12        71-h mean          (1979) 
Frankfurt - Airport        1983           9-11         23       half-hour mean      BGA (1985) 
Frankfurt - City           1983           7-13          9-25                        BGA (1985) 
Köln - Neumarkt            December 1975  2.3           8.5     95-percentile       Deimel (1978) 
                           June 1978      8.2          18.3     95-percentile       Deimel (1978) 
                           June 1978                   23.1     rush-hour traffic   Deimel (1978) 
Mainz - University         1979           4.4           7.5     65 measurements     Seiler (1982) 
Mainz - Finthen            1979-80        1.6           3.8     33 measurements     Seiler (1982) 
 
Switzerland 
 
Street air                 1976           11.4-12.3      -                          Wanner et al. (1977) 
 
USA 
 
California                 1960-80        8-70         160                          Versar Inc.(1986) 

Los Angeles, California    1961-66        6-197          -                          Kitchens et al. 
                                                                                    (1976) 
Northeastern coastal site  1982-83        1-48           -                          Tanner & Meng 
                                                                                    (1984) 
--------------------------------------------------------------------------------------------------------
a   From: BGA (1985). 
5.1.1.2  Emissions from industrial plants

    (a)  Chemical industry

    The  following emission factors  per metric tonne  of  formaldehyde
produced  by formaldehyde-manufacturing plants in  the Federal Republic
of Germany are given on a 100% basis (section 3.2.1.1).

    Silver  catalyst process  with afterburning  of flue  gas in  power
plant and gas displacement devices: 0.003-0.008 kg/metric tonne formal-
dehyde  produced;  silver catalyst  process  with flaring  of  off-gas,
without  gas  displacement devices:  0.05-0.2 kg/metric tonne produced;
metal-oxide   catalyst  process  without   afterburning:  approximately
0.5 kg/metric  tonne produced; metal-oxide catalyst process with after-
burning  but without gas displacement devices: 0.08-0.2 kg/metric tonne
produced.

    (b)  Wood-processing industry

    Several studies are available that deal with formaldehyde emissions
at  particle board factories in  the Federal Republic of  Germany (WKI,
1978; Marutzky et al., 1980; Schaaf, 1982).

    In 1980, the emissions in the exhaust air of several plants reached
a mean value of 40 mg formaldehyde/m3 off-gases.   No measures had been
taken  at any of the plants to clean the off-gases.  Pilot studies at a
particle board factory showed that a concentration (pure gas)  of  less
than  20 mg/m3 could  be obtained using bioabsorption equipment.  Mean-
while,  the  emittable  formaldehyde content  of  the  resins used  was
further reduced, resulting in even lower formaldehyde concentrations in
the off-gases (BGA, 1985).

5.1.1.3  Emissions from furnaces

    Incomplete combustion in furnaces is also a cause  of  formaldehyde
emission  (Schmidt &  Götz, 1977).   Various types  of furnaces  differ
considerably in their emission of formaldehyde, depending on  the  rate
of combustion.

    Investigations  on  a  small  solid-fuel  boiler  running  on  wood
(Schriever et al., 1983) showed that there was a  formaldehyde  concen-
tration  of more than  1000 mg/m3 in  the gaseous  emission during  the
first  phase of combustion, i.e.,  that of degasification.  During  the
subsequent  burning-out phase, the emissions of formaldehyde were about
50-100 mg/m3.

    Lipari et al. (1984) measured formaldehyde emissions in the exhaust
gases  of  a free-standing  wood-burning  fireplace in  the laboratory.
When  burning green ash (quartered logs), values of 708 mg/kg wood were
found;  the formaldehyde content of the exhaust gases, when burning red
oak, ranged from 89 mg/kg (quartered logs) to 326 mg/kg  (split  wood).
It is likely that wood burning in the home is a major source of primary
aldehydes during the winter.

    In  the Federal Republic of Germany, it is estimated that about 2.8
million  tonnes  of  firewood off-gas  are  consumed  in small  heating
systems for heating buildings.  On the basis of an average formaldehyde
concentration  of  100 mg/m3 firewood,   an overall  annual emission of
approximately 1000 tonnes of formaldehyde has been calculated.

5.1.1.4  Emissions from motor vehicles

    Formaldehyde  is also emitted as a product of incomplete combustion
by  internal combustion engines.  The amounts emitted depend greatly on
the  operating conditions.  Very high  values are reached in  emissions
from  a cold engine.   Kitchens et al.  (1976) reported a  formaldehyde
emission  of 700 mg/litre gasoline  or diesel fuel.   Given an  assumed
average  value for gasoline  consumption of 23  million tonnes and  for
diesel fuel consumption of 13 million tonnes in the Federal Republic of
Germany,  the total formaldehyde  emission would be  35 000 tonnes  per
year.   Hence, motor vehicles are  by far the most  important source of
formaldehyde emission.  The use of exhaust catalytic converters reduces
the  emissions to less than one-tenth.  Emission factors of between 1.8
and 2.4 mg/km have been reported for the USA (VDA, 1983).

    Four-stroke engines, running on alcohol, emit more  aldehydes  than
similar engines fuelled with petrol.  The formaldehyde concentration in
the  exhaust  fumes  can be  reduced by  a factor  of 10  by installing
exhaust catalytic converters in vehicles powered with methanol, but the
concentration is still higher than that of vehicles with petrol-burning
engines.  Emission factors of about 250-300 mg/km have been  given  for
vehicles  with  methanol-burning  engines without  an exhaust catalyser
(Menrad & König, 1982).  The odour of such amounts of  formaldehyde  is
perceptible near the vehicle.  Diesel engines also  emit  formaldehyde;
diesel   oil   produces   1-2 g aldehydes/litre  of   which  50-70%  is
formaldehyde (Guicherit & Schulting, 1985).

5.1.2  Water

    In the atmosphere, formaldehyde is absorbed during the formation of
cloud   droplets  ("rainout")  or  scavenged   by  falling  raindrops
("washout").   Some   concentrations  in rainwater  and  aerosols are
given  in  Table 13.   When the rainfall  continued for a  long period,
remaining  concentrations in the air  of 0.05 µg/m3 (detection   limit:
0.03 µg/m3)      were  found  by  Seiler  (1982).   Concentrations   in
rainwater   at a remote site in the central equatorial Pacific averaged
8 ± 2 µg/kg    (Zafiriou et al., 1980). Kitchens et al. (1976) reported
concentrations of 0.31-1.38 mg/litre.

Table 13.  Formaldehyde concentrations in rainwater and 
           aerosola
-------------------------------------------------------
Location (year)          Rainwater       Aerosol  
                         concentration   concentration
                         (mg/litre)      (ng/m3) 
-------------------------------------------------------
 
Mainz, Federal Republic  0.174 ± 0.085   -
 of Germany (1974-77) 
 
Deuselbach, Federal      0.141 ± 0.048   40.9 ± 26.0 
 Republic of (1974-76) 
 
Ireland (1975, 1977)     0.142 ± 0.059   5.36 ± 2.4 
 
Irelandb (1977)        0.111 ± 0.059   -
-------------------------------------------------------
 
a From: Klippel & Warneck (1978). 
b Very clean air. 

    Fish-culture  activities are also a  source of formaldehyde in  the
aquatic  environment. Formalin is one of the most widely and frequently
used  chemicals for treating fish  with fungal or ectoparasitic  infec-
tions.  After use, formaldehyde solutions are often discharged into the
hatchery effluent (NRC, 1981).

5.1.3  Soil

    Formaldehyde  is  formed  in the  early  stages  of  plant  residue
decomposition in soil (Berestetskii et al., 1981).  It is  degraded  by
certain  bacteria in the soil,  and therefore bioaccumulation does  not
occur.   Completely polymerized urea-formaldehyde resins persist in the
environment and do not emit formaldehyde. Partially polymerized conden-
sation  products of low relative molecular mass degrade gradually, thus
releasing  formaldehyde vapour that can  be broken down by  soil micro-
flora (Kitchens et al., 1976; Hsiao & Villaume, 1978).

5.1.4  Food

    There  is  some natural  formaldehyde  in raw  food.   Formaldehyde
concentrations in various food are given in Table 14.

Table 14.  Formaldehyde content of foodstuffs 
-----------------------------------------------------------------------------
Food                       Formaldehyde content      Reference 
                                (mg/kg) 
-----------------------------------------------------------------------------
 
Fruits and vegetables 
 
    pear                   60a (38.7)b          Möhler & Denbsky (1970) 
    apple                  17.3 (22.3)          Tsuchiya et al. (1975) 
    cabbage                4.7 (5.3)            Tsuchiya et al. (1975) 
    carrot                 6.7 (10)             Tsuchiya et al. (1975) 
    green onion            13.3 (26.3)          Tsuchiya et al. (1975) 
    spinach                3.3 (7.3)            Tsuchiya et al. (1975) 
    tomato                 5.7 (7.3)            Tsuchiya et al. (1975) 
    white radish           3.7 (4.4)            Tsuchiya et al. (1975) 
 
Meat 
 
    pig                    20                   Florence & Milner (1981) 
    sheep                  8                    Mills et al. (1972) 
    poultry                5.7                  Möhler & Denbsky (1970) 
 
Milk and milk products 
 
    goat's milk            1                    Mills et al. (1972) 
    cow's milk             up to 3.3            Möhler & Denbsky (1970) 
    cheese                 up to 3.3            Möhler & Denbsky (1970) 
 
Fish     
 
    freshwater (fumigated) 8.8                  Möhler & Denbsky (1970) 
    sea (fumigated)        20                   Möhler & Denbsky (1970) 
    cod (frozen)           20                   Rehbein (1986) 
    shrimp (live)          1                    Radford & Dalsis (1982) 
    crustacea              1-60                 Cantoni et al. (1977) 
    (Mediterannean) 
    crustacea (ocean)      3-98                 Cantoni et al. (1977) 
-----------------------------------------------------------------------------
a       Analysis by chromotropic acid. 
b       Analysis using Schiff's reagent. 

    Accidental  contamination  can  occur through  fumigation (e.g., in
grain) or by using formaldehyde-containing food additives.

    Hexamethylenetetramine  has been reported to decompose gradually to
formaldehyde  under acidic conditions  or in the  presence of  proteins
(Hutschenreuter,  1956; WHO, 1974a).  Its  use is not recommended  when
there  is  a possibility  that nitrate might  also be present  in food,
because of the risk of nitrosamine formation (WHO, 1974b).

    Formaldehyde  can  be  introduced  into  food  through  cooking and
especially  through smoking of food, from utensils, and as a combustion
product; it can be eluted from formaldehyde-resin plastic  dishes  with
water, acetic acid, and ethanol in amounts directly proportional to the
temperature (Table 15, 16).

    Release  of formaldehyde  may increase  with the  repeated  use  of
melamine  resin tableware (Table 16).  The molar concentration ratio of
formaldehyde to melamine (y), in 4% acetic acid maintained at 95 °C for
30 min  in melamine cups,  decreases biexponentially between  the first
and fifth treatments according to the following formula: 1n y = -1.0755
ln x + 2.2462, where x = the number of times that the heat treatment is
repeated.   After the sixth  treatment, the value  of y is  reported to
remain constant (Inoue et al., 1987).

    Daily intake of formaldehyde through food is difficult to evaluate,
but  a  rough estimate  from available data  is in the  range of 1.5-14
mg/day  for  an average  adult, most of  it in a  bound and unavailable
form.

5.2  Indoor Air Levels

    Indoor  air  levels  of  formaldehyde  in  various  countries  were
presented  during the International Conference on Indoor Air Quality in
Stockholm (Berglund et al., 1984).

    A  survey of indoor air quality under warm weather conditions, in a
variety  of residences in Houston, Texas, USA, not selected in response
to  occupant complaints, revealed a distribution of indoor formaldehyde
concentrations  ranging from < 0.01 to 0.35 mg/m3,   with an arithmetic
mean  of 0.08 mg/m3 (Stock  &  Mendez, 1985).  Levels  in approximately
15%  of the monitored  residences exceeded 0.12 mg/m3.     Formaldehyde
levels  depended on the age and structural type of the dwelling.  These
factors were not independent and reflected the influence of more funda-
mental  variables, i.e., the rate of exchange of indoor and outdoor air
and the overall emission potential of indoor materials.  The results of
this   survey suggested that considerable population exposure to excess
(>0.12 mg/m3)    formaldehyde concentrations might have occurred in the
residential  environment,  indicating  the need  for  improved  control
strategies.

    Hawthorne  et al. (1984) measured  formaldehyde levels in 40  East-
Tennessee homes.  Levels in older houses averaged  0.048 mg/m3    while
those in houses less than 5 years old averaged 0.096 mg/m3.

    The  effects of foliage plants on the removal of  formaldehyde from
indoor air in energy-efficient homes is discussed in section 7.3.

    Measurements  made in living  areas, schools, hospitals,  and other
buildings are listed in Table 17 to 19.


Table 15.  Migration of formaldehyde from melamine and urea-resin tableware (mg/litre) into 
           different solvents. Detection limit 0.4 mg/litrea.
-------------------------------------------------------------------------------------------- 
Resin   Temperature        Water         4% Acetic acid       15% Ethanol      35% Ethanol 
                     30 minb  30 minc  30 minb  30 minc   30 minb  30 minc  30 minb  30 minc 
--------------------------------------------------------------------------------------------
 
           25 °C      n.d.d     n.d.     n.d.     n.d.      n.d.     n.d.     n.d.     n.d.
           60 °C      n.d.      n.d.     0.5      n.d.      0.4      n.d.     n.d.     n.d.
Melamine   70 °C      n.d.      n.d.              
resin      80 °C      0.5       1.4      0.6      3.0       0.5      1.6      0.5      1.4
           90 °C      2.2       2.6 
          100 °C      2.6       5.2      0.8      8.9       0.5      4.6      0.5      4.8
--------------------------------------------------------------------------------------------
           25 °C      0.4       0.4      0.4      0.5       0.5      0.5      0.4      0.5
           60 °C      2.9       4.3      3.1      8.3       3.1      3.8      2.9      4.1
Urea       70 °C      5.0      13.0 
resin      80 °C      9.1      23.4      9.6    126.0       7.4     30.0      8.6     28.2 
           90 °C     13.0      39.2 
          100 °C     18.0      48.2     27.6    648.0      19.0     54.0     18.5     50.4 
--------------------------------------------------------------------------------------------
a       From: Homma (1980). 
b       Standing at room temperature. 
c       Maintained at a definite temperature. 
d       Not detected. 
Table 16.  Migration from melamine cups with 4% acetic acid 
           concentration in the migration solutiona
-------------------------------------------------------------------
Conditions                         Melamine     Formaldehyde 
                                   mg/litre     mg/litre 
-------------------------------------------------------------------
 
60 °C, 30 min                      0.5 ±  0.6   ndb
 
Microwave oven 1.5 min (90 °C) 
and stood at room temperature for 
30 min (60 °C)                     1.7 ±  1.2   (1.1 ± 0.4) 
 
95 °C, 30 min 
  repetition 1                     9.5 ±  3.1   (4.1 ± 0.8) 
             2                     28.1 ±  6.0  (12.0 ± 2.6) 
             3                     37.7 ± 10.3  (17.3 ± 3.4) 
             5                     46.4 ± 13.9  (19.4 ± 2.8) 
             7                     50.4 ±  3.6  (22.2 ± 2.2) 
-------------------------------------------------------------------
a From: Ishiwata et al. (1986). 
b Not detected. 
 
    Tobacco smoke contains an average of 48 mg formaldehyde/m3   and is
an  important source  of formaldehyde  in indoor  air.  Two  cigarettes
smoked in a 30 m3 room  increased the formaldehyde level to  more  than
0.1 mg/m3 (Jermini   et al., 1976).  Formaldehyde from tobacco smoke is
absorbed  by furniture, carpets, and curtains, and only slowly desorbed

if  the formaldehyde concentration in  the indoor air decreases.   Par-
ticle boards and, to a lesser extent, urea-formaldehyde-foam insulation
(UFFI) were also listed as causes of increased indoor exposure.  Disin-
fectant  products may cause high  exposure.  These sources of  emission
are described in Table 17, 18, and 19.

    Formaldehyde concentrations in 49 Dutch houses and 3  old  peoples'
homes where no UF-foam or particle board had been used were analysed by
Cornet  (1982).  The houses  were of different  construction types  and
periods,  in which it  could be established  that no particle  board as
construction material nor UF-foam had been used.  However,  several  of
these houses had particle board furniture.  Overall, construction types
and  conditions of use were  typical for Dutch circumstances.   Average
formaldehyde concentrations were 65 µg/m3,    ranging mainly from 30 to
100 µg/m3.  Ventilation rates  ranged  usually from 0.3-1.5 air changes per
hour in living rooms and 0.2-1.2 in bedrooms. During  the  measurements
no smoking took place.

    No  clear correlations could be  established between the amount  of
particle board present in furnishings, ventilation rates,  and  formal-
dehyde concentrations.

5.2.1  Indoor exposure from particle boards

    Nuisance from bad smells led to complaints by students and teachers
in  several new schools in  Köln, Federal Republic of  Germany, in 1975
and 1976. Formaldehyde concentrations of up to 1.2 mg/m3 were  measured
with  the windows closed (Deimel, 1978).  A combination of ceilings and
furniture  made of particle boards and insufficient ventilation was the
cause  of these  high indoor  concentrations (Anderson  et al.,  1975).
There  have been complaints from schools, kindergartens, private homes,
and,  especially in the USA, mobile homes.  Formaldehyde concentrations
of  more  than 0.12 mg/m3 and   sometimes  more than  1.2 mg/m3    were
measured.

    During  the  1970s, increased  use  of  UF-bonded   particle  board
as   a  construction  material in  The  Netherlands  resulted  in  many
consumer complaints, attributed to formaldehyde.  In 1978, a  level  of
120 µg/m3 was     officially recommended as an  acceptable upper limit.
In  the  years 1978-81,  measurements  of indoor  formaldehyde  concen-
trations were carried out, guided by consumer complaints.  In  1981,  a
summary  of 950  measurements was  presented to  the  Dutch  Parliament
(Dutch State Secretary of Health and Environment, 1981).  In 435 cases,
formaldehyde  concentrations  exceeded 120 µg/m3,     whereas  in   515
cases,   notwithstanding  complaints,  levels   were  below 120 µg/m3.
Since  1981, many hundreds  of measurements of  formaldehyde levels  in
houses, schools, hospitals etc. have been carried out, guided  also  by
consumer  complaints.  But the overall  picture has remained the  same,
except  for extremes; values exceeding 200-250 µg/m3 have   seldom been
reported since the introduction of the new standard. However, occasion-
ally,  higher  concentrations of  up  to 400 µg/m3 have   arisen  as  a
result  of  the use  of particle board  or trimmings of  bad quality in
furniture.


Table 17.  Formaldehyde levels in homesa 
---------------------------------------------------------------------------------------------------------
Country       No.    Average    Room    Air     Humidity     HCHO             Comments         Reference 
(Year)        of     age of     volume  temp.   (% relative  (mg/m3)b         
              homes  homes      (m3)    (°C)    humidity or    
                                                gH2O/kg air)
---------------------------------------------------------------------------------------------------------
 
Canada        378    -          -                            0.042            homes without    UFFI  
(1981)                                                       (2.6% > 0.123)  UFFI             (1981)
 
              1897   -          -                            0.066            homes with UFFI  UFFI  
                                                             (10.4% > 1.23)                   (1981)
 
Canada        6      67                 21.5    61%          0.014            homes without    Georghiou 
(1981)               (8-100)            (21-23) (59-65)      (<0.012-0.027)  UFFI             & Snow  
                     years                                                                     (1982)
 
              43     52                 20.4    62%          0.066            homes with UFFI  Georghiou 
                     (3-140)            (15-25) (54-71)      (<0.012-0.246)                   & Snow  
                     years                                                                     (1982)
 
Canada        46     -          -       -       23-48%       0.11             low leakage      Dumont  
(1983)                                                       (0.04-0.30)      homes            (1984)
                                                39%          > 0.123 
 
Denmark       25c    15.3       23d     22.8    7.1          0.62                              Andersen 
(1973)               months                                                                    et al. 
                                                                                               (1975) 
              25g    15.3       23d     23      7            0.64             corrected for    Andersen 
                     months                                                   standard         et al. 
                                                                              conditionse      (1979) 
                                                                                         
 
Denmark       7f     -          -       26      9.7          0.64 
(1976)        7g     -          -       23      7            0.30             corrected for    Andersen 
                                                                              standard con-    et al.  
                                                                              ditions          (1979)
 
Finland       432    -                  -       -            0.20             average          Niemalä  
                                                             0.11             25th percentile  (1985)
                                                             0.33             75th percentile 
---------------------------------------------------------------------------------------------------------
 

                                   
Table 17 (contd). 
---------------------------------------------------------------------------------------------------------
Country       No.    Average    Room    Air     Humidity     HCHO             Comments         Reference 
(Year)        of     age of     volume  temp.   (% relative  (mg/m3)b         
              homes  homes      (m3)    (°C)    humidity or 
                                                gH2O/kg air) 
---------------------------------------------------------------------------------------------------------
 
Germany,      1                                              0.069            middle of living Schulze  
Federal                                                                       and bedroom      (1975)
Republic of   
(1974)        1                                              0.10             room near cup-   Schulze  
                                                                              boards           (1975)
              1      furniture  60                           0.039            middle of sick-  Schulze  
                     1-1.5                                                    room near        (1975)
                     years old                                                cupboards
              1                 60                           0.050            near cupboards   Schulze 
                                                                                               (1975) 
              1      new house  11                           0.16             kitchen, fitted  Schulze  
                                                                              cupboards        (1975)
 
              1      new house  54                           0.10             living room      Schulze 
                                                                                               (1975) 
 
              1      new house                               0.084            kitchen          Schulze 
                                                                                               (1975) 
 
              1      new house                               0.075            living room      Schulze 
                                                                                               (1975) 
 
              1      old        35                           0.242            living room      Schulze  
                     house                                                    (7 m3 of         (1975)
                                                                              cupboard space)
Germany,      984                               57.3%        < 0.05                           Prescher 
Federal                                         22.3%        < 0.05                           & Jander 
Republic of                                     22.3%        0.05-0.07                         (1987) 
                                                11.4%        0.071-0.096 
                                                3%           0.097-0.12 
                                                6%           > 0.12 
 
Italy         15                                             0.029            apartments and   De Bortoli 
(1983-84)                                                    (0.008-0.052)    housing          et al.
                                                                                               (1985) 
---------------------------------------------------------------------------------------------------------
 

                                  
Table 17 (contd). 
-----------------------------------------------------------------------------------------------------------

Japan                                                        up to 
                                                             0.041            living room      Matsumura 
                                                             0.113            pre-fabricated   et al. 
                                                                              house            (1983) 
 
Switzerland   8      < 6 months                             0.33             just after       Wanner & 
(1981-82)            to 1 year                               0.14             occupancy        Kuhn (1984) 
 
The Nether-   15                                             0.27             before           Dept. Nat. 
lands                                                                         corrective       Housing & 
(1980)                                                                        measures taken   Phys. 
                                                                                               Planning 
                                                                                               (1981) 
 
              8                                              0.29             before treatment 
                                                             0.10             6 weeks after 
                                                                              treatment 
 
The Nether-   5                         21      56%          0.17             living rooms,    Van der 
lands                                                                         before           wal 
(1977-1980b)                                                                  treatment        (1982)  
 
                                        21      60%          0.09             after treatment 
              
              5                         20      54%          0.32             bedrooms before 
                                                                              treatment 
 
                                        21      60%          0.20             after treatment 
 
              36                                             0.34             average of highest 
                                                                              measurements 
 
USA (1982)    40     0-30 years                              0.076 ± 0.095    5903             Hawthorne 
              18     0-5 years                               0.103 ± 0.112    measurements     et al. 
              11     5-15 years                              0.052 ± 0.052                     (1983) 
              11     >15 years                              0.039 ± 0.052 
                
              18     0-5 years                               0.107 ± 0.114    spring 
                                                             0.136 ± 0.125    summer 
                                                             0.058 ± 0.068    autumn 
---------------------------------------------------------------------------------------------------------
 

                                   
Table 17 (contd). 
---------------------------------------------------------------------------------------------------------
Country       No.    Average    Room    Air     Humidity     HCHO             Comments         Reference 
(Year)        of     age of     volume  temp.   (% relative  (mg/m3)b         
              homes  homes      (m3)    (°C)    humidity or
                                                gH2O/kg air) 
---------------------------------------------------------------------------------------------------------
USA (1982) contd. 
                                         
              11     5-15 years                              0.053 ± 0.049    spring           Hawthorne 
                                                             0.060 ± 0.059    summer           et al. 
                                                             0.042 ± 0.043    autumn           (1983) 
              11     >15 years                              0.044 ± 0.063    spring 
                                                             0.036 ± 0.046    summer 
                                                             0.032 ± 0.028    autumn 
 
USA (1981)    41                                             0.04             homes without    Ulsamer 
                                                             (0.012-0.098)    UFFI             et al. 
                                                                                               (1982) 
              636                                            0.15             homes with UFFI 
                                                             (0.012-4.2) 
                                         
USA           244                                                             UFFI homes       Breysse 
                                                             >1.23           2.8% of samples  (1984) 
                                                             0.61-1.22        1.9% of samples 
                                                             0.12-0.60        24.1% of samples 
                                                             <0.12           71.2% of samples 
 
                                                                              non-UFFI homes and 
                                                                              apartments 
              59                                             >1.23           1.8% of samples 
                                                             0.61-1.22        1.8% of samples 
                                                             0.12-0.60        36.3% of samples 
                                                             <0.12           60.1% of samples 
 
USA           13     building                                0.12 (median)                     Dally 
(1978-79)            material                                                                  et al. 
                     3-92 months                                                               (1981) 
                     (5.2 months 
                     median) 
---------------------------------------------------------------------------------------------------------
 

                                   
Table 17 (contd). 
---------------------------------------------------------------------------------------------------------
                                     
USA (1979)    1                                              0.098            energy           Berk et 
                                                             (0.04-0.15)      efficient        al. (1980) 
                                                                              house (0.01 mg    
                                                                              HCHO/m3 outdoors)
              1                                              0.081            unoccupied without 
                                                             ±0.007           furniture 
 
                                                             0.225            unoccupied with 
                                                             ±0.016           furniture 
                                     
                                                             0.263 ± 0.026    occupiedh, 
                                                                              daytime 
 
                                                             0.141 ± 0.044    occupiedh, 
                                                                              nighttime 
 
USA           9      2 years    445                          0.044 ± 0.022    airtight         Offermann 
(1980/81)                       (total)                                       construction     et al. 
                                                                              (half had        (1982) 
                                                                              gas appliances)
                                                             0.033 ± 0.020    mechanical venti-
                                                                              lation 
 
              1      6 years    441                          0.017            "loose" construc-
                                (total)                                       tion 
 
USA (1983)    20     <6                                     0.076            energy-          Grimsrud 
                     years                                                    efficient        et al. 
                                                                              new homes        (1983) 
 
              16                                             0.037            low ventilation 
                                                                              modernized homes 
---------------------------------------------------------------------------------------------------------
 
a Modified from:  Meek et al. (1985).  Where blanks appear, relevant information not provided by authors. 
b Means, ranges or standard deviations, unless otherwise specified. 
c Ventilation = 0.8 air changes/h. 
d Loading (ratio of unit area of formaldehyde source to room volume) = 1.2 m2/m3. 
e Standard conditions were: 23 °C, 7 g H2O/kg air, 1 air change/h. 
f Ventilation = 0.32 air change/h. 
g Ventilation = 1 air change/h. 
h House had a gas stove and 3 occupants, no cigarette smokers. 

Table 18.  Formaldehyde levels in mobile homesa
--------------------------------------------------------------------------------------------------------
Country      No. of mobile   Age of        HCHO         Comments                      Reference 
             homes studied   homes         (mg/m3) 
--------------------------------------------------------------------------------------------------------
 
Germany,                     1 year        5.26         trailer                       Schulze (1975) 
Federal                      1 year        1.06         trailer 
Republic of                                             opened up for 1 h 
                             3 years       0.06         trailer shut for 1 day 
                  3          1 year        0.11         trailer 
                  3          2 years       0.05         trailer 
 
USA             110          < 2 years     0.95         complaint homes, Washington   Stone et al.  
                 38          < 2 years     0.89         complaint homes, Wisconsin    (1981)
                 66          < 2 years     1.04         complaint homes, Minnesota 
                             < 2 years     0.66         random sample, Wisconsin 
                 77          2-10 years    0.58         complaint homes, Washington 
                  9          2-7 years     0.56         complaint homes, Wisconsin 
                 43          2-10 years    0.34         complaint homes, Minnesota 
 
USA              65          0.2-12 years  0.59         complaint homes, Wisconsin    Dally et al.  
                             median 1.3    (median)                                   (1981)
                             years 
 
USA             430                        > 1.23        4 % of sample                Breysse (1984) 
                                           0.61-1.22    18% of sample 
                                           0.12-0.60    64% of sample 
                                           < 0.12       14% of sample 
 
USA             431                        0.47                                       Ulsamer et al.  
                                           (0.012-3.60)                               (1982)
 
USA              65                        0.20         65 out of 208; random         Hanrahan et al.  
                                           (median)     sample of mobile homes        (1984)
                                                        in Wisconsin 
--------------------------------------------------------------------------------------------------------
 
a From: Meek et al. (1985). 

Table 19.  Formaldehyde levels in public buildingsa
--------------------------------------------------------------------------------------------------------
Country    No. of  Average    Loading,  Air   Ventila-   HCHO         Comments             Reference 
           build-  age of     (m2/m3)b  temp. tion (air  (mg/m3)c         
           ings-   buildings            (°C)  changes/h) 
--------------------------------------------------------------------------------------------------------
 
Denmark      7     6 months      -       -    0.5        0.45         mobile day care      Olsen (1982) 
                                                                      centre 
 
Germany,     3        -          -       -     -         0.469        schools containing   Burdach & 
Federal                                                               some UF building     Wechselberg 
Republic of                                                           material             (1980) 
 
           441                                                        dwellings, offices,  Prescher  
                                                                      hospitals, joiner's  (1984)
                                                                      workshops, complaints 
 
             -        -          -       -     -         0.014-0.31   dwellings with 
                                                         mean 0.06    gas cooking 
 
             -        -          -       -     -         0.064-0.2    dwellings without 
                                                         mean 0.06    gas cooking 
 
             -        -          -       -     -         0.01-0.13    offices, smokers 
                                                         mean 0.05 
 
             -        -          -       -     -         0.02-0.1     offices, non-smokers 
                                                         mean 0.05 
 
             -        -          -       -     -         0.026-0.22   joiner's workshops 
                                                         mean 0.12 
 
             -        -          -       -     -         0.012-0.1    hospital rooms 
                                                         mean 0.05 
--------------------------------------------------------------------------------------------------------


                                   
Table 19 (contd). 
--------------------------------------------------------------------------------------------------------
Country    No. of  Average    Loading,  Air   Ventila-   HCHO         Comments             Reference 
           build-  age of     (m2/m3)b  temp. tion (air  (mg/m3)c         
           ings-   buildings            (°C)  changes/h) 
--------------------------------------------------------------------------------------------------------
                                              
Japan        -        -          -       -     -         0.048        department store     Matsumura 
                                                         up to                             et al. (1983) 
                                                         0.046        grocer's shop 
                                                         0.035        offices 
                                                         0.003        cinema 
 
Switzerland  11    < 6 months   -       -     -         0.410        office: measure-     Wanner & Kuhn 
                                                                      ment taken after     (1984) 
                                                                      recent occupancy 
                   1 year        -       -     -         0.160        and after ageing, 
             16    < 6 months                           0.60         school: measurement 
                   1 year                                             taken after recent 
                                                                      occupancy and 
                                                         0.23         after ageing 
 
The Nether-  10       -          -       -     -         0.758        average of highest   Van Der Waal 
lands                                                                 measurements in      (1982) 
                                                                      schools 
 
             13       -          -       -     -         0.245        average of highest 
                                                                      measurements in 
                                                                      commercial esta-
                                                                      blishments 
 
             1        -          -       -     -         2.30         highest value in 
                                                                      UFFI building 
 
Yugoslavia  24        -          -      26     -         1.083        offices              Kuljak (1983) 
             2        -          -      30     -         2.60         stores 
             3        -          -      18     -         0.15         furniture stores 
--------------------------------------------------------------------------------------------------------
 

                                   
Table 19 (contd). 
--------------------------------------------------------------------------------------------------------
 
Yugoslavia   6     1-3 years     -       -     -         0.143        offices              Kalinic 
             6     11-43 years                           0.087        offices              et al. (1985) 
             7     1-10 years                            0.141        kindergarten 
             3     11-50 years                           0.109        kindergarten 
             8     4-23 years                            0.043        schools 
             2     90-100 years                          0.023        schools 
 
USA          1     4 years       -       -     -         0.025-0.037  office recently      Konopinski 
                                                                      renovated with       (1983) 
                                                                      UF material 
             2     4 years       -       -     -         0.36-1.22    office recently 
                                                                      renovated with 
                                                                      particle board 
             1        -          -       -     -         0.14-0.45    particle board 
                                                                      shelving 
             1        -          -       -     -         0.11-0.14    particle board 
                                                                      furniture and 
                                                                      plywood floors 
--------------------------------------------------------------------------------------------------------
 
a Modified from:  Meek et al. (1985).  Where blanks appear, relevant information not provided by authors. 
b Ratio of unit area of formaldehyde source to room volume. 
c Means or ranges, unless otherwise specified. 

5.2.2  Indoor  air  pollution from  urea-formaldehyde foam insulation
(UFFI)

    Foam made from specific aminoplastic resins is used for the thermal
insulation  of spaces in walls  or other elements of  construction.  In
this process, an acidic surfactant solution is foamed by compressed air
and  continuously mixed with aqueous UF resin.  Formaldehyde is emitted
during and after completion of the hardening process. The resulting in-
door exposure depends, among other factors, on the age of the building,
type of resin, the application and the care taken, the amount of excess
formaldehyde,  the amount and rate of emission, the prevailing tempera-
ture, humidity, and rates of ventilation.

    Most  of the studies performed  on UFFI and mobile  homes have been
carried out in Canada and the USA (Table 18), but they are currently of
less importance.

    Studies  by Everett (1983)  showed that there  is some increase  in
formaldehyde levels in dwellings, directly after foaming, but that this
decays over a period of a few weeks.  Everett (1983) noted that, though
there were isolated high values up to 1.2 mg/m3,   70% of  the  results
after foaming were below 0.1 mg/m3.

    Girman  et al. (1983), conducting the 40-home East Tennessee study,
obtained  formaldehyde  measurements that  led  to the  following major
conclusions:

    The  average formaldehyde levels exceeded  0.12 mg/m3 (0.1 ppm)  in
25% of the homes;

    Formaldehyde  levels were positively related  to temperature levels
in  homes.  In houses  with UFFI, a  temperature-dependent relationship
with measured formaldehyde levels frequently existed;

    Formaldehyde  levels generally decreased with increasing age of the
house. This is consistent with decreased emission from materials due to
aging;

    Formaldehyde  levels  were  found to  fluctuate  significantly both
during the day and seasonally.

5.2.3  Indoor air pollution from phenol-formaldehyde plastics

    Popivanova  &  Beraha  (1984)  carried  out  a  study  on   phenol-
formaldehyde penoplast in order to establish the amount and dynamics of
formaldehyde migration into the indoor air in relation to  three  major
factors, i.e., age of the material, air temperature, and  air  exchange
rate.   Age  of  the material was found to be the most important factor
influencing  formaldehyde migration, followed by temperature elevation.
The  rate  of  air  exchange  was  inversely  related  to  formaldehyde
migration  level.  A  mathematical model  of these  processes has  been
developed  and a  regression equation  proposed.  A  review of  factors
influencing   formaldehyde  migration  from  formaldehyde   resins  was
published by Popivanova (1985).

5.2.4  Exposure to indoor air containing cigarette smoke

    As  with all other incomplete combustion processes, formaldehyde is
emitted in the smoke from cigarettes.  About 1.5 mg of formaldehyde was
found  in  the total  smoke from one  cigarette, which was  distributed
between  the main and side stream in the ratio of 1:50, i.e., 30 µg  in
the  main stream  (= inhaled smoke)  and 1526 µg  in  the  side  stream
(Jermini et al., 1976; Klus & Kuhn, 1982). Other investigators measured
up  to 73 µg  of formaldehyde per cigarette in the main stream (Newsome
et  al., 1965; Mansfield et al., 1977). Concentrations of 60-130 mg/m3
were  measured in mainstream smoke.  For an individual smoking 20 ciga-
rettes  per  day, this  would lead to  an exposure of  1 mg/day (Weber-
Tschopp  et al., 1977).  Exposure to sidestream smoke (or environmental
tobacco  smoke) can be estimated from chamber measurements.  Thus, in a
50-m3 chamber  with one air exchange per hour, 6 cigarettes  smoked  in
15 min  yield  over 0.12 mg/m3    (WKI,  1982).  Weber-Tschopp  et  al.
(1976) measured the yield of 5-10 cigarettes in a  30-m3 chamber   with
0.2-0.3  air exchanges per  hour as 0.21-0.35 mg/m3,    which would  be
about 0.05-0.07 mg/m3 at  one air exchange per hour. This concentration
is  in  the  same range as that likely to be found in the rooms of most
conventional buildings where there is no smoking (section 5.2).  Levels
of  formaldehyde emitted from  combustion sources other  than cigarette
smoke are presented in Table 20.


Table 20.  Formaldehyde levels from combustiona 
--------------------------------------------------------------------------------------------------------
Source                   Comments                          Emission rate  Air change  HCHO    Reference 
                                                           (g fuel/min)   per h       (mg/m3) 
--------------------------------------------------------------------------------------------------------
 
Gas stove in test        ventilation conditions: 
kitchen, 27 m3           no stove vent or hood                            0.25        0.40    Hollowell        
                         hood vent (without fan) above stove              1.0         0.26    et al. 
                         hood vent, fan at low speed                                          (1979)
                         (1.4 m3/min)                                     2.5         0.14 
                         hood vent, fan at high speed 
                         (4 m3/min)                                       7.0         0.035 
                         outdoor concentration during test                            0.010 
 
Undiluted exhaust gases:                                                              10      Schmidt & 
                                                                                              Götz (1977) 
 Household natural gas 
 appliances                                                                           6       Altshuller
 Cooking range (oven)                                                                 4       et al. 
 Floor furnace                                                                        1.5     (1961)
 
Kerosine heaters:        27 m3 environmental chamber,                     0.4 
                         temp. < 26 °C 
 
 radiant (new)           fired in chamber                    3.13         5.1         5.1b    Traynor  
                         10-min warm-up outside chamber      3.16         4.0                 et al.
                                                                                              (1983) 
 
 radiant (1 year old)    10-min warm-up outside              2.54         0.67 
 convection (new)        fired in chamber                    3.03         0.36 
 
                         10-min warm-up outside chamber      3.0          1.3 
 
 convection              fired in chamber                    2.1          6.7 
 (5 years old)           10-min warm-up outside chamber      2.2          5.6 
--------------------------------------------------------------------------------------------------------


                                   
Table 20 (contd). 
--------------------------------------------------------------------------------------------------------
 
Radiant heater           21 m3 room, closed door,            3.6          0.5         0.025   Caceres  
Radiant heater                                               3.6                      1.0b    et al.       
Convection heater                                            2.7                      0.9b    (1983)
                                                                                      0.4b 
 
Cigarette smoke          30 m3 climate chamber,                           0.3 
                         1 cigarette (1 min)                                          0.06    Weber- 
                         3 cigarettes (2 min)                                         0.16    Tschopp         
                         5 cigarettes (3 1/2 min)                                     0.29    et al.
                         10 cigarettes (7 min)                                        0.55    (1976)
                         15 cigarettes (10 1/2 min)                                   0.76 
 
Cigarette smoke          45.8 m3 room, 5 subjects,                                            Sundin 
                         20 cigarettes smoked over 30 min:                                    (1978) 
                         original background level         
                         level after 30 min                                           0.01 
                                                                                      0.33 
                                                                                      
Cigarette smoke          undiluted smoke                                              40-140  Auerbach 
                                                                                              et al. 
                                                                                              (1977) 
--------------------------------------------------------------------------------------------------------

a From: Dept National Health Welfare Canada (1985). 
b mg/h. 

5.3  General Population Exposure

    The  possible routes of  exposure to formaldehyde  are  inhalation,
ingestion, dermal absorption, and, rarely, blood exchange, as in dialy-
sis.

5.3.1  Air

    The daily inhalation exposure for an average adult can be estimated
by  assuming a respiratory volume  of 20 m3/day,   given the  exposures
mentioned above, and making different assumptions about the duration of
exposure periods (Table 21).  Average time estimates lead to  the  con-
clusion  that  people spend  60-70% of their  time in the  home, 25% at
work, and 10% outdoors. If it is assumed that normal work exposures are
similar  to home exposures, the daily exposure resulting from breathing
is  about 1 mg/day, with a few exposures of > 2 mg/day, and  a  maximum
of  5 mg/day; this compares   favourably with  the  estimated range  of
0.3-2.1 mg/day,  based on the work of Kalinic et al. (1984), with esti-
mated weighted average exposures of 0.02-0.14 mg/m3.

    Matsumura et al. (1985) determined the levels of exposure  to  for-
maldehyde  of  housewives  by  using  personal  air  sampling apparatus
(Sampler:  silica  gel  impregnated  with  triethanolamine,  Hydrazine-
method).  The highest exposure level was 0.311 mg/m3 (0.259 ppm)  (3.73
mg/day),  while the lowest was  0.011 mg/m3 (0.009 ppm)  (0.13 mg/day).
The   usual   exposure  range   was  0.018-0.030 mg/m3 (0.015-0.025 ppm)
(0.22-0.36 mg/m3).   The highest exposure level was that of a housewife
living in a newly constructed house, where irritation of the  eyes  and
throat, lachrymation, and cough were observed in the family.

    Chemical  toilet fluids,  used in  caravans, on  camping sites,  in
aeroplanes, and in boats often include formaldehyde.  In an experiment,
a  10% formaldehyde solution (normally found on the market) was applied
in  a 2 m3 toilet  room (Reus, 1981a).  The toilet bowl was filled with
1 1/2 litres of water and 110 ml of the disinfectant, giving a solution
of  0.75% formaldehyde.  The ventilation  rate was not determined,  but
estimated  to be 3-5  air changes per  hour, temperature 20-22 °C.  Air
concentrations  of formaldehyde, which rose  to 150-350 µg/m3    during
the filling of the toilet, gradually decreased within 1 h to 60-90 µg/m3 and
then   remained constant.  Closing the lid caused a further decrease to
< 20 µg/m3.

5.3.1.1  Smoking

    Concentrations  of  60-130 mg/m3,    measured in  mainstream smoke,
would  lead  to an  average daily intake  of 1 mg formaldehyde  per day
(daily consumption: 20 cigarettes; WHO, 1987).

    Formaldehyde  produced by cigarettes can also mean considerable ex-
posure for the non-smoker through passive smoking, the more so since it
has been reported that the effects of gaseous formaldehyde  are  poten-
tiated by smoke particles and aerosols (Rylander,  1974;  Weber-Tschopp
et al., 1977; WHO, 1987).

Table 21.  Contribution of various atmospheric environments 
           to average exposurea 
----------------------------------------------------------------
Source                                         Average exposure 
                                               (mg/day) 
----------------------------------------------------------------
Air 
 
    Ambient air (10% of the time)              0.02 
 
    Indoor air 
      Home (65% of the time) 
      - Conventional                           0.5-2 
      - Prefabricated (particle board)         1-10 
 
    Work-place air (25% of the time) 
      - Without occupational exposureb         0.2-0.8 
      - Exposed occupationally to 1 mg/m3      5 
      - Environmental tobacco smoke            0.1-1.0 
 
Smoking 
 
    20 cigarettes/day                          1.0 
----------------------------------------------------------------
a       From: WHO (1987). 
b       Assuming the normal formaldehyde concentration in conventional 
        buildings. 
 
5.3.2  Drinking-water

    Concentrations  in  drinking-water  are normally  less than 0.1 mg/
litre,  which means that,  except for accidental  ingestion of  formal-
dehyde-contaminated water, intake is negligible (below 0.2 mg/day; WHO,
1987).

5.3.3  Food

    The  daily formaldehyde intake  depends on the  composition of  the
meal  and  may range  between 1.5 and  14 mg for an  average adult (see
Table 14, section 5.1.4).

    In   a  residue  study  of  the  Food  Inspection  Service  in  The
Netherlands,  it was  found that  53% of  162 samples  of soft  drinks,
alcoholic  beverages,  sugar-containing foodstuffs,  such as marmalade,
and meat and meat products contained formaldehyde at  levels  exceeding
1 mg/kg.   Up to  20% of  samples contained  levels exceeding  2 mg/kg;
levels  in 15 samples of meat and meat products even exceeded 10 mg/kg,
with  some reaching  about 20 mg/kg.   The source  of the  formaldehyde
could not be established for any of the cases (Nijboer, 1984).   In  an
additional study, the formaldehyde contents of meat and  meat  products
were  analysed (Nijboer, 1985) and, in 62 out of 86 samples, were found
to  exceed a level of  1 mg formaldehyde/kg.  Levels in  50% of samples
were  between 1 and 2 mg/kg  and 22% exceeded 2 mg/kg  with some levels
as  high as 14-20 mg/kg.  Again, no source for the formaldehyde residue
could be established.



5.3.4  Other routes of exposure

    Dermal  exposure  and absorption  occur  through contact  with cos-
metics,  household  products,  disinfectants, textiles  (especially  of
artificial  origin) and orthopaedic casts.  Most of these exposures are
likely  to remain localized (though gaseous formaldehyde will be avail-
able  for inhalation). The estimates of the systemic absorption of for-
maldehyde through the entire epidermal layer and across the circulatory
layer, are negligible (Jeffcoat, 1984; Robbins et al., 1984; Bartnik et
al.,  1985). Contact  with liquid  barriers, as  in the  eyes does  not
appear  to lead to absorption.  There have been case reports of newborn
infants  being  exposed  to  formaldehyde-containing  disinfectants  in
incubators.

    In certain rare events, formaldehyde in aqueous solution enters the
blood  stream directly.  These events  are most likely to  occur during
dialysis or in circulation-assisted surgery in which the  dialysis  ma-
chine  and tubes that  have been disinfected  with formaldehyde,  still
contain the compound because of adsorption or back wash, and it is then
introduced into the patient's bloodstream (Beall, 1985).

5.4  Occupational Exposure

    In  the work-place, exposure may  be caused by either  producing or
handling  formaldehyde  or  products containing  formaldehyde.  Concen-
trations  of formaldehyde  in occupational  settings in  the  USA  were
reported  by the Consensus Workshop  on Formaldehyde (1984) (Table  22,
see also section 9.2).

    Airborne  formaldehyde concentrations in 7 funeral homes in 1980 in
the  USA ranged from 0.12  to 0.42 mg/m3 during  the embalming  of non-
autopsied  bodies and from  0.6 to 1.4 mg/m3 during   the embalming  of
autopsied bodies (Williams et al., 1984).  In a study  on  formaldehyde
exposure  in an embalming room,  levels of up to  4.8 mg/m3 were  found
when  the  exhaust  ventilation  system  was  not  functioning  (Anon.,
1980a,b).

    Formaldehyde  concentrations were determined in  Dutch pathological
laboratories,  under  practical conditions,  where  a 4-6%  solution of
formaldehyde in water was used.  No detailed information on ventilation
is  available, but  a special  ventilation system  was applied  at  the
dissection  table, where concentrations amounted to 75 µg/m3.    A con-
centration  of 195 µg/m3 was    found in  the  cleaning section  of the
laboratory (Reus, 1981).


Table 22. Formaldehyde monitoring data in occupational settingsa 
--------------------------------------------------------------------------------------------------------
Industry           Job or         Exposure levels mg/m3 (ppm)  Area or   Number of  Methodb  Reference 
                   work                                        personal  observa-
                   area           range        mean    median  monitor-  tions 
                                                               ing
--------------------------------------------------------------------------------------------------------

Formaldehyde       production      -           1.68     -      personal    -        CT, IC   NIOSH 
production         operator                    (1.4)                                         (1980a) 
 
                   laboratory      -           1.57     -      personal    -        CT, IC   NIOSH 
                   technician                  (1.31)                                        (1980a) 
 
Resin and plastic  production      -           1.67     -      personal    -        CT, IC   NIOSH 
materials          operator                    (1.39)                                        (1980a) 
production
                   resin plant    0.06-0.44    0.29     -      area        8        BI, CT,  NIOSH 
                                  (0.05-0.37)  (0.24)                               GC       (1976a) 
 
                   resin plant    0.11-0.20    0.16     -      area        2        BI, CO   NIOSH 
                                  (0.09-0.17)  (0.13)                                        (1978a) 
 
                   UF resin       0.14-0.66      -      -      area        -        SS, IC   Herrick et 
                   production     (0.12-0.55)                                                al. (1983) 
                   (2 plants)     0.22-6.48      -      -      area        -        SS, IC   Herrick et 
                                  (0.18-5.4)                                                 al. (1983) 
                                  0.24-0.89      -      -      area        -        SS, IC   Herrick et 
                                  (0.2-0.74)                                                 al. (1983) 
                                  0.72-0.41      -      -      area        -        SS, IC   Herrick et 
                                  (0.6-0.34)                                                 al. (1983) 
 
                   UF resin       0.14-6.48    1.08     -      personal   18        BI, CA   NIOSH 
                   production     (0.12-5.4)   (0.90)                                        (1980b) 
                                  0.24-0.89    0.47     -      personal    5        BI, CA   NIOSH 
                                  (0.20-0.74)  (0.39)                                        (1980b) 
                                  0.72-0.41    0.23     -      personal    5        BI, CA   NIOSH 
                                  (0.06-0.34)  (0.19)                                        (1980b) 
--------------------------------------------------------------------------------------------------------


 
Table 22 (contd). 
--------------------------------------------------------------------------------------------------------
Industry           Job or         Exposure levels mg/m3 (ppm)  Area or   Number of  Methodb  Reference 
                   work                                        personal  observa-
                   area           range        mean    median  monitor-  tions 
                                                               ing
--------------------------------------------------------------------------------------------------------

Textile finishing  textile        0.05-0.88    0.37     -      area,       11       CT, SP   NIOSH 
                   warehouse      (0.04-0.73)  (0.31)          personal                      (1979a) 
                                  0.10-0.61    0.30     -      area,       11       BI, SP   NIOSH 
                                  (0.08-0.51)  (0.25)          personal                      (1979a) 
 
                   textile        < 0.12-1.56   -     0.96    area,       28          -     NIOSH 
                   facilities     (< 0.1-1.3)         (0.8)   personal                      (1979b) 
                                  < 0.12-1.68   -     0.84    area,       15          -     NIOSH 
                                  (< 0.1-1.4)         (0.7)   personal                      (1979b) 
 
                   textile        0.13-1.60    0.83    0.77    personal     6          -     NIOSH 
                   manufacture    (0.11-1.33)  (0.69)  (0.64)                                (1981) 
                                  0.18-1.44    0.64    0.54    area        13                NIOSH 
                                  (0.15-1.2)   (0.53)  (0.54)                                (1981) 
 
Clothing           permanent      0.18-0.46    0.37     -      area         9       BI, I    US DHEW 
production         press          (0.15-0.38)  (0.31)                                        (1966) 
                                  0-3.24       0.89     -      area        32       BI, I    US DHEW 
                                  (0-2.7)      (0.74)                                        (1968) 
                   warehouse      0.13-0.68    0.47    0.44    personal    13          -     NIOSH 
                                  (0.11-0.57)  (0.39)  (0.37)                                (1979a) 
                                  0.05-0.23    0.14    0.18    area         9          -     NIOSH 
                                  (0.04-0.19)  (0.12)  (0.15)                                (1979a) 
 
                   sewing         0.61-1.09    0.86    0.85    personal    16          -     NIOSH 
                   machine        (0.51-0.91)  (0.72)  (0.71)                                (1979a) 
                   operators      0.36-2.16    1.44    1.44    personal    41          -     NIOSH 
                                  (0.3-1.8)    (1.2)   (1.2)                                 (1979a) 
 
                   clothing       0.006-1.14   0.08    0.065   personal    40          -     NIOSH 
                   pressers       (0.005-0.95) (0.07)  (0.054)                               (1976a) 
--------------------------------------------------------------------------------------------------------


                                   
Table 22 (contd). 
--------------------------------------------------------------------------------------------------------
 
Plywood particle-  all workers        -        1.2-3.0  -      area        -           -     NIOSH 
board production                               (1-2.5)                                       (1979b) 
 
Wood furniture     particle       0.01-0.3     0.14     -      area        11       BI, CA   Herrick et 
manufacture        board          (0.008-0.25) (0.12)                                        al. (1983) 
                   veneering      1.08-7.68    3.30     -      area        -        BI, CA   Herrick et 
                                  (0.9-6.4)    (2.75)                                        al. (1983) 
                                  0.24-0.66    0.48     -      area         9       BI, CA   Herrick et 
                                  (0.2-0.55)   (0.40)                                        al. (1983) 
                                  0.24-3.0     0.84     -      area        13       BI, CA   Herrick et 
                                  (0.2-2.5)    (0.70)                                        al. (1983) 
 
Plastic moulding   injection      0.01-0.12    0.044    -      personal     9       CA       NIOSH 
                   mold           (0.01-0.1)   (0.037)                                       (1973a) 
 
                   area samples   0.01-0.64    0.24     -      area         8       CA       NIOSH 
                                  (0.01-0.53)  (0.20)                                        (1973a) 
 
                   operators      < 2.4       < 2.4  < 2.4  personal    28       DT       NIOSH 
                                  (< 2)       (< 2)  (< 2)                                (1973a) 
 
                   near grinder   2.4-4.8      3.6     3.6     area         3       DT       NIOSH 
                   hopper         (2-4)        (3)     (3)                                   (1973a) 
 
                   sand mould     0.12-0.84    0.37    0.24    personal    28         -      NIOSH 
                   production     (0.1-0.7)    (0.31)  (0.2)                                 (1976a) 
                                  ND-1.32      0.20    0.12    area        29          -     NIOSH 
                                  (ND-1.1)     (0.17)  (0.1)                                 (1976a) 
 
Paper and paper-   paper          0.05-0.19    0.10     -      personal    15       BI, CT   NIOSH 
board manufacture  treatment      (0.04-0.16)  (0.08)                               CA       (1976b) 
                   resin)         0.04-0.08    0.07     -      area         7       BI, CT,  NIOSH 
                   impregnated    (0.03-0.07)  (0.06)                               CA       (1976b) 
                                  0.01-0.28    0.06     -      personal    30       BI, CT,  NIOSH 
                                  (0.01-0.23)  (0.05)                               CA       (1976b) 
--------------------------------------------------------------------------------------------------------


                                   
Table 22 (contd). 
--------------------------------------------------------------------------------------------------------
Industry           Job or         Exposure levels mg/m3 (ppm)  Area or   Number of  Methodb  Reference 
                   work                                        personal  observa-
                   area           range        mean   median   monitor-  tions 
                                                               ing
--------------------------------------------------------------------------------------------------------
Paper and paper-
board manufacture 
(contd).                          0.02-0.34    0.06     -      personal    10       BI, CT,  NIOSH 
                                  (0.02-0.28)  (0.05)                               CA       (1976b) 
 
                   treated        0.17-1.19      -     0.70    area        64          -     NIOSH 
                   paper          (0.14-0.99)          (0.59)                                (1979b) 
                   products       0.17-1.08      -     0.41    personal    37          -     NIOSH 
                                  (0.14-0.90)          (0.34)                                (1979b) 
 
                   coating        < 0.01-3.6  1.2     0.01    area         7          -     NIOSH 
                   preparation    (< 0.01-3)  (1.0)   (0.01)                                (1980a) 
                                  0.96-0.50    0.61    0.50    area         4          -     NIOSH 
                                  (0.8-0.42)   (0.51)  (0.42)                                (1980a) 
 
Foundries (steel,  bronze         0.29-0.96    0.64    0.66    personal     4       BI, CA   NIOSH 
iron, and non-     foundry,       (0.24-0.80)  (0.53)  (0.55)                                (1976c) 
ferrous)           core machine   0.14-0.83    0.47    0.47    area        11       BI, CA   NIOSH 
                   operators      (0.12-0.69)  (0.39)  (0.39)                                (1976c) 
 
                   iron foundry,  < 0.02-22.0   -     0.52    personal    14          -     NIOSH 
                   core machine   (0.02-18.3)          (0.43)                                (1979b) 
                   operators      0.08-0.40    0.19     -      personal     3       BI, CA   NIOSH 
                                  (0.07-0.33)  (0.16)                                        (1973b) 
 
                   moulding       0.04-0.16    0.11     -      personal     6       BI, CO   NIOSH 
                                  (0.03-0.13)  (0.09)                                        (1977a) 
                                  0.08-0.94    0.25     -      area         6       BI, CO   NIOSH 
                                  (0.07-0.78)  (0.21)                                        (1977a) 
 
Rubber hose pro-      -           ND-0.05      0.05     -      personal    10       BI, CO   NIOSH 
duction                           (ND-0.04)    (0.04)                                        (1977b) 
--------------------------------------------------------------------------------------------------------


 
Table 22 (contd). 
--------------------------------------------------------------------------------------------------------

Asphalt shingle    producers      0.04-0.08    0.06    0.06    area         2       BI, CO   NIOSH 
production                        (0.03-0.07)  (0.05)  (0.05)                                (1978b) 
 
Fibreglass insul-  installers     0.008-0.04   0.028   0.023   personal    13          -     NIOSH 
ation                           (0.007-0.033)  (0.023) (0.019)                               (1980a) 
                                               (TWA)c 
 
Urea-formaldehyde  suburban       0.08-2.4       -      -       -           -       IC       Herrick et 
foam insulation    shopping       (0.07-2)                                                   al. (1983) 
dealing and in-    centre         0.96-1.92    1.26     -      area        36       BI, CA   NIOSH 
stallation         insulated      (0.8-1.6)    (1.05)                                        (1979b) 
                   with UF foam   0.36-3.72    1.73     -      area        30       CT, IC   NIOSH 
                                  (0.3-3.1)    (1.44)                                        (1979b) 
                                  < 0-6.36    1.87     -      area        16       DT       NIOSH 
                                  (< 0.5-3)   (1.56)                                        (1979b) 
 
Fertilizer manu-      -           0.24-2.28    1.08     -      personal,   11          -     NIOSH 
facturing                         (0.2-1.9)    (0.9)           area                          (1979b) 
 
Mushroom farming      -           < 0.61-12+  3.22     -      area        12       DT       NIOSH 
                                  (0.51-10+)   (2.68)                                        (1980b) 
                                  ND-3.24                      personal     3       CT, IC   NIOSH 
                                  (ND-2.7)                                                   (1980b) 
                                  ND-5.92        -      -      area         3       CT, IC   NIOSH 
                                  (ND-4.93)                                                  (1980b) 
 
Funeral homes      embalmers      0.1-6.3      0.89     -      area       187       CA       Kerfoot & 
                                  (0.09-5.26)  (0.74)                                        Mooney 
                                                                                             (1975) 
                                  0.24-4.79    1.32    0.65    area         8       CT       NIOSH 
                                  (0.20-3.99)  (1.1)   (0.54)  personal                      (1980c) 
                                  1.56-4.72    3.24    2.99    area         5       CT       NIOSH 
                                  (1.30-3.99)  (2.7)   (2.49)  personal                      (1980c) 
 
Pathology          autopsy room   0.07-9.5     5.76     -      area        10       BI, CA   Covino 
                                  (0.06-7.9)   (4.8)                                         (1979) 
                                  2.64-9.5     5.22     -      area         6          -     NIOSH 
                                  (2.20-7.9)   (4.35)                                        (1979b) 
--------------------------------------------------------------------------------------------------------


                                   
Table 22 (contd). 
--------------------------------------------------------------------------------------------------------
Industry           Job or         Exposure levels mg/m3 (ppm)  Area or   Number of  Methodb  Reference 
                   work                                        personal  observa-
                   area           range        mean    median  monitor-  tions 
                                                               ing
--------------------------------------------------------------------------------------------------------

Biology teaching   laboratory     3.30-17.76   9.96     -      area         8       BI, CA   US EPA 
                                  (2.75-14.8)  (8.3)                                         (1981) 
 
Hospital           laboratory     2.64-2.76    2.70            personal     2       BI       Blade 
                                  (2.2-2.3)    (2.25)                                        (1983) 
                                  2.28 (1.9)     -             personal     1       CT       Blade 
                                  2.64 (2.2)   2.4 (2)         area         2       CT       (1983) 
 
Government         laboratory     2.88 (2.4)     -             personal     1       CT       Blade 
                                  0.96 (0.8)     -             area         1       CT       (1983) 
 
Hospital           dialysis       ND-1.08      0.50            area         9       CT       Blade 
                   unit           (ND-0.90)    (0.42)                                        (1983) 
                                  0.32-0.76    0.49            personal     5       CT       Blade 
                                  (0.27-0.63)  (0.41)                                        (1983) 
                                  0.05-0.60    0.61            area                 CEA      Blade 
                                  (0.04-0.50)  (0.51)                                        (1983) 
 
Animal dissection  laboratory     < 0.46-1.25    -            personal    15       CA       Blade 
                                  (< 0.38-1.04)                                             (1983) 
                                  0.06-0.48    0.18            area         6    
                                  (0.05-0.40)  (0.15) 
                                  0.13-0.22    0.22            area         3       CEA      Blade 
                                  (0.11-0.29)  (0.18)                                        (1983) 
 
Garment manufac-      -         < 0.17-0.76   0.28-0.40       personal    40       CT       Blade 
turing (3 plants)               (< 0.14-0.63) (0.23-0.33)                                   (1983) 
                                < 0.04-0.48   0.23-0.31       area        43       CT       Blade 
                                (< 0.03-0.40) (0.19-0.26)                                   (1983) 
                                0.04-0.48      0.25            area        43       BI       Blade 
                                (0.03-0.40)    (0.21)                                        (1983) 
--------------------------------------------------------------------------------------------------------


 
Table 22 (contd). 
--------------------------------------------------------------------------------------------------------
Garment manufac-
turing (contd) 
                                  0.06-1.34    0.55            area        42       CEA      Blade 
                                  (0.05-1.2)   (0.46)                                        (1983) 
 
Chemical manu-        -           0.05-1.92    0.66     -      personal     3       BI       Blade 
facturing                         (0.04-1.6)   (0.55)                                        (1983) 
                                  0.04-0.52    0.20     -      area         5       BI       Blade 
                                  (0.03-0.43)  (0.17)                                        (1983) 
 
Glass manufac-        -           0.50 (0.42)  0.50     -      personal     1       CT       Blade 
facturing                                      (0.42)                                        (1983) 
                                  0.54-0.80    0.65     -      area         2       CT       Blade 
                                  (0.45-0.64)  (0.54)                                        (1983) 
 
Hospital work         -           0.44-0.88    0.66     -      area         2       BI       Blade 
                                  (0.37-0.73)  (0.56)                                        (1983) 
 
Paraformaldehyde      -         < 0.30-1.02   0.66     -      personal    10       CA       Blade 
packaging                       (< 0.25-0.85) (0.55)                                        (1983) 
                                0.34-4.08      1.40     -      area         8       CEA      Blade 
                                (0.28-3.4)     (1.17)                                        (1983) 
 
Office work           -           0.02-0.14    0.07     -      area        39       BI       Blade 
(3 locations)                     (0.02-0.12)  (0.06)                                        (1983) 
                                  < 0.05      < 0.05  -      area         9       CT       Blade 
                                  (< 0.04)    (< 0.04)                                     (1983) 
--------------------------------------------------------------------------------------------------------


                                   
Table 22 (contd). 
--------------------------------------------------------------------------------------------------------
Industry           Job or         Exposure levels mg/m3 (ppm)  Area or   Number of  Methodb  Reference 
                   work                                        personal  observa-
                   area           range        mean    median  monitor-  tions 
                                                               ing
--------------------------------------------------------------------------------------------------------
 
Autopsy rooms      resident          -         1.90d           personal    10       CA       Makar et 
                                               (1.58)                                        al. (1975) 
                   pathologist       -         1.50d           personal     9       CA 
                                               (1.24) 
                   technician        -         0.68d           personal     2       CA       Makar et 
                                               (0.57)                                        al. (1975) 
                   assistants    0.16-16.28    0.86            area        23       CA 
                                 (0.13-13.57)  (0.72) 
--------------------------------------------------------------------------------------------------------

a       From: Consensus Workshop on Formaldehyde (1984). 
b        Abbreviations for analytical procedures:
 
        AA = acetylacetone. 
        BI = bisulfite impingers. 
        CA = chromotropic acid procedure. 
        CL = chemiluminescence procedure. 
        CO = colorimetric analysis. 
        CT = charcoal tubes. 
        SS = solid sorbents. 
        DT = Draeger tubes. 
        FS = Fourier transform spectrometer. 
        GC = gas chromatography. 
        IC = ion chromatography. 
        MB = MBTH procedure. 
        SP = spectrophotometric procedure. 
        CEA = CEA instruments Model 555. 
c       TWA = time-weighted average. 
d       Average. 

6. KINETICS AND METABOLISM

6.1  Absorption

6.1.1  Inhalation

6.1.1.1  Animal data

    Eight  male  F-344 rats  were  exposed to  17.3 mg  formaldehyde/m3
(14.4 ppm) by nose only inhalation for 2 h, and the blood was collected
immediately  after exposure.  Formaldehyde concentrations  in the blood
were determined by gas chromatography/mass spectrometry. The blood of 8
unexposed  rats was collected and analysed in the same manner. Measured
formaldehyde  concentrations (mg/kg blood) were:  exposed, 2.25 ± 0.07;
controls, 2.24 ± 0.07 (mean ± SE) (Heck et al., 1985).

    Under  normal conditions, absorption  is expected to  occur in  the
upper  respiratory  tract  (nasal passages  in obligate nose-breathers;
trachea, bronchi in oral breathers)  where first contact  occurs  (Heck
et al., 1983).

    Absorption  through the upper respiratory tract was estimated to be
100%  at all respiratory rates tested.  Detailed studies on the distri-
bution of 14C-formaldehyde  in the rat nasal cavity have confirmed that
it  is absorbed primarily in the upper respiratory system.  Following a
6-h  exposure by inhalation,  the amount of 14C-formaldehyde   absorbed
appeared  to  be approximately  proportional  to the  airborne  concen-
tration.   The amount retained  did not appear  to vary following  pre-
exposure (Heck et al., 1982).

    Chang et al. (1983) reported studies on the effects of inhaled for-
maldehyde vapour on respiratory minute volumes in mice and  rats.   The
results  showed that both rats and mice responded to formaldehyde inha-
lation  by a reduction in  their respiratory rates and  minute volumes.
However, mice responded to lower formaldehyde concentrations than rats.
For  example,  respiratory  rates were  reduced  by  50%  at  7.2 mg/m3
(6 ppm)  in mice and  18 mg/m3 (15 ppm)  in rats.  Rats developed  some
tolerance   to  formaldehyde  during  exposure.   Both  rats  and  mice
pretreated  with  18 mg  formaldehyde/m3 (15 ppm)  were  slightly  more
sensitive  to respiratory-rate depression, but  pretreated rats compen-
sated  for  the decrease  in respiratory rate  by an increase  in tidal
volume.   Thus, following pretreatment,  the difference in  sensitivity
between the two species became more marked. As a result, mice were able
to  minimize the inhalation of formaldehyde more efficiently than rats,
so that, at 18 mg/m3 (15 ppm),  the nasal mucosa in mice was exposed to
approximately  one-half of the dose  of formaldehyde to which  the rats
were exposed.  This species difference contributes to  the  differences
in respiratory tract toxicity from inhaled formaldehyde.

    The respiratory retention of inhaled formaldehyde (0.15-0.35 µg/ml)
was  studied in 4  sedated dogs by  enforced ventilation (Egle,  1972).
The  percentage uptake was calculated by determining the amount inhaled
by means of a respirometer and the amount recovered after exhaling into
a collection bag (Method:  MBTH, Hauser & Cummins,  1964).   Absorption
was determined to be near 100%, even when the ventilation rate  of  the
dogs was increased to 20 litre/min.

6.1.1.2  Human Data

    In  human volunteers exposed to  2.3 mg formaldehyde/m3   (1.9 ppm)
for  40 min, there was no significant difference between pre- and post-
exposure  formaldehyde  levels  in  the  blood  (2.77 ± 0.28 µg     and
2.61 ± 0.14 µg/100 ml,    respectively). Individual human subjects dif-
fered  in terms of  their blood-formaldehyde levels  and, in some  sub-
jects,  there were significant differences between formaldehyde concen-
trations  in the blood before and after exposure suggesting that blood-
formaldehyde concentrations may vary with time (Heck et al., 1985).

    In  an earlier study, Einbrodt  et al. (1976) measured  the formate
levels  in blood and urine following formaldehyde inhalation. They con-
cluded that the determination of formic acid is appropriate  for  esti-
mating  previous formaldehyde exposure.   This could not  be  confirmed
using  modern analytical methods (Triebig et al., 1980, 1986; Bernstein
et  al., 1984).  It has been demonstrated that biological monitoring of
formaldehyde exposure is not a feasible technique for  exposure  levels
of less than 0.6 mg/m3 (0.5 ppm) (Gottschling et al., 1984).

6.1.2  Dermal

    In in vitro experiments, Usdin & Arnold (1979) studied the transfer
of 14C-formaldehyde  into  guinea-pig  skin.   Aqueous 14C-formaldehyde
(0.20 µg)   was applied in  diffusion cells (area,  2 cm2),   and  some
were occluded to avoid uncontrolled evaporation of formaldehyde.

    Under  both occluded and non-occluded conditions, 14C  was found on
and  in  the  dehaired skin (up to 0.8% of the initial dose), and small
amounts  (0.4%  of  the  initial  dose)  were  excreted in  the  urine.
However,  the labelled material found was not identified, and it is not
known whether or not it was formaldehyde.

    In another in vitro experiment, the permeability of human  skin  to
formaldehyde  was examined using  excised skin in  a flow-through  dif-
fusion  cell.  The rate of  resorption was determined by  measuring the
amount  of substance found  in the receptor  fluid beneath the  skin at
steady-state. The rates of resorption were: formaldehyde from a concen-
trated solution of formalin, 319 µg/cm2 per    h, formaldehyde  from  a
solution  of 10%  formalin in  phosphate buffer,  16.7 µg/cm2    per  h
(Loden, 1986).

    An   ointment containing 0.1%  of 14C-formaldehyde  was applied  to
the  shaved backs of rats by Bartnik et al. (1985).  Three to 5% of the
14C-formaldehyde was found to have been absorbed within 48 h.

    14C-formaldehyde     or   dimethyloldihydroxyethyleneurea  (DMDHEU)
were incorporated into cotton. Patches were applied to the shaved backs
of rabbits for a period of 48 h; 0.09-2.61% of the total 14C  contained
in   the  patches  was found  in the  skin.  Other  tissues and  organs
showed  only low  levels of  radioactivity (0.001-0.005%  of the  total
14C  (Robbins et al., 1984).

    Twenty-four  hours  after  dermal application  of 0.4-0.9 µg 14C-
formaldehyde/cm2 in   5 male monkeys, most  of the dose had  been lost,
mainly  by evaporation from the  skin (52%) or was  bound (34%) to  the
surface layers of the skin at the application site.  Percutaneous  pen-
etration  was very low,  calculated to be,  at the most,  0.5%  of  the
applied  dose. The total body burden of a necropsied monkey, 24 h after
dermal  dosing, was 0.2% of  the dose, confirming that  aqueous formal-
dehyde does not penetrate the skin to any appreciable degree, even when
applied directly to it (Jeffcoat, 1984).

6.1.3  Oral

    Following oral exposure (gavage) of 5 anaesthetized dogs to formal-
dehyde (70 mg/kg), formate levels in the blood increased rapidly.  How-
ever,  fifteen minutes  after treatment,  all the  dogs vomited  making
quantitative determinations impossible (Malorny et al., 1965).

6.2  Distribution

    The  normal values of  blood-formaldehyde have been  determined  in
both  rats and human beings.   In rats, the analyses  were performed by
gas  chromatography/mass spectrometry using  a stable isotope  dilution
technique  (Heck et al., 1982); values of 2.24 ± 0.07 mg/kg (mean ± SE)
were found.

    The  mean  formaldehyde  concentration in  the  blood  of  6  human
volunteers (4 males, 2 females) was 2.61 ± 0.14 mg/kg (mean ± SE) (Heck
& Casanova-Schmitz, 1984) (see section 6.1.1.2).

    Malorny  et al. (1965)  intravenously infused 0.2 mol  formaldehyde
into  dogs and cats; McMartin et al. (1977) performed similar infusions
in cynomolgus monkeys. There was no accumulation of formaldehyde in the
blood, because of its rapid conversion to formate.

    The disposition of radioactive formaldehyde was studied in A/J mice
to determine its elimination and to assess its accumulation in tissues.
Mice  were dosed ip with 14CH2O    at 6 mg/kg or 100 mg/kg body weight.
Most  of the dose (70-75%)  was excreted as 14CO2 within   4 h,  but an
additional 10% of the dose was eliminated as 14CO2 in   24 h.  The rate
of 14CO2 excretion    in mice given 14CH2O was    slower  than the rate
of 14CO2 excretion    in mice given  an equivalent dose  (100 mg/kg) of
formate (HCOOH), the obligatory intermediate in the oxidation  of  for-
maldehyde to carbon dioxide.  These results suggest  that  formaldehyde
might  accumulate in tissues.   To assess this  possibility, whole-body
levels  of 14CH2O were     determined  by  the  dimedone  precipitation
method following a dose of 100 mg/kg. The elimination half-time of for-
maldehyde was calculated to be 100 min, with a rate constant of 0.42/h.
However,  several rate constants were  observed, 80% of the  dose being
recovered   as  formate  at 30 min.  At 2 h, the level  of 14CH2O    in
the  plasma was  1.07 ± 0.25 mg/litre, and  the liver  level was  1.7 ±
0.87 mg/kg. Levels of 14CH2O    in other tissues were similar  to  that
in the liver.  This level of 14CH2O    is at least 50% lower  than  the
endogenous level of formaldehyde that has been reported.  These results
suggest  that there is more than a single formaldehyde pool in mice but
that,  nevertheless, it does not  accumulate in tissues at  levels that

are  significant relative to the  endogenous tissue level (Billings  et
al., 1984).

    Whole-body  autoradiography of mice,  sacrificed 5 min after  an iv
injection  of 14C-formaldehyde,  showed localization  of radioactivity,
primarily in the liver and, to a lesser extent, in the kidneys. Follow-
ing  a survival time of  30 min or more, radioactivity  appeared in the
tissues  with a high cell turnover (blood-forming organs, lymphoid sys-
tem,  gastrointestinal mucosa) and in those with a high rate of protein
synthesis  (exocrine  pancreas,  salivary glands)  (Johansson & Tjalve,
1978).

    Following  a 6-h  inhalation exposure  of rats  to up  to  18 mg/m3
(15 ppm) 14C-formaldehyde,   radioactivity was extensively  distributed
in other tissues, the highest concentrations occurring in  the  oesoph-
agus,  followed by the kidney,  liver, intestine, and lung,  indicating
that  absorbed 14C-formaldehyde  and its  metabolites were rapidly  re-
moved by the mucosal blood supply. Studies on distribution and kinetics
indicated  that  inhaled  formaldehyde is  extensively  metabolized and
incorporated (Heck et al., 1982).

    DNA,  RNA, protein, and lipid fractions of liver and spleen tissues
of  rats  showed  significantly elevated  levels  of 14C  incorporation
after  a single ip injection  of 72 mg 14C-formaldehyde  (14.7 µCi/kg)
(Upreti et al., 1987).

    The retention of formaldehyde gas in the nasal passages  of  anaes-
thetized male F-344 rats exposed in a nose-only  system  to 14C-formal-
dehyde  at 2.4-60 mg/m3 for   30 min was  studied by  Patterson et  al.
(1986).   More than 93%  was retained, regardless  of airborne  concen-
trations.

    In order to localize absorption and distribution within  the  nasal
cavity,  rats and  mice, not  previously exposed  or  pretreated,  were
exposed  to 18.0 mg 14C-formaldehyde/m3 (15 ppm)   for 6 h and prepared
for   whole-body  autoradiography.   Formaldehyde-associated 14C    was
heavily deposited in the anterior nasal cavity in both rats  and  mice.
The amount of radioactivity was well correlated with  the  distribution
of lesions in exposed animals. However, the radioactivity may represent
metabolically  incorporated material rather than  covalently bound for-
maldehyde.   No differences in  the distribution of  formaldehyde  were
observed between rats and mice (Swenberg et al., 1983).

6.3  Metabolic Transformation

    The overall metabolism of formaldehyde is summarized in Fig. 3.

    The  oxidation into formic  acid and carbon  dioxide, the  reaction
with glutathione, and the covalent linkage with proteins and nucleic
acids,  which are partly reversible,  are of importance.  The  covalent
linkage  to formaldehyde cannot  be directly determined,  since  radio-
active  formaldehyde  is also  incorporated into the  DNA via the  one-
carbon metabolism.

FIGURE 3

    In studies on several species, including human beings, formaldehyde
underwent  rapid biotransformation, immediately after  resorption, and,
therefore,  could not be traced in tissue (Simon, 1914; Malorny et al.,
1965; Rietbrock, 1965; Einbrodt et al., 1976; Delbrück et  al.,  1982).
Heck  & Casanova-Schmitz (1984) showed  that blood-formaldehyde concen-
trations  did  not  rise in  human  volunteers  even immediately  after
inhalation exposure.

    Kitchens  et al. (1976) summarized  the chemical reactions in  bio-
logical systems as: (a) hydration in the presence of water;  (b)  reac-
tions with the active hydrogen of ammonia, amines, or amides, resulting
in  the  formation  of stable  methylene  bridges;  such reactions  are
important, because of the ubiquity of nitrogen compounds; and (c) reac-
tions  with  active  hydrogen (thiols,  nitroalkanes, hydrogen cyanide,
phenol).

    Formaldehyde  may  be  formed  endogenously  (Hutson,  1970)  after
contact  with xenobiotics; 18  chemicals have been  shown to be  metab-
olized  by the nasal microsomes of rats to produce formaldehyde (Dahl &
Hadley,  1983).   Formaldehyde  is  a  normal  metabolite  in mammalian
systems.   It is rapidly metabolized to formate (Malorny et al., 1965),
which  is partially incorporated via normal metabolic pathways into the
one-carbon  pool  of the  body or further  oxidized to carbon  dioxide.
Formaldehyde  also reacts  with proteins  (French &  Edsall, 1945)  and
nucleic  acids (Haselkorn & Doty,  1961; Lewin, 1966; Collins  & Guild,
1968; Feldman, 1973; Chaw et al., 1980); it reacts  with  single-strand
DNA,  but not with double-stranded DNA.  This link is reversible.  Only
formaldehyde cross-links of DNA and protein are stable (Brutlag et al.,
1969) (section 8.5). The biological reactions and metabolism of formal-
dehyde are shown in Fig. 4.

    The  oxidation of absorbed formaldehyde to formic acid is catalyzed
by  several enzymes (Strittmatter  & Ball, 1955).   The most  important
enzyme  is the NAD-dependent formaldehyde dehydrogenase, which requires
reduced  glutathione (GSH) as a cofactor.  Thus, exogenous formaldehyde
becomes  a source  for the  so-called one-carbon  pool in  intermediary
metabolism.  Sources of formate are presented in Fig. 5.

    There are at least 7 enzymes that catalyze the oxidation of formal-
dehyde  in animal tissues,  namely aldehyde dehydrogenase,  xanthinoxi-
dase, catalase, peroxidase, glycerinaldehyde-3-phosphate dehydrogenase,

aldehyde oxidase, and a specific DPN-dependent formaldehyde dehydrogen-
ase (Cooper & Kini, 1962).

6.4  Elimination and Excretion

    As discussed in section 6.3, absorbed formaldehyde  is  metabolized
rapidly  to formate or  enters the one-carbon  pool to be  incorporated
into  other molecules.  Besides this,  there are two pathways  of final
elimination  via exhalation or renal elimination (Fig. 3).  Du Vigneaud
et al. (1950) administered 14C-formaldehyde  subcutaneously to rats and
found  81% of the radioactivity  as carbon dioxide; a  small amount was
found  in choline.  Neely (1964) administered formaldehyde intraperito-
neally to rats; 82% of the radiolabel was recovered as  carbon  dioxide
and 13-14% as urinary methionine, serine, and a cysteine adduct.

    Even after high formaldehyde uptake, the elimination of formate via
the  kidneys of rats is  virtually negligible (Delbrück et  al., 1982).
Robbins et al. (1984) injected 14C-formaldehyde  (100 µCi   in a volume
of  1 ml) in rabbits.   Four hours after  administration, 28.5% of  the
total  dose of radioactivity was expired and 37%, after 48 h.  By 48 h,
4.1% of the radioactivity had been excreted in the  urine;  significant
levels  or radioactivity  were detected  in the  liver  (2.4%),  kidney
(0.6%), and blood (2.2%).

6.5  Retention and Turnover

    Elimination of formate is slower than its formation  from  absorbed
formaldehyde  and depends  on the  species.  Stratemann  et al.  (1968)
found  a relationship between folate level shown in two biological test
systems  and the half-life of formic acid in the plasma of some mammals
(Table 23).

    Malorny  et al. (1965)  infused 0.2 mol formaldehyde  intravenously
into  dogs;  the  plasma  half-life for formate ranged between  80  and
90 min,  and formaldehyde could not be detected.  In similar studies on
cynomolgus monkeys, by McMartin et al. (1979),  infusing  intravenously
1 mmol/kg over a 3-4 min period the blood half-life of formaldehyde was
estimated  to  be  1.5 min.  Rietbrock  (1969)  administered  1.17 mmol
formaldehyde/kg iv to rats, guinea-pigs, rabbits, and cats,  and  found
the  plasma half-life to be  1 min.  The half-life of  formate in human
beings  given 50-60 mg Na-formate/kg,  body weight orally,  was  45 min
(Malorny 1969).

FIGURE 4


FIGURE 5

Table 23.  Relationship between folate level and the 
           half-life of formic acid in plasmaa 
--------------------------------------------------------------
Species  Number        Folate activity (ng/ml)      Formate           
         of                                         half-life   
         analyses   L. casei         Strept. faec.    (min)
--------------------------------------------------------------

Man      11        15.5  ±  2.2    6.6  ±  0.7      55 
Dog      37        15.5  ±  1.7    6.1  ±  0.9      77 
Rabbit   17        49.2  ±  6.9    15.2  ±  1.4     32 
Rat      21        126  ± 16.6     37.8  ±  8.9     12 
--------------------------------------------------------------
a       From: Stratemann et al. (1968). 

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1  Microorganisms

    Formaldehyde is used as a disinfectant to kill  viruses,  bacteria,
fungi,  and  parasites and  has found wide  use as a  fumigant (section
3.2.2).

    It produces mutagenic effects in prokaryotic and  lower  eukaryotic
test systems (Table 31, and section 8.6).

    In   a   population   of   Aerobacter   aerogenes ,  treatment  with
50 µg   formaldehyde/ml of medium produced  a reversible change in  the
base ratio of non-ribosomal RNA and induced enzymes capable  of  metab-
olizing formaldehyde at an increased rate (Neely, 1966).

    Approximately 20-40% of the total nitrogen in most surface soils is
in the form of amino acids.  Because of the importance of  amino  acids
as  a nitrogen source for  plant and microbial growth,  Frankenberger &
Johanson  (1982) studied  the enzyme  (EC 4.3.1.3)  that catalyzes  the
deamination  of L-histidine in soils; treatment with formaldehyde mark-
edly inhibited its activity. Negative effects on the biological proper-
ties of the soil owing to increased doses of  urea-formaldehyde  ferti-
lizers have been reported by Rakhmatulina et al. (1984).

    Berestetskii et al. (1981) found that formaldehyde was one  of  the
volatile compounds formed in the early stages of plant residue decompo-
sition  in the soil.  Kanamura  et al. (1982) isolated  a microorganism
(genus  Hyphomicrobium ) from the soil that can use formaldehyde  as the
only  source of carbon.   Furthermore, formaldehyde has  a  significant
role  in the  complex batch  growth behaviour  of a  methanol-utilizing
bacterium ( Methylomonas ) (Agrawal & Lim, 1984).

    The  bacterial  content of  the  soil near  industrial  enterprises
polluted with formaldehyde was 28-40 million bacteria/kg polluted soil;
the  level in control areas was 900 million bacteria/kg soil.  There is
no  information  on  other pollutants  or  concentrations (Zhuravliova,
1969).  Species of  Pseudomonas were able to assimilate formaldehyde and
formate  (Grabinska-Loniewska, 1974).  Hingst et al. (1985) studied the
microorganism  contents  of  sewage samples;  species  of   Pseudomonas 
survived   a 30-min exposure  to formaldehyde at  5 g/kg (admixture  to
sewage samples).

    Exposure to 2.4 mg formaldehyde/m3 for  24 h killed all spores from
pure  cultures of various species of  Aspergillus ,  Scopulariopsis , and
 Penicillium crustosum (Dennis & Gaunt, 1974).

    The  phytopathogenic  fungi  Fusarium  oxysporum ,  lycopersici , and
 Rhizoctonia  solani  were  completely  eradicated  after  exposure  for
30 min  to an aqueous  solution of formaldehyde  at 4-5 g/litre.   When
tested  in  tuff  (a granular  plant  growth  medium of  volcanic  rock
origin),  the effectiveness of formaldehyde was lower compared with the
corresponding amounts in aqueous solutions (Sneh et al., 1983).

7.2  Aquatic Organisms

    The acute toxicity of formaldehyde for various species  of  aquatic
organisms is shown in Table 24.

    Many early studies conducted to determine the toxicity  of  formal-
dehyde  and safe levels for therapeutic treatment against fungal infec-
tions  and  ectoparasites have  been reported.  This  type of study  is
difficult to evaluate with respect to environmental hazard  because  of
very short exposure periods and the way the data are presented.

    From the data shown in Table 24, it appears that formaldehyde has a
relatively low toxicity for fish, 96-h LC50 values  being  higher  than
10 mg/litre in all cases.

    The toxic effects of formaldehyde on fresh-water trout  and  salmon
included  changes in gill  function, hypochloraemia, depressed  plasma-
calcium and carbon dioxide, reduced blood pH, and decreased oxygen con-
sumption (Wedemeyer, 1971). Effects in rainbow trout  occurred  rapidly
after  a 1 h  exposure at 200 mg/litre, and ca. 24 h was  required  for
recovery (Wedemeyer & Yasutake, 1974).  In rainbow trout  and  Atlantic
salmon,  formalin treatment caused increased  blood-haemoglobin, packed
cell  volume,  blood-glucose levels,  and plasma-protein concentrations
(Nieminen  et al.,  1983).  The  toxicity of  formaldehyde for  rainbow
trout  was increased by high water temperature, soft water, and high pH
levels (Bills et al., 1977).

    Algae and some invertebrates seem to be more susceptible to formal-
dehyde.  Acute toxicity occurs in green algae at  formaldehyde  concen-
trations  of 0.3-0.5 mg/litre ( Scenedesmus sp. ), in several species of
protozoa, at 4.5-22 mg/litre, in  Daphnia , at 2-20 mg/litre (EC50)  and
in  Cyprinodopris species at 0.42 mg/litre (96-h EC50).   Other invert-
ebrates differ widely in their responses to formalin (Table 25).

    For  amphibia, the 24-, 48-, and 72-h LC50 values  for larva of the
frog,  Rana pipiens , were 8.4, 8.0, and 8.0 mg formaldehyde/litre, with
a  72-h  LC100 at   11.4 mg/litre.   Tadpoles  of  the  bullfrog,  Rana 
 catesbeiana , were more  resistant,  having  24-,  48-,  and  72-h LC50
values  of 20.1,  17.9, and  17.9 mg/litre, respectively,  with a  72-h
LC100 of   30.4 mg formaldehyde/litre.  In toad  larvae ( Bufo sp. ) the
72-h  LC50 and  LC100 values  were 17.1 and 19.0 mg/litre, respectively
(Helms,  1964).  Carmichael (1983) exposed tadpoles of  Rana berlandieri 
to  formalin for 24 h and found that no mortality occurred  at  concen-
trations  < 6.0 mg formaldehyde/litre,   but  at 9.2,  13.6, 20.4, and
30.5 mg formaldehyde/litre,  mortality  was  13,  35,  78,  and   100%,
respectively.

7.3  Terrestrial Organisms

    Persson  (1973) studied the influence  of formalin on the  eggs and
larvae  of  the  cattle parasites  Ostertagia  ostertagia  and  Cooperia 
 oncophora  in liquid cattle manure.  A  1% solution destroyed the  eggs
and a 5% solution affected the larvae.  It also had a  negative  effect
on the germination and growth of crops fertilized with the manure.


Table 24.  Acute toxicity of formaldehyde for some aquatic organisms (static bioassay) 
--------------------------------------------------------------------------------------------------------
Organism/species           Temperature     pH     Hardness  Duration   (LC50)     Reference 
                              ( °C)               degree    of ex-     (mg/litre) 
                                                            posure (h) 
-------------------------------------------------------------------------------------------------------- 

Algae 
 
  Scenedesmus quadricauda      -           7.5       12         -         0.3      Bringmann & Kühn 
                                                                                  (1960) 
  Scenedesmus                  27        7.5-7.8     12        24         0.4      Bringmann & Kühn 
                                                                                  (1980a) 
Bacteria 
 
  Escherichia coli             25        7.5-7.8      -         -         1        Bringmann & Kühn 
                                                                                  (1960) 
  Pseudomonas fluorescens      25        7.5-7.8      -         -         2        Bringmann & Kühn 
                                                                                  (1960) 
Protozoa 
 
  Chilomonas paramaecum        -           6.9        -        48         4.5      Bringmann et al. 
                                                                                  (1980) 
  Mikroregma                   27        7.5-7.8     12        24         5        Bringmann & Kühn 
                                                                                  (1980b) 
  Uronema parduczi             -           6.9        -        20         6.5      Bringmann & Kühn 
                                                                                  (1980b) 
  Entosiphon sulcatum          25          6.9        -        72         22       Bringmann (1978) 
 
Water fleas 
 
  Daphnia magna                27        7.5-7.8     12        24         2        Corstjens & 
                                                                                  Monnikendam (1973) 
 
  Daphnia magna                23          7.5       12        48         2        Corstjens & 
                                                                                  Monnikendam (1973) 
--------------------------------------------------------------------------------------------------------


 
Table 24 (contd). 
--------------------------------------------------------------------------------------------------------
Water fleas (contd). 
 
  Daphnia magna (IRCHA)        -           8         16        24         42       Bringmann & Kühn 
                                                                                  (1982) 
  Daphnia magna              20-22       7.6-7.7     16        24         52       Bringmann & Kühn 
                                                                                  (1977) 
  Daphnia magna                -            -         -        24      100-1000    Dowden & Bennett 
                                                                                  (1965) 
Fish 
 
 Black bullhead               12        6.5-9.5      8        96         62.1a    Bills et al. (1977) 
 - fingerling -
 
 Channel catfish              12          6.5        8        96         65.8a    Bills et al. (1977) 
 - fingerling -
 
 Bluegill                     12          6.5        8        96        100a      Bills et al. (1977) 
 - fingerling -
 
 Lake trout                   12          6.5        8        96        100a      Bills et al. (1977) 
 - fingerling -
 
 Smallmouth bass              12          6.5        8        96        136a      Bills et al. (1977) 
 ( M. dolomieuri) 
 - fingerling -
 
 Largemouth bass              12          6.5        8        96        143a      Bills et al. (1977) 
 ( M. salmoides) 
 - fingerling -
 
 Atlantic salmon              12          6.5        -        96        173       McKim et al. (1976) 
--------------------------------------------------------------------------------------------------------


 
Table 24 (contd). 
--------------------------------------------------------------------------------------------------------
Organism/species           Temperature     pH     Hardness  Duration     (LC50)   Reference 
                              ( °C)               degree    of ex-     (mg/litre) 
                                                            posure (h) 
--------------------------------------------------------------------------------------------------------
Fish (contd). 
 
 Atlantic salmon              12          6.5        8         3        564a      Bills et al. (1977) 
 (fingerling)                 12          6.5        8         6        336a      Bills et al. (1977) 
                              12          6.5        8        24        156a      Bills et al. (1977) 
                              12          6.5        8        96         69.2     Bills et al. (1977) 
 
 Green sunfish                12           -         -        96        173       McKim et al. (1976) 
 
 Green sunfish                12          6.5        8        24        129a      Bills et al. (1977) 
 (fingerling)                 12          6.5        8        96         69.2a    Bills et al. (1977) 
                              -            -         -        72       > 34.2     Helms (1967) 
 
 Rainbow trout                12        6.5-9.5   46-48       96      565-1020    McKim et al. (1976) 
 (green egg) 
 
 Rainbow trout                12        6.5-9.5      -        96      198-435     McKim et al. (1976) 
 (eyed egg) 
 
 Rainbow trout                12        6.5-9.5      -        96     89.5-112     Brungs et al. (1978) 
 (sac larvae) 
 
 Rainbow trout                12        6.5-9.5      -        96     61.9-106     Brungs et al. (1978) 
 (fingerling) 
 
 Rainbow trout                12          6.5        8         3        492a      Bills et al. (1977) 
 (fingerling)                 12          6.5        8         6        262a      Bills et al. (1977) 
                              12          6.5        8        24        120a      Bills et al. (1977) 
                              12          6.5        8        96         47.2a    Bills et al. (1977) 
 
 Rainbow trout                12           -        20        96        118       Brungs et al. (1978) 
--------------------------------------------------------------------------------------------------------


 
Table 24 (contd). 
--------------------------------------------------------------------------------------------------------
Fish (contd). 
 
 Rainbow trout                12          7.5     40-48       24      214-7200    McKim et al. (1976) 
 
 Rainbow trout                12        7.5-8.2   30-245      96      440-618     McKim et al. (1976) 
 
 Rainbow trout                -            -        -         48         59.2     Schneider (1979) 
                              -            -        -         24         76.6     Willford (1966) 
                              -            -        -         48         62.2     Willford (1966) 
 
 Brown trout                  -            -        -         24        120.3     Willford (1966) 
                              -            -        -         48         68.5     Willford (1966) 
 
 Brook trout                  -            -        -         24         72.5     Willford (1966) 
                              -            -        -         48         58.1     Willford (1966) 
 
 Lake trout                   -            -        -         24         81.4     Willford (1966) 
 (fingerling)                 -            -        -         48         61.8     Willford (1966) 
                              12          6.5       8          6        241a      Bills et al. (1977) 
                              12          6.5       8         24         56.4a    Bills et al. (1977) 
                              12          6.5       8         96         40.0a    Bills et al. (1977) 
 
 Bluegill sunfish             -            -        -         24         68.5     Willford (1966) 
 (fingerling)                 -            -        -         48         51.8     Willford (1966) 
                              -            -        -         72         30.4     Helms (1967) 
                              12          6.5       8          3        916a      Bills et al. (1977) 
                              12          6.5       8          6        640a      Bills et al. (1977) 
                              12          6.5       8         24         84.4a    Bills et al. (1977) 
                              12          6.5       8         96         40.0a    Bills et al. (1977) 
                              -            -        -         24         53.7     Schneider (1979) 
                              -            -        -         48         34.0     Schneider (1979) 
                              -            -        -         96         25.2     Schneider (1979) 
 
 Largemouth bass              -            -        -         72         38       Helms (1967) 
 (fingerling)                 12          6.5       8          6        412a      Bills et al. (1977) 
                              12          6.5       8         24        113a      Bills et al. (1977) 
                              12          6.5       8         96         57.2a    Bills et al. (1977) 
--------------------------------------------------------------------------------------------------------


 
Table 24 (contd). 
--------------------------------------------------------------------------------------------------------
Organism/species           Temperature    pH      Hardness  Duration     (LC50)   Reference 
                              ( °C)               degree    of ex-     (mg/litre) 
                                                            posure (h) 
--------------------------------------------------------------------------------------------------------
Fish (contd). 
 
 Smallmouth bass              12          6.5       8         24         88.8a    Bills et al. (1977) 
 (fingerling)                 12          6.5       8         96         54.4a    Bills et al. (1977) 
 
 Striped bass                 -            -        -         24         31.8     Wellborn (1969) 
                              -            -        -         48         11.8     Wellborn (1969) 
                              -            -        -         96          6.7     Wellborn (1966) 
 
 Channel catfish              -            -        -         24         50.7     Willford (1966) 
                              -            -        -         48         35.5     Willford (1966) 
                              -            -        -         96         25.5b    Clemens & Sneed 
                                                                                  (1958, 1959) 
 
 (fingerling)                 12          6.5       8          3        198a      Bills et al. (1977) 
                              12          6.5       8          6         92.8a    Bills et al. (1977) 
                              12          6.5       8         24         48.8a    Bills et al. (1977) 
                              12          6.5       8         96         26.3a    Bills et al. (1977) 
 
 Black bullhead               -            -        -         72         17.1     Helms (1967) 
 (fingerling)                 12          6.5       8         24         69.2a    Bills et al. (1977) 
                              12          6.5       8         96         24.8a    Bills et al. (1977) 
 
 Golden shiner                                                72         23.6     Helms (1967) 
 
 American eel                                                            31.1     Hinton & Eversole 
  glass stage                 -            -        -         96                  (1978, 1979, 1980) 
  black stage                 -            -        -         96         83.1     Hinton & Eversole 
                                                                                  (1978, 1979, 1980) 
  yellow stage                -            -        -         96        122.1     Hinton & Eversole 
                                                                                  (1978, 1979, 1980) 
--------------------------------------------------------------------------------------------------------


 
Table 24 (contd). 
--------------------------------------------------------------------------------------------------------
Fish (contd). 
 
 Carp                         -            -        -         72       > 26.6     Helms (1967) 
                              -            -        -          2         74a      Suzuki & Kimara (1977) 
                                        
                                        
 Zebrafish                    -            -        -         96         41       Wellens (1982) 
 
 Golden orfe                  -            -        -         48         22       Wellens (1982) 
                              -            -        -         48         32.4b    Juhnke & Luedemann 
                              -            -        -         48         15.0b    (1978) 
 
 Harlequin fish               -            -        -         24         76       Alabaster (1969) 
                              -            -        -         48         50       Alabaster (1969) 
 
 Tilapia                      -            -        -         72       > 38.0     Helms (1967) 
--------------------------------------------------------------------------------------------------------
 
a       Flow through bioassay. 
b       Method not stated. 

Table 25.  Toxicity of formalin (37% formaldehyde) for selected aquatic 
           invertebrates in soft water at 16 °Ca 
------------------------------------------------------------------------------------------------------
Species                                  LC50 and 95% confidence interval (µlitre/litre) at 
 
                               1 h             3 h             6 h            24 h          96 h 
------------------------------------------------------------------------------------------------------

Seed shrimp (ostracods)b       9.00            6.40            1.20           1.15          1.05 
 Cypridopsis sp.             6.83-11.9       4.91-8.34      0.664-2.17     0.690-1.97    0.590-1.87 
 
Freshwater prawnb              -              2150            1900           1105           465 
 Palawmonetes kadiakensis       -            1948-2373       1588-2273       896-1362      368-588 
 
Bivalvesc                                                                     800           126 
 Corbicula sp.                  -                -               -           638-1003     80.9-196 
 
Snaild                        3525            1340             780            710          93.0 
 Helisoma sp.               3201-3881         953-1883        629-967        544-925      69.5-124 
 
Backswimmerd                   -                -               -            4500           835 
 Notonecta sp.                                                              3006-6735      652-1069 
------------------------------------------------------------------------------------------------------
a       From: Bills et al. (1977). 
b       Toxicity based on immobility. 
c       Toxicity based on ability to resist attempts to open valves and respond to tactile stimulus. 
d       Toxicity based on ability to respond to tactile stimulus. 
    Nematodes  in peat  were killed  by application  of  370 g  formal-
dehyde/litre solution at 179 ml/m3 (Lockhart, 1972).

    Changes  in  populations of  the  cereal cyst  nematode  Heterodera 
 avenae  and in crop growth in a sandy loam soil were studied in 1974-78
(Kerry et al. 1982). Fungal parasites attack  H. avenae females and eggs
resulting  in poor multiplication of the nematode.  The number of cysts
containing nematode eggs, after harvest, was not affected  by  formalin
(380 g formaldehyde/litre)  applied  as  a drench  at  3000 litre/ha in
1977. However, fecundity doubled in treated soil, and  nematode  multi-
plication  increased  18.6 times  compared with  3.8 times in untreated
plots.  When the plots were irrigated in 1978, the numbers of cysts and
fecundity increased in formalin-treated soils, resulting in a  0.3-  to
14.6-fold increase due to suppression of fungal parasites.

    The yellow rice borer ( Tryporyza incertulas ) ( Lepidoptera ) is one
of  the most serious pests of rice.  To obtain sterile males, it has to
be mass-reared on an artificial diet containing formaldehyde  (Wang  et
al.,  1983); the same  has been reported  for the pink  borer ( Sesamia 
 inferens ) (Siddiqui et al., 1983).

    In  ruminants,  deamination of  dietary  proteins by  rumen  micro-
organisms  is of importance, because of loss of essential nitrogen from
the  rumen  as  ammonia.  Formaldehyde  protects  dietary-protein  from
microbial proteolysis in the rumen by reacting with free  amino  groups
in  the protein, forming  inter- and intramolecular  methylene  bridges
(Siddons et al., 1982).  Thus, there is an increase in  the  efficiency
of utilization of amino acids for wool  (10 g formaldehyde/kg  protein)
and body growth in sheep and other ruminants (Faichney, 1970; Ferguson,
1970;  Hemsley et al., 1973).   Differences in nitrogen retention  were
found,  but no significant  differences in wool  growth or  live-weight
gain,  when  sheep  were  fed  formaldehyde-treated  linseed  meal  and
meatmeal  (2.5% formalin) (Rattray & Joyce, 1970).  Mills et al. (1972)
showed  that 14C-formaldehyde  bound to a  sodium caseinate-oil mixture
was  rapidly metabolized by sheep  and goat tissues and  eliminated via
expired  air, urine, and faeces, but was not accumulated in the milk or
in the carcass.  To study the digestion in the small intestine of young
bulls  of  the protein  of rapeseed meal,  treated or not  treated with
formaldehyde, Kowalczyk et al. (1982) fitted each bull with cannulae in
the  rumen and abomasum.  Formaldehyde-treated rapeseed meal was poorly
digested.   The nutritional value of soybean meal that had been treated
with  3 g formaldehyde/kg was investigated  by Crooker et  al.  (1983).
Analysis of covariance revealed that the digestibility of dietary crude
protein  by cows fed formaldehyde-treated  meal was lower than  that in
the  controls (62.4%  versus 65.4%)  as was  the milk-protein  content.
Erfle  et  al.  (1986)  fed  lactating  cows  with formaldehyde-treated
soybean  meal  and found  that  milk-protein levels  were significantly
decreased.  After treatment with formaldehyde, lysine and tyrosine were
lost from the soybean meal.

    Grenet (1983) studied the utilization of grass-silage  nitrogen  in
growing  sheep  and  found that  formic  acid  had a  beneficial effect
(decreased  urinary-nitrogen loss).  However, the addition of 1.5 litre
formalin/tonne  of  green  forage did  not  improve nitrogen-retention;
higher  quantities  of  formaldehyde  tended  to  have  an unfavourable
effect, particularly with lucerne silage.



7.4  Plants

    A  study  was  carried out by Sangines et al. (1984) to examine the
protective  effects  of formaldehyde  on  ensilaged whole  peanut plant
protein.  Formaldehyde (50, 100, 150, and 200 g/litre) was added at the
rate  of  5 litres/tonne.   A  control  without  any  formaldehyde  was
included.  There were no significant differences in pH among treatments
(5.56-5.70).   The ammonia concentration  dropped significantly in  all
treatments,  a  finding  that  suggests  a  protective  effect  against
protein-nitrogen  degradation to non-protein nitrogen  (NH3).    Lactic
acid  fermentation was observed, without any difference between treated
and  control  silage.   Nevertheless, there  was  a  reduction  in  the
propionic acid and ethanol concentrations in all the silages.   It  was
concluded that there was an inhibition of the fermentation  process  in
all the silages treated, and that the addition of formaldehyde  at  the
5% level is a satisfactory way of protecting this type of feed.

    In  agriculture, urea-formaldehyde fertilizers are  used to improve
crops.   At  concentrations  of up  to  0.3 g/kg  soddy podsolic  soil,
formaldehyde did not change the nitrogen and carbohydrate metabolism in
barley plants (Lebedeva et al., 1985).  However, increased doses of the
fertilizer  caused negative effects on the biological properties of the
soil (Rakhmatulina et al., 1984).

    Doman  et al. (1961) studied the conversion of gaseous formaldehyde
absorbed  by leaves of kidney  beans and barley plants  from the atmos-
phere,  using 14C  tracing.  The  activity appeared first  in phosphate
ester  fractions and later in the amino acids alanine, serine, aspartic
acid  and unidentified products,  especially when the  experiments were
conducted  in the  dark.  Zemlianukhin  et al.  (1972), also  using 14C
tracing,  studied  the metabolism  in  12-day-old maize  seedlings,  of
formic  acid, which was  oxidized to carbon  dioxide or metabolized  to
cellular constituents.

    Pollen  germination has been shown  to be sensitive to  various air
pollutants.   Masaru et al.  (1976) sowed lily  pollen grains  ( Lilium 
 longiflorum ) on culture medium. After being exposed to formaldehyde in
a fumigation chamber, for 24 h, pollen tube length was measured.  A 5-h
exposure to formaldehyde at 0.44 mg/m3 (0.37 ppm)  resulted in  a  sig-
nificant  reduction in pollen-tube length, whereas a 1- or 2-h exposure
was  innocuous.  When the  formaldehyde concentration was  increased to
2.88 mg/m3 (2.4 ppm),  a 1-h exposure caused a decrease in tube length.
The investigators observed that, with respect to pollen,  the  activity
of  formaldehyde was comparable with that of nitrogen dioxide.  To test
combinations  of  pollutants,  pollen  grains  were  exposed  to sulfur
dioxide  at 1.79 mg/m3 (0.69 ppm)  for 30 min or to nitrogen dioxide at
0.28 mg/m3 (0.15 ppm)   for 30 or 60 min.  This treatment led to slight
inhibition  of tube elongation.  A  second exposure to formaldehyde  at
0.3 mg/m3 (0.26 ppm)   led  to  significant inhibition  of  pollen tube
length (about 30-40% of the length of control pollen-tubes).

    A  sealed Plexiglas  chamber with temperature  and humidity control
and illuminated externally with wide spectrum grow lights was  used  to
evaluate  the ability of golden pothos ( Scindapsus aureus ), nephthytis

( Syngonium  podophyllum ), and  the  spider plant ( Chlorophytum elatum 
 var. vittatum ) to remove formaldehyde from contaminated air at initial
concentrations of 18-44 mg/m3.    Under the conditions of  this  study,
the spider plant proved most efficient by sorbing and/or removing up to
2.27 µg formaldehyde/cm2 leaf      surface  area  in  a   6-h  exposure
(Wolverton et al., 1984).

    Various  factors influence  the response  of a  plant  receptor  to
formaldehyde  exposure. These include  genetic factors, stage  of plant
development,  age  of tissue,  climatic  factors, such  as temperature,
relative humidity, light quality, light intensity, photoperiod, rate of
air  movement, and soil factors, such as moisture, aeration, and nutri-
ents.  Most studies dealing with the influence of formaldehyde exposure
on plants suffer from lack of such information.

8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    Concern  about the toxicological effects of formaldehyde is related
to  effects resulting from single or repeated exposures including irri-
tation,   cytotoxicity,  cell  proliferation,  and  sensitization,  and
effects resulting from long-term exposures, particularly cancer.

    The most significant properties of formaldehyde are  its  potential
to  cause  irritation  and,  at  high  concentrations  after  long-term
exposure, nasal tumours in rats and statistically not significant nasal
tumours in mice.

8.1  Skin and Eye Irritation, Sensitization

    Formaldehyde  is known to be  a primary skin and  eye irritant, the
local tissue reaction increasing with increased dose.  However, this is
based on anecdotal evidence rather than animal studies. The only report
is that of Carpenter & Smyth (1946) who found formaldehyde to be an eye
irritant for rabbits.

    The  sensitizing  potential  of aqueous  formaldehyde was evaluated
with  the  guinea-pig  maximization  test  (GPMT)  in  two laboratories
(Copenhagen    and   Stockholm)  using   different  guinea-pig  strains
(Andersen et al., 1985). Six intradermal (0.1-30 g/litre) and 6 topical
(5-200 g/litre)  concentrations  were  used for  induction, and formal-
dehyde  at 10 and 1 g/litre  was used for challenge.   The incidence of
contact  sensitivity  depended  on the  intradermal,  but  not  on  the
topical,  induction  dose.   Statistical analyses  showed  a non-linear
dose-response  relationship.  The estimated maximal  sensitization rate
in  Copenhagen was 80% after  intradermal induction with 0.65%  formal-
dehyde;  in Stockholm, it was 84% after induction with 0.34%.  The data
from the two laboratories gave parallel displaced dose-response curves,
suggesting  that the guinea-pig strain  used in Stockholm was  signifi-
cantly  more  susceptible  to formaldehyde  than  the  strain  used  in
Copenhagen.   The EC50 (formaldehyde  concentration at which 50% of the
guinea-pigs  were sensitized at 72 h) at a 10 g/litre challenge concen-
tration was 0.6 g/litre in Copenhagen and 0.24 g/litre in Stockholm.

    Other  studies are summarized in  Table 26.  The results  show that
aqueous formaldehyde solution is a sensitizer for the skin.

    Lee et al. (1984) exposed guinea-pigs to formaldehyde at 7.2 mg/m3
or  12 mg/m3,   for 6 or  8 h/day, on 5 consecutive  days.  The animals
were  evaluated for skin  sensitivity (production of  anti-formaldehyde
antibody)  and  respiratory  sensitivity (both  immediate  and delayed-
onset) to formaldehyde, which was shown to be a skin sensitizer without
causing detectable pulmonary hypersensitivity.

8.2 Single Exposures

    Acute  toxicity has been studied  in several animal species  (Table
27).

Table 26.  Contact allergy predictive tests in guinea-pigs 
----------------------------------------------------------------------------
Induction  Challenge  Sensitization      Test                Reference      
dose (%)   dose (%)   (number positive/                                     
                      number tested)                                        
----------------------------------------------------------------------------
                                                                            
30         1          2/7                open epicutaneous   Maibach (1983) 
10         1          5/8                                                   
3          1          3/8                                                   
1          1          2/6                                                   
0.3        1          2/6                                                   
0.1        1          0/6                                                   
                                                                            
5          5          7/20               epicutaneous        Guillot & Gonnet
                                         maximization        (1985)          
                                                                             
10         5          3/10               cumulative contact  Tsuchiya et al. 
5          5          2/10               enhancement test    (1985)          
1          5          0/10                                                   
0.2        5          0/10                                                   
                                                                             
10         1          4/10                                   Tsuchiya et al. 
5          1          2/10                                   (1985)          
1          1          0/10                                                   
0.2        1          0/10                                                   
                                                                             
10         0.2        1/10                                   Tsuchiya et al.
5          0.2        0/10                                   (1985)
1          0.2        0/0                               
0.2        0.2        0/0                               
-----------------------------------------------------------------------------


 
Table 27.  Acute toxic effects of formaldehyde on laboratory animals 
--------------------------------------------------------------------------------------------------------
Species    Route         Dose (duration)           Effect/response   Reference 
--------------------------------------------------------------------------------------------------------

Rat        oral          800 mg/kg body weight     LD50              Smyth et al. (1941); Tsuchiya 
                                                                     et al. (1975) 
 
           subcutaneous  420 mg/kg body weight     LD50              Skog (1950) 
 
           intravenous    87 mg/kg body weight     LD50              Langecker (1954) 
 
           inhalation    984 mg/m3 (30 min)        LC50              Skog (1950) 
 
           inhalation    578 mg/m3 (4 h)           LC50              Nagorny et al. (1979) 
 
Mouse      subcutaneous  300 mg/kg body weight     LD50              Skog (1950) 
 
           inhalation    497 mg/m3 (4 h)           LC50              Nagorny et al. (1979) 
 
Rabbit     dermal        270 mg/kg body weight     LD50              Lewis & Tatken (1980) 
 
           dermal        0.1-20%                   skin irritation:  NRC (1981) 
                                                   mild to moderate 
 
           eye           0.5 ml                    eye irritation:   Carpenter & Smyth (1946) 
                                                   grade 8 on a  
                                                   scale of 10

Guinea-    oral          260 mg/kg body weight     LD50              Smyth et al. (1941) 
pig
           dermal        0.1-20%                   skin irritation:  Colburn (1980) 
                                                   mild to moderate 
 
           dermal        1% (open application)     sensitization:    US CPSC (1978) 
                                                   positive
                         3% (open application)     sensitization:    US CPSC (1978) 
                                                   positive
                         1% (intradermal)          sensitization:    Colburn (1980) 
                                                   positive
--------------------------------------------------------------------------------------------------------
    The odour and irritant properties of formaldehyde serve  as  repel-
lents.  Kane & Alarie (1977) used the decrease in respiratory  rate  of
mice  as an index  of irritation.  At  0.6 mg formaldehyde/m3 air,   an
irritant effect on the eyes, nose, and throat occurred,  and  tolerance
to the irritant effects of formaldehyde did not develop.

    Exposure  to  high  concentrations of  formaldehyde  vapour  (> 120
mg/m3)    caused  hypersalivation,  acute dyspnoea,  vomiting, muscular
spasms,  and can finally lead to the death of test animals (Skog, 1950;
Horton et al., 1963; Bitron & Aharonson, 1978).

8.3  Short-term Exposures

8.3.1  Inhalation studies

    Inhalation studies are summarized in Table 28.

    A  range finding study  was conducted in  which rats and  mice were
exposed  to  atmospheres  containing 4.8,  15, or 46 mg formaldehyde/m3
(4,  12.7, or  40 ppm). Exposures  were for  approximately  6 h/day,  5
days/week,  for  13 weeks,  except for the  high dose level,  which was
terminated  after 2 weeks (Mitchell  et al., 1979).   Exposure of  both
mice  and rats to  concentrations of inhaled  formaldehyde of  46 mg/m3
(40 ppm)  resulted in  ulceration or  necrosis of  the nasal  turbinate
mucosa  in a significant number of animals of each species.  Both sexes
of  rats  had  a high  incidence  of  tracheal mucosal  ulceration  and
necrosis,  whereas only a few male mice exhibited this lesion.  Pulmon-
ary congestion was prominent in both male and female rats and  in  male
mice  at  the  highest dose level.  Female mice of both the control and
high-dose group had a similar incidence of pulmonary  congestion.  Sec-
ondary lesions encountered in rats exposed to this dose of formaldehyde
seemed  to be related to bacterial septicaemia due to a damaged respir-
atory mucosa.

    Groups  of  10  male and 10 female B6C3F1 mice were exposed to 2.4,
4.8, 12, 24, or 48 mg formaldehyde vapour/m3 (2,  4, 10, 20, or 40 ppm)
for  6 h/day,  5 days/week,  over 13  weeks  (Maronpot  et al.,  1986).
Clinical  abnormalities (dyspnoea, listlessness, and  hunched posture),
significant  mortality,  and  body weight  loss  were observed  in  the
48 mg/m3 groups.    Pathological  changes  were observed  in  the nose,
larynx, trachea, and bronchi of treated males and females, and  in  the
uterus and ovaries of treated females.  Squamous metaplasia and inflam-
mation were present in the nasal tissues of both male and  female  mice
in the 12-48 mg/m3 (10,  20, 40 ppm) groups and in the larynx  of  both
males and females in the 24 and 48 mg/m3 (20,  40 ppm) groups.  In some
mice,  epithelial-lined, irregular connective tissue  bands spanned the
tracheal lumen.  Metaplasia of the bronchial epithelium was confined to
the groups exposed to 48 mg/m3.   The effects on the respiratory system
were  more prevalent in  male than in  female mice.  Hypoplasia  of the
uterus  and ovaries, probably secondary  to body weight loss,  was con-
fined to the 48 mg/m3 (40 ppm) exposure group.


Table 28.  Short-term formaldehyde inhalation studies 
--------------------------------------------------------------------------------------------------------
Species       Exposure                   Concentration          Effect                        Reference 
                                         mg/m3   (ppm) 
--------------------------------------------------------------------------------------------------------

               Nose-only inhalation 
 
Rat           6 h/day, 5 days/week,      3.6     (3)            no adverse findings           AIHA  
              for 4 weeks                                                                     (1983)
 
              6 h/day, 5 days/week,      19, 73, (16, 61,       antibody inhibition           AIHA 
              for 4 weeks                120      99)                                         (1983) 
 
               Inhalation 
 
Rat           8 h/day (continuous),       6, 12  (5, 10)        slightly increased prolifer-  Wilmer 
              5 days/week, for           (equivalent to         ation of nasal epithelium;    et al. 
              4 weeks                    40 ppm x h or          slight hypermetaplasia of     (1987)
                                         80 ppm x h)            nasal epithelium 
 
              8.5 h/day (interrupted),   12, 24  (10, 20)       strongly increased prolifer-  Wilmer
              5 days/week, for           (equivalent to         ation of nasal epithelium;    et al. 
              4 weeks                    40 ppm x h or          moderate hypermetaplasia of   (1987)
                                         80 ppm x h)            nasal epithelium 
 
Rat           22 h/day, for 90 days      1.9     (1.6)          no adverse findings           Dubreuil 
                                                                                              et al. 
                                                                                              (1976) 
              22 h/day, for 45 days      5.4     (4.55)         decreased weight gain         Dubreuil 
                                                                                              et al. 
                                                                                              (1976) 
              22 h/day, for 60 days      9.6     (8.07)         decreased liver weight;       Dubreuil
                                                                eye irritation                et al. 
                                                                                              (1976)
              6 h/day, 5 days/week,      4.8     (4)            no adverse effect             Mitchell  
              for 13 weeks                                                                    et al. 
                                                                                              (1979)
--------------------------------------------------------------------------------------------------------


 
Table 28 (contd). 
--------------------------------------------------------------------------------------------------------
 
               Inhalation (contd). 
 
Rat           6 h/day, 5 days/week,      15      (12.7)         nasal erosion                 Mitchell  
              for 13 weeks                                                                    et al. 
                                                                                              (1979)
              6 h/day, 5 days/week,      48      (40)           nasal ulceration              Mitchell  
              for 2 weeks                                                                     et al. 
                                                                                              (1979)
              8 h/day (continuous),      1.2     (equivalent    no adverse effects            Wilmer 
              5 days/week, for           9.6     to 8 ppm x h)                                et al. 
              13 weeks                                                                        (1986)
 
              8.5 h/day (intervals),     2.4     (equivalent    no adverse effects            Wilmer
              5 days/week, for           9.6     to 8 ppm x h)                                et al. 
              13 weeks                                                                        (1986)
 
              8 h/day, 5 days/week,      2.4     (equivalent    no adverse effects            Wilmer 
              for 13 weeks               19.2    to 16 ppm x h)                               et al. 
                                                                                              (1986)
              8.5 h/day, 5 days/week,    4.8     (equivalent    hyper- and metaplasia of      Wilmer
              for 13 weeks               19.2    to 16 ppm x h) nasal respiratory epithelium  et al. 
                                                                                              (1986)
              6 h/day, 5 days/week,      0.36    (0.3)          transient, slight increase    Zwart
              for 13 weeks                                      in cell turnover rate of the  et al. 
                                                                nasal respiratory epithelium  (1987)
 
              6 h/day, 5 days/week,      1.2     (1)            transient, slight increase    Zwart
              for 13 weeks                                      in cell turnover rate of      et al. 
                                                                the nasal respiratory         (1987)
                                                                epithelium 
 
              6 h/day, 5 days/week,      3.6     (3)            5- to 10-fold increase in     Zwart
              for 13 weeks                                      cell turnover rate and        et al. 
                                                                squamous metaplasia of the    (1987)
                                                                nasal respiratory epithelium 
---------------------------------------------------------------------------------------------------------


 
Table 28 (contd). 
---------------------------------------------------------------------------------------------------------
Species       Exposure                   Concentration          Effect                        Reference 
                                         mg/m3   (ppm) 
---------------------------------------------------------------------------------------------------------
               Inhalation (contd). 
 
Rat           6 h/day, 5 days/week,      1.2     (1)            questionable hypermetaplasia  Woutersen
              for 13 weeks                                      of the nasal respiratory      et al. 
                                                                epithelium                    (1987)
 
              6 h/day, 5 days/week,      12      (10)           squamous metaplasia of nasal  Woutersen
              for 13 weeks                                      respiratory epithelium        et al. 
                                                                                              (1987)
              6 h/day, 5 days/week,      24      (20)           transient excitation and      Woutersen
              for 13 weeks                                      uncoordinated locomotion;     et al. 
                                                                growth retardation; de-       (1987)
                                                                creased level of plasma-
                                                                protein; increased activity 
                                                                of several plasma enzymes; 
                                                                squamous metaplasia of the 
                                                                nasal respiratory and olfac-
                                                                tory epithelium; squamous 
                                                                metaplasia of laryngeal 
                                                                epithelium 
 
              6 h/day, 5 days/week,      2.4-48  (2-40)         12-48 mg/m3: histological     Maronpot
              for 13 weeks                                      lesions in the upper respira- et al. 
                                                                tory system; 48 mg/m3: death  (1986)
 
              22 h/day, 7 days/week,     1.2     (1)            no adverse findings           Rusch et 
              for 26 weeks                                                                    al. (1983)
 
              22 h/day, 7 days/week,     3.6     (3)            squamous metaplasia; depres-  Rusch et  
              for 26 weeks                                      sion in body weight gain      al. (1983)
---------------------------------------------------------------------------------------------------------


 
Table 28 (contd). 
---------------------------------------------------------------------------------------------------------
               Inhalation (contd). 
 
Mouse         6 h/day, 5 days/week,      4.8     (4)            no adverse findings           Mitchell
              for 13 weeks                                                                    et al. 
                                                                                              (1979)
              6 h/day, 5 days/week,      15      (12.7)         no adverse findings 
              for 13 weeks 
 
              6 h/day, 5 days/week,      48      (40)           nasal ulceration in males 
              for 2 weeks 
 
Hamster       22 h/day, 7 days/week,     1.2 and (1 and         no adverse findings           Rusch et
              for 26 weeks               3.6     3)                                           al. (1983)
 
Guinea-pig    6 h/day, 5 days/week,      1.2     (1)            hyperkeratosis in the cavity  Marshall  
              for 8 weeks                                       (reversible after 30 days);   (1983)
                                                                mucus flow elevated; foci of 
                                                                squamous metaplasia of res-
                                                                piratory epithelium 
 
Monkey        22 h/day, 7 days/week,     1.2     (1)            metaplasia in nasal turbin-   Rusch et 
(cynomolgus)  for 26 weeks                                      ates in 1/6 exposed           al. (1983)
 
              22 h/day, 7 days/week,     3.6     (3)            metaplasia in nasal turbin-   Rusch et 
              for 26 weeks                                      ates in 6/6 exposed           al. (1983)
 
Monkey        6 h/day, 5 days/week,      7.2     (6)            mild degeneration and early   Monticello
(rhesus)      for 1 or 6 weeks                                  squamous metaplasia of nasal  et al. 
                                                                passages, trachea and bronchi (1989)
                                                                in 6/6 exposed. Percentage of 
                                                                nasal surface area affected 
                                                                was greater in 6-week exposure 
                                                                group 
---------------------------------------------------------------------------------------------------------
    Groups  of 6 male cynomolgus monkeys, 20 male and 20 female Fischer 
344 rats, and 10 male and 10 female Syrian golden hamsters were exposed 
to  0, 0.24,  1.2, or  3.7 mg/m3 (0,  0.2,  1, or  3 ppm)  formaldehyde 
vapour (98.8% pure) for 22 h/day, 7 days/week, over 26 weeks.  Squamous 
metaplasia of the nasal turbinates was evident in 6/6  monkeys  exposed 
to  3.7 mg/m3 (3 ppm)   and  in  1/6  exposed  to  1.2 mg/m3   (1 ppm). 
Squamous  metaplasia  and basal  cell  hyperplasia of  the  respiratory 
epithelium  of the nasal  cavity were significantly  increased in  rats 
exposed  to  3.7 mg/m3 (3 ppm).    The  same  group  exhibited   marked 
depressions  in  body weight  gain.   No exposure-related  effects were 
demonstrated in hamsters (Rusch et al., 1983). 

    Two  groups of 3 adult  (aged 4-5 years) male  rhesus monkeys  were 
exposed  to 7.2 mg/m3 (6 ppm)  formaldehyde in inhalation chambers. One 
group was exposed 6 h/day for 5 days; the other group was  exposed  for 
6 h/day, 5 days/week for 6 weeks. A control group of 3 monkeys was sham 
exposed to filtered room air for 6 h/day, 5 days/week for 6 weeks. Both 
exposed groups showed mild degeneration and early  squamous  metaplasia 
in  parts of the transitional  and respiratory epithelium of  the nasal 
passages and respiratory epithelium of the trachea and  major  bronchi. 
The  nasal surface  area involved  was significantly  increased in  the 
6 week  exposure  group.   Cell proliferation  rates were significantly 
increased  and  remained  elevated  6 weeks  after  the  termination of 
exposure (Monticello et al., 1989). 

    Fifteen-week-old male Hartley guinea-pigs were exposed for 6 h/day, 
5 days/week,  for  8 weeks,  to  0.12,  1.2,  or  12 mg formaldehyde/m3 
(Marshall  et  al., 1983).   Animals were sacrificed  at 1 and  30 days 
after the end of exposure, and tissue samples were taken to  study  the 
histology and lung biochemistry.  Body weight, nasal  mucous  clearance 
velocity,  and airway sensitivity  to inhaled histamine  were  measured 
after  2, 4, and 8 weeks of exposure and 2 and 4 weeks after completion 
of  exposure.  Nasal mucous clearance velocity increased by 25% after 4 
weeks of exposure to 12 mg/m3,   but returned to control values 2 weeks 
after the end of exposure.  Dose-related histological findings included 
hyperkeratosis  and squamous metaplasia  of the respiratory  epithelium 
occurring in foci in the anterior half of the nasal  cavities.   Thirty 
days  after exposure, squamous metaplasia had resolved; however, slight 
hyperkeratosis of respiratory epithelium was still present  in  guinea-
pigs  exposed to 12 mg formaldehyde/m3.    Altered airway sensitization 
to  inhaled histamine was not noted in exposed guinea-pigs.  No differ-
ences  were observed in  body weights and  lung biochemical  end-points 
between control and exposed guinea-pigs. 

    The  acute effects of inhaled formaldehyde on the nasal mucociliary 
apparatus   of  male F-344  rats were studied  by Morgan et  al. (1986) 
using  whole-body  exposures.   Formaldehyde exposures  ranged  from  a 
single  6-h period up to repeated 6-h exposures daily for 3 weeks, with 
exposure  concentrations of 18, 7.2, 2.4, or 0.6 mg/m3.     Within  1 h 
of  the last  exposure, the  rats were  killed and  the nasal  passages 
examined  for  effects  on  nasal  mucociliary  function.   Exposure to 
18 mg formaldehyde/m3 induced   inhibition  of mucociliary  function in 
specific  regions of the nose, and mucostasis was generally more exten-
sive than ciliastasis.  These effects, which were initially confined to 
the anterior regions of the nose, became progressively  more  extensive 

for  up to 2 weeks of exposure with only very slight progression during 
the  third week.   Inhibition of  mucociliary function  was  much  less 
severe  with exposure to 7.2 mg/m3,    minimal at 2.4 mg/m3,   and  not 
detected in rats following exposure to 0.6 mg/m3. 

    Woutersen et al. (1987) exposed male and female rats to 0, 1.2, 12, 
or  24 mg formaldehyde/m3 for   6 h/day,  5  days/week, over  13 weeks; 
definite  adverse effects were observed  at 12 and 24 mg/m3,    but the 
study was inconclusive with respect to whether 1.2 mg/m3 was   a  cyto-
toxic effect level for the nasal epithelium. 

    The  possibility of the hepatotoxicity of formaldehyde for rats was 
investigated  by Woutersen et al. (1987). It was concluded that formal-
dehyde  was  not  hepatotoxic at  concentrations  as  high as  12 mg/m3 
(10 ppm).   At 24 mg/m3 (20 ppm),  there was  a slight increase in  the 
levels  of certain plasma-enzymes suggesting a hepatotoxic effect, how-
ever, histopathological examinations did not reveal any  liver  damage, 
and  there were no changes in liver weight or liver-glutathione concen-
trations.   The slight increase in  plasma-enzyme levels may have  been 
caused by growth retardation (Woutersen et al., 1987). 

    Zwart et al. (1987) exposed rats (50 per sex and group) to 0, 0.36, 
1.2,  or  3.6 mg formaldehyde/m3 for   6 h/day,  5 days/week,  over  13 
weeks.   Definite adverse effects on the nasal epithelium were observed 
at 3.6 mg/m3.    The authors concluded there was some  indication  that 
formaldehyde  at  levels of  0.36  and 1.2 mg/m3 challenged   the nasal 
mucociliary  and regenerative defence systems at the beginning, but not 
at the end, of the study. 

    In  a 13-week inhalation study,  male rats were exposed  for 5 days 
per  week to 0, 1.2, or 2.4 mg formaldehyde/m3,   continuously (8 h per 
day), or to 2.4 or 4.8 mg formaldehyde/m3 intermittently  (8 successive 
1-h  periods a day, each consisting of 30 min of exposure and 30 min of 
non-exposure) (Wilmer et al., 1986).  The only adverse  effect  (hyper-
metaplasia  of the nasal respiratory  epithelium) was found in  animals 
exposed  to 4.8 mg/m3.    This study  showed that the concentration  is 
more important than the total dose for the cytotoxic effects of formal-
dehyde on the nose. 

    A 4-week inhalation study on male rats was carried out by Wilmer et 
al. (1987) in which the animals were exposed for 5 days/week to  0,  6, 
or  12 mg formaldehyde/m3,   continuously for  8 h/day, or 12  or 24 mg 
formaldehyde/m3 intermittently  (8 successive 1-h periods per day, each 
consisting  of 30 min of  exposure and 30 min  of non-exposure).   This 
study  also showed that the concentration rather than the total dose of 
formaldehyde  determined the severity of  the cytotoxic effects on  the 
nasal epithelium. 

    Fifteen male rats were exposed to vapourizing 10% formalin solution 
(3.7% formaldehyde)  by inhalation for 2-22 weeks;  their tracheas were 
removed and examined microscopically after various periods of exposure; 
a wide spectrum of morphological changes in the epithelium  and  under-
lying  connective tissues was observed.  In addition to chronic inflam-
mation,   metaplastic   changes,  including   squamous  metaplasia  and 
dysplasia  of the epithelium, were induced by formaldehyde (Al-Abbas et 
al., 1986). 

    The   immunotoxicity of formaldehyde was studied in mice by Dean et 
al.  (1984).   Female  B6C3F1  mice  underwent  inhalation  exposure to 
18 mg/m3 for  6 h/day, 5 days/week, over 3 weeks. Most immune functions 
involving  T and B  lymphocytes and macrophages  were not impaired  and 
there  was  an enhanced  resistance  to  Listeria monocytogenes .   In a 
later study by the same group (Adams et al., 1987), exposure of mice to 
18 mg  formaldehyde/m3 (15 ppm)  for 6 h  daily over 3 weeks  caused an 
increased  (approximately two-fold) competence for  release of hydrogen 
peroxide (H2O2)     from the peritoneal macrophages.  Enhanced function 
of  the macrophages may be responsible for the enhanced lost resistance 
reported by Dean et al.  (1984). 
 
8.3.2  Oral studies

    In  a  4-week, drinking-water  study  on rats,  using  formaldehyde
levels of 0, 5, 25, or 125 mg/kg body weight per day,  adverse  effects
attributable  to formaldehyde were  encountered in the  high-dose group
only,  and comprised decreased plasma-protein levels and hyperkeratosis
and  gastritis in the fore- and glandular stomach, respectively (Til et
al., 1987).

    Administration  of formaldehyde in  the drinking-water to  Sprague-
Dawley  rats at a dose of 150 mg/kg body weight per day and in the diet
to  beagle dogs at a dose of 100 mg/kg body weight per day for a period
of 13 weeks was found to result in a slightly depressed growth rate; no
effects on the stomach were observed (Johannsen et al., 1986).

    During  an  18-day  study, rats  were  fed  a diet  of soybean meal
treated with formaldehyde (Schmidt et al., 1973).  The use of more than
2 ml  formalin  (40%)/100 g soybean  protein reduced  growth,  and also
nitrogen retention in nitrogen balance studies.

8.4  Long-Term Exposure and Carcinogenicity

8.4.1  Inhalation

    Exposure   of  B6C3F1  mice  and Fischer 344  rats to 2.4,  7.2, or
18 mg formaldehyde  vapour/m3 (2,  6, or  15 ppm) for up  to  24 months
resulted in chronic toxicity.  The survival of mice did not  appear  to
be  related  to the  concentration of formaldehyde  to which they  were
exposed;  however,  exposure  to  a  level  of  17.6 mg/m3 resulted  in
reduced body weight.  Several lesions were seen in the  nasal  cavities
of mice exposed to concentrations of 7.2 or 18 mg/m3   (6  or  15 ppm),
including  dysplasia and squamous  metaplasia of the  respiratory  epi-
thelium, purulent or seropurulent rhinitis, and atrophy of  the  olfac-
tory   epithelium.   Three  months  after   exposure  was  discontinued
(27 months),  the nasal lesions  had regressed.  In  the rats,  several
lesions  occurred  in the  nasal cavities at  the low concentration  of
2.4 mg/m3 (2 ppm);   these  increased  in  extent  and  severity   with
increasing concentrations.  The lesions included dysplasia and squamous
metaplasia  of the respiratory epithelium, goblet-cell hyperplasia, and
purulent or seropurulent rhinitis.  Rats exposed to 18 mg/m3   (15 ppm)
also  exhibited  goblet-cell  metaplasia of  the  olfactory epithelium,
respiratory  epithelial  hyperplasia, squamous  epithelial hyperplasia,
squamous  atypia,  and  papillary hyperplasia;  dysplasia  and squamous

metaplasia of the tracheal epithelium were also detected. The incidence
of  squamous metaplasia  in rats  exposed to  2.4 or  6.7 mg/m3 (2   or
5.6 ppm)  regressed  within 3 months  of  the termination  of  exposure
(Swenberg et al. 1980; Kerns et al., 1983) (see Table 30).  Male Syrian
golden  hamsters exposed to diethylnitrosamine by sc injection (0.5 mg,
once per week, for 10 weeks) and to formaldehyde  (36 mg/m3 via   inha-
lation, 48 h/week prior to each injection, and  subsequently  continued
for  the  life-time  of  each  animal)  developed  tracheal  carcinomas
(Dalbey,  1982).  Male Syrian  golden hamsters exposed  to up to  12 mg
formaldehyde/m3 (10 ppm)   for 5 h/day and  5 days per week  for  their
life-time did not show any tumours but 5% showed hyperplastic and meta-
plastic  areas  on  the nasal  epithelium.  The  author concluded  that
formaldehyde may act as a cofactor in carcinogenesis in the trachea.

    Following    exposure  of  Sprague-Dawley  rats   to   formaldehyde
17 mg/m3 (14 ppm)   alone,  or  in combination  (pre-mixed  or non-pre-
mixed)  with HCl 14 mg/m3 (10 ppm),  for 6 h/day, 5 days/week, for life
(Table 29),  rhinitis,  hyperplasia,  and squamous  metaplasia  in lar-
yngeal-tracheal segments and nasal mucosa were observed (Albert et al.,
1982; Sellakumar et al., 1985).

    Albert et al. (1982) exposed rats to a mixture of  gaseous  formal-
dehyde (17.9 mg/m3)   and hydrogen chloride (16.9 mg/m3)   for 6 h/day,
5 days/week,  for life. In  the exposure chamber,  a  bis-chloromethyl-
ether  (BCME)  concentration of  0.5-2 µg/m3,      due to  the chemical
reaction   of  formaldehyde  and  hydrogen   chloride,  was  estimated.
Sellakumar et al. (1985) calculated levels of BCME under  similar  con-
ditions of 0.5-2.05 µg/m3 (0.1-0.4 ppb).     Nasal squamous cell carci-
nomas  were found in 25/99  rats and papillomas in  3/99 rats; squamous
metaplasia  of the nasal epithelium  was found in 64/99  of the exposed
rats.

    A  subsequent  report  (Sellakumar et  al.,  1985)  of  studies  on
combined exposure to hydrogen chloride and formaldehyde showed that the
carcinogenic  response to formaldehyde  does not result  from the  BCME
formed by the mixture of the gases.

    Tobe  et  al.  (1985)  exposed  male  F-344  rats  for  6 h/day,  5
days/week,  over  28 months,  to 0.36,  2.4,  or 17 mg formaldehyde/m3.
Rhinitis accompanied by desquamation was found in all groups.   In  all
formaldehyde-exposed  groups, nasal epithelial hyperplasia and squamous
metaplasia  with  hyperplasia  were  seen.   In  the  17 mg/m3   group,
squamous cell carcinoma was recognized in 14 rats and papilloma in 5 of
32 rats exposed.


Table 29.  Summary of carcinogenicity studies of formaldehyde on animals 
---------------------------------------------------------------------------------------------------------
Species/  Number of  Route of      Dosage                        Findings                      Reference 
Strain     animals   exposure 
            (sex) 
---------------------------------------------------------------------------------------------------------

Mouse     42-60      inhalation    0, 50, 100, or 200 mg/m3;     no pulmonary tumours at       Horton  
                                   three l-h periods/week,       0-100 mg/m3                   et al. 
                                   for 35 weeks                                                (1963)
 
Mouse     36         inhalation    50 mg/m3 for 35 weeks         no pulmonary tumours          Horton  
                                   + 150 mg/m3 for 29 weeks;                                   et al. 
                                   three l-h periods/week                                      (1963)
                                   in addition 
 
Mouse     26         inhalation    100 mg/m3; three 1-h          formaldehyde did not modify   Horton  
                                   periods/week for 35 weeks     the pulmonary carcinogenesis  et al. 
                                   followed by a coal-tar        of coal-tar                   (1963)
                                   aerosol for 35 weeks 
 
Mouse:    119-121    inhalation    0, 2.4, 6.72, or 17.16 mg/m3; squamous cell carcinoma of    Kerns  
B6C3F1    (male)                   6 h/day, 5 days/week, for     the nasal cavity in 2 males   et al. 
          119-121                  up to 24 months; 6-month      (at high exposure only)       (1983)
          (female)                 follow-up 
 
Mouse:    29-99      ingestion     0 or 0.5 HMT in drinking-     no increased tumour           Della  
CTM, SWR  (male)                   water for 60 weeks or 5%      incidence                     Porta  
+C3Hf     27-100                   for 30 weeks (CTM only);                                    et al.
          (female)                 follow-up for 110-130 weeksa                                (1968)
 
Mouse:    39         subcutaneous  5 g/kg on alternate days,     no increased tumour           Della  
CTM       (male)                   for 110-130 weeksa            incidence                     Porta  
          44                                                                                   et al.
          (female)                                                                             (1968)

Mouse     60         Injection     µl "formol oil" 50 times      no tumoursd                   Klenitzky  
                     (route not    to the cervix uteri (dose                                   (1940)
                     described)    not defined) 
----------------------------------------------------------------------------------------------------------


                                   
Table 29 (contd). 
----------------------------------------------------------------------------------------------------------
 
Mouse:    30         topical,      3.7% formaldehyde             formaldehyde is probably      Spangler  
SENCAR    (female)   back skin     in acetone                    not a complete carcinogen     & Ward 
                                   once a week, 48 weeks         or an initiator               (1983)
                                                                 (preliminary findings only)

Mouse:    30         subcutaneous  0.1-1.0 mg,                   no incidence of initiator/    Krivanek  
CD-1      (female)                 3 times a week                promotor activity             et al. 
                                   for 180 days                  (preliminary findings)        (1983a)
 
Mouse     16         topical,      200 µg 1% or 10%              no tumours                    Iversen  
          (male)     back skin     sol., twice a week,                                         (1986)
          16                       60 weeks 
          (female)

Rat:      100        inhalation    17 mg/m3 (14.2 ppm); 382      10 squamous cell carcinomas   Albert  
Sprague   (male)                   exposures over a 588-day      of the nasal cavity           et al. 
Dawley                             period; 6 h/day, 5 days/week  (significantwith regard       (1982)
                                                                 to controls (preliminary                
                                                                 findings only)

Rat:      99         inhalation    16.80 mg/m3 (14.7 ppm)        25/99 squamous cell           Albert  
Sprague                            formaldehyde + 14.80 mg/m3    carcinomas of the nasal       et al. 
Dawley                             (10.6 ppm) HCl (BCME estima-  cavity and 3 papillomas       (1982)
                                   ted 1 µg/m3), 6 h/day, 
                                   5 days/week, for life 
 
Rat:      100        inhalation    17.16 mg/m3 (14.3 ppm)        12 squamous cell carcinomas   Albert  
Sprague   (male)                   formaldehyde + 14 mg/m3-      of the nasal                  et al. 
Dawley                             (10 ppm) HCl (pre-mixed);     cavity (significant           (1982)
                                   378 exposures over 588 days;  with regard to controls)   
                                   6 h/day, 5 days/week          (preliminary results only)
 
Rat:      100        inhalation    16.92 mg/m3 (14.1 ppm) for-   6 nasal (significant with     Albert  
Sprague   (male)                   maldehyde + 13.30 mg/m3 (9.5  regardto controls)            et al. 
Dawley                             ppm) HCl (not pre-mixed);     (5 squamous cell              (1982)
                                   378 exposures over 588 days;  carcinomas, 1 adenocarcinoma)
                                   6 h/day, 5 days/week          (preliminary results only) 
----------------------------------------------------------------------------------------------------------------------


 
Table 29 (contd). 
----------------------------------------------------------------------------------------------------------------------
Species/  Number of  Route of      Dosage                        Findings                      Reference 
Strain     animals   exposure 
            (sex) 
----------------------------------------------------------------------------------------------------------------------

Rat:      119-121    inhalation    0, 2.4, 6.72, or 17.16 mg/m3; non-significant polypoid      Kerns  
F-344     (male)                   for up to 24 months; 6 h/     adenoma at all doses; 2/235   et al. 
          119-121                  day, 5 days/week; 6-month     (non-significant) and 103/232 (1983)
          (female)                 follow-up                     (significant) squamous cell 
                                                                 carcinomas of nasal cavity,
                                                                 at the medium and high  
                                                                 doses, respectively  
                                                                 (see also Table 30) 
 
Rat:      32         inhalation    0.36, 2.4, or 17 mg/m3;       rhinitis; epithelial cell     Tobe  
F-344                              6 h/day, 5 days/week, for     hyperplasia; squamous         et al. 
                                   28 months                     metaplasia at 17 mg/m3, 14/   (1985)
                                                                 32 squamous cell carcinomas 
                                                                 (P < 0.01) and 5/32  
                                                                 papillomas (P < 0.05)        

Rat:      100        inhalation    18.24 mg/m3 (15.2 ppm) for-   13 polyps/papillomas; 45      Sella- 
Sprague   (male)                   maldehyde + 13.86 mg/m3 (9.9  squamous cell carcinomas;     kumar 
Dawley                             ppm) HCl (pre-mixed) (BCME,   1 adenocarcinoma              et al. 
                                   0.1-0.4 µg/m3); 6 h/day,      1 fibrosarcoma; esthesic                          (1985)
                                   5 days/week, for life         neuroepithelioma resp
 
Rat:      100        inhalation    17.88 mg/m3 (14.9 ppm) for-   27 squamous cell carcinomas;  Sella- 
Sprague   (male)                   maldehyde + 13.58 mg/m3 (9.7  2 adenocarcinomas; 11         kumar  
Dawley                             ppm) HCl (not pre-mixed);6 h/ polyps/papillomas             et al.
                                   day, 5 days/week for life                                   (1985)
 
Rat:      100        inhalation    17.76 mg/m3 (14.8 ppm) for-   38 squamous cell carcinomas;  Sella- 
Sprague   (male)                   maldehyde; 6 h/day, 5 days/   1 fibrosarcoma; 1 mixed car-  kumar  
Dawley                             week, for life                cinoma                        et al.
                                                                                               (1985)

Rat       30         stomach tube  0.4 g/daya, for 333 days      no treatment-related tumours  Brendel
                                                                                               (1964) 
---------------------------------------------------------------------------------------------------------


 
Table 29 (contd). 
---------------------------------------------------------------------------------------------------------

Rat:      48         ingestion     1% HMT in drinking-water      no increased tumour           Della  
Wistar    (male)                   for 104 weeks, for 3 yearsa   incidence                     Porta  
          48                                                                                   et al.
          (female)                                                                             (1968)

Rat:      280        ingestion     0, 1.2, 15, or 81 mg/kg bw    no tumours (except 1 skin     Til  
Wistar    (male)                   (males); 0, 1.8, 21, or 109   mesenchymoma in high-dose     et al. 
          280                      mg/kg bw (females)            male)                         (1988)
          (female)                 (drinking-water, 2 years) 
 
Rat:      80         ingestion     0, 10, 50, or 300 mg/kg bw;   no significant increase in    Tobe  
Wistar    (male)                   (drinking-water, 2 years)     tumours                       et al. 
          80                                                                                   (1988)
          (female)

Rabbit    6          oral tank     3% formalin, 90 min,          2/6 leukoplakiasb             Mueller  
                                   5 times/week for 10 months                                  et al. 
                                                                                               (1978)

Syrian    88         inhalation    12 mg/m3, 5 h/day,            no increase in                Dalbey  
golden                             5 day/week, lifetime          tumour incidence              (1982)
hamsters 
 
Syrian    50         inhalation    36 mg/m3, 5 h/day,            no increase in nasal          Dalbey  
golden                             5 day/week, lifetime          tumour incidence              (1982)
hamsters                           (with diethylnitrosamine) 
 
Rat       10         subcutaneous  1 ml/week for 15 months       4/10 injection-site sarcomas  Watanabe  
                                   0.4% solution                                               et al. 
                                                                                               (1954)
Rat       20         subcutaneous  1-2 ml/week till tumour       7/20 injection-site sarcomas; Watanabe & 
                                   development 9-40%a            1/20 injection-site adenoma   Sugimoto  
                                                                                               (1955)
Rat:      20         subcutaneous  5 g/kg on alternate days,     no increased tumour           Della  
Wistar    (male)                   for 2 yearsa                  incidence                     Porta  
          20                                                                                   et al.
          (female)                                                                             (1968)
---------------------------------------------------------------------------------------------------------
a   Hexamethylenetetramine (HMT) (from which formaldehyde is liberated  in vivo). 
b   Showed "histological features of carcinoma in situ" (Mueller et al., 1978). 
c   Aspartame (sweetener) was administered to rats at a dosage level of 8 g/kg body weight, which 
    has been assumed to biodegrade (10%) in the animals yielding 800 mg formaldehyde/kg. 
d   No tumours, even after treatment with dibenzpyrene and coal tar. 

Table 30.  Neoplastic changes in the nasal cavities of Fischer 344 ratsa 
---------------------------------------------------------------------------------------------------------
Formaldehyde  Sex     Number of   Squamous   Nasal       Undifferen-   Malignant   Polypoid   Osteo- 
mg/m3 (ppm)           nasal       cell       carcinomas  tiated        sarcomas    adenomas   chondromas
                      cavities    carcinomas             carcinomas/                                    
                      evaluated                          sarcomas                                       
---------------------------------------------------------------------------------------------------------
                                                                                                         
0    (0)      male    118         0          0           0             0           1          1    
              female  114         0          0           0             0           0          0    
                                                                                                         
2.4  (2)      male    118         0          0           0             0           4          0    
              female  118         0          0           0             0           4          0    
                                                                                                         
6.7  (5.6)    male    119         1          0           0             0           6          0    
              female  116         1          0           0             0           0          0    
                                                                                                         
17.2 (14.3)   male    117         51c        1b          2b            1           4          0    
              female  115         52d        1           0             0           1          0    
---------------------------------------------------------------------------------------------------------

a From: Kerns et al. (1983) and BGA (1985). 
b One animal also exhibited a squamous cell carcinoma.   
c 36 of these animals were among the 57 that died prematurely. 
d 15 of these animals were among the 67 that died prematurely. 
 
    Male rats were exposed to 0, 12, or  24 mg formaldehyde/m3 for   4,
8,  or  13 weeks  (6 h/day, 5 days/week)  and  were  then observed  for
periods of up to 126 weeks (Feron et al., 1987a). Non-neoplastic histo-
pathological  changes in the  nasal respiratory epithelium  (hyper- and
metaplasia)  and  olfactory  epithelium (disarrangement,  thinning, and
simple cuboidal or squamous metaplasia) occurred at  24 mg/m3,    simi-
lar, but less pronounced, changes of the nasal  respiratory  epithelium
were  seen at 12 mg/m3 and  a limited and not statistically significant
number of nasal tumours occurred at 24 mg/m3,   mainly in rats that had
been  exposed for 13 weeks (6/132: 3 squamous cell carcinomas, 1 carci-
noma  in situ and 2 polypoid adenomas).

    Feron et al. (1987b) carried out an inhalation study on  male  rats
with  a  severely damaged  (by  electrocoagulation) or  undamaged nasal
mucosa.   They were exposed to  0, 0.12, 1.2, or  12 mg formaldehyde/m3
6 h/day,  5 days/week, over periods  of either 28 months  or  3 months,
followed by an observation period of 25 months.  A  significant  number
of  nasal squamous cell carcinomas (17/60) occurred only in rats with a
damaged  nose  that had  been exposed to  12 mg/m3 for  a period  of 28
months.

    Basal-cell  hyperplasia and/or squamous metaplasia were observed in
the   tracheo-bronchial epithelium of C3H  mice exposed to 50,  100, or
200 mg formaldehyde/m3,    for  4 h/day,  3 days/week,  over  35 weeks;
atrophic metaplasia was also observed in the highest dose group (Horton
et al., 1963).

    Neoplastic  lesions found in the nasal cavities of Fischer 344 rats
exposed to formaldehyde gas are summarized in Table 30 (Kerns  et  al.,
1983).   Several studies were performed to examine whether formaldehyde
acts  as a complete carcinogen, a promoter, or an initiator of tumours.
Horton  et al. (1963) exposed  mice to coal-tar aerosol  and to formal-
dehyde (48 or 120 mg/m3,   1 h/day, 3 days/week, over 35 weeks).  Coal-
tar aerosol exposure resulted in lung tumour formation, but  there  was
no evidence of any co-carcinogenic effect of formaldehyde.

8.4.2  Dermal studies

    Studies  were carried out on mice (Krivanek et al., 1983a; Spangler
&  Ward, 1982;  Iversen, 1986)  to test  whether formaldehyde  solution
applied  to  the  skin induced  papilloma  or  malignant tumours  as an
initiator, or promoter of cancer, or as a complete carcinogen.  Formal-
dehyde  proved to be  neither a complete  carcinogen, nor an  initiator
(with phorbolmyristateacetate as a promoter). With respect to promoting
activity   (with   benzo(a)pyrene   or  dimethylbenyanthracene   as  an
initiator) the results were either negative or  inconclusive.   Details
can be found in Table 29.

8.4.3  Oral studies

    Some  studies were performed using HMT instead of formaldehyde.  It
is  used as an urinary tract antiseptic and antimicrobial food additive
(Della  Porta et al., 1968) and owes its activity to its degradation to
formaldehyde  and ammonia  in an  acid medium  (digestive  tract)  with
conversion  of 20% of  the theoretical amount  of formaldehyde at  pH 5
(Goodman & Gilman, 1975).

    Slightly reduced growth rate and survival were observed in CTM mice
given  5%  hexamethylenetetramine (HMT)  in  the drinking-water  for 30
weeks;  a slightly reduced  growth rate was  also observed in  SWR mice
exposed  to 1% HMT in  the drinking-water for 60 weeks  (Della Porta et
al., 1968) (Table 29).

    Formaldehyde,  and other compounds were tested for tumour-promoting
activity in a 2-stage stomach carcinogenesis study (Takahashi  et  al.,
1986).   Male  Wistar  rats were  given N-methyl- N'-nitro-N-nitroso-
guanidine  (MNNG)  in  the  drinking-water  (100 mg/litre)  and  a diet
supplemented  with 10% sodium  chloride for 8 weeks.   Thereafter, they
were  maintained  on drinking-water  containing  0.5% Formalin  for  32
weeks.  Formaldehyde increased the incidence of adenocarcinoma  in  the
glandular stomach, after initiation with MNNG and sodium chloride.  The
incidence  of squamous cell papilloma  in the forestomach was  signifi-
cantly  increased  in the  groups  given formaldehyde,  irrespective of
prior  initiation.   The  results indicate  that  formaldehyde  induces
forestomach papilloma and exerts tumour-promoting activity.

    Groups  of 70 male and 70 female SPF Wistar rats, 31 days old, were
administered formaldehyde at 1.2, 15, or 81 and 1.8, 21,  or  109 mg/kg
body  weight  per  day, respectively,  as  a  5% (w/w)  solution in the
drinking-water for up to two years.  A group of 70 males and 70 females
served as controls.  Groups of 10 rats per sex per group were killed at
weeks 53 and 79 and the remaining animals at week 105.   Mortality  was
elevated  among mid-dose males by the end of the study but there was no
difference among other groups.  Mean body weights were lower  in  high-
dose animals; this was accompanied by a decrease in food and liquid in-
take. The limiting ridge of the forestomach was raised and thickened in
most  animals of the high-dose group at each interim killing and at the
end of the study; a similar effect was observed in some  other  treated
groups and occasionally in controls.  Papillary epithelial hyperplasia,
hyperkeratosis, and focal ulceration in the forestomach  were  observed
in  high-dose animals as  were chronic atrophic  gastritis, ulceration,
and hyperplasia in the glandular stomach. In addition, a  higher  inci-
dence  and  degree of  renal papillary necrosis  was seen in  high-dose
animals  at  the  end of the study compared to other treated groups and
controls. One mesenchymoma of the skin was observed in a high-dose male
killed at 52 weeks and two gastric papillomas were observed, one  in  a
low-dose male and one in a female control, at the end of the study.  No
other  gastric tumours were  reported and no  treatment-related tumours
were found (Til et al., 1988).

    A similar study was carried out on Wistar rats administered formal-
dehyde  in the drinking-water (Tobe  et al., 1989).  Groups  of 20 male
and 20 female Wistar rats, four weeks old, were administered 10, 50, or
300 mg  formaldehyde/kg  body  weight per  day  as  0.02, 0.1,  or 0.5%
solutions,  respectively, in the  drinking-water for up  to 2 years.  A
group  of 20 males and 20 females served as controls.  Groups of 6 rats
per  sex per group were  killed at 12 and  18 months and the  remaining
surviving  animals were killed at 24 months.  Mortality was elevated in
the  high-dose group  and reached  45% and  55% in  males and  females,
respectively,  at  12  months; all animals in this group had died by 21
months (females) and 24 months (males). Body weight gain and  food  and
liquid   intake  were  significantly  reduced   in  high-dose  animals.

Erosions,  ulcers, squamous cell hyperplasia, hyperkeratosis, and basal
cell hyperplasia with submucosal cell infiltration were observed in the
forestomach  in  animals  of  both  sexes  in  the high-dose  group  at
12 months.   Erosions,  ulcers,  and submucosal  cell infiltration also
occurred  in the glandular  stomach among this  group at 12 months  and
glandular  hyperplasia was  observed along  the limiting  ridge of  the
fundic mucosa.  In the mid-dose group, hyperkeratosis occurred  in  the
forestomach in one male and one female among animals killed at  18  and
24 months.  No such lesion was found in animals in the  low-dose  group
at any time.  There was no significant increase in the incidence of any
neoplastic  lesion in any  treated group compared  with controls.   The
types  of  tumours  observed were  similar  to  those that  occur spon-
taneously in this strain of rats.

8.5  Mutagenicity and Related End-Points

    The  mutagenic properties of formaldehyde have been studied in dif-
ferent test systems (Tables 31 and 32).  Extensive data  have  resulted
from   the   treatment  of  Drosophila with   formaldehyde-treated  food
(Auerbach et al., 1977).

    In  general, the available data show that formaldehyde is mutagenic
in  different  test systems,  especially  when high  concentrations act
directly  on cells (gene and chromosome mutations).  Addition of metab-
olizing  systems to the  assay system tends  to reduce the  activity of
formaldehyde.   The  mutagenic  effects of  formaldehyde in  Drosophila 
depend   on the route  of administration.  Inconsistent  responses were
obtained   in  in  vitro mammalian  mutagenicity  assays,  increases  in
mutation frequency being obtained in the mouse lymphoma assays, but not
with Chinese hamster ovary cells.

    Positive  cell transformation assays  have been reported  in vitro .
After  inhalation of the compound, local DNA adducts were  observed  in
rats without simultaneous systemic genetic effects (Casanova-Schmitz et
al., 1984b).

Table 31.  The genetic toxicology of formaldehyde:  in vitro studies 
---------------------------------------------------------------------------------------------------------
Assay                     Strain/type        Metabolic        Result  Comments                 Reference 
                                             activation 
---------------------------------------------------------------------------------------------------------
Procaryotes 
 
   Escherichia coli        WP2 Hcr+           none                -                             Nishioka  
                          WP2 Hcr-                               +                             (1973)

   Escherichia coli        WP2                ± Aroclor           +                             De Flora  
                          WP67               induced rat         +                             et al. 
                          CM871              liver S-9           +                             (1984)
                          spot test                              +    strain was not speci-
                                                                      fied for spot test, nor 
                                                                      was metabolic acti-
                                                                      vation used 
 
   Escherichia coli        WP2 uvrA           none                -                             Hemminki 
                                                                                               et al.    
                                                                                               (1980)

   Salmonella typhimurium  TM677              ± Aroclor           +    toxicity and mutageni-   Temcharoen 
                                             induced rat              city reduced with S-9    & Thilly  
                                             liver S-9                                         (1983)
 
   Salmonella typhimurium  no strain data                         -                             Gocke     
                                                                                               et al. 
                                                                                               (1981)

   Salmonella typhimurium  Ames; no strain    ± hepatic           -    paraformaldehyde         Bruisick  
                          data               activation                                        et al. 
                                                                                               (1980)

   Salmonella typhimurium  TA1535,            none                -                             De Flora  
                          TA1538,                                -                             et al. 
                          TA1537,                                -                             (1984)
                          TA97                                   -
                          TA98                                   -
                          TA100                                  -
---------------------------------------------------------------------------------------------------------


                                   
Table 31 (contd). 
---------------------------------------------------------------------------------------------------------
 
   Salmonella typhimurium  TA97               ± Aroclor           -    effects of S-9 not       Hughes  
                          TA98               induced rat and     -    given; assumed from      et al. 
                          TA100              hamster liver S-9   -    abstract all strains     (1984)
                                                                      negative 
 
   Salmonella typhimurium  TM677              ± Aroclor           +                             Donovan  
                          TA97               induced rat         +                             et al. 
                          TA98               liver S-9           +                             (1983)
                          TA100                                  + 
 
   Salmonella typhimurium  TM677              none                +                             Sarrit  
                          TA100                                  +                             et al.
                                                                                               (1983) 
 
   Salmonella typhimurium  TA98               ± Aroclor           +    formaldehyde as          Connor  
                          TA100              induced rat         +    formalin (10-15%         et al. 
                          UTH8414            liver S-9           -    methanol)                (1983)
                          UTH8413                                -
 
   Salmonella typhiurium   TA1535             none                -    formalin tested          De Flora  
                          TA1537                                 -                             (1981)
                          TA1538                                 -
                          TA98                                   -
                          TA100                                  -
 
   Salmonella typhimurium  TA98               ± KC500             -    negative with S-9        Sasaki  
                          TA100              induced rat         +                             & Endo 
                                             liver S-9                                         (1978)
 
   Salmonella typhimurium  TA98               ± rat liver         +    activity of formal-      Oerstavik 
                          TA100              microsomes          +    dehyde was reduced in    & Hongslo  
                                                                      the presence of rat      (1985)
                                                                      liver microsomes 
 
   Salmonella typhimurium  TA1535 + plasmids  none                +                             Yoshimitsu
                          5310002/psk1002                                                      et al.
                                                                                               (1985) 
---------------------------------------------------------------------------------------------------------


 
Table 31 (contd). 
---------------------------------------------------------------------------------------------------------
Assay                     Strain/type        Metabolic        Result  Comments                 Reference 
                                             activation 
---------------------------------------------------------------------------------------------------------
 
   Salmonella typhimurium  TA97               ± Aroclor           -    weak response            De Flora  
                          TA102              induced rat         +                             et al. 
                                             liver S-9                                         (1984)
 
   Salmonella typhimurium  TA100              ± Aroclor           +    pre-incubation           Simmons  
                          TA102              induced rat              procedure                et al. 
                                             liver S-9                                         (1986)
 
   Salmonella typhimurium  no strain data     ± hepatic           -                             Brusick  
                                             activation                                        (1983)
 
   Salmonella typhimurium  TA100              ± clophen           +                             Schmid  
                                             A50 induced rat     (weak)                        et al. 
                                             liver S-9                                         (1986)
 
   Salmonella typhimurium  TA102              none                -                             Levin  
                          TA2638                                                               et al.
                                                                                               (1982) 
 
   Salmonella typhimurium  TA98               ± PCB, KC-100       -    formalin; positive in    Ishidate  
                          TA100              induced rat              strain TA100 without     et al. 
                          TA1537             liver S-9           -    S-9                      (1981)
 
   Salmonella typhimurium  TA98               ± Aroclor           -                             Haworth  
                          TA100              induced rat and     -                             et al. 
                          TA1535             hamster liver S-9   -                             (1983)
                          TA1537                                 -
 
Eucaryotes
 
  Nematode                 Caenorhapolitis    -                        Point mutation in        Moerman & 
                           elalgans                                    unc-22 gene for          Baillie  
                                                                      "twitching" on expo-     (1981)
                                                                      sure to nicotine 
---------------------------------------------------------------------------------------------------------


                                   
Table 31 (contd). 
---------------------------------------------------------------------------------------------------------
                                                                                                     
   Neurospora crassa       H-59 (repair       -                   +                             Brockman  
                          deficient)                                                           et al. 
                          H-12                                   +                             (1981)
 
   Neurospora crassa       Ade                                    +                             Jensen  
                                                                                               et al.
                                                                                               (1951) 
 
   Drosophila                                                     +    FA generated ADH         Benyajati  
                                                                      mutants                  et al.
                                                                                               (1983) 
 
   Drosophila              -                  -                   -    not susceptible to       Auerbach  
                                                                      mutagenicity when fed    et al. 
                                                                      formaldehyde in the      (1977)
                                                                      food; mutations on in-
                                                                      jection into the larvae 
 
   Tradescantia                               -                   -    strain absorption        Ma et al.  
  (micronucleus)                                                 +    fumigation               (1985)
 
   Saccharomyces           D4                 -                   +                             Chanet  
   cerevisiae              D3                                     +                             et al. 
  (recombination)                                                                              (1975)
 
   Saccharomyces           N123                                   +    mitotic                  Chanet & 
   cerevisiae                                                          recombination            Von   
  (recombination)                                                                              Borstel
                                                                                               (1979)
Mammalian cell mutation
 
  Mouse lymphoma          L5178Y             ± hepatic           +    paraformaldehyde         Brusick  
                                             activation                                        (1980)
 
  Mouse lymphoma          L5178Y TK±         ± S-9               +    negative on the ad-      Dooley  
                                                                      dition of cofactors FDH  (1985)
                                                                      and NAD+ 
---------------------------------------------------------------------------------------------------------


 
Table 31 (contd). 
---------------------------------------------------------------------------------------------------------
Assay                     Strain/type        Metabolic        Result  Comments                 Reference 
                                             activation 
---------------------------------------------------------------------------------------------------------
Mammalian cell mutation (contd).
 
  CHO cells               HGPRT locus        none                -                             Hsie et al. 
                                                                                               (1978) 
 
  CHO cells               HGPRT locus        ± Aroclor           equivocal                     Stankowski  
                                             induced rat         (without                      et al. 
                                             liver S-9           S-9) +                        (1986)
                                                                 (with S-9 
                                                                 very weak) 
 
  CHO cells               AS52 locus                             + 
 
  Human lymphoblasts      TK6                none                +                             Goldmacher 
                                                                                               & Thilly  
                                                                                               (1983)
Cell transformation
 
                          C3H10T 1/2         none                -                             Ragan &  
                                                                                               Boreiko 
                                                                                               (1981)

                          hamster embryo     none                +                             Sonner &  
                                                                                               Riverdal
                                                                                               (1983) 
 
                          rat kidney cell    none                ±    formaldehyde trans-      Sonner &  
                                                                      formed cells when        Riverdal 
                                                                      incubated with TPA       (1983)
 
                          Balb/C3T3 1/2      none                +                             Brusick  
                                                                                               (1983)

                          BKH-21/C1.13       ± Aroclor           +                             Plesner &  
                                             induced rat                                       Henson 
                                             liver S-9                                         (1983)
---------------------------------------------------------------------------------------------------------


 
Table 31 (contd). 
---------------------------------------------------------------------------------------------------------

DNA repair                                                            
                          hamster embryo     none                +                             Hatch  
                          cells (SA7 virus)                                                    et al. 
                          (enhanced viral                                                      (1983)
                          transformation) 
 
                          human diploid                          +    nick translation did     Snyder & 
                          fibroblasts                            -    not inhibit repair       Van Houten  
                                                                                               (1986)

  DNA cross-linking       CHO-KI             none                +                             Marinari  
                                                                                               et al. 
                                                                                               (1984)
DNA assay
 
  DNA-cell binding                           none                ?                             Kubinski  
                                                                                               et al.
                                                                                               (1981)

  Unscheduled DNA         Hela                                   +                             Martin  
  synthesis                                                                                    et al. 
                                                                                               (1978)

  DNA damage              L1210 mouse                            +    DNA-protein cross-       Ross  
                          leukaemia cells                             links                    et al. 
                                                                                               (1981)

  Unscheduled DNA         rat tracheal epi-  none                -                             Doolittle & 
  synthesis               thelial cells                                                        Butterworth 
                                                                                               (1984) 
 
                          bronchial epi-     none                +    DNA-protein cross-       Grafstrom  
                          thelial and                                 links; single-strand     et al. 
                          fibroblast cells                            breaks in DNA and inhi-  (1983)
                                                                      bited resealing inhi-
                                                                      bition of DNA repair 
                                                                      (UDS) 
 
                          human fibroblasts                      +                             Levy  
                                                                                               et al. 
                                                                                               (1983) 
---------------------------------------------------------------------------------------------------------

  
 
Table 31 (contd). 
---------------------------------------------------------------------------------------------------------
Assay                     Strain/type        Metabolic        Result  Comments                 Reference 
                                             activation 
---------------------------------------------------------------------------------------------------------
 
  DNA-protein cross-      rat nasal          none                +                             Bermudez & 
  linking                 epithelium                                                           Delahanty  
                                                                                               (1986)

  Unscheduled DNA         rat nasal          none                -                             Bermudez & 
  synthesis               epithelium                                                           Delahanty  
                                                                                               (1986)

  Scheduled DNA           rat nasal          none                +                             Bermudez & 
  synthesis               epithelium                                                           Delahanty  
                                                                                               (1986)

  RNA synthesis           rat nasal          none                -                             Bermudez & 
                          epithelium                                                           Delahanty  
                                                                                               (1986)
Cytogenetic assays
 
  Sister chromatid        CHO                hepatic activation  +    paraformaldehyde         Brusick  
  exchange                                                                                     et al. 
                                                                                               (1980)
  Chromosome aberration   CHO                hepatic activation  + 
 
  Sister chromatid        V79                ± Aroclor           +    FA induced sister        Basler  
  exchange                                   induced rat              chromatid exchanges;     et al. 
                                             liver S-9                frequency decreased      (1985)
                                             ± hepatocytes            with S-9 to almost 
                                                                      that of control values; 
                                                                      this was shown to be due 
                                                                      to metabolism, not bind-
                                                                      ing to macromolecules 
 
  Sister chromatid        human lymphocyte                       +                             Garry &  
  exchange                                                                                     Kreiger 
                                                                                               (1981)

  Sister chromatid        human lymphocyte                       +                             Kreiger &  
  exchange                                                                                     Garry 
                                                                                               (1983)
---------------------------------------------------------------------------------------------------------

 
 
Table 31 (contd). 
---------------------------------------------------------------------------------------------------------

                          human lymphoblast                      +    TK locus DNA-            Craft  
                          TK6                                    +    protein cross-links      et al. 
                                                                                               (1987)

  Chromosome aberration   CHO                ± metabolic         +                             Natarajan  
                                             activation                                        et al. 
                                                                                               (1983)

  Sister chromatid        human lymphocytes  none                +                             Bassendow-
  exchange                                                                                     stakarska & 
                                                                                               Zawadzkakos  
                                                                                               (1983)
  Sister chromatid        CHO                none                +                             Obe & Beek 
  exchange                human lymphocytes  none                +                             (1979) 
 
  Chromosome aberration   embryonic kidney   none                -    formalin                 Kalmykova  
                          culture                                                              (1979)
 
  Sister chromatid        CHO                ± hepatic           +    metabolic activation     Brusick  
  exchange                                   activation               decreased the dose at    (1983)
  Chromosome aberration   CHO                                    -    which sister chromatid 
                                                                      exchange activity was 
                                                                      detected 
 
  Chromosome aberration   human lymphocyte   ± clophen           +                             Schmid  
  Sister chromatid        human lymphocyte   A50 induced rat     +                             et al. 
  exchange                                   liver S-9                                         (1986)
 
  Chromosome aberration   CHO cells          ± PCB KC-400        + (in                         Ishidate  
                                             induced rat         absence                       et al. 
                                             liver S-9           of S-9)                       (1981)
 
  Chromosome aberration   CHO                ± Aroclor           +                             Galloway  
  Sister chromatid        CHO                induced rat         +                             et al. 
  exchange                                   liver S-9                                         (1985)
---------------------------------------------------------------------------------------------------------

 
Table 32.  The genetic toxicology of formaldehyde:  in vivo studies 
---------------------------------------------------------------------------------------------------------
Assay                   Strain/type      Result         Comments                            Reference 
---------------------------------------------------------------------------------------------------------

 Cytogenetic assays 
 
  Sister chromatid      mouse            + in female    formaldehyde concentrations were    Brusick et al. 
  exchange                               mice at mid-   greater that the target concen-     (1983) 
                                         and higher     trations of 14.4 and 30 mg/litre 
                                         dose levels 
 
  Chromosome            mouse            ?              formalin (correct CAS number not    Kalmykova  
  aberration                                            given); 24-h and 25-month exposures (1979)
                                                        caused insignificant increase in 
                                                        cells with chromosomal aberrations; 
                                                        symmetrical translocations in the 
                                                        germ cells found in the spermato-
                                                        cyte stage and increased post-
                                                        implantation embryonic mortality 
 
  Chromosome            CBA mouse        -              bone marrow + spleen; 0.4 ml ip     Natarajan  
  aberration                                            at doses of 6.25, 12.5, and         et al.       
  Micronucleus          CBA mouse        -              25 mg/kg                            (1983)

  Micronucleus          NMRI mouse       -              bone marrow; single ip injection    Gocke et al. 
                                                        of 10, 20, or 30 mg/kg; sampled     (1981) 
                                                        at 3 and 6 years; 2 males and 2 
                                                        females per group 
 
  Sister chromatid      Fischer rat      -              0.6, 7.2, or 18 mg/m3 (0.5, 6, or   Kligerman  
  exchanges/chromosome                                  15 ppm); 6 h/day, for 5 days        et al. (1984) 
  aberration 
---------------------------------------------------------------------------------------------------------


 
Table 32 (contd). 
---------------------------------------------------------------------------------------------------------
 
  Chromosome            rat            - at week 1      0, 0.6, 3.6, or 18 mg/m3 (0, 0.5,   Scott et al. 
  aberration                           and 32 months    3, or 15 ppm) paraformaldehyde);    (1985) 
                                       bone marrow; +   6 h/day, 5 days/week, for 6 months; 
                                       at high dose     at 4 and 6 months the mitotic index 
                                       in lung macro-   in the lung cells of all animals, 
                                       phage at 1 week  including controls had dropped, 
                                       and 2 months     and the number of cells available 
                                                        for scoring was inadequate 
 
 Unscheduled DNA synthesis 
 
                        rat              -              0.47, 2, 5.9, or 14.8 mg/litre      Doolittle & 
                        (tracheal                       for 1, 3, or 5 days                 Butterworth 
                        epithelial cells)                                                   (1984) 
 
 Dominant lethal 
 
                        mouse          - (spermato-     mixture of formaldehyde and         Fontignie-
                                       gonial chromo-   hydrogen peroxide (30 mg/kg,        Houbrechts  
                                       some)            90 mg/kg)                           et al.       
                                                                                            (1982)
                                       weak dominant    number of pregnancies not reduced; 
                                       lethal effects   no increase in post-implantation 
                                       weeks 1 and 6    lethality; number of live embryos 
                                                        never decreased below 7.4/female; 
                                                        pre-implantation loss significantly 
                                                        increased during the whole study, 
                                                        except for the 5th and 7th weeks 
 
                        ICR-Ha Swiss     -              32, 40, 16, or 20 mg/kg ip; mated   Epstein et al. 
                        mouse (8- to 10-                for 3 or 8 weeks (females replaced  (1972) 
                        week-old males)                 weekly) 
---------------------------------------------------------------------------------------------------------


 
Table 32  (contd). 
---------------------------------------------------------------------------------------------------------

Assay                   Strain/type      Result         Comments                            Reference 
---------------------------------------------------------------------------------------------------------
 Dominant lethal (contd). 
 
                        Q-strain         - (spermato-   50 mg/kg ip                         Fontignie-
                        mouse            gonial chromo-                                     Houbrechts        
                                         some                                               (1981)
 
                                         weak dominant  no effect was observed on the number 
                                         lethal effect  of pregnant females; an increase in 
                                                        embryonic mortality observed in the 
                                                        first week after treatment is attri-
                                                        butable to an increase in the number 
                                                        of pre- and post-implantation deaths; 
                                                        only in the 3rd week was the number of 
                                                        pre-implantation deaths significantly 
                                                        increased 
 
 Spot test 
 
  Somatic cell          C57B1/6J"Ha"     -              6 - 6.1 and 17.8 - 18.1 mg/m3,      Jensen & Cohr 
  mutation              mouse                           6 h/day, for 3 days                 (1983) 
                        (T-stock)
---------------------------------------------------------------------------------------------------------
    DNA-protein  cross-links have been studied in cultures of mammalian
cells.   Some DNA strand breakage was reported, but DNA-DNA cross-links
were  not observed.  Formaldehyde has  been shown to induce  chromosome
aberrations and sister chromatid exchanges in a number of  cell  lines.
The results of studies on the induction of sister  chromatid  exchanges
in  human lymphocyte cultures (Kreiger & Garry, 1983) demonstrated that
there  was no significant sister  chromatid exchange response below  an
apparent "threshold" of 5 ml culture medium.

    Craft  et al. (1987) exposed human lymphoblasts  in vitro to various
concentrations  of  formaldehyde  (0-150 µmol/litre x 2 h).   Both  the
induction  of mutations and the formation of DNA-protein cross-links by
formaldehyde  are non-linear functions occurring at overlapping concen-
tration  ranges.  Holding  the culture  for 24 h  resulted in  complete
removal of the cross-links.

    Definite  evidence  that  formaldehyde  may  induce  mutations   in 
 vivo has not been found.  Tests for the induction of  sister  chromatid
exchanges  in mouse bone marrow cells gave equivocal results.  Dominant
lethal tests in ICR-Ha Swiss mice were reported to be negative at doses
up  to 40 mg/kg; more recent  studies on Q-strain mice  showed effects,
except during the first and third week, after treatment of  males  with
50 mg  formaldehyde/kg.  Micronucleus and chromosomal  assays failed to
reveal  any formaldehyde-induced lesions in both exposed rats and mice.
The  results of a  mouse somatic cell  mutation assay (spot  test) were
also negative for formaldehyde.

    Formaldehyde  damage induced in DNA in different human cell culture
systems comprised DNA-protein cross-links and DNA single-strand breaks;
these lesions undergo efficient repair by complex mechanisms (Grafstrom
et  al., 1984).  An earlier  finding that formaldehyde may  inhibit DNA
repair  (Grafstrom et al., 1983)  has not been confirmed  (Snyder & van
Houten, 1986).

8.6  Reproduction, Embryotoxicity, and Teratogenicity

    This topic has been studied in inhalation, feeding, drinking-water,
gavage, and dermal studies.  The results are summarized in Table 33.

    In a dominant-lethal study, formaldehyde did not appear  to  affect
spermatogenesis  or  fertility  in  mice  at single dose levels  up  to
40 mg/kg  body weight (ip) or  produce any increases in  fetal death or
pre-implantation losses (Epstein et al., 1972).

    Yasamura  et al. (1983)  gave mice doses  of 0, 30,  40,  or  50 mg
formaldehyde/kg  per day by intraperitoneal  injection on days 7-14  of
pregnancy.   The  mean body  weight of treated  fetuses was lower  than
that  in the controls, and the incidence of prenatal death was slightly
increased  in treated mice.   There was a  significant increase in  the
frequency  of abnormal  fetuses from  treated dams,  the major  malfor-
mations being cleft palate and malformations of the extremities. Strain
differences were observed.

    A  teratology study on the  rat was undertaken by  the Formaldehyde
Council of Canada (Martin, 1985). Twenty-five mated Sprague-Dawley rats

were  exposed through inhalation  (whole-body exposure) for  6 h/day to
formaldehyde  doses  of  2.4, 6, or 12 mg/m3,   from day 0 to day 15 of
gestation, inclusive.  Two control groups were included in  the  study.
The females used for the study were 13 weeks of age and weighed between
221 and 277 g. Proven males of the same strain and source were used for
mating.  The  pregnancy rate  in all groups  was at least  80%. Uterine
parameters,  including  numbers  of corpora  lutea, implantation sites,
live fetuses, dead fetuses, and resorptions, fetal weight,  sex  ratio,
and  pre- and post-implantation  losses, were unaffected  by treatment.
The  overall incidence of litters and fetuses with major malformations,
minor  external and visceral  anomalies, and minor  skeletal  anomalies
was not affected by treatment with formaldehyde.

    Pregnant  hamsters were treated with dermal applications of formal-
dehyde  solution  on  day 8, 9, 10, or 11 of gestation (Overman, 1985).
Fetuses were removed on day 15 and were weighed, measured, and examined
for  teratogenic effects.  The resorption rate increased in the formal-
dehyde-treated  groups,  but  treatment did  not  significantly  affect
weight  or length, and no malformations that could be related to treat-
ment appeared. It was concluded that fetal risk due to topical exposure
to formaldehyde was minimal in this model system.  However, there is no
information  in  this  study on  the  amount  of formaldehyde  actually
absorbed.


Table 33.  Reproduction and teratology studies 
---------------------------------------------------------------------------------------------------------
Species Route of    Number   Dosage      Time of        Effects on offspring/   Remarks          Refer-
        exposure  of animals             treatment      reproduction                             ence 
                 Female Male 
---------------------------------------------------------------------------------------------------------

Rat     inhalation 12    3  0.012 mg/m3  10-15 days     14-15% increase in      no data con-     Gofmekler 
                   12    3  1 mg/m3      before ges-    duration of gestation;  cerning ratio    et al.  
                                         tation         increase in body,       of pregnancy,    (1968)
                                         (females)      heart, and kidney       litter size; 
                                                        weight; decrease in     insufficient 
                                                        weight of liver and     number of dose 
                                                        lungs                   levels 
 
Rat     inhalation 12    3  0.012 mg/m3  10-20 days     decrease in ascorbic    no data concern- Gofmekler 
                   12    3  1 mg/m3      before ges-    acid in the whole       ing ratio of     et al. 
                                         tation         lower DNA               pregnancy, lit-  (1968);
                                         embryo;        content in fetal liver; ter size; insuf- Pushkina  
                                         (females)      increase in liver       ficient number   et al. 
                                                        ascorbic acida          of dose levels   (1968) 
 
Rat     inhalation 12    3  0.012 mg/m3  10-20 days     changes in kidney and   no gross         Gofme- 
                   12    3  1 mg/m3      before ges-    liver; decrease in myo- fetal mal-       kler & 
                                         tation         cardial glycogen; dis-  formations       Bonashe- 
                                         (females)      integration of lympho-                   vskaya
                                                        cytesa; involution of                    (1969)
                                                        thymic lymphoid tissuea 
 
Rat     inhalation 15    -  0.0005       4 h/day, on    sacrifice on day 20;    none             Sheveleva 
                            mg/litre     days 1-19 of   increase in number of                    (1971) 
                   15    -  0.005        gestation      preimplantation deaths; 
                            mg/litre                    no external malfor-
                                                        mations; offspring of 6 
                                                        dams delivered on day 
                                                        22; at one-month post-
                                                        partum, females, but 
                                                        not males, were shorter; 
                                                        decrease in mobility of 
                                                        females 
---------------------------------------------------------------------------------------------------------

                                   
 
Table 33 (contd). 
---------------------------------------------------------------------------------------------------------

Rat     combined   6     3b 0.005 mg/    6 months;      no adverse effects on   no information   Guseva  
        inhalation          litre and    water; 4 h,    reproduction; decrease  concerning       (1972)
        and in-    -     -  0.12 mg/m3;  5 times/week   in the amount of        macroscopic exa-
        gestion             0.01 mg/litre               nucleic acid in the     mination of 
                            and 0.25 mg/                testes                  offspring 
                            m3; 0.1 mg/ 
                            litre and 
                            0.5 mg/m3 
 
Rat     inhalation 334      0.4 mg/m3    4 h/day for    decrease in suscepti-   female rats;     Sanotskii 
                   in 12    6 mg/m3      20 days        bility to adverse ef-   other chemicals  et al.  
                   groups                               fects on pregnant rats  also tested be-  (1976)
                                                        (compared with non-     side formaldehyde 
                                                        pregnant rats); altered 
                                                        renal and hepatic func-
                                                        tiona, decrease in 
                                                        blood haemoglobina 
 
Dog     ingestion 9-11   -  125 mg/kg    4 days after   no adverse findings     dams delivered   Hurni &  
                            (125 ppm)    mating to                              naturally        Ohder 
                            375 mg/kg    day 56                                                  (1973)
                            (375 ppm) 
 
Rat     ingestion 16     16 0.16% HMT    parents: from  no adverse findings     dams delivered   Natvig  
                                         2 to 5 months                          naturally        et al. 
                                         of age; off-                                            (1971)
                                         spring: from 
                                         birth to 123 
                                         days of age 
 
Rat     ingestion 12     6  1%  HMT in   start: at 8    no adverse findings     body weight of   Della       
                            drinking-    weeks of age                           treated ani-     Porta   
                            water        during preg-                           mals was less    et al.
                                         nancy and nurs-                        than controls    (1970)
                                         ing F1 treated 
                                         until 20 weeks 
                                         post-partum 
---------------------------------------------------------------------------------------------------------

                                   
 
Table 33 (contd). 
---------------------------------------------------------------------------------------------------------
Species Route of   Number   Dosage       Time of        Effects on offspring/   Remarks          Refer-     
        exposure  of animals             treatment      reproduction                             ence
                 Female Male 
---------------------------------------------------------------------------------------------------------
 
Rat     ingestion  2     1  1% HMTc      F1, F2, and    no adverse findings     small number of  Della       
                                         F3; 2.5 years                          animals; only    Porta   
                                                                                one dose level   et al.
                                                                                                 (1970)
Rat     ingestion  5        2% HMTc      P and F1; 2.5  no adverse findings     no control       Della  
                                         years                                                   Porta
                                                                                                 et al.
                                                                                                 (1970)
Mouse   stomach   34     -  74 mg/kg     days 6-15 of   no malformations;                        Marks  
        tube                per day;     gestation      toxic for 22/34a                         et al. 
                            148 mg/kg                                                            (1980)
                            per day; 
                            185 mg/kg 
                            per day 
 
Mouse   stomach    -     7  100 mg/kg    5 days         no effects on sperm     a total of 500   Ward 
        tube                                                                    sperm per rat    et al.  
                                                                                were evaluated   (1984)
 
Hamster dermal    22        0.5 ml of    day 8, 9, 10,  increased resorp-       total of 259     Overman  
                            37% formal-  or 11 of       tions, but no effects   fetuses in 22    (1985)
                            dehyde sol-  gestation      on fetal weight or      litters 
                            ution (but                  length and no mal-
                            no infor-                   formations 
                            mation on 
                            amount 
                            absorbed) 
---------------------------------------------------------------------------------------------------------

a       Only after exposure to the high dose. 
b       Female untreated, male treated. 
c       Hexamethylenetetramine (HMT) (from which formaldehyde is liberated  in vivo). 
    The  results  in Table 33  do not show  any evidence of  the embryo
being  unusually sensitive to formaldehyde, and there is no information
to show that formaldehyde is teratogenic in rodents  when  administered
orally  or applied dermally in non-toxic amounts to the dams.  Further-
more, the data do not provide any evidence indicating that formaldehyde
causes  terata at exposure  concentrations that are  not toxic for  the
adult.

8.7  Mechanisms of Carcinogenicity

8.7.1  Reactions with macromolecules

    Formaldehyde  reacts  readily with  a  variety of  cellular nucleo-
philes,  including  glutathione,  forming adducts  of varying stability
(Feldman, 1973; Uotila & Koivusalo, 1974; McGhee & von  Hippel,  1975).
The glutathione adduct of formaldehyde is the true substrate of formal-
dehyde  dehydrogenase,  which catalyzes  the  oxidation of  the  adduct
to S-formyl-glutathione  (Uotila & Koivusalo, 1974).  Reaction products
with  DNA,  which have  been  demonstrated  in vitro ,  include  adducts
(McGhee  & von Hippel, 1975a,b) and DNA protein cross-links (Brutlag et
al., 1969; Doenecke, 1978; Ohba et al., 1979).

    Investigations  in rats exposed to  formaldehyde through inhalation
have  shown that  formaldehyde induces  the formation  of  DNA  protein
cross-links  in the nasal respiratory  mucosa  in vivo (Casanova-Schmitz
&  Heck,  1983; Casanova-Schmitz  et  al., 1984).   The  concentration-
response  curve  for  DNA  protein  cross-linking  was  sublinear below
7.2 mg/m3 (6 ppm)   but  apparently  linear  at  higher  concentrations
(Casanova-Schmitz  et  al., 1984).   In  rats depleted  of glutathione,
either by simultaneous exposure to acrolain (Lam et al., 1985) or by ip
injection  with phorone (2,6-dimethyl-2,5-heptadien-4-one)  (Casanova &
Heck, 1987) a significant increase in the yield of formaldehyde-induced
DNA  protein cross-links was observed, suggesting that the formaldehyde
dehydrogenase-catalyzed  oxidation  of  formaldehyde  is  an  important
defence  mechanism against the  covalent binding of  formaldehyde  with
nucleic acids in the nasal respiratory mucosa.

    DNA  protein cross-links could not  be detected in the  bone marrow
of rats exposed to formaldehyde through inhalation (Casanova-Schmitz et
al.,  1984; Casanova &  Heck, 1987), suggesting  that these are  formed
only at the site of entry.  Minini (1985) found DNA protein cross-links
in  the  stomach  and beginning of the small intestine of rats that had
been  administered  formaldehyde  by gavage.   These  cross-links  were
detected only after the administration of a very high dose  of  formal-
dehyde (750 mg/kg, i.e., about 3/4 of the LD50)   (McGhee & von Hippel,
1975a,b).

8.7.2  Cytotoxicity and cell proliferation

    Increased  cell replication  occurs as  a result  of the  cytotoxic
effects of formaldehyde on the nasal mucosa.

    Morphological  changes (acute degeneration, swelling,  formation of
"dense bodies", and vacuoles in epithelial cells) were  described  in
the respiratory epithelium of rats after a single 6-h exposure to 18 mg
formaldehyde/m3 (Chang  et al., 1983; Swenberg et al., 1983). When such

exposure was repeated 3-5 times, ulceration was observed in the respir-
atory  epithelium in most experimental animals. After a 9-day exposure,
reparative hyperplasia and metaplasia were found. At  7.2 mg/m3,    hy-
perplasia  and  slight degenerative  changes  were still  detected.  In
contrast, morphological changes could not be proved at 0.6  and  2.4 mg
formaldehyde/m3 (Starr & Gibson, 1985).

    Further research clarified the dependence of cytotoxic  effects  on
the concentration of formaldehyde and on the length of exposure.  After
exposing  rats to 7.2 or  18 mg formaldehyde/m3 (6  or 15 ppm) for  6 h
per  day over 3 days, the  rate of incorporation of 3H-thymidine   into
the  DNA of the respiratory  epithelium, 2 h after the  end of the  ex-
posure, was increased by a factor of 20 or 10, respectively, indicating
increased cell proliferation.  On the other hand, no statistically sig-
nificant  increase in thymidine incorporation compared with that in the
controls was found in rats after exposure to 0.6 or 2.4 mg/m3   (0.5 or
2 ppm)  and in mice after exposure to 0.6, 2.4, or 7.2 mg/m3   (0.5, 2,
or  6 ppm)  for  6 h/day over  3 days.   Exposure  to  formaldehyde  at
18 mg/m3 (15 ppm)   led to thymidine incorporation being increased by a
factor of 8, in mice (Swenberg et al., 1983).

    Despite  nearly  equal doses  (concentration x time), significantly
increased effects were observed with exposure to  18 mg/m3,    (15 ppm)
for  6 h/day, 5  days/week (= 448 mg/m3 (540 ppm) x h/week)  (Kerns  et
al.,  1983)  compared  with  exposure  to  3.6 mg/m3,    for  22 h/day,
7 days/week  (= 460 mg/m3 (554 ppm) x h/week)   (Rusch  et al.,  1983).
This indicates that formaldehyde concentration is more  important  than
the accumulated dose (Swenberg et al., 1985).

    A  slight increase in cell proliferation (3H-thymidine   labelling,
18 h after the end of exposure) was observed after a single  6-h  inha-
lation  exposure  of rats  to  0.6 or  2.4 mg formaldehyde/m3 (0.5   or
2 ppm),  but not after 3 or 9 such exposures carried out on consecutive
days (Swenberg et al.,1985). In contrast, exposure to 7.2 mg/m3 (6 ppm)
6 h/day  for  1 or  3 days caused a  marked increase in  cell turnover,
which  did  not  normalize as it did after exposure to 0.6 or 2.4 mg/m3
(0.5 or 2 ppm).

    The  results of recent inhalation  studies have confirmed that  the
concentration  rather than  the dose  determines the  severity  of  the
cytotoxic effects.  In a 4-week study, Wilmer et al. (1987) showed that
there  were no appreciable differences  in the type, degree,  and inci-
dence  of nasal  lesions between  rats continuously  exposed  to  12 mg
(10 ppm)  formaldehyde/m3 (66 mg/m3     (80 ppm)/h  per day)  and those
exposed  intermittently to 12 mg/m3 (10 ppm)  (33 mg/m3 (40 ppm)/h  per
day).  Moreover, intermittent exposure of rats to  12 mg/m3    (10 ppm)
(33 mg/m3 (40 ppm)/h   per day)  induced more severe nasal changes than
continuous  exposure  to 6 mg/m3 (also   48 mg/m3 (40 ppm)/h  per day).
From a subsequent 13-week study (Wilmer et al., 1986), it appeared that
hyperplasia and metaplasia of the nasal respiratory epithelium occurred
in  rats intermittently exposed to 4.8 mg/m3 (13 mg/m3 (16 ppm)/h   per
day) but did not occur in rats continuously exposed to 2.4 mg/m3 (2 ppm)
(also 13 mg/m3 (16 ppm)/h  per day).  In a 28-month  inhalation  study,
male  rats with severely  damaged (by electrocoagulation)  or undamaged
nasal  mucosa were  exposed to  formaldehyde concentrations  of  up  to

12 mg/m3 (10 ppm);   exposure to 12 mg/m3 (10 ppm)  resulted  in a much
higher incidence of nasal tumours in rats with a damaged mucosa (17/60)
than in rats with an undamaged nose (1/29)  (Feron et al., 1987).

    Small ultrastructural changes were reported in the cell membrane of
nasal ciliated epithelial cells of rats exposed to formaldehyde through
inhalation  (Monteiro-Riviere & Popp, 1986).  Similar changes were also
found in the controls, but the significance is unclear.

9.  EFFECTS ON MAN

9.1  Sources of Exposure

    The  general population may be  exposed to formaldehyde in  tobacco
smoke,  automobile  emissions, from  materials  used in  buildings  and
home  furnishings, in consumer  and medicinal products,  and in  nature
(section 3).

9.2  General Population Exposure

    A  large  number of  occupations  are associated  with formaldehyde
exposure (Tables 4 and 34).

Table 34.  Potential occupational exposure to formaldehydea 
----------------------------------------------------------------------------- 

Anatomists                           Glass etchers 
Agricultural workers                 Glue and adhesive makers 
Bakers                               Hexamethylenetetramine makers 
Beauticians                          Hide preserversb         
Biologists                           Histology technicians (assumed to 
Bookbinders                           including necropsy and autopsy 
Botanists                             technicians) 
Carpenters                           Ink makers 
Crease-resistant textile             Lacquerers and lacquer makers 
 finishers                           Medical personnel (assumed to include 
Deodorant manufacturers               pathologists) 
Disinfectant manufacturers           Mirror makers 
Disinfectors                         Oil-well workers 
Dress shop personnel                 Paper makersb 
Dressmakers                          Particle board makersb 
Drugmakers                           Pentaerythritol makers 
Dyemakers                            Photographic film makers 
Electrical insulation makers         Plastic workers 
Embalmers                            Resin makers 
Embalming fluid makers               Rubber makersc 
Ethylene glycol makers               Soil sterilizers and greenhouse 
Fertilizer makers                     workers 
Fire-proofers                        Surgeons 
Formaldehyde resin makers            Tannery workersb 
Formaldehyde employees               Taxidermists 
Foundry employees                    Textile mordanters and printers 
Fumigators                           Textile waterproofers 
Fungicide workers                    Varnish workersb 
Furniture workers                    Wood-based material workers 
Fur processorsb                      Zoologists 
----------------------------------------------------------------------------- 

a From: NIOSH (1976a). 
b See IARC (1981). 
c See IARC (1981). 
 
    The  most  predominant  effects of  formaldehyde  exposure  usually
reported  in  human  beings are  various  kinds  of  physical  symptoms
emanating  from the  irritation of  the mucosa  in the  eyes and  upper
airways  as well as the sensitivity of the skin.  Sensory reactions are
apparently  the  most  typical  effects  in  the  non-industrial indoor
environment.   Most human beings are  exposed to low concentrations  of
formaldehyde  (less than 0.06 mg/m3)    in the environment  and sensory
effects  (odour and irritation)  are by far  the most common  response;
symptoms  of hyperactivity in the  lower respiratory tract may  also be
produced.

    It  should be realized  that extrapolation from  animal studies  to
estimate human response is dubious in most cases and, for some effects,
impossible.  Although some effects, e.g., skin reactions may be compar-
able between animals and human beings, other effects, such as pulmonary
function reactions, are more questionable and others, such  as  sensory
irritation, cannot be compared.

9.2.1  Sensory effects

    The  odour of formaldehyde  is detected and/or  recognized by  most
human  beings at concentrations below  1.2 mg/m3 (1 ppm)  (Leonardos et
al.,   1969;  Gemert &  Nettenbreijer,  1977; Fazzalari,  1978; Brabec,
1981).  The absolute odour threshold is defined as the concentration at
which a group of observers can detect the odour in 50% of  the  presen-
tations  (from a series of concentrations) (WHO, 1987) and, for formal-
dehyde,  it has been shown to be between 0.06 and 0.22 mg/m3   (Feldman
& Bonashkevskaya, 1971; Berglund et al., 1985, 1987; Ahlström  et  al.,
1986).  However, the individual odour detection thresholds cover a wide
concentration  range, over two powers  of ten, and the  distribution is
extremely   positively skewed.  Berglund et al. (1987) showed that over
a  period of one year,  the odour detection and  odour strength reports
for  formaldehyde were consistent for  a group of 10  observers.  For a
group of 50 observers, they also showed that the  50-percentile  detec-
tion  threshold  for formaldehyde  odour  (ED50,   method  of  constant
stimuli including blanks) was 180 µg/m3 (145    ppb), the 10-percentile
(ED10)    threshold  was  25 µg/m3 (20 ppb),    and  the  90-percentile
(ED90) threshold was 600 µg/m3 (500 ppb).

    If  formaldehyde  is  mixed with  contaminated  indoor  air from  a
"sick" building, an increase in the odour intensity of  the  stimulus
mixture   is  found  at   formaldehyde  concentrations  of   less  than
0.25 mg/m3 while,  at higher concentrations, the odour strength remains
largely unchanged (Ahlström et al., 1986). At high concentrations, for-
maldehyde has a distinct and pungent odour.

    The  difference between odour  and irritation concentration  may be
noticeable, but there is no evidence that there is a threshold at which
odour is superceded by irritation.  However, for most  inhaled  odorous
compounds,  the trigeminal nerve has a higher threshold than the olfac-
tory nerve (Moncrieff, 1955).  When the formaldehyde  concentration  is
increased  and affects both  the eyes and  the nostrils, sensory  irri-
tation is first experienced in the eyes, then the odour  is  perceived,
and finally nasal irritation occurs (Moncrieff, 1955).

    In  recent studies with  short-term exposures, eye  irritation  was
reported for formaldehyde from a level of 0.06 mg/m3 and  irritation of
the respiratory tract, from 0.12 mg/m3 (Niemelä  & Vainio,  1981;  NRC,
1981).   Clinical and epidemiological data  show substantial variations
in  individual irritant responses to formaldehyde.  The sensory effects
of  formaldehyde determined for odour and sensory irritation are listed
in Table 35. The table only lists the reports that have included infor-
mation on reasonable experimental control.  In evaluating the different
studies,  it should be noted  that many of the  reported elevated lower
limit values for sensory irritation emanate from studies in  which  the
observers were not exposed to very low concentrations  of  formaldehyde
or clean air was not included as the control condition.

    Anderson (1979) showed that eye, nose, and throat  irritation  were
reported by 3 of 16 observers exposed for 5 h daily to 0.288 mg formal-
dehyde/m3 and   by  15 of  16 observers  exposed to  0.96 mg/m3 in   an
environment  chamber.  A direct relationship  between concentration and
sensory  irritation was observed only above 0.96 mg/m3 and  only at the
highest  concentration, 1.92 mg/m3,   was slight discomfort experienced
(18 on  a scale of 100).  Bender et al. (1983) evaluated eye irritation
according  to the time of detection of the first trace of irritation as
well  as according to  subjective ranking of  severity.  Both time  and
severity  appeared  to  be  functions  of  formaldehyde  concentration;
severity  of response was above  "slight" only with the  highest test
concentration of 1.2 mg/m3 (28 observers).

    In  a  study  by Cain et al. (1986), a group of 33 observers judged
the  perceived  irritation  and  odour  of  formaldehyde  during 29-min
chamber  exposures  to concentrations  ranging  from 0.3  to 2.4 mg/m3.
The sensory irritation increased with time for the lower concentrations
and decreased with time for the highest. This effect was true for irri-
tation  of eyes,  nose, and  throat and  the sensitivity  proved to  be
roughly  equal  for all  three sites.  The  sensory irritant effect  of
formaldehyde  at 1.2 mg/m3   was  shown to decrease  when the  chemical
pyridine was injected into the chamber; such sensory interactions occur
in  environmentally realistic situations  (see Ahlström et  al., 1986).
Apart from Cain et al. (1986), Weber-Tschopp et al. (1977)  and  Bender
et  al.  (1983)  have shown  sensory  adaptation  to occur  with longer
exposure durations.

    Weber-Tschopp   et  al.  (1977) exposed healthy volunteers (24 men,
9 women)  to  formaldehyde  concentrations ranging  between  0.036  and
4.8 mg/m3 air   (33 volunteers for 35 min, 48 volunteers  for 1.5 min).
Eye blinking rates as well as subjective irritation effects were deter-
mined.   The irritation threshold  was found to  range between 1.2  and
2.4 mg formaldehyde/m3.    A similar threshold (1 mg/m3)   was found in
other studies (BGA, 1985). Triebig et al. (1980)  noted that 9  out  of
53 medical student volunteers exposed to formaldehyde concentrations of
between  0.39 and 0.60 mg/m3 for  8 h/week, over 8 weeks, complained of
headaches,  a burning sensation in the eyes, sore throat, and annoyance
because of the smell.

    Formaldehyde  has been identified as one of the chemical components
of photochemical smog.  However, photochemical smog is a  complex  mix-
ture of chemicals in which not all the components have been identified.

Schuck  et al. (1966) showed  that eye irritation appeared  at 0.012 mg
formaldehyde/m3,     but  the  formaldehyde   had  been  generated   by
irradiating  ethylene  or  propylene-nitrogen  dioxide  mixtures.   The
authors  noted that irritating components other than formaldehyde, such
as peroyzlacyl nitrate, which is also a potent sensory irritant present
in  photochemical  smog, may  have  been generated  during irradiation.
Since  formaldehyde usually appears  in complex mixtures  in the  human
environment  (automobile  exhaust,  photochemical smog,  tobacco smoke,
contaminated  indoor  air), it  is evident that  the mixture may  cause
sensory  irritation at much lower formaldehyde concentrations than when
formaldehyde is present alone. For example, Weber-Tschopp et al. (1976)
showed  that,  during  29-min chamber  exposures,  formaldehyde concen-
trations  of  0.3 mg/m3 in  a  tobacco  smoke environment  resulted  in
moderate, strong, or very strong eye irritation.

    It  has been shown  that sensory irritation  is the earliest  human
reaction  to formaldehyde, both in exposure studies and from complaints
about  indoor environments.   An expert  committee at  the US  National
Academy  of Sciences (NRC,  1980) calculated that  less than 20%  of an
exposed  human population would react  to concentrations of  less  than
0.3 mg/m3 with   slight  sensory  irritation  of  the  eyes,  nose, and
throat,   and  possibly  also  with   a  slight  decrease  in   mucosal
secretion/flow  in the nose (Newell, 1983).  Since differences in indi-
vidual  reactions to formaldehyde  are large in  both the normal  popu-
lation  and in hyperreactive and sensitized persons, it is difficult to
estimate a concentration guaranteed not to produce  negative  reactions
in the general population.


Table 35.  Sensory effects of formaldehyde on man 
---------------------------------------------------------------------------------------------------------
Type of   Exp.      Method   Site  Conc.     (No. stim-   Length   No.     Irritant   Effect      Refer-
exposure  control                  range     uli) conc.     of     volun-  and odour              ence 
                                   mg/m3     in air      stimulus  teers   detection 
                                   (ppm)     mg/m3 (ppm)           (sex)   (d) thres-
                                                                           holds mg/m3 
                                                                           (ppm) 
---------------------------------------------------------------------------------------------------------

30-m3        -      Constant  Eye  0.04-4.8    (4) 
chamber             stimuli        (0.03-4)  0.04; 1.2;  1 1/2     35 (M)  1.2-2.4    Eye         Weber-
                                             2.4; 3.6;   min       13 (F)  (1-2 ppm)  irritation  Tschopp 
                                             4.8 (0.03;  (short                                   et al. 
                                             1; 2; 3; 4) exposure)                                (1977) 
---------------------------------------------------------------------------------------------------------
30-m3        -      Constant  Eye  0.04-4.8    (4) 
chamber             stimuli        (0.03-4)  0.04; 1.2;  37 min    24 (M)  1.2-2.4    Eye         Weber-
                                             2.4; 3.6;   (long      9 (F)  (1-2 ppm)  irritation  Tschopp 
                                             4.8 (0.03;  continuous                               et al. 
                                             1; 2; 3; 4) exposure)                                (1977) 
---------------------------------------------------------------------------------------------------------
17-m3 alu-   -      Constant  Eye  0.01-1.2    (5)       6 min     5-28    0.46-1.1   Slight eye  Bender 
minium smog         stimuli        (0.01-1)  0; 0.4; 0.7;                  (0.38-0.9  irritation  et al. 
chamber                                      0.8; 1.1; 1.2                 ppm)                   (1983) 
equipped                                     (0; 0.35;                     1.2 (1.0   Severe eye 
with 7                                       0.56; 0.7;                    ppm)       irritation 
sets of                                      0.9; 1.0)             
eye ports 
---------------------------------------------------------------------------------------------------------
Chamber   23 ± 0.5  Constant  Eye  0.3-2.0     (4)       5 min             1.0        Eye, nose   Andersen & 
          °C        stimuli   throat         0.3; 0.5;             11 (M)             and throat  Mölhave 
          50 ± 5% RH          nose           1.0; 2.0               5 (F)             irritation  (1983) 
---------------------------------------------------------------------------------------------------------
Exposure  22 + 1    Limit          0.06-1.15   (7)       6 second          0.06                   Ahlström 
hood      °C        with                     0.06; 0.10;            8 (M)  (50% d)        -       et al. 
          Pyridine  forced    nose           0.17; 0.28;           14 (F)  0.20                   (1986) 
          as master choice                   0.46; 0.77;                   (100% d)
          stimulus  responses                1.15 
---------------------------------------------------------------------------------------------------------


9.2.2  Toxic effects

    The clinical features of toxicity are weakness, headache, abdominal
pain,  vertigo, anaesthesia, anxiety, burning sensation in the nose and
throat, thirst, clammy skin, central nervous system  depression,  coma,
convulsions,  cyanosis, diarrhoea, dizziness, dysphagia, irritation and
necrosis  of  mucous  membranes and  gastrointestinal  tract, vomiting,
hoarseness,  nausea,  pallor,  shock, and  stupor.   Respiratory system
effects  caused  by  high formaldehyde  concentrations  are  pneumonia,
dyspnoea,  wheezing,  laryngeal  and  pulmonary  oedema,  bronchospasm,
coughing  of frothy fluid, respiratory depression, obstructive tracheo-
bronchitis,  laryngeal  spasm,  and sensation  of  substernal pressure.
Coagulation  necrosis  of  the skin,  dermatitis  and hypersensitivity,
lachrymation and corrosion of the eyes, double vision,  and  conjuncti-
vitis  can occur.   Acute ingestion  may cause  renal injury,  dysuria,
anuria,  pyuria,  and haematuria,  and lead to  an increase in  formate
levels  in the urine.   Death is due  to pulmonary oedema,  respiratory
failure,   or  circulatory  collapse  (Hallenbeck  &  Cunningham-Burns,
1985).

    Kline (1925) reported 12 cases where ingestion of  formaldehyde  (a
few drops to 89 ml of concentrated solution) led to death.  The largest
amount  ingested from which a  patient has recovered is  120 ml.  A 60-
year-old man swallowed 60-90 ml of a 40% formaldehyde solution.  Thirty
hours  after  death, the  mucosa of the  lower part of  the oesophagus,
stomach,  and first portion  of duodenum were  dark chocolate brown  in
colour  and of the consistency  of leather.  All organs  and tissues in
contact  with the stomach  were "hardened" to  a depth of  about 8 mm
(Levison, 1904).

    Allen  et al. (1970) reported corrosive injuries of the stomach due
to formaldehyde ingestion.

9.2.3  Respiratory effects

    No cases of death from formaldehyde inhalation have been published.
There  are numerous reports that exposure to formaldehyde vapour causes
direct irritation of the respiratory tract.  However,  precise  thresh-
olds  have  not been  established for the  irritant effects of  inhaled
formaldehyde  but,  within the  range  of 0.1-3.1 mg/m3,    most people
experience irritation of the throat (Table 35).

    The  effects of formaldehyde  on ciliary movement  and  mucociliary
clearance  were studied by  Andersen & Mölhave  (1983).  They  measured
nasal  mucociliary flow by external detection of the motion of a radio-
labelled  resin particle placed on  the surface of the  inferior turbi-
nate.  The nasal mucous flow rate in the nose decreased during exposure
to  formaldehyde, but the response  did not increase at  concentrations
ranging  from 0.5 mg/m3 to  2 mg/m3 or  on prolongation of the exposure
period from 3 h to 5 h.

    The  potential of formaldehyde to produce chronic respiratory tract
disease  was studied by Yefremov  (1970).  At a wood-processing  plant,
the  incidence of chronic upper  respiratory disease was higher  in 278

workers  exposed to formaldehyde than in 200 controls. However, formal-
dehyde  concentrations were not measured, and possible confounders were
not evaluated.

    Forty-seven  subjects  exposed  to formaldehyde  (mean  air concen-
tration  0.45 mg/m3)    and 20 unexposed  subjects,  all of  whom  were
employed  at  a carpentry  shop, were studied  by Alexandersson et  al.
(1982)  with  regard  to  symptoms  and  pulmonary  function.  Symptoms
involving the eyes and throat as well as chest oppression were signifi-
cantly  more  common  in the  exposed  subjects  than in  the unexposed
controls.   Spirometry and simple  breath nitrogen washout  were normal
on  the Monday morning, before exposure to formaldehyde.   A  reduction
in  forced expiratory volume  in 1 second by  an average of  0.2 litres
(P = 0.002),    percent forced expiratory  volume by 2%  (P =    0.04),
maximum  mid-expiratory  flow  by 0.3 litre/second  (P = 0.04)   and an
increase  in  closing volume  in percentage of  vital capacity by  3.4%
(P = 0.002)    were seen after  a day of  work and exposure  to formal-
dehyde,   suggesting   bronchoconstriction.   Smokers   and  nonsmokers
displayed similar changes in spirometry and nitrogen washout.

    Schoenberg  &  Mitchell  (1975) performed  standardized respiratory
questionnaire and  pulmonary function tests (FVD, FEV1,   MEF  50%)  on
63 employees in an acrylic-wool filter department (40  production  line
workers,  8 former production line  workers, and 15 employees  who  had
never  been on the production  line).  Formaldehyde levels in  the work
environment  were between 0.5 and 1 mg/m3,   and phenol levels, between
7  and 10 mg/m3;   particles and  fibres were not well  suppressed.  In
spite  of the high proportion (85%) of subjects reporting acute respir-
atory  symptoms,  only small  and  insignificant changes  in  pulmonary
function were found.

    Andersen & Mölhave (1983), in a study of 16 healthy volunteers in a
chamber,  could  not  find any  increase  in  airway resistance  or any
effects  on vital  capacity and  maximum expiratory  flow  volume  from
exposure to formaldehyde levels of up to 2.0 mg/m3 in a 5-h study.

    To  study pulmonary function during  and after exposure to  formal-
dehyde, Schachter et al. (1986) exposed 15 non-smoking  healthy  volun-
teers  (mean age, 25.4 years) in  a double-blind random manner  to 0 or
2.4 mg formaldehyde/m3,   for 40 min on one day and again on  a  second
day  but with the  subjects performing moderate  exercise (450 kpm/min)
for 10 min. No significant bronchoconstriction was noted (FEV1   test),
and  subjective  complaints following  such  exposure were  confined to
irritative  phenomena of the upper airways.  Post-exposure symptoms (up
to 24 h following exposure) were infrequent and confined  to  headache.
Another  study  by  the same  group  (Witek  et  al.,  1986,  1987)  on
15 healthy and 15 asthmatic volunteers resulted in similar findings.

    Main  & Hogan (1983)  examined 21 subjects exposed  to formaldehyde
(0.14-1.9 mg/m3)   in a mobile home trailer.  Eighteen  unexposed  con-
trols were included. No differences in lung function were found between
the 2 groups.  However, there were significantly more complaints of eye
and throat irritation, headache, and fatigue among the exposed.

    In controlled studies, Day et al. (1984) exposed  18 volunteers  to
a  formaldehyde concentration of  1.2 mg/m3.    Nine subjects  had pre-
viously  complained of various non-respiratory adverse effects from the
urea  formaldehyde foam insulation  (UFFI) in their  homes.   Pulmonary
function  was assessed before and after exposure in a laboratory.  Each
subject   was  exposed,  on  separate  occasions,  to  formaldehyde  at
1.2 mg/m3 in   a environmental chamber for  90 min and to UFFI  off-gas
yielding  a formaldehyde concentration of 1.4 mg/m3 in  a fume hood for
30 min.   None of the  measures of pulmonary  function used showed  any
clinically  or  statistically  significant responses  to  the  exposure
either  immediately or 8 h after, commencement of exposure.  There were
no statistically significant differences between the responses  of  the
group  that  had previously  complained of adverse  effects and of  the
groups that had not.  There was no evidence that either formaldehyde or
UFFI off-gas behaved as a lower airway allergen or  important  broncho-
spastic irritant in this heterogeneous population but, because  of  the
small number of persons under study, it cannot be excluded.

    Fifteen  non-smoking volunteers (mean age, 25.1 years) who suffered
from  substantial bronchial hyperreactivity, were studied by Harving et
al.  (1986).  The mean provocation concentration of histamine producing
a 20% decrease (PC20)   in peak expiratory flow rate  was  0.37 g/litre
(standard  deviation (SD) = 0.36).   All  except one  patient regularly
required   bronchodilator  treatment.   None  used  methylxanthines  or
corticosteroids.  They were exposed to formaldehyde once a week  for  3
consecutive  weeks.  The  studies were  carried out  in a  double-blind
random  fashion, under controlled conditions, in a climate chamber with
particle-free  air.  All underwent the same 3 treatments, being exposed
to   mean  formaldehyde  concentrations  of  0.85 mg/m3    (SD = 0.07),
0.12 mg/m3 (SD = 0.07),  and zero.  The mean exposure time at a steady-
state concentration was 89.4 min (SD = 9.5).  Bronchodilator drugs were
withheld  for 4 h before the  studies.  During the exposure,  each par-
ticipant rated his symptoms of asthma every 15 min on a visual analogue
scale,  and forced expiratory  volume in one  second was measured  on a
spirometer every 30 min.

    Before  and  after  exposure to  formaldehyde,  functional residual
capacity  and airways  resistance were  determined in  a body  plethys-
mograph,  and  flow-volume  curves were  measured.   Immediately  after
exposure, a histamine challenge test was performed.

    No significant changes in forced expiratory volume in  one  second,
airways resistance, functional residual capacity flow-volume curves, or
subjective ratings of symptoms of asthma were found in the group  as  a
whole,   or  among the  9 participants  with high  histamine reactivity
(PC20 < 0.50 mg/ml).    Histamine challenge tests were highly reproduc-
ible and were unaffected by exposure to formaldehyde.   No  appreciable
symptoms were reported after exposure.

    Asthma-like  symptoms have been elicited by irritant concentrations
of  formaldehyde.  Precise thresholds have not been established for the
irritant  effects of inhaled  formaldehyde.  However, lower  airway and
pulmonary effects are likely to occur between 6 and  36 mg/m3,    inde-
pendent of confirmed sensitization.

    Several  studies have  addressed the  problem of  the  mobile  home
situation,  especially in Canada and  the USA, without measurements  of
other confounders (section 9.2.8).

9.2.4.  Dermal, respiratory tract, and systemic sensitization

    Formaldehyde is a known sensitizer for the skin (DFG, 1987), but no
thresholds  for  induction of  dermal,  respiratory tract,  or systemic
sensitization have been reliably determined.

9.2.4.1  Mucosal effects

    Wilhelmsson  &  Holmström  (1987) investigated  possible mechanisms
underlying  nasal  symptoms  in 30 formaldehyde-exposed  workers  in  a
factory  producing  formaldehyde.   The mean  concentration of airborne
formaldehyde was somewhat below 1 mg/m3,   but there were  higher  peak
values.  About 40% of the workers had rhinitis with  nasal  obstruction
and discharge associated with the work place.  The sera of the subjects
were analysed for IgE antibodies by RAST and 2 workers were found to be
positive with a high level of IgE.

    There  is no evidence in  the literature of allergic  reactivity of
the  mucous membranes of the eyes being caused by airborne formaldehyde
or  by formaldehyde solutions.  There are only a few case reports about
asthmatic symptoms caused by formaldehyde.

9.2.4.2  Skin effects

    Allergic  sensitization is caused by formaldehyde in solution only,
not by gaseous formaldehyde. Prolonged and repeated contact with liquid
solutions  can cause skin  irritation or allergic  contact  dermatitis,
including sensitization. It is not known whether dermal reactions occur
in human beings from airborne exposure to formaldehyde.

    Formaldehyde  allergy may be associated  with the use of  disinfec-
tants,  formaldehyde-based plastics, and contact  with textiles impreg-
nated with formaldehyde-based resins. Patch-test studies with different
concentrations  of  formaldehyde  have shown  that concentrations below
0.05% rarely elicit an allergic reaction, even in sensitive individuals
(Schulz,  1983).  Marzulli & Maibach (1973) reported that one of 5 sen-
sitized volunteers reacted, under controlled conditions, to a challenge
concentration of 0.01% formaldehyde.

    Formaldehyde  solution is a primary skin-sensitizing agent inducing
allergic contact dermatitis (Type IV, T-cell mediated delayed hypersen-
sitivity  reaction);  it  may induce  immunological  contact  urticaria
(Type I, perhaps IgE mediated, immediate hypersensitivity reaction).

    Patch tests performed with formaldehyde challenge concentrations of
1% or less resulted in positive reactions in about 2% of  all  patients
tested  throughout  the  world; higher  formaldehyde  challenge concen-
trations may be irritant (Anon., 1987).

    There are geographical and demographical differences in  the  inci-
dence  of  contact  sensitivity  to  allergens.   The  Japanese Contact
Dermatitis  Research Group (1982)  published a study  dealing with  the

results of patch tests performed at 17 Japanese hospitals in  1981.   A
total  of more than  900 patients and healthy  volunteer subjects  were
patch-tested  with  2% formaldehyde  solution (10 mg formaldehyde/cm2).
This  caused irritation in 2.78% and a delayed reaction in 2.62% of the
patients.

    An allergic contact dermatitis reaction was provoked by a  dose  of
formaldehyde of 0.25 µg/cm2 skin    (challenge dose: 50 µg/cm2     with
0.5% percutaneous penetration).

    In  the past, formaldehyde dermatitis provoked by clothing textiles
was  a problem in certain  countries.  Modern textile finishing  agents
contain N-methylol  compounds with only low amounts of  free  formalde-
hyde,  so  that formaldehyde  allergies due to  textiles are no  longer
expected to occur (Bille, 1981; Edman & Möller, 1982).

    Contact eczema caused by formaldehyde may clear  within  1-3 weeks,
even  without treatment, when the cause has been recognized and contact
is strictly avoided.

    Allergic reactions to cosmetics containing formaldehyde as  a  pre-
servative,  especially shampoos, are unusual (Eckardt, 1966) and appear
mostly among those who have been sensitized by occupational exposure.

    In a haemodialysis unit where formalin was used as a  sterilant,  6
out of 13 staff members developed dermatitis within  3 weeks  (Sneddon,
1968); 4 of the 6 were positive in patch tests with 3% formalin.

9.2.4.3  Respiratory tract sensitization

    Well-controlled  scientific studies on allergic airway responses to
formaldehyde are few.

    Nordman  et al. (1985) gave  a total of 230 patients,  who suffered
from "asthma like" respiratory symptoms, a bronchial provocation test
with formaldehyde. On the basis of the medical and occupational histor-
ies  of the patients, the specific bronchial provocation test and other
tests results, 12 cases were considered to be caused by specific sensi-
tization to formaldehyde.

    Burge  et  al. (1985)  reported  tests on  15  formaldehyde-exposed
workers  with symptoms suggesting occupation-related asthma.  Bronchial
provocation    tests   with   a  mean   formaldehyde  concentration  of
4.8 mg/m3 (range   not given) showed 3 subjects  with delayed bronchio-
spasm  and 6 with an immediate reduction in forced expiratory volume in
one second (FEV1).

    In  a similar study on  13 patients with asthma suspected  of being
related to formaldehyde exposure, no significant drop in FEV  was  seen
when bronchial provocation tests with formaldehyde concentrations of up
to  3.6 mg/m3 were  carried out.  Five of the subjects were on broncho-
dilator treatment at the time (Frigas et al., 1984).

    Eight  cases of occupational asthma (3 smokers, 5 non-smokers) were
reported  among 28 members of the nursing staff at a haemodialysis unit
where  formalin was  used to  sterilize the  artificial kidney  machine

(Hendrick  &  Lane, 1977).   In 2 out  of 5 subjects with  histories of
recurrent  attacks  of wheezing,  inhalation  provocation tests  led to
asthmatic attacks similar to those at work.

    Hendrick et al. (1982) reinvestigated the nurses of the haemodialy-
sis unit. One nurse had not worked with formaldehyde since 1976 and had
had  no further symptoms. Her 1981 test (15-min exposure to 7.2 mg for-
maldehyde/m3)   did not provoke any asthmatic response. The other nurse
had  continued to work  with formaldehyde, though  under much  improved
conditions,  and had continued to  suffer mild intermittent attacks  of
asthma.  Her test (5-min exposure to 3.6 mg formaldehyde/m3)   provoked
a late asthmatic reaction similar to the one observed in 1975.

9.2.4.4  Systemic sensitization

    A  case report has been  described involving an anaphylactic  shock
reaction  after  accidental  iv  application  of  formaldehyde   during
haemodialysis  treatment due to formaldehyde remaining in the equipment
after  disinfection.  No measurements  of the residual  formaldehyde in
the reconditioned dialyser were given.  There was no personal or family
history  of atopy.  Prick  tests and radioallergosorbent  tests  (RAST)
with  common food and  inhalant allergens were  negative.  Prick  tests
performed  with 0.1 and 1%  formaldehyde were positive in  the patient,
whereas they were negative in control subjects. The RAST  with  formal-
dehyde  was performed using  discs specially prepared  and coated  with
serum-albumin.  RAST was strongly positive.  RAST to ethylene oxide was
negative.  A patch test with  formaldehyde (concentration 1%) was  per-
formed  and induced an anaphylactic  shock, 26 h after the  skin appli-
cation of formaldehyde.  The patient did not present  any  anaphylactic
symptoms  with the use  of non-reconditioned dialysers.   An immediate-
type  allergy to formaldehyde mediated by IgE may have occurred in this
patient  (Maurice et al., 1986).   Because, after 26 h, the  patch test
resulted  in an anaphylactic, but  not delayed allergic contact  derma-
titis, reaction, the findings seem to be contradictory.

    Wilhelmsson  &  Holmström  (1987) investigated  possible mechanisms
underlying  nasal symptoms in  30 formaldehyde workers exposed  through
inhalation  in  a formaldehyde-producing  factory.  Two cases  showed a
positive   RAST with formaldehyde with  high total IgE values  (177 and
360 kU/litre).   One of them suffered  from severe rhinitis, the  other
from  nasal and skin symptoms  associated with the work  place.  A skin
test with formaldehyde was negative at 15 min but positive at 72 h.

    Systemic  sensitization  arising  from the  release of formaldehyde
into  the circulation in chronic haemodialysis patients showed evidence
of  formaldehyde-dependent immunization.  The production  of auto-anti-
nuclear-like  antibodies was  dependent on  the length  (years) of  the
haemodialysis  treatment (Lynen et al.,  1983) and on the  formaldehyde
concentration released from the dialysers (Lewis, 1981).

    Auto-anti-nuclear-like  antibodies  were  found  in  5  out  of  18
patients  after  1 year of  dialysis; 10 out  of 12 patients after  3-5
years, and in all 9 patients exposed to formaldehyde  through  dialysis
for more than 5 years (Lynen et al., 1983).

    Auto-anti-nuclear-like  antibodies  were  observed in  30%  of  the
patients  when  the  formaldehyde concentration  in  the  rinse of  the
dialysers  was 8 mg/litre (8 ppm); however, the incidence was zero at a
concentration of 0.6-1.2 mg/litre (Lewis et al., 1981).

    The  presence  of auto-anti-nuclear-like  antibodies and autoimmune
haemolytic  anaemia are evidence of  Type II autoallergy.  Some  severe
asthmatic reactions suggest Type I allergy in dialysis patients.

    Pross  et al. (1987),  using a wide  range of immunological  tests,
studied  the  effects of  controlled  short exposures  to formaldehyde.
They  found a minimal increase  in the percent eosinophils,  basophils,
and T8 positive cells and a reduction in the response of natural killer
cells to low-dose human alpha-Interferon.   According to the  authors,  the
meaning  of  these  minimal,  but  statistically  significant,  changes
remains unclear.

    The  antigenicity  of  formaldehyde-treated proteins  were reported
70 years ago by Landsteiner & Lample (1917).  A study by  Patterson  et
al.   (1986)   demonstrated  that  sera  of  human  beings  exposed  to
intravenous  formaldehyde  during  dialysis,  contained  antibodies  of
various  immunoglobulin classes against  formaldehyde-serum-albumin, as
did  sera of two dialysis nurses with histories of formaldehyde-induced
asthma.

9.2.4.4.1  Allergic reaction following the dental use of paraformaldehyde

    Adverse  reactions have  been reported  following the  use of  root
canal  filling materials containing paraformaldehyde.  The extrusion of
a root canal sealant containing paraformaldehyde beyond the apex may be
followed  by an allergic reaction in sensitive individuals.  The number
of  cases is  very small  in relation  to the  extensive  use  of  such
materials.   However, 3 cases of  allergic angiooedema in  response  to
periapical   paraformaldehyde  have  recently  been  reported  (UK-CSM,
1987).

9.2.5  Skin Irritation

    Primary  toxic or irritative  skin reactions occur  through  direct
contact with formaldehyde solutions.

    The concentration of aqueous formaldehyde solution causing irritant
contact  reactions after application  on human skin  has not been  con-
firmed.  For human skin, a single application of 1% formalin  in  water
with occlusion will produce an irritant response in approximately 5% of
the population (Maibach, 1983).

    Cosmetics containing a formaldehyde concentration of 0.2% as a pre-
servative and nail hardeners containing at least 5%  formaldehyde  did
not provoke toxic or irritative contact reactions on normal skin.

    Other  reactions may  occur in  cases of  previously  damaged  skin
surfaces and/or atopic individuals.

    There  are observations but  no published experimental  or clinical
findings  confirming the induction  of irritant contact  dermatitis  by
gaseous formaldehyde (Axelson, 1987, Personal Communication).

9.2.6  Genotoxic effects

    Studies on pathology staff, occupationally exposed to formaldehyde,
failed  to demonstrate  any increase  in the  incidence of  chromosomal
aberrations  or the frequency of sister chromatid exchanges (Thomson et
al.,  1984).  Similarly, there  were no increases  in the incidence  of
chromosomal aberrations in workers exposed to formaldehyde  during  its
manufacture and processing (Fleig et al., 1982), or in the incidence of
sister  chromatid exchanges  in workers  exposed to  formaldehyde in  a
paper factory (Bauchinger & Schmid, 1985).

    Yager  et al.  (1986) reported  an increased  incidence  of  sister
chromatid exchanges in anatomy students, but the values  reported  fell
within the normal range.   Furthermore, the authors reported  that  the
subjects  were  in  a "stress situation" at the time of the study and
were  also exposed  to other  agents, including  phenol.  Bauchinger  &
Schmid  (1985)  reported an  increased  incidence of  chromosomal aber-
rations  in  a  study of workers in a paper factory who were exposed to
formaldehyde;  the statistical methods  used and the  relevance of  the
types  of aberrations found  have been questioned  (Engelhardt et  al.,
1987).

    No  increase was  found in  the mutagenicity  of urine  of  autopsy
workers  exposed to formaldehyde  (Corren et al.,  1985).  Ward et  al.
(1984) did not observe any effects on sperm morphology or  sperm  count
attributable to formaldehyde.

    Goh  & Cestero (1979) studied  chromosomal patterns of direct  bone
marrow  preparations  from  40 patients  undergoing  maintenance haemo-
dialysis.   Aneuploidies,  chromosomal  structure  abnormalities,   and
chromosomal  breaks were seen in  the metaphase.  During the  period of
this  study, each  patient could  have received  up to  126 ± 50 mg  of
formaldehyde during each dialysis.

9.2.7  Effects on reproduction

    Shumilina  (1975)  reported  an increased  incidence  of  menstrual
disorders,  mainly dysmenorrhoea, and  problems with pregnancy  in  446
women workers using urea-formaldehyde resins (130 exposed to work-place
formaldehyde   concentrations  of  1.4-4.3 mg/m3 and   316  exposed  to
concentrations  of 0.005-0.67 mg/m3).    There  were no differences  in
fertility between the exposed and control group, but anaemia, toxaemia,
and  low birth weight  of offspring were  more frequent in  the exposed
group.   However, possible confounding  factors were not  evaluated  in
this study.  There is a lack of information on the workers' environment
and the socioeconomic conditions of the study and control groups.

    Hemminki  et al. (1982,  1983) studied spontaneous  abortions among
hospital staff engaged in sterilizing instruments with chemical agents.
They  reported that  there was  no increase  in  spontaneous  abortions
associated with the use of formaldehyde.

    In  a population of  hospital autopsy service  workers, 11  exposed
individuals  and 11 matched  controls were evaluated  for sperm  count,
abnormal sperm morphology, and 2F-body frequency (Ward et  al.,  1984).
Subjects were matched for age, and use of alcohol, tobacco,  and  mari-
juana.  Additional information was collected on health, medication, and
other  exposures to toxic substances.   Ten subjects were employed  for
4.3 months  (range: 1-11 months) prior to the first sample, and one was
employed for several years. Formaldehyde exposures were  episodic,  but
with a time-weighted average of between 0.73 and  1.58 mg/m3    (weekly
exposure  range, 3.6-48 mg/m3 per  h).  Samples were taken from exposed
and   control   subjects   3 times  at   2- to 3-month  intervals.   No
statistically  significant differences in  the variables were  observed
between the exposed and control groups.  Reduced sperm count was corre-
lated with increased abnormal morphology and 2F-body frequency  in  the
exposed group but not in the control group.  Evaluation of  the  impact
of incidental exposures suggests a reduced count with marijuana use and
increased  abnormal morphology with  medications used by  controls.  No
effects on sperm due to formaldehyde or its metabolites  were  observed
in  this occupationally-exposed population.  However, it was considered
that  the  lack of an  effect in this study  might be due to  a lack of
statistical power to detect effects at this exposure level.

9.2.8  Other observations in exposed populations

    Dally  et al. (1981) measured formaldehyde in the air of 100 homes,
containing  particle  board  or urea-formaldehyde  foam  insulation, in
which  residents reported symptoms of eye, nose, and throat irritation.
They  found levels ranging  from < 0.12 to  4.42 mg/m3   (< 0.1 ppm  to
3.68 ppm) and concluded that indoor environmental exposure to formalde-
hyde may exceed occupational exposure levels.  Sardinas et  al.  (1979)
studied  individuals from 68 households in which 167 complaints related
to urea-formaldehyde insulation were being investigated.  Twice as many
individuals  reported eye irritation in homes in which formaldehyde was
detected  by Draeger tubes (0.5-10 µg/litre)   compared with the number
in homes in which there was no detectable formaldehyde.

    In a study by Woodbury & Zenz (1983), 20 symptomatic  infants  were
followed  up, whose mobile home environment was suspected to be related
to  their illness.  The authors noted a relationship between the occur-
rence  of symptoms and the  time spent at home.   However, no statisti-
cally significant association was found between symptoms and air levels
of formaldehyde.

    All  three studies suffer from possible selection bias, the absence
of  appropriate controls,  and no  mention of  whether  other  chemical
exposures and smoking habits were considered.

    In a pilot study, Schenker et al. (1982) studied the health  of  24
full-time  residents  from  6 homes containing  urea-formaldehyde  foam
insulation.   The  results  of  standardized  allergy  skin  tests  and
spirometry  tests were normal in all subjects.  Memory difficulty was a
frequently  reported  symptom.  Memory  storage  deficits could  not be
demonstrated,  but the results of tests of attention span were abnormal
in  11/14 subjects; furthermore, 8 out of the 11 subjects suffered from
elevated  depression scores.  The sample  size in this pilot  study was

small  (adults: 9 males, 9 females;  children: 2 males, 4 females)  and
may have been biased by self-referrals; there was no control group.

    The  Consensus  Workshop  on Formaldehyde  (1984)  reviewed several
reports linking long-term formaldehyde exposure to a range  of  psycho-
logical or behavioural problems (depression, irritability, memory loss,
decreased  attentional  capacity,  sleep disturbances).   Most  of  the
studies used subjective self-report symptom inventories.  Control data,
describing  the incidence of such  symptoms from unexposed persons  are
often inadequate or completely absent.  Olson & Dossing (1982) adminis-
tered a standardized questionnaire based on the linear  analogue  self-
assessment  method to 70 employees (66 responded)  at 7 mobile day-care
centres,  in which urea-formaldehyde  glued particle  boards  had  been
used,  and to 34  (26 responded) employees at  3 control  institutions,
selected  at random, which did  not contain any particle  boards.  Mean
concentrations  of  formaldehyde  were 0.43  and 0.08 mg/m3,   respect-
ively.   Among the staff  at the mobile  day-care centres, there  was a
significantly  greater prevalence and  intensity of symptoms  of mucous
membrane  irritation,  headache, abnormal  tiredness, menstrual irregu-
larities, and use of analgesics, but there were no differences in terms
of  memory  disturbance  and concentration  (50%  of  the  cohort  were
smokers).

    Two  groups  of  male workers  exposed  to  formaldehyde  (group  1
employed  in the phenol-formaldehyde-plastic  foam matrix embedding  of
fibreglass  (batt making);  group 2,  in the  fixation of  tissues  for
histology)  were studied  by Kilburn  et al.  (1985)  for  work-related
neurobehavioural,  respiratory,  and  dermatological symptoms,  and for
pulmonary  function impairment.  Forty-five male fibreglass batt makers
were studied during the initial work shift after a holiday, with regard
to combined neurobehavioural (impact on sleep, memory, equilibrium, and
mood),  respiratory, and dermatological symptoms.   Average frequencies
of  17.8 (for the  hot areas of  the process) and  14.6 (for  the  cold
areas) were found.  Their symptom counts were significantly higher than
those  for 18 male histology  technicians (average 7.3), and  those for
26 unexposed male hospital workers (average 4.8).

    The  fibreglass batt  makers were  also exposed  to numerous  other
products,  such as phenol, surfactants, particulate smoke, glass fibre,
etc.  The formaldehyde work-place concentrations were not measured.  No
consideration  was given to  potential respondent bias  in symptoms  or
exposures or to the socioeconomic differences between the  workers  and
the technicians.

9.2.9  Carcinogenic effects

    The evaluation of the risks for human health from  occupational  or
environmental  agents  relies  heavily  on  the  evidence  gleaned from
epidemiological  studies.  It is, therefore, important to emphasize the
procedures that should be adopted, in order to assess the value of such
epidemiological  investigations,  particularly  with reference  to  the
shortcomings inherent in the epidemiological method.

    For  practical purpose, three types of study are in common use: The
cohort,  the  case-control,  and the  correlation (surveillance) study.

Cohort and case-control studies relate individual exposure to the agent
under  study with  the occurrence  of a  health effect  (in this  case,
cancer) in individuals, and provide an estimate of relative risk as the
main  measure of association.  Cohort studies, which follow populations
prospectively,  are  inherently  less subject  to  bias  than the  more
commonly  used retrospective (historical) cohort studies as the data on
health  outcome are not acquired  from past records.  However,  because
retrospective  cohort studies cannot be  based on a well  defined popu-
lation,  it is possible to  use proportionate mortality (or  morbidity)
studies  which give,  by definition,  less precise  estimates of  risk.
Case-control  studies always rely on retrospective exposure assessments
and  although such studies  are usually easier  to execute than  cohort
studies, they are sensitive to various types of bias that are difficult
to eliminate.  Correlation (surveillance) studies use whole populations
according  to geographical area or time period as the initial data base
and  health  outcome (cause-specific  deaths  or cancer  incidence)  is
related  to a summary measure  of the population exposure.   Individual
exposure  is not documented, thus causal relationships are difficult to
infer from the results.

    All epidemiological studies are subject to some extent  to  factors
that can affect their quality with, as a general rule,  cohort  studies
being  superior to case-control studies.  Four factors are particularly
important:   bias,  confounding,  chance, and  qualitative  measures of
exposure and outcome. Bias means the operation of factors in the design
or  execution of  the study  that can  lead to  erroneous  associations
between  the exposure and the  health outcome, because of  a failure to
estimate these factors independently. Confounding refers to a situation
in which the relationship between the exposure and the  health  outcome
is  altered by one  or more factors  that separately and  independently
influence  the outcome.  The likelihood  that the results of  the study
could have occurred by chance is estimated by using  appropriate  stat-
istical analyses.  Finally, the accuracy and completeness of the infor-
mation  gathered on exposure and  health outcome needs to  be reviewed.
Cancer  is a relatively  easy outcome to  document but  epidemiological
studies  are often seriously deficient in their assessments of exposure
to  the agent of interest, i.e., the degree, the duration, and even the
misclassification  of exposure of individual members of the study popu-
lation.

    Thus,  epidemiological studies need to  be evaluated, not only  for
their  results, but also  for the way  in which the  investigators have
addressed  the methodological problem outlined above. Sufficient infor-
mation  should be available  in the study  reports to make  these value
judgements.

    Thereafter,  the reviewer is frequently confronted with a series of
studies  from which to make an evaluation.  Causality, that is the con-
tention  that  the agent  in question causes  the disease in  question,
depends on a number of considerations. The most important are: the size
of  the relative risk estimate (coupled with a relatively narrow confi-
dence  interval), the observation  of a putative  relationship  between
agent  and disease in  a number of  studies using similar  or different
designs  in different  populations; evidence  that the  agent  acts  on
specific  organ systems which are biologically plausible; and, finally,

that the effect of the agent has been assessed in studies  covering  an
observation period long enough to allow for the latent period  and  the
period of induction of disease.  In cancer studies, this may require an
observation period of several decades for each study member.

    In  short,  the  evaluation of  epidemiological  studies  initially
requires  value judgements  regarding the  quality of  the  design  and
execution of the study.  Thereafter an assessment is needed  of  groups
of studies to estimate the likelihood or otherwise that  the  relation-
ship between the exposure and the disease is causal.   Such  evaluation
procedures have been adopted here for formaldehyde and human cancer.

    Observed  and  expected  deaths  for  professional  and  industrial
workers  exposed to formaldehyde are summarized in Table 36.  The occu-
pations  studied consisted of professionals who use formaldehyde in the
preservation  of  biological  tissues (embalmers,  anatomists,  pathol-
ogists,  and zoologists), and industrial  workers involved in the  pro-
duction and use of formaldehyde.  The pattern and intensity of exposure
to formaldehyde differed for both groups.

Table 36.  Observed and expected deaths for professional and industrial 
           workers exposed to formaldehyde (with 95% confidence limits)a 
----------------------------------------------------------------------------- 
 Cause                            Professional              Industrial 
                           Observed/   Confidence   Observed/  Confidence 
                           expected      limits     expected     limits 
----------------------------------------------------------------------------- 
 Cancer 
 Nasal                       0/1.7        0-2.17      0/1.3       0-2.84 
 Mouth                      20/23.8    0.51-1.30     12/9.2    0.67-2.28 
 Brain                      40/22.6    1.26-2.41      6/13.2   0.17-0.99 
 Lymphatic and 
  haematopoietic            80/64.0    0.98-1.53     25/30.6   0.53-1.21 
 Leukaemia                  40/27.2    1.05-2.00      9/11.4   0.36-1.50 
 Other lymphatic 
  and haematopoietic        40/36.8    0.78-1.48     16/19.2   0.48-1.35 
 Lung                      175/243.6   0.62-0.83    214/227.3  0.82-1.08 
 Prostate                   61/51.6    0.90-1.52      2/0.6    0.40-12.04 
 Skin                       12/11.4    0.54-1.84      0/0.4       0-9.22 
 Bladder                    23/24.3    0.60-1.42      1/0.3    0.18-18.6 
 Kidney                     21/18.6    0.70-1.73      1/0.4    0.06-13.93 
 Digestive system          211/245.2   0.74-0.98      8/10.4   0.33-1.52 
 
 Other causes 
 Cirrhosis of liver         83/59.3    1.11-1.74     10/9      0.53-2.04 
 Non-neoplastic 
  respiratory disease      109/163.7   0.55-0.80    243/241.1  0.88-1.14 
--------------------------------------------------------------------------- 
 a From: Consensus Workshop on Formaldehyde (1984). 

    A summary of epidemiological studies with formaldehyde is presented
in  Tables 37, 38, and 39.  An excess of several forms of cancer, i.e.,
Hodgkin's disease, leukaemia, cancers of the buccal cavity and pharynx,
lung,  nose, prostate, bladder, brain, colon, skin and kidney, has been
seen  in  more  than one  of  the  epidemiological studies  relating to

formaldehyde.   Some of these excesses  may be due to  random variation
and  others may  depend on  factors other  than formaldehyde  exposure.
Such  explanations might be suggested, especially when only a few cases
are involved or when the risk ratios are low.  Some studies involve the
same  populations and therefore  do not provide  completely independent
information (Marsh, 1983; Wong, 1983; Liebling et al., 1984).
Table 37.  Summary of epidemiological proportional mortality rate (PMR) studies with 
formaldehydea 
-----------------------------------------------------------------------------------------------
Author(s)   Study             Study      Site                    Risk       Decedents  Control 
(Year)      population        period                             estimates             Tobacco 
                                                                 (PMR) 
-----------------------------------------------------------------------------------------------

Marsh       chemical workers  1950-76                                        136        no 
(1982)      (USA)                        respiratory system        80 
                                         digestive system         127 
                                         genital system           121 
                                         lymphatic system          86 
 
Walrath &   male embalmers    1925-80                                       1010        no 
Fraumeni    (New York)                   buccal and pharyngeal    126 
(1983)                                   nasopharynx               -
                                         respiratory              102 
                                         nasal                     -
                                         prostate                  89 
                                         bladder                   92 
                                         brain                    157 
                                         leukaemia                132 
                                         colon                    140 
                                         skin                     253 
                                         Hodgkins                  -
                                         kidney                   170 
                                         lymphatic and haemato-  
                                           poietic                115 
-----------------------------------------------------------------------------------------------


                                   
Table 37 (contd). 
-----------------------------------------------------------------------------------------------
Author(s)   Study             Study      Site                    Risk       Decedents  Control 
(Year)      population        period                             estimates             Tobacco 
                                                                 (PMR) 
-----------------------------------------------------------------------------------------------
 
Walrath &   embalmers         1925-80                                       1007        no 
Fraumeni    (California)                 buccal                   131 
(1984)                                   respiratory               94 
                                         nasal                     -
                                         prostate                 175 
                                         brain & CNS              194 
                                         leukaemia                175 
                                         colon                    187 
                                         skin                      59 
                                         Hodgkins                  -
                                         bladder                  138 
                                         kidney                   100 
                                         rectum                   102 
                                         gallbladder and liver     85 
                                         pancreas                 135 
                                         stomach                   79 
 
Stayner      garment workers   1959-82                                        256       no 
et al.                                   buccal                   229 
(1985)                                   nasal Pha.                -
                                         digestive                126 
                                         gallbladder and liver    313 
                                         lung                      95 
                                         skin                     179 
                                         bladder and kidney        92 
                                         lymphatic                163 
                                         leukaemia                168 
-----------------------------------------------------------------------------------------------

a Exposure characteristics described. 

                                  
Table 38.  Summary of epidemiological case-control studies with formaldehyde 
---------------------------------------------------------------------------------------------------------
Author(s)  Study          Study    Type of      Cases  Controls  Site            Risk   Comments 
(Year)     population     period   exposure 
---------------------------------------------------------------------------------------------------------

Jensen     physicians     1943-76  speciality    84     252      lung            1.0         -
et al.                    
(1982) 
                                                                                Odds Ratio 
Fayer-     chemical wor-  1957-79  levels and   481     481      multiple                    -
weather    kers                    duration                      buccal cavity   1.0 
et al.                                                           oesophagus      0.5 
(1983)a,b                                                        stomach         1.0 
                                                                 liver, gall-
                                                                 bladder,        0.9 
                                                                 lung            0.8 
 
Coggon     workers        1975-79  occupational 296     472      bronchus        1.5    r.r. 0.9 in 
et al.     (United                                                                      higher exposure 
(1984)c    Kingdom)       1975-79  occupational 132     268      bladder         1.0    r.r. 1.5 in 
                                                                                        higher exposure 
 
Olsen      workers        1970-82  exposure     754    2465      nasal           2.8    o.r. 1.8 for ex-
et al.     (Denmark)               assessed                      nasopharynx     0.7    posure to wood 
(1984)                                                                                  dust men 
 
Partanen   wood workers   1957-80  levels and    57     171      respiratory     1.3    no exposure-
et al.                             duration                                             response  
(1985)a                                                                                 relationship
 
Bond       chemical wor-  1940-80  ever         308     588      lung            0.6    dose-response 
et al.     kers                    exposed                                              relationship 
(1986)a 
 
Hayes      wood workers   1978-81  levels        91     195      nose and nasal  2.5    low wood-dust 
et al.     (Netherlands)                                         sinuses                exposure 
(1986)a                                                                          1.9    high wood-dust 
                                                                                        exposure 
---------------------------------------------------------------------------------------------------------

                                   
                                   
Table 38 (contd). 
---------------------------------------------------------------------------------------------------------
Author(s)  Study          Study    Type of      Cases  Controls  Site            Risk   Comments 
(Year)     population     period   exposure 
---------------------------------------------------------------------------------------------------------
 
Vaughan    Tumour regis-  1979-83  occupational  285    552      nasopharynx     1.4    for high exposure 
et al.     try                                                   nasopharynx     2.1    20+ years 
(1986a)a                                                         buccal cavity   0.6    for high exposure 
                                                                 buccal cavity   1.3    20+ years 
 
                                                                                Odds Ratio 
Vaughan    Tumour regis-  1979-83  residential   285    552      nasopharynx     5.5    10+ years 
et al.     try                                                   nasal cavity    0.6    mobile 
(1986b)a                                                         buccal cavity   0.8    home 
 
Brinton    industrial     1970-80  occupational  160    290      nasal cavity    0.4         -
et al.     workers        
(1984)a 
 
Olsen &    Tumour regis-  1970-82  occupational  759   2465      nasal cavity    2.3    squamous cell car-
Asnaes     try                                                   nasopharynx     2.2    cinoma only; wood 
(1986)     Denmark                                                                      dust adencarcinoma 
                                                                                        looked for but not 
                                                                                        found 
 
Roush      Tumour regis-  1940-81  occupational  371    605      nasopharynx     1.1 
et al.     try                                                   nasal cavity    0.8 
(1985) 
 
Hardell    Tumour regis-  1970-79  occupational   44    541      nasal           6.1    r.r. calculation 
et al.     try                                                                          based on 2 exposed 
(1982)a    Sweden                                                                       out of 44 nasal 
                                                                                        cancers versus  
                                                                                        4 out of 541 
                                                                                        controls 
---------------------------------------------------------------------------------------------------------

a Study controlled for tobacco use. 
b Selection criteria < 20 years after first exposure.    
c Selection criteria male < 40 years. 

                                   
                                   
Table 39.  Summary of epidemiological cohort studies with formaldehydea 
---------------------------------------------------------------------------------------------------------
Author(s)   Study           Study    Site              Risk     Study   Type of    Comments 
(Year)      population      period                   estimates  popu-   exposure 
                                                       (SMR)    lation 
---------------------------------------------------------------------------------------------------------

Acheson     chemical wor-   1941-81                             7680    levels     a) lung cancer  
et al.      kers                     bucco-pharyngeal  109              and           increased with 
(1984)                               nasopharynx        -               duration      level of exposure   
                                     lung               95                            in one factory
                                     nasal              -                          b) lung cancer not 
                                     digestive         101                            increased with 
                                     larynx             88                            cumulative exposure 
 
Harrington  male            1974-80                             2307    none       all brain cancers were 
& Oakes     pathologists             digestive          20                         gliomas 
(1984)                               lung               41 
                                     bladder           107 
                                     brain, CNS        331 
                                     lymphatics         54 
                                     leukaemia          90 
 
Levine      embalmers,      1950-77                             1477    none       all brain cancers were 
et al.      (Canada)                 bucco-pharyngeal   48                         gliomas 
(1984)                               lung               94 
                                     prostate           88 
                                     urinary organs     54 
                                     brain, CNS        115 
                                     colorectal         85 
                                     leukaemia         160 
                                     lymphatic         124 
                                     digestive          75 
---------------------------------------------------------------------------------------------------------

                                   
                                   
Table 39 (contd). 
---------------------------------------------------------------------------------------------------------
Author(s)   Study           Study    Site              Risk     Study   Type of    Comments 
(Year)      population      period                   estimates  popu-   exposure 
                                                       (SMR)    lation 
---------------------------------------------------------------------------------------------------------
 
Stroup      anatomists      1925-79                             2317    duration   brain cancers were 
et al.                               bucco-pharyngeal   15              special    gliomas and increased 
(1986)                               nasopharynx        -                          with duration of 
                                     lung               28                         employment 
                                     nasal              -
                                     prostate          100 
                                     bladder            68 
                                     brain, CNS        270 
                                     leukaemia         147 
                                     colon             108 
                                     lymphatic         123 
 
Blair       industrial      1934-80                             26 561  levels,    exposure-response 
et al.      workers                  buccal cavity      96              duration,  relationship 
(1986)                               nasopharynx       300              and        for prostate and 
                                     lung, pleura      111              peaks      Hodgkin's disease 
                                     nasal cavity       91 
                                     prostate          115 
                                     bladder            96 
                                     kidney            123 
                                     brain              81 
                                     leukaemia          80 
                                     colon              87 
                                     skin               80 
                                     Hodgkin's         142 
 
Blair       industrial      1930-80                             26 561  none       dose-response 
et al.      workers                  nasopharynx       384                         relationship for those 
(1987)                               oropharynx        167                         also exposed to 
                                                                                   particulates 
---------------------------------------------------------------------------------------------------------

                                   
                                
Table 39 (contd). 
---------------------------------------------------------------------------------------------------------
                                                                  
Bertazzi    resin workers   1959-80                             1332                      -
et al.                               bucco-pharyngeal   -
(1986)                               digestive         156 
                                     oesophagus         -
                                     stomach           148 
                                     lung              236 
                                     lymphatic         201 
 
Edling      abrasive manu-  1958-83                              521               no correlation with 
et al.      facturers                bucco-pharyngeal   -                          exposure 
(1987)                               nasopharynx        -
                                     stomach            80 
                                     colon             100 
                                     pancreas          180 
                                     lung               57 
                                     prostate           85 
                                     lymphatic         200 
 
Stayner     textile         1953-77                             11 030 
et al.      workers                  buccal cavity     343 
(1988)                               digestive system   58 
                                     lung              114 
                                     bladder           112 
                                     kidney             55 
                                     brain              71 
                                     lymphatic system   91 
                                     leukaemia         114 
---------------------------------------------------------------------------------------------------------
 
a There are no cohort studies with control of tobacco use. 
    In  view of  the solubility  and rapid  metabolism of  formaldehyde
(section 6.3),  it seems that  (upper) respiratory tract  cancers would
be  more likely to  be causally related  to formaldehyde exposure  than
other  forms of cancer. Besides various types of occupational exposure,
smoking  and other  use of  tobacco would  have to  be considered  with
regard  to  potential  confounding factors,  especially  when  exerting
strong  effects, such as those  of tobacco smoking in  relation to lung
cancer. Furthermore, because of the formaldehyde contents of mainstream
and  side-stream smoke,  there would  be a  potential increase  in  any
reference population, and this would mask the effects  of  formaldehyde
with regard to cancers that might be related to occupational  or  other
specified exposure to formaldehyde. Finally, it should be noted, within
this general epidemiological context, that there is  experimental  evi-
dence providing a relatively clear suggestion of a possible cancer risk
for human beings from exposure to formaldehyde.

    Excess of nasal or nasopharyngeal cancer in relation  to  formalde-
hyde  exposure was reported in  6 of the case-control  studies reviewed
(Table 38)  (Hardell,  1982; Olsen  et al., 1984;  Roush et al.,  1985;
Hayes  et al., 1986; Vaughan et al., 1986a,b).  In 2 other case-control
studies (Fayerweather et al., 1983; Brinton et al., 1984), the question
of  a relationship with  formaldehyde was addressed  either by  primary
design  or  by  reporting formaldehyde  exposure  for  either cases  or
controls, but no excess risk was demonstrated.  None of the  cohort  or
PMR  studies listed in  Tables 37 and 39  had adequate power  to detect
even  a considerably increased risk  though, in aggregate, the  studies
might have had the power to reveal, at least, a higher risk  for  nasal
cancer.   It  should  also be noted that with regard to nasal and naso-
pharyngeal  cancer, smoking  is not  likely to  exert any  particularly
strong  confounding effect, since the relation of these cancer types to
smoking  is  only  moderately strong, i.e., up to a risk ratio of about
five  (Axelson  &  Sundell, 1978; IARC 1986) and has been lower in many
studies.

    Cancers  of the  buccal cavity  and pharynx  have either  not  been
included  in  studies  or in  some  case-control  studies the  risk has
appeared  about normal  (Fayerweather et  al., 1983;  Vaughan  et  al.,
1986a,b),   There was no  excess in the  largest cohort (Blair  et al.,
1986),  though an  excess appeared  in other  studies  involving  small
numbers (Stayner et al., 1985, 1988; Walrath & Fraumeni, 1983, 1984).


Table 40.  Mortality from subsites of cancer of the buccal cavity and 
           pharynx through cumulative exposure to formaldehydea 
---------------------------------------------------------------------------------------------------------
Cancer   
                                        Mortality after formaldehyde exposure at: 
 
                    0 mg/m3-years      < 0.6 mg/m3-years    0.6 - 6.6 mg/m3-years   >  6.6 mg/m3-years 
               Observed Expected SMR  Observed Expected SMR  Observed Expected SMR  Observed Expected SMR
---------------------------------------------------------------------------------------------------------
                                                                  
Lip                0       0.1    -b      1       0.2   477     0        0.2    -b     1        0.1   764
Tongue             0       0.5    -b      0       1.8    -b     2        2.1    96     0        1.3   -b 
Salivary glands    0       0.2    -b      0       0.5    -b     0        0.6    -b     0        0.3   -b 
Gum, floor, other  0       0.4    -b      1       1.5    66     0        1.8    -b     1        1.1   88 
 mouth sites                                                                                             
Nasopharynx        1       0.2   530      2       0.7   271     2        0.8   256     2        0.5   433
Oropharynx         0       0.3    -b      4       0.9   443c    1        1.0    95     0        0.7   -b 
Hypopharynx        1       0.2   594      1       0.6   172     0        0.7    -b     0        0.4   -b 
Other parts of     0       0.4    -b      1       1.4    73     0        1.6    -b     0        1.0   -b 
 pharynx 
---------------------------------------------------------------------------------------------------------
 
a From: Blair et al. (1986). 
b No deaths. 
c P < 0.05. 
    Some  excess of respiratory  cancer has appeared  in 3 case-control
studies  in comparison with  low exposures in  general (Coggon et  al.,
1984)  or comparable  unexposed workers  (Partanen et  al.,  1985)  and
between  physicians  in surgery  and  internal medicine,  though  these
findings  were based on small numbers (Jensen et al., 1982).  Two other
studies  have come out as non-positive (Fayerweather et al., 1983; Bond
et  al., 1986).  Of  these cohort and  PMR studies, which  had adequate
power  and were designed  to elucidate the  risk of respiratory  cancer
from  formaldehyde, 3 (Walrath, 1983;  Bertazzi et al., 1986;  Blair et
al.,  1986)  showed  an excess  (significantly  high  in the  study  by
Bertazzi  et al.,  1986). Blair  et al.  (1986) showed  some excess  in
laryngeal  cancer (Table 40).  Seven studies with reasonable power were
negative  (Harrington & Oakes, 1984; Stroup et al., 1984, 1986) or non-
positive  with regard to  respiratory cancer (Marsh,  1983; Acheson  et
al.,  1984; Levine et al.,  1984; Walrath & Fraumeni,  1984; Stayner et
al.,  1985, 1988).  The deviations in both directions from the expected
in  these studies are  explainable by the  lack of control  for smoking
and/or  the so-called "healthy worker  effect", which means that  the
study population is not comparable with the general population.

    Leukaemia has come out somewhat high in all the  studies  involving
reasonable  numbers of  cases (Stroup  et al.,  1984, 1986;  Walrath  &
Fraumeni,  1983) and even  significantly high in  one study (Walrath  &
Fraumeni,  1984).   Three of  these  studies involved  either embalmers
(Walrath  & Fraumeni, 1983, 1984)  or anatomists (Stroup et  al., 1984,
1986),  which  might suggest  some  other alternative  or  contributing
etiological factor operating.  Similarly, for brain cancer,  which  was
found  in significant excess in some studies (Harrington & Oakes, 1984;
Stroup  et al., 1984,  1986; Walrath &  Fraumeni, 1984), a  confounding
factor may be suspected regarding the relationship between brain cancer
and social class (Table 41).  An excess of colon cancer among embalmers
(Walrath & Fraumeni, 1983, 1984; Stroup et al., 1984, 1986) may perhaps
be  explained by a  recently observed association  with sedentary  work
(Garabrant  et al.,  1984; Gerhardsson  et al.,  1986).  Of  the  other
cancer forms previously mentioned as appearing in excess in  more  than
one  study, cancers of the skin, bladder, kidney, and prostate, as well
as  Hodgkin's disease  are represented  by small  numbers and/or  small
excesses, though prostatic cancer was significantly high in  one  study
on  embalmers, based on 23 cases  (Walrath & Fraumeni, 1984)  and skin,
but not prostatic cancer was significantly high in the other  study  on
embalmers (Walrath & Fraumeni, 1983).


Table 41.  Mortality ratios of men according to social classa 
---------------------------------------------------------------------------------------------------
Disease                    Population               Social class              Reference 
Place             Age   Year    Ratiob      High                     Low 
  Race          (years)                    I    II     III      IV    V 
---------------------------------------------------------------------------------------------------

Brain cancer 
 
United Kingdom 
 all            15-64   1970-72   SMR     108   101   111, 105  100    92  Registrar General (1978) 
 all            65-74   1970-72   PMR     225   137   109, 99    85    56  Registrar General (1978) 
 all            20-64   1949-53   SMR     133    96     104      88    99  Registrar General (1978) 
 all             65     1949-53   PMR     136   112     105      90    71  Registrar General (1978) 
 all            35-65   1930-32   SMR     167    92     116      97    66  Registrar General (1978) 
 all            20-65   1921-23   CMFR    160   160     120      80    60  Registrar General (1978) 
USA 
California 
 all            20-64   1949-51   SMR     130   127     108      77    58  Buell et al. (1960) 
Massachusetts 
 white           20     1971-73   SMOR    164    97     114      62c       Dubrow & Wegman (1984) 
USA 
 all            20-64   1950      SMR     136   121     109      94    81  Guralnick (1963) 
 
Leukaemia 
 
United Kingdom 
 all            15-64   1970-72   SMR     113   100   107, 101  104    95  Registrar General (1978) 
 all            65-74   1970-72   PMR     138   124   108, 98    90    77  Registrar General (1978) 
 all            20-64   1949-53   SMR     123    98     104      93    89  Registrar General (1978) 
 all             65     1949-53   PMR     202   115     101      78    74  Registrar General (1978) 
 all            20-65   1930-32   SMR     152   126      97      95    86  Registrar General (1978) 
 
USA 
California 
 all            20-64   1949-51   SMR     104   116     101      86   104  Buell et al. (1960) 
Massachusetts                   
 white           20     1971-73   SMOR    126    97     108      89c    -  Dubrow & Wegman (1984) 
USA 
 all            20-64   1950      SMR     117   100     105      89    98  Guralnick (1963) 
---------------------------------------------------------------------------------------------------
 
a       From: Levine (1985). 
b       SMR = standardized mortality ratio. 
        PMR = proportional mortality ratio. 
        SMOR = standardized mortality odds ratio. 
        CMFR = comparative mortality figure ratio. 
c       Including classes IV and V. 

10.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

10.1  Evaluation of Human Health Risks

    The absolute odour threshold for formaldehyde is between  0.06  and
0.22 mg/m3 (a   group  of observers  detected the odour  in 50% of  the
presentations,   10% of  an untrained  population detected  a level  of
0.03 mg/m3).     There is a low  probability that human beings  will be
able   to   detect  formaldehyde   in   air  at   concentrations  below
0.01 mg/m3.

    Since  interaction and adaptation  processes are characteristic  of
the sensory systems involved in the perception of odour and irritation,
the  duration of exposure and the other components of environmental air
exposure influence the perception.  Although sensory adaptation because
of  length of exposure may  weaken the perceptual response,  there is a
high  probability that exposure  duration will enhance  the perception,
especially  at  low  concentrations.  In  addition,  formaldehyde often
appears in complex gas mixtures that contain other  low  concentrations
of  odorous or irritating components.  Examples are photochemical smog,
automobile  exhaust,  environmental  tobacco  smoke,  and  contaminated
indoor air, with building materials as the source.

    There  are  no  data  on  the  absolute  irritation  threshold  for
formaldehyde,  but sensory irritation has been reported for the eyes at
0.06 mg/m3 and for the respiratory tract at 0.12 mg/m3.

    Formaldehyde vapour causes direct irritation of the  human  respir-
atory tract.  However, precise thresholds have not been established for
the irritant effects of inhaled formaldehyde.  Some  people  experience
throat irritation at 0.1 mg/m3 and  almost everybody will experience it
before a level of 3.0 mg/m3 is reached.

    The effects on the nasal cavity, the site of impact for most of the
inhaled formaldehyde, is impairment of mucociliary flow at or  above  a
level  of  0.5 mg/m3.    This effect  may  also  lead to  the secondary
complication  of respiratory disease.  There  is a higher incidence  of
chronic  respiratory  disease  in  occupationally-exposed  subjects  or
children  living  in  a formaldehyde-polluted  environment.   Long-term
exposure  to 0.45 mg/m3,   independent  of tobacco-smoking habits,  may
cause bronchoconstriction.

    Formaldehyde has been shown to cause pulmonary effects  on  healthy
and on asthmatic subjects (not sensitized to formaldehyde) at a concen-
tration  that is already  irritant.  Precise thresholds  have not  been
established for the pulmonary irritant effects of inhaled formaldehyde.
However,  lower  airway and  pulmonary effects are  likely to occur  at
levels above 6 mg/m3.

    There  are  no data  on the exact  exposure level at  which inhaled
formaldehyde  has  a sensitizing  effect,  but once  sensitization  has
developed, short-term exposure to concentrations that can be  found  in
occupational or home environments is sufficient to produce  an  asthma-
like  response.  Asthmatic responsiveness  may persist if  intermittent
exposure to low levels continues. Removal from exposure has  a  favour-
able effect on symptoms.

    Although  few proven formaldehyde-induced asthma patients have been
reported, it appears likely that this condition is underreported.

    There is a possibility of the induction of sensitisation via haemo-
dialysis,  where  formaldehyde may  enter  the circulation  through the
disinfecting  of the dialysis equipment.  This can be influenced by the
state of health and previous medication of the patient.

    Skin  sensitisation in human  beings is induced  by direct  contact
with  formaldehyde solutions, only  in concentrations higher  than  2%.
The lowest patch-test challenge concentration producing a  reaction  in
sensitized  persons  was 0.05%  formaldehyde  in an  aqueous  solution.
Patch   tests  performed with formaldehyde  challenge concentrations of
< 1%  formaldehyde resulted in  positive reactions in  about 2% of  all
patch-tested patients throughout the world.

    Positive  patch tests results  with formaldehyde challenge  concen-
trations of 2% or more may be due to skin irritation.

    Formaldehyde may induce contact urticarial reactions, but these are
rarely  observed and  have not  been confirmed  as IgE-mediated  Type I
reactions.

    Cell-mediated  allergic dermatitis, arising from systemic exposure,
and  antibody  (IgE)-mediated  exanthematous phenomena  have  not  been
observed after ingestion of formaldehyde.

    Irritant skin reactions occur through direct contact  with  formal-
dehyde  solutions.  A single application  of 1% formalin in  water with
occlusion  will produce an irritant response in approximately 5% of the
test population.

    Mental  or  behavioural  problems at  levels  present  in the  home
environment  have been  claimed to  be due  to  long-term  formaldehyde
exposure,  as adjudged by questionnaires, but there were no differences
in terms of memory loss, sleep disturbance, and concentration. Possible
impaired  memory, equilibrium, and  dexterity, in some  cases has  been
suggested in relation to long-term, high-level occupational exposure.

    Animal  data do not  indicate that formaldehyde  is embryotoxic  or
teratogenic.

    Formaldehyde   reacts  with  macromolecules,  including  DNA.   The
genotoxic effects of formaldehyde have been reported in a wide range of
mutagenicity tests  in vitro in the absence of a metabolizing system.

     In  vivo , most  mutagenicity  tests are  negative.   However, DNA-
protein cross-links are induced at the site of exposure, after inhaling
formaldehyde.   The  importance of  this  local genotoxic  effect  with
respect to the induction of cancer requires further evaluation.

    The  importance of positive  mutagenicity findings with  regard  to
germ-cell  mutations is limited.  In the light of known metabolic mech-
anisms, it should not be assumed that formaldehyde induces mutations in
germ  cells and it is  unlikely that formaldehyde leads  to a heritable
genetic risk.

    Formaldehyde is a nasal carcinogen in rats.  A  highly  significant
incidence  of nasal cancer was  induced in rats exposed  to a level  of
18 mg/m3,    but  the  concentration-response curve  was extremely non-
linear,  and only a  low, not statistically  significant, incidence  of
nasal tumours occurred at 7.2 mg/m3.    The results of this  and  other
studies  consistently indicate that, at low concentrations, the risk of
cancer is  disproportionately low.  It is likely that defence mechanisms
in  the respiratory tract,  including the mucociliary  clearance appar-
atus, metabolism by formaldehyde dehydrogenase and other  enzymes,  and
DNA  repair,  are effective  at low concentrations,  but that, at  high
concentrations,  these defence mechanisms  can be overwhelmed  and  may
even be inactivated, thus resulting in tissue damage.

    On the basis of these data it can be concluded that  the  induction
of nasal cancer in rats by formaldehyde requires repeated  exposure  to
high  concentrations, i.e., concentrations that are very irritating and
cause  considerable damage to the nasal mucosa followed by regenerative
hyperplasia  and metaplasia.  The increased  cell turnover, as well  as
subsequent  cycles  of DNA-damage  provoked  by continuous  exposure to
formaldehyde,  may  strongly increase  the  likelihood of  relevant DNA
damage,  and subsequently may greatly  enhance the progression of  pre-
neoplastic cells to cancer. Formaldehyde, in concentrations not leading
to cell damage, probably cannot act as a complete  carcinogen,  causing
initiation,  promotion, and  progression, and,  as a  result,  is  very
unlikely to induce cancer by itself.  From the above, it  appears  that
the cytotoxic effects are likely to play a highly significant  role  in
the formation of nasal tumours by formaldehyde.

    Despite  differences in the anatomy  and physiology of the  respir-
atory  tract  between  rats and  human  beings,  the respiratory  tract
defence mechanisms are similar. Therefore, it is reasonable to conclude
that the response of the human respiratory tract mucosa to formaldehyde
will  be  qualitatively similar  to that of  the rat respiratory  tract
mucosa.

    Evidence  from rat studies  suggests that recurrent  tissue  damage
occurs in conjunction with exposure to high,  cytotoxic  concentrations
of  formaldehyde, and that  this is necessary  for nasal tumours  to be
produced.   If  respiratory-tract  tissue is  not  repeatedly  damaged,
exposure  of  human  beings  to  low,  non-cytotoxic  concentrations of
formaldehyde  can be  assumed to  represent a  negligible cancer  risk.
However,  if exposure were to be accompanied by recurrent tissue damage
at  the initial site  of contact, formaldehyde  may be assumed  to have
carcinogenic potential for man.

    Some excess has been shown for several types of cancer in more than
one  of  the epidemiological  studies  relating to  formaldehyde, i.e.,
Hodgkin's  disease, leukaemia,  and cancers  of the  buccal cavity  and
pharynx,  lung, nose, prostate, bladder, brain, colon, skin and kidney.
Some  of  these  excesses may be due to random variation and others may
depend on factors other than formaldehyde exerting confounding effects.
Such  explanations might be suggested, especially when only a few cases
are involved or when the risk ratios are low.

    In  view of the solubility and rapid metabolism of formaldehyde, it
seems that upper respiratory tract cancers would be more likely  to  be
causally related to formaldehyde exposure than other forms  of  cancer,
especially  as there is  experimental evidence providing  a  relatively
clear  suggestion  of  a possible  cancer  risk  for human  beings from
exposure  to  formaldehyde.   Besides  various  types  of  occupational
exposure,  smoking and other use of tobacco would have to be considered
as  potentially  confounding  factors, especially  when exerting strong
effects, such as those of tobacco smoking in relation to  lung  cancer.
Furthermore,  because  of the  formaldehyde  content of  mainstream and
environmental tobacco smoke, there is exposure of any  reference  popu-
lation, and this would mask effects with regard to cancers  that  might
be  related to  occupational or  other specified  exposure  to  formal-
dehyde.

    Some  excess of  nasal or  nasopharyngeal cancer  was  reported  in
relation  to formaldehyde  exposure in  6 of  the case-control  studies
reviewed.  In 2 other case-control studies, the question of a relation-
ship  with formaldehyde was  addressed either by  primary design or  by
reporting formaldehyde exposure, but no excess risk  was  demonstrated.
None of the cohort or PMR studies reviewed had adequate power to detect
even  a considerable increased risk  though, in aggregate, the  studies
might have had the power to reveal, at least, a higher risk  for  nasal
cancer. It should be noted that, with regard to nasal  and  nasopharyn-
geal  cancer, smoking is  not likely to  exert any particularly  strong
confounding  effect,  since the  relationship  between these  types  of
cancer  and smoking is only moderately strong, i.e., a risk ratio of up
to about five, and considerably less in many studies.

    Cancers  of the  buccal cavity  and pharynx  have either  not  been
included  in studies or else the risk has appeared approximately normal
in  some case-control  studies.  There  was no  excess in  the  largest
cohort,  though an excess had appeared in other studies involving small
numbers.

    Some  excess respiratory cancer appeared in 3 case-control studies,
but  these studies were based on small numbers.  Two other studies came
out  as non-positive.   Four of  the cohort  and PMR  studies that  had
adequate power and were designed to elucidate the risk  of  respiratory
cancer  from formaldehyde exposure showed an excess risk (significantly
high in workers producing resins containing formaldehyde,  Bertazzi  et
al., 1986). There was an excess of laryngeal cancer in one study. Seven
studies with reasonable power were either negative or non-positive with
regard to respiratory cancer.  The deviations in both  directions  from
the  expected in these  studies are explicable  by lack of  control for
smoking and/or the so-called "healthy worker effect" due to  lack  of
comparability of the study population with the general population.

    The  incidence of leukaemia was  increased in all the  studies with
reasonable numbers and was significantly high in one study.   Three  of
these  studies  involved either  embalmers  or anatomists,  which might
suggest  the  operation  of  some  other  alternative  or  contributing
etiological factors.  Similarly, a confounding effect from  some  other
factors  might be suspected with  regard to the relation  between brain

cancer  (which  was found  in significant excess  in some studies)  and
social  class.   An  excess of  colon  cancer  among embalmers  must be
considered against a recently observed association between this type of
cancer and sedentary work.  Of the other cancer forms  previously  men-
tioned  as  appearing  in excess in more than one study, cancers of the
skin,  bladder, kidney, and prostate, as well as Hodgkin's disease, are
represented  by small numbers and/or  small excesses.  However, in  one
study based on 23 cases, prostate cancer was significantly high but not
skin  cancer, whereas in  another study on  embalmers, skin cancer  was
significantly high but not prostate cancer.

    The available human evidence indicates that formaldehyde  does  not
have  a high carcinogenic potential. There are some studies which indi-
cate  an excess of nasal and/or nasopharyngeal tumours in exposed indi-
viduals  or  population  though the  relative  risks  are, in  general,
small.

    Given  the relative rarity of tumours in the biologically plausible
area  of  the upper  respiratory tract, and  the widespread past  occu-
pational exposures to formaldehyde in various work situations,  it  can
be concluded that formaldehyde is, at most, a weak human carcinogen.

    Human  exposure to formaldehyde should  be minimized, not only  for
its probable carcinogenic effect, but also for its potential for tissue
damage.   One practical way of  moving towards an effective  preventive
strategy would be to control the formaldehyde level in the  work  place
below that likely to produce a significant irritant effect.

    The  epidemiological studies on  carcinogenicity that contain  some
exposure assessments imply that, in the past, working populations show-
ing an excess of nasal epithelial tumours had generally been exposed to
formaldehyde levels in excess of the tissue-damage threshold.   Such  a
threshold is probably about 1.0 mg/m3 (range 0.5-3 mg/m3).

    With  regard to  atmospheric exposure  limit values  for odour  and
sensory  irritation for the  general population and  the non-industrial
indoor  environment,  formaldehyde  concentrations  should  not  exceed
0.1 mg/m3.     In the  case of  specially sensitive  groups  that  show
hypersensitivity  reactions  without immunological  signs, formaldehyde
concentrations   should  be  kept  to a minimum  and should not  exceed
0.01 mg/m3.

    To  avoid strong sensory reactions in work-place environments where
formaldehyde   is  being  produced  or used, peak  concentrations above
1.0 mg/m3 should  not be allowed and mean concentrations should be kept
below 0.3 mg/m3.

10.2  Evaluation of Effects on the Environment

    Formaldehyde is present in the environment as a result  of  natural
processes  and from man-made  sources; the quantities  produced by  the
former  greatly  exceed  those  from  the  latter.   Nevertheless,  the
compound  should be considered as an environmental contaminant, because
it has been detected at levels higher than background concentrations in
areas influenced by man-made sources. Air is the most relevant compart-
ment  in the formaldehyde cycle,  as most of the  formaldehyde produced

and/or emitted enters the atmosphere and this is also where most of the
degradation  processes occur.  The half-life of formaldehyde in the air
is short, due to photodegradation.  Formaldehyde is also biodegraded in
water  and  soil  in a relatively short time and does not accumulate in
organisms.  Data available for ecotoxicological assessment refer almost
exclusively  to formaldehyde in water.   It can be classified  as toxic
for aquatic biota, with a lowest acute effect level for several aquatic
organisms of about 1 mg/litre.  However, fish seem to be more tolerant.
No long-term toxicity tests have been performed, but the possibility of
elimination via biodegradation, the low bioaccumulation factor, and the
ability  of  organisms to  metabolize  formaldehyde, suggest  that  its
impact  on the aquatic environment would be limited, except in the case
of  massive discharge.  With regard to the terrestrial environment, the
lack  of ecotoxicological data gives  rise to concern, because  most of
the  formaldehyde  is distributed  in the air.   However, it should  be
noted  that photooxidation in air  is the main degradation  process and
that  the reaction is fast.   Data on the effects  on plant foliage  of
exposure to peak concentrations of formaldehyde could be  of  relevance
for a complete evaluation, though the highest  concentrations  detected
have not lasted for very long.

10.3  Conclusions

 -  Formaldehyde occurs naturally and is a widely  produced  industrial
    chemical.

 -  Formaldehyde is a product of normal metabolic pathways.

 -  Formaldehyde  undergoes rapid decomposition and does not accumulate
    in the environment.

 -  Major sources of formaldehyde are:

    -   automobile and aircraft exhaust emissions;
    -   tobacco smoke;
    -   natural gas;
    -   fossil fuels;
    -   waste incineration; and
    -   oil refineries.

 -  Formaldehyde  exposure varies widely  because of local  variations.
    Significant  levels of formaldehyde  have been reported  in  indoor
    air.   Among the sources are tobacco smoke, building and furnishing
    materials, and disinfectants.

 -  In work places, exposure may occur during the production  or  hand-
    ling of formaldehyde or products containing formaldehyde.

 -  The  most prominent features of formaldehyde vapour are its pungent
    odour  and  its irritant  effects on the  mucosa of eyes  and upper
    airways.   Odour-detection thresholds are generally  reported to be
    in the range of 0.1-0.3 mg/m3.

 -  Eye  and respiratory-tract irritation generally occurs at levels of
    about  1 mg/m3,   but discomfort  has been reported  at much  lower
    levels.

 -  Direct  contact with formaldehyde  solutions (1-2%) may  cause skin
    irritation  in approximately 5% of patients attending dematological
    clinics.

 -  Long-term  exposure can lead  to allergic contact  dermatitis; this
    has  been  demonstrated for  formaldehyde  solution only,  not  for
    gaseous formaldehyde.

 -  Reversible  airways  obstruction  has  been  produced  by  irritant
    concentrations of formaldehyde.

 -  Long-term    exposure   to  formaldehyde  at  a  level  as  low  as
    0.5 mg/m3 may cause a slight elevation in airway resistance.

 -  Formaldehyde-related  asthma has rarely  been reported despite  the
    widespread population exposure to formaldehyde.

 -  To avoid adverse reactions in dental surgery practice,  root  canal
    sealers  should  not  be extruded  beyond  the  apex in  short-term
    exposure situations.

 -  There is no convincing evidence that formaldehyde is  a  teratogen,
    in either animals or human beings.

 -  Formaldehyde has not produced any adverse effects  on  reproduction
    in test animals or in human beings.

 -  Formaldehyde  is positive  in a  wide range  of  mutagenicity  test
    systems  in  vitro ;  results  of  in  vivo test  systems  are   con-
    flicting.

 -  Formaldehyde  has  been shown  to  form DNA-protein  crosslinks   in 
     vitro and  in  vivo .  In vivo , this  has been shown to  occur at an
    exposure concentration of 1.1 mg/m3.

 -  Formaldehyde interferes with DNA repair in human cells  in vitro .

 -  Following inhalation exposure at levels causing cell damage, a sig-
    nificant  incidence of squamous cell carcinomas of the nasal cavity
    was induced in 2 strains of rats.

    Nasal  tumours in mice have  also been reported, but  the incidence
    was  not statistically significant.  There were no tumours at other
    sites.
    
    A  limited number of forestomach  papillomas have been reported  in
    rats  following  administration  of formaldehyde  in  the drinking-
    water.

    Formaldehyde-related  tumours were not observed  beyond the initial
    site of contact.

 -  Although an excess has been reported for a number of  cancers,  the
    evidence for a causal role of formaldehyde is likely only for nasal
    and nasopharyngeal cancer.

11.  RECOMMENDATIONS

11.1  Recommendations for Future Research

 -  The   absolute   detection  and   recognition  thresholds  for
    formaldehyde  should  be determined.   Psychophysical function
    relating  the  perceived  irritation to  the  concentration of
    formaldehyde  should be determined.  Special  attention should
    be  given to low-concentration effects on the skin of the face
    (cheeks,  eyes)  for both  surface  exposure and  inhaled  air
    mixtures.   The possible potentiation of sensory irritation by
    formaldehyde  at low concentrations should be further investi-
    gated  in mixtures of  irritants with different  durations  of
    exposure.   Sensory  effects,  when human  beings  are exposed
    either to air containing formaldehyde or air  without  formal-
    dehyde, should be compared.

 -  The  link  between the  perception  of irritation  and  hyper-
    reactivity   and  allergic  reactions  to  formaldehyde  needs
    further  study, in order to  evaluate fully the health  impli-
    cations of sensory effects.

 -  General interaction effects of physical, environmental factors
    (humidity,  radiant  heat, temperature,  etc.) and low-concen-
    tration  formaldehyde  exposure  should be  investigated  with
    regard to odour and sensory irritation.

 -  The combined effects of skin exposure to  formaldehyde  vapour
    and  inhalation exposure, on various  symptoms, including sen-
    sory  irritation, feeling of warmth on the skin surface, qual-
    ity  of tactile perception, itching, tickling, and smarting of
    the eyes, need investigation.  Both air and  contact  exposure
    of  various body  skin sites  to formaldehyde  at low  concen-
    trations  should be studied  for sensory effects  and irritant
    contact  dermatitis.  The interaction effects  of various host
    factors, such as age, psychological stress, skin disease, skin
    sensitivity,  genetic  factors  (e.g., atopic),  and  hormonal
    balance, should be studied.

 -  the possible production of antibodies (IgE or other)  to  for-
    maldehyde  should be investigated.  The detection of IgE anti-
    bodies by RAST should be included.

 -  Workers, who have undergone long-term exposure to formaldehyde
    should be examined for immunological effects, including clini-
    cal and laboratory findings.

 -  Animal  studies  on the  induction  of antibodies  and T-cells
    specifically reacting with formaldehyde should be undertaken.

 -  More  knowledge is needed  about the factors  involved in  the
    induction  of an irritant contact  dermatitis by formaldehyde,
    dependent  on  occupational  and/or other  factors.   Research
    should  be directed to the formaldehyde concentrations produc-
    ing  such effects as well as to the skin parameters condition-
    ing the start of the irritative skin contact reaction.

 -  Mechanisms  involved  in the  carcinogenicity of formaldehyde,
    such as the effectiveness of mucus as a barrier, the genotoxic
    consequences  of  DNA-protein  cross-links, and  the  role  of
    tissue damage, should be studied in more detail.

 -  More knowledge is needed on the interactions  of  formaldehyde
    with other air pollutants.

 -  Further  epidemiological studies are needed  including studies
    on  groups of people believed to be susceptible to the effects
    of formaldehyde.

 -  There  is a need  for extensive follow-up  studies on  working
    populations  already  investigated  (maybe  in  excess  of  20
    years),  because a long minimum latent period may be a feature
    of  the response  of the  human nasal  epithelium  to  cancer-
    causing agents.

 -  Epidemiological   studies  should  also  be  re-evaluated  for
    mortality  due to cancers  of the buccal  cavity and  pharynx,
    (human beings are not obligate nose breathers).

11.2  Recommendations for Preventive Measures

    To prevent unacceptable risks, exposure to cytotoxic concentrations
of formaldehyde should be avoided.

    It  is  recommended  that consumer  goods  containing  formaldehyde
should  be labelled, in  order to protect  persons with a  formaldehyde
allergy.

(a) Indoors:

    The formaldehyde air concentration allowed in living, sleeping, and
working rooms should not be higher than 0.12 mg/m3,   in order to mini-
mize the risk of repeated or continuous low concentration  exposure  to
formaldehyde.

(b) Occupational areas:

    It  is  recommended that  formaldehyde  concentrations in  the work
place  air  should  be reduced  to  non-toxic  concentrations.   A  no-
observed-adverse-effect  level in monkeys was  1.2 mg/m3 (1 ppm).   For
protective reasons, the concentration at the work place should be below
1.2 mg/m3 (1 ppm).

    The  exposure may reach a  maximum of 1.2 mg/m3 (1 ppm)  for  5 min
with not more than 8 peaks in one working period (up to 8 h).

(c) Cosmetics:

    Formaldehyde  concentrations in cosmetics (creams)  that are higher
than 0.05% should be labelled and levels should be limited to  0.1%  in
oral cosmetics.

    The  upper-level for the use  of formaldehyde as a  preservative in
cosmetics should be 0.2%, except in nail hardeners, which  may  contain
up to 5% formaldehyde.

(d) Hospitals:

1)  Because of the sensitizing effect, skin contact  with  formaldehyde
    should be avoided by wearing impermeable gloves.

2)  Thermal  procedures are preferred for the disinfection or steriliz-
    ation of appliances and instruments.  Closed containers  should  be
    used in the disinfection of instruments using  formaldehyde.  Incu-
    bators, scopes, and tubes should not be treated with formaldehyde.

3)  Thermal laundering procedures are preferred for the disinfection of
    clothing. Any "tub-disinfection" of clothing in formaldehyde sol-
    ution  should be exceptional. The tub must be closed with a lid. On
    handling  clothing, gloves (and eventually  respirators)  should be
    worn.

4)  Steam disinfecting is the method of choice for mattresses; spraying
    with  disinfectants is obsolete.  Mattresses covered with synthetic
    materials  can be disinfected by wiping with formaldehyde solution,
    providing ventilation is sufficient.

5)  Area  disinfection:  Wiping  or  scrubbing  is  recommended,  while
    spraying  with formaldehyde-containing solutions should be confined
    to  non-accessible  places.   Direct contact  with the disinfectant
    should  be avoided by the use of gloves. Large-area disinfecting, -
    laboratories  etc., should be  scheduled for off-work  times.  Suf-
    ficient ventilation is mandatory.

6)  Fixation of tissues in formalin baths should be performed in closed
    containers and/or using an exhaust hood. If possible, tissue slices
    should  be washed with  water, to remove  superfluous formaldehyde,
    before viewing them under the microscope.

12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    In  1983,  a  WHO Study  Group  reviewed  formaldehyde in  order to
recommend  a health-based occupational exposure limit (WHO, 1984).  The
recommendations were as follows:

        "The Study Group recommends a short-term (15 minutes), health-
    based occupational exposure limit for formaldehyde in air of 1.0 mg
    of formaldehyde per m3 of air.

        "A  tentative health  based exposure limit of 0.5 mg of formal-
    dehyde  per m3 of  air  is recommended as  an 8-hour  time-weighted
    daily average during a 40-hour working week.

        "In view of the reported dose-dependent carcinogenic effect of
    formaldehyde in the rat, and the present inadequate epidemiological
    data on the cancer risk in man, it is advisable to reduce workplace
    exposure to formaldehyde to the lowest feasible level."

    The  carcinogenic  risks  for human  beings  were  evaluated by  an
International  Agency  for Research  on Cancer ad  hoc expert group  in
1981.   The evaluation was  updated in 1987  and it was  concluded that
there was limited evidence for carcinogenicity to humans and sufficient
evidence for carcinogenicity to animals (IARC, 1987).

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    See Also:
       Toxicological Abbreviations
       Formaldehyde (HSG 57, 1991)
       Formaldehyde (ICSC)
       Formaldehyde  (SIDS)
       Formaldehyde (CICADS 40, 2002)
       Formaldehyde (IARC Summary & Evaluation, Volume 62, 1995)
       Formaldehyde (IARC Summary & Evaluation, Volume 88, 2006)