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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 24




    TITANIUM









    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, 1982


         The International Programme on Chemical Safety (IPCS) is a
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        ISBN 92 4 154084 2        

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR TITANIUM

1. SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES

    1.1. Summary
         1.1.1. Properties and analytical methods
         1.1.2. Sources and uses
         1.1.3. Environmental levels and exposures
         1.1.4. Chemobiokinetics and metabolism
         1.1.5. Effects on experimental animals and man
         1.1.6. Evaluation of health risks
    1.2. Recommendations for further studies

2. PROPERTIES AND ANALYTICAL METHODS

    2.1. Chemical and physical properties
    2.2. Analytical methods
         2.2.1. Air analysis
         2.2.2. Water analysis
         2.2.3. Food analysis
         2.2.4. Analysis of biological materials

3. SOURCES OF ENVIRONMENTAL POLLUTION

    3.1. Natural occurrence
    3.2. Industrial production
    3.3. Uses of titanium
    3.4. Disposal of wastes

4. ENVIRONMENTAL LEVELS AND EXPOSURES

    4.1. Levels in air, soil, water, and other media
         4.1.1. Air
         4.1.2. Soils and sediments
         4.1.3. Water
         4.1.4. Plants
         4.1.5. Food
    4.2. Occupational exposure
    4.3. Cosmetic and medical uses
    4.4. Estimate of exposure of man through environmental media

5. CHEMOBIOKINETICS AND METABOLISM

    5.1. Absorption, distribution, and excretion
         5.1.1. Animal studies
         5.1.2. Human studies
         5.1.3. Biological half-life

6. EFFECTS ON ANIMALS
    6.1. Acute toxicity
    6.2. Subacute toxicity
    6.3. Long-term toxicity
    6.4. Mutagenicity
    6.5. Carcinogenicity
    6.6. Teratogenicity and effects on reproduction

7. EFFECTS ON MAN - CLINICAL AND EPIDEMIOLOGICAL STUDIES

    7.1. Clinical studies
    7.2. Epidemiological studies

8. EVALUATION OF HEALTH RISKS TO MAN

REFERENCES

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TITANIUM

 Members

Professor M. Berlin, Institute of Environmental Health,
 University of Lund, Lund, Sweden

Dr R. Dolgner, Medical Institute for Environmental Hygiene,
 Dsseldorf, Federal Republic of Germany

Dr G.J. Van Esch, State Institute of Public Health, Bilthoven,
 Netherlands

Professor A. Furst, Institute of Chemical Biology, Harney
 Science Center, University San Francisco, California, USA

Dr J.K. Piotrowski, Department of Chemical Toxicology,
 Institute of Environmental Research & Bioanalysis, Medical
 Academy of Lodz, Poland


 Representatives of Other Agencies

Dr W. Hunter, Health and Safety Directorate, Commission of the
 European Communities, Luxembourg

 Observer

Dr E. Loeser, Institute for Toxicology, Wuppertal, Federal
 Republic of Germany


 Secretariat

Dr Y. Hasegawa, Medical Officer, Control of Environmental
 Pollution and other Hazards, Division of Environmental

Dr R. Horton, WHO Collaborating Center for Air Pollution
 Control, National Environmental Research Center, Research
 Triangle Park, NC, USA  (Temporary Adviser)
 Health Organization, Geneva, Switzerland

Dr V.B. Vouk, Chief, Control of Environmental Pollution and
 other Hazards, Division of Environmental Health, World Health
 Organization, Geneva, Switzerland  (Secretary)a

-----------------------------------------------------------
a Present address: National Institute for Environmental
  Health Sciences, Department of Health and Human Services,
  Research Triangle Park, North Carolina, USA.

NOTE TO READERS OF THE CRITERIA DOCUMENTS                          
                                                                   
    While every effort has been made to present information in the 
criteria documents as accurately as possible without unduly        
delaying their publication, mistakes might have occurred and are   
likely to occur in the future.  In the interest of all users of the
environmental health criteria documents, readers are kindly        
requested to communicate any errors found to the Division of       
Environmental Health, World Health Organization, Geneva,           
Switzerland, in order that they may be included in corrigenda which
will appear in subsequent volumes.                                 
                                                                   
    In addition, experts in any particular field dealt with in the 
criteria documents are kindly requested to make available to the   
WHO Secretariat any important published information that may have  
inadvertently been omitted and which may change the evaluation of  
health risks from exposure to the environmental agent under        
examination, so that the information may be considered in the event
of updating and re-evaluation of the conclusions contained in the  
criteria documents.                                                

                         *   *   *


     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. 988400 -
985850).

ENVIRONMENTAL HEALTH CRITERIA FOR TITANIUM

    Further to the recommendations of the Stockholm United Nations 
Conference on the Human Environment in 1972, and in response to a 
number of World Health Assembly resolutions (WHA23.60, WHA24.47, 
WHA25.58, WHA26.68) and the recommendation of the Governing 
Council of the United Nations Environment Programme, (UNEP/GC/10, 3 
July 1973), a programme on the integrated assessment of the health 
effects of environmental pollution was initiated in 1973.  The 
programme, known as the WHO Environmental Health Criteria 
Programme, has been implemented with the support of the Environment 
Fund of the United Nations Environment Programme.  In 1980, the 
Environmental Health Criteria Programme was incorporated into the 
International Programme on Chemical Safety (IPCS).  The result of 
the Environmental Health Criteria Programme is a series of criteria 
documents. 

    The first draft of the present document was prepared by 
Dr L. Fishbein, National Center for Toxicological Research, US Food 
and Drug Administration, Jefferson, AZ, USA.  The draft was 
reviewed by the Task Group on Environmental Health Criteria for 
Titanium and then revised and updated by Dr H. Nordman, Institute 
of Occupational Health, Helsinki, Finland.  Finally, the revised 
document was circulated to the members of the Task Group for their 
comments, in March 1982. 

    The Secretariat wishes to thank Dr H. Nordman for his help in 
the preparation and scientific editing of the final draft. 

    The document is based primarily on original publications listed 
in the reference section.  However, several publications reviewing 
the health effects of titanium have also been used.  These include 
reviews by Berlin & Nordman (1979), Browning (1969), CEC (1974), 
Katari et al. (1977), Lynd & Hough (1980), Schroeder et al. (1963), 
Stamper (1970), Stokinger (1963), US EPA (1973), Valentin & 
Schaller (1980), and Vinogradov (1959). 

    Details of the WHO Environmental Health Criteria Programme, 
including definitions of some of the terms used in the documents, 
may be found in the general introduction to the Environmental 
Health Criteria Programme, published together with the 
environmental health criteria document on mercury ( Environmental 
 Health Criteria I - Mercury, Geneva, World Health Organization, 
1976) and now available as a reprint. 


                             *  *  *


    Partial financial support for the development of this criteria 
document was kindly provided by the Department of Health and Human 
Services through a contract from the National Institute of 
Environmental Health Sciences, Research Triangle Park, North 
Carolina, USA - an IPCS Lead Institution. 

1.  SUMMARY AND RECOMMENDATIONS FOR FURTHER STUDIES

1.1.  Summary

1.1.1.  Properties and analytical methods

    Titanium is a grey metal with an atomic number of 22 and a 
relative atomic mass of 47.9.  It is extremely resistant to 
corrosion and, in the form of a powder or dust, is highly flammable 
and explosive.  The most common oxidation state of titanium is +4, 
but +3 and +2 states also exist.  Titanium occurs in both a cationic 
state (e.g., titanium chlorides, phosphates, and sulfates) and an 
anionic state (e.g., calcium, iron, and sodium titanates).  Metallic 
titanium, titanium dioxide, and titanium tetrachloride are the 
compounds most widely used in industry. 

    A wide variety of analytical methods has been used for the 
determination of titanium in various media.  Spectrographic and 
photometric methods have been employed for the determination of 
titanium in food and water.  X-ray fluorescence and neutron 
activation analysis have been widely used for the measurement of 
titanium in air.  Spark-source mass spectrography has been used to 
determine titanium in biological samples, food, and water.  Titanium 
does not easily atomize and has a tendency to form refractory 
oxides, which may influence the use of atomic absorption assays. 
The detection limit for titanium in air using atomic absorption 
spectrophotometry (AAS) is about 0.07 g/m3.  Using X-ray 
fluorescence for the determination of titanium in air, a detection 
limit of 0.011 g/m3 can be achieved; for human tissues, a 
detection limit of 0.3 mg/kg has been reported.  Proton-induced 
X-ray emission spectrometry can be used for the determination of 
titanium in air and water. 

1.1.2.  Sources and uses

    Titanium, the ninth most abundant element in the earth's crust, 
is widely distributed.  Metallic titanium is mainly used in the 
aircraft industry and in the production of high-strength, 
corrosion-resistant alloys.  It is also used in the chemical 
industry as a lining material, because of its corrosion-resistant 
properties.  Titanium dioxide is extensively used as a white 
pigment in paints, enamels, plastics, and cosmetics as well as a 
colouring agent in food.  Titanium carbide is important in the 
production of cutting tools.  Titanium tetrachloride is the common 
intermediate in the production of titanium catalysts and is also 
used for the synthesis of organic titanium compounds.  Smaller 
amounts of titanium compounds are used in the electrical and dyeing 
industries. 

    The main sources of contamination of the general environment 
with titanium are the combustion of fossil fuels and the 
incineration of titanium-containing wastes.  In occupational 
settings, exposure mainly occurs during the processing of titanium-
containing minerals, metallic titanium, and titanium dioxide. 

1.1.3.  Environmental levels and exposures

    Owing to its great affinity for oxygen and other elements, 
titanium does not exist in the metallic state in nature.  The 
average concentration in the earth's crust is 4400 mg/kg.  Titanium 
concentrations in the urban air are mostly below 0.1 g/m3, though 
levels exceeding 1.0 g/m3 have been reported, especially in 
industrialized areas.  In rural air, concentrations are still 
lower.  In working environments, the air concentration may reach 
several mg/m3.  The titanium concentration in drinking-water 
supplies is generally low, having an approximate range of 0.5-15 
g/litre.  Large variations in the concentrations of titanium in 
different types of foods have been reported.  A typical diet may 
contribute some 300-400 g/day, but higher intakes ranging up to 2 
mg per day have been reported. 

1.1.4.  Chemobiokinetics and metabolism

    Quantitative information on absorption through inhalation is 
lacking.  Absorption of titanium from the gastrointestinal tract 
takes place, but the extent of this absorption is not known.  Based 
on average titanium concentrations found in human urine of about 10 
g/litre, it can be calculated that the absorption is about 3%, 
assuming a daily intake of at least 500 g. 

    The highest concentrations of titanium have usually been found 
in the lungs, followed by the kidney and liver.  In most studies on 
concentrations of titanium in blood, levels reported have been 
about 0.02-0.07 mg/litre.  Titanium crosses the blood-brain barrier 
and is also transported through the placenta into the fetus.  It 
seems to accumulate with age in the lungs, but not in other organs. 
In the two reports available, the biological half-life for titanium 
in man has been calculated to be about 320 days and 640 days, 
respectively. 

    Most ingested titanium is eliminated unabsorbed.  In man, 
titanium is probably excreted with urine at an approximate average 
rate of 10 g/litre.  Excretion by other routes is unknown. 

1.1.5.  Effects on experimental animals and man

    There is no evidence of titanium being an essential element for 
man or animals. 

    Studies on experimental animals as well as human clinical 
studies have shown that titanium in implants and prostheses is 
extremely well tolerated by osseous and soft tissues.  This is 
shown by lack of irritation, normal wound-healing, and 
encapsulation of the metal by fibrous tissues.  Titanium dioxide, 
salicylate, oxide, and tannate have been used in various 
dermatological and cosmetic formulations, without any known adverse 
effects.  However, exposure to different titanium compounds appears 
to induce various levels of slight pulmonary fibrosis. 

    Titanium dioxide is a frequently used compound in lung 
clearance studies, where a biologically inert substance is 
required.  Acute and subacute toxicity studies have not shown any 
detrimental effects of titanium dioxide in the lungs.  In some 
experimental studies in which rats and guinea-pigs were exposed to 
titanium dioxide dusts, slight fibrosis was occasionally found in 
the lung tissue.  However, the exposure in these studies was not to 
pure titanium dioxide and a possible explanation for the fibrogenic 
activity may be concomitant exposure to other elements, such as 
silica (SiO2).  Autopsy studies on workers exposed to titanium 
dioxide for long periods have not shown any evidence of fibrogenic 
activity.  This is consistent with the few epidemiological surveys 
made on working populations exposed to titanium dioxide dusts.  In 
one report, slight fibrosis was observed, but this may have been 
due to the coating material containing aluminium silicate rather 
than the titanium dioxide. 

    In studies on rats, intratracheal administration of 50 mg of 
titanium nitride induced a weak fibrogenic effect after 6 months. 
Slight fibrosis was detected in similar studies in which rats were 
exposed to titanium hydride, boride, or carbide.  Data on the 
exposure of man to such titanium compounds are lacking. 

    Results of long-term toxicity studies showed that titanium, in 
the form of a soluble salt, administered to mice in the drinking-
water at a concentration of 5 mg Ti/litre from weaning to natural 
death, did not significantly affect life span.  Feeding technical 
grade titanium dioxide to guinea-pigs (0.6 g/day), rabbits (3 
g/day), cats (3 g/day), and one dog (9 g/day) for 390 days did not 
cause any adverse effects in the animals.  Few data exist on the 
systemic effects of titanium and its compounds.  Intratracheal 
administration of 50 mg of titanium hydride to rats induced 
dystrophic changes in the myocardium, liver, and kidneys.  Similar 
effects were seen after administration of titanium boride or 
carbide to rats. 

    A dose-related mortality rate was found in mice exposed to 
hydrolytic products of titanium tetrachloride through inhalation 
for 2 h (titanium compounds plus hydrochloric acid). 

    Accidental splashing of workers with titanium tetrachloride and 
exposure to aerosols of titanic acid and titanic oxychloride led to 
skin burns with scarring, and congestion of the mucosa in the upper 
respiratory tract, followed later by cicatrization and laryngeal 
stenosis.  Accidental exposure to liquid titanium tetrachloride, 
which was then washed off, resulted in severe burning of the skin, 
due to an exothermic reaction between the titanium tetrachloride 
and water. 

    The only carcinogenic effect of titanium, so far reported, 
consisted of the development of fibrosarcomas at the site of 
injection in rats injected with either titanium metal or titanocene 
suspended in trioctanoin. 

    In a 3-generation study on rats, titanium potassium oxalate (5 
mg/litre) in the drinking-water caused a marked reduction in the 
numbers of animals surviving to the third generation. 

1.1.6.  Evaluation of health risks

    Titanium compounds are poorly absorbed from the gastro-
intestinal tract, which is the main route of exposure for the 
general population.  Available data on the occurrence of titanium 
and titanium compounds in the environment, as well as data on 
toxicity, indicate that the current level of exposure of the 
general population does not present a health risk.  In the 
occupational environment, exposure occurs through inhalation and 
titanium is retained in the lungs.  Dose-effect and dose-response 
relationships have not yet been established for any of the effects 
of various titanium compounds. 

    Titanium metal in surgical implants is well tolerated by 
tissues and titanium compounds, such as titanium dioxide, 
salicylate, and tannate, have been used in cosmetics and in 
pharmaceutical and food products, without any reported adverse 
effects. 

    A variety of animal and human studies have shown that inhaled 
titanium dioxide is biologically inert.  Weak fibrosis, found in 
association with exposure to various titanium dusts, is likely to 
be due to concomitant exposure to other components rather than to 
the titanium dioxide. 

    According to animal studies, titanium nitride, hydride, 
carbide, and boride may have fibrogenic effects.  These compounds 
have also been observed to cause liver and kidney dystrophy. 
Titanium tetrachloride causes skin burns and is strongly irritant 
to mucous membranes and the eyes.  Powdered titanium metal may 
induce fibrosarcomas and lymphosarcomas in rats, when injected 
intramuscularly, but there is no evidence of titanium being 
carcinogenic in man. 

    Administration of a soluble titanate disturbed reproduction in 
a 3-generation study on rats.  Teratogenic effects of titanium have 
not been reported. 

1.2.  Recommendations for Further Studies

    There is not sufficient information available on titanium, to 
estimate the actual exposure of the general population from all 
environmental media.  Dose-effect and dose-response relationships 
have not been established and it is therefore proposed that more 
information be generated to cover the following aspects: 

(a) environmental aspects; size distribution of particles in
    ambient and occupational environments;

(b) metabolic aspects; balance studies including metabolic
    mechanisms;

(c) toxicological aspects; effects of various types of
    titanium dust, taking into account differences in crystal
    lattices; effects of titanium compounds such as the
    nitride, hydride, boride, and carbide in short- and
    long-term studies;

(d) occupational aspects; effects of exposure to titanium
    tetrachloride and organotitanium compounds.

2.  PROPERTIES AND ANALYTICAL METHODS

2.1.  Chemical and Physical Properties

    Titanium (atomic number 22; relative atomic mass 47.90; density 
4.507 g/cm3 at 20C) is a silvery grey metal in group IV of the 
periodic table and is a member of the first transition series of 
elements.  Titanium has both metallic and non-metallic 
characteristics.  Its most common oxidation state is +4 (titanic 
compounds), but +3 (titanous compounds) and +2 forms are also 
known, in addition to oxy forms such as titanyl chloride (TiOCl2). 
The metallic characteristics of titanium are shown in compounds 
such as titanium chloride, phosphate, sulfate, and nitrate, whereas 
the non-metallic characteristics are exhibited in a series of 
titanates, e.g., calcium, iron, and sodium titanates.  Titanium(IV) 
compounds are easily hydrolysed into titanium dioxide (Stamper, 
1970; ACGIH, 1973; Weast, 1980). 


Table 1.  Some physical and chemical data on titanium and selected titanium 
compoundsa
-------------------------------------------------------------------------
Compound          Melting    Boiling             Solubility              
                  point      point      Soluble        Insoluble
                  (C)       (C)
-------------------------------------------------------------------------
Titanium (Ti)     166010    3297       dilute acids   cold & hot water

- dioxide (TiO2)  1830-1850  2500-3000  alkalies,      cold & hot water
                                        sulfuric acid

- tetrachloride   -25        136.4      cold water,    decomposes in hot
  (TiCl4)                               alcohol,       water
                                        dilute hydro-
                                        chloric acid

- sulfate                               diluted acids  cold & hot water,
  (Ti[SO4]3)                                           alcohol, ether

- carbide (TiC)   314090    4820       aqua regia,    cold & hot water
                                        nitric acid
-------------------------------------------------------------------------
a Adapted from: Weast (1980).

    The metal is highly resistant to corrosion by many agents 
including concentrated nitric acid, 5% sulfuric acid, and sea 
water.  Titanium powders are highly pyrophoric and molten titanium 
burns in air.  Thus, an explosion hazard is associated with the 
production of the metal.  Titanium and its alloys may react 
strongly with oxidizing agents, especially when in the form of 
powdered metal (Mogilevskaja, 1972; ACGIH, 1973).  Titanium dioxide 
(TiO2) is a white, tasteless powder.  It exists in three crystalline 
forms; anatase, brookite, and rutile. 

    Titanium tetrachloride is a liquid, which is stable in dry air, 
but decomposes in cold water to form titanium oxide and hydrochloric
acid.  The physical and chemical properties of titanium and some of 
its compounds are listed in Table 1 (Stamper, 1970; Weast, 1980). 

    A large number of organotitanium compounds are known.  The most 
common types are the alkyl and aryl titanates of the general 
formula Ti(OR)4.  In addition, there are complex organic compounds 
of titanium such as titanocene.  Titanium has an atomic radius 
similar to, and thus is capable of substitution for, other 
transitional metals, e.g., vanadium, iron, cobalt, nickel, and zinc 
(Barksdale, 1966; Stamper, 1970; Katari et al., 1977). 

2.2.  Analytical Methods

    A wide variety of analytical procedures has been used for 
the determination of titanium in various media.  Spectrographic 
and photometric methods have been employed for the determination 
of titanium in food and water.  X-ray fluorescence has been 
widely used for the determination of titanium in air.  Neutron 
activation analysis has been employed to estimate titanium levels 
in air and spark-source mass spectrography to determine titanium 
concentrations in biological samples, food, and water. 

    Atomic absorption spectroscopy (AAS) is the generally preferred 
method for the determination of trace elements.  However, titanium 
is not easily atomized in flame media and has a tendency to form 
refractory oxides, which detracts from the usefulness of atomic 
absorption assays.  Nevertheless, a variety of atomic absorption 
techniques has been reported using high-temperature reducing flames 
such as the nitrous oxide-acetylene flame (Kirkbright et al., 
1969).  Slavin & Manning (1963) achieved a sensitivity of 12 
mg/litre (1% absorption) when determining titanium in an alcohol 
solution.  In order to obtain a higher sensitivity, indirect atomic 
absorption techniques have been developed.  The sensitivity 
obtainable in the AAS determination of molybdenum being higher 
than that of titanium, Kirkbright et al. (1969) used the 
molybdenumtitanium ratio (11:2) in molybdotitanophosphoric acid.  
The sensitivity obtained at 1% absorption was 0.0013 mg/litre.  An 
indirect method reported by Ottaway et al. (1970) is based on the 
enhancement of the atomic absorption signal of iron by titanium. 
This method is suitable for the determination of titanium in 
concentrations of 0.01-10 mg/litre.  Suppression of the absorbance 
of strontium by titanium was used by Chakrabarti & Katyal (1971) in 
an assay with which it was possible to determine titanium in 
concentrations of 0.2-10 mg/litre.  Atomic absorption spectrometry 
for the determination of titanium in pharmaceutical products has 
been reported by Mason (1980). 

    Potentiometric and photometric methods of titration have been 
reported for the determination of titanium but most of these 
methods are not very sensitive (Skaravskij, 1965; Ozawa, 1971). 

2.2.1.  Air analysis

    The determination of trace metal particulates, including 
titanium, in atmospheric samples by X-ray fluorescence (XRF) 
techniques has been widely reported (National Air Pollution 
Control Administration, 1969; Shono & Shinra, 1969; Dittrich & 
Cothern, 1971; Frigieri et al., 1972; Rhodes et al., 1972).  For 
example, trace metals collected on filter paper by a high volume 
air sampler for 25 h were analysed by Dittrich & Cothern (1971) 
using the XRF technique.  Elements in the periodic table between 
titanium and caesium were found to have a sensitivity limit of 
0.5 g/m3 of air.  The XRF technique has the advantage of being 
non-destructive, and a single analysis provides simultaneous 
estimates of several metals.  The method can be easily automated. 

    Rhodes et al. (1972) measured titanium among other elements in 
samples of suspended particulate matter, collected in 38 air 
quality control network stations in Texas.  The X-ray fluorescence 
method proved useful for air particulate survey measurements and 
for pollution source location.  No sample preparation was necessary. 
Once loaded with samples, the apparatus could operate unattended. 
The detection limit of XRF for titanium was 0.011 g/m3.  In an 
analytical study described by Giauque et al. (1974), sensitivities 
routinely established within a 20-min counting interval corresponded 
to less than 0.01 g/m3 of air.

    Non-destructive neutron activation analysis has also been used 
for the determination of trace elements in aerosols (Dams et al., 
1970, 1972; Zoller & Gordon, 1970; Harrison et al., 1971).  The 
multi-elemental specificity of activation analysis aids in the 
determination of the chemically complex and highly variable 
composition of an aerosol.  A useful irradiation-counting scheme 
and simplified flow diagram of automated spectrum analysis has been 
developed by Dams et al. (1970) with detection limits for titanium 
of the order of 0.2 g. 

    Most techniques in which neutron activation analysis is used 
require a large nuclear reactor, with the minimum flux for best 
overall performance acknowledged to be around 1012 neutrons/second 
per cm2.  However, it was suggested by Dittrich & Cothern (1971) 
that the future availability of californium (252Cf5) should provide 
adequate portable activation sources for atmospheric trace metal 
analysis. 

    The determination of a variety of metals in atmospheric 
particulate matter by atomic absorption spectroscopic (AAS) 
procedures has also been widely reported (Beyer, 1969; Burnham et 
al., 1970; Ranweiler & Moyers, 1974).  Ranweiler & Moyers (1974) 
described an AAS procedure for the determination of 22 metals 
including titanium in 24-h, high-volume samples of atmospheric 
particulate matter collected on a polystyrene filter.  The 
practical detection limit for titanium was 0.07 g/m3. 

    Johansson et al. (1975) used proton X-ray emission spectroscopy 
for the determination of titanium and 13 other elements in airborne 
particles.  In this method, particles were collected and segregated 
according to size, using cascade impactors. 

2.2.2.  Water analysis

    The determination of trace metals, including titanium, in water 
has been accomplished principally by X-ray fluorescence (Blasius et 
al., 1972), spectrography (Durum & Haffty, 1961), spark-source mass 
spectrophotometric (Crocker & Merritt, 1972; Hamilton & Minski, 
1972), and photometric techniques (Nikitina & Basargin, 1970). 
Elements in the periodic table between titanium and caesium were 
detectable by X-ray fluorescence with sensitivities of the order of 
30 g/kg for metals in the particulate form and 0.4 g/kg for 
metals in the ionic form (Blasius et al., 1972). 

    Problems with the XRF technique are primarily concerned with 
sample preparation and matrix effects.  However, the most important 
need defined by Blasius et al. (1972) was the determination of the 
chemical and/or the physical form in which the metal occurred.  It 
appeared that some of the metals were in the suspended state, while 
the rest were either ionized or attached to colloidal particles. 

    Proton-induced X-ray emission spectrometry has been used for 
the determination of titanium in water (Johansson, 1974; Johansson 
et al., 1975). 

    Crocker & Merrit (1972) and Hamilton & Minski (1972) used 
spark-source mass spectroscopy for the determination of trace 
elements, including titanium, in water.  A selective and sensitive 
photometric method employing tichromin was developed by Nikitina & 
Basargin (1970) for the determination of 0.1 mg titanium/litre in 
highly mineralized thermal waters of volcanic origin. 

2.2.3.  Food analysis

    Titanium levels in various food sources have mainly been 
determined by spectrographic and colorimetric techniques.  Emission 
spectrum analysis has been used for the determination of titanium 
in canned fruit and vegetable juices (Klyacko et al., 1971, 1972). 
The determination of titanium dioxide in cheese was accomplished by 
Leone (1973) using the procedure of Kolthoff & Sandell (1952) in 
which titanium solutions are treated with hydrogen peroxide and the 
resulting yellow-orange colour due to (TiO2(SO4)2) is measured 
spectrophotometrically. 

    The occurrence of titanium together with a large number of 
other chemical elements in samples of prepared diets from the 
United Kingdom and the possible relationship with environmental 
factors has been determined by Hamilton & Minski (1972/1973) using 
spark-source mass spectrometry (Hamilton et al. 1972/1973; Hamilton 
& Minski, 1972/1973) and X-ray fluorescence (Hamilton et al., 
1972/1973). 

2.2.4.  Analysis of biological materials

    Titanium in biological samples has mainly been determined by 
photometric (Lojko, 1967; Urusova, 1969; Mal'ceva, 1973a,b) and 
spectroscopic (Timakin & Bagdasarova, 1969; Cekotilo & Torohtin, 
1970) techniques.  Mal'ceva (1973a,b) determined titanium in ashed 
bone samples with a detection limit of 0.16 mg/kg of bone tissue, 
or 350 g/kg of biological material or litre of urine. 

    Titanium in tissues was measured by Schroeder et al. (1963) 
using chromotropic acid in a colorimetric microanalytical 
technique of Sandell (1959).  The method was sensitive to about 
0.025 mg/kg.  A colorimetric method using the sodium salt of 
chromotropic acid was used for the determination of titanium in 
biological samples by Urusova (1969). 

    The determination of titanium in excreta and human diets using 
arc-emission spectroscopy has been reported by Tipton & Stewart 
(1969) and Tipton et al. (1969).  The limits of detection expressed 
as mg/kg ash were: food sample, 2; faeces, 9; and urine, 0.03. 

    Carroll et al. (1971) described the use of electron probe 
microanalysis for the determination of localized concentrations of 
titanium in various human tissues, both normal and pathological, as 
well as in human blood, bone marrow, leukocytes, and lymph nodes. 
The estimated detection limit was about 10-8 g of metallic atoms 
per cell (Carroll & Tullis, 1968). 

    The concentration and distribution, in healthy human tissues, 
of a large number of stable elements including titanium was studied 
by Hamilton et al. (1972, 1973).  The methods of analysis were 
spark-source mass spectroscopy and X-ray fluorescence.  The 
detection limits for titanium in human tissues were 0.007 mg/kg for 
spark-source mass spectroscopy and 0.3 mg/kg wet weight for the XRF 
assay. 

    Alternating current polarographic determination of titanium in 
tissues has also been reported (Hoff & Jacobsen, 1971; Petit, 
1973). 

    A histochemical method for the identification of titanium and 
iron oxides in pulmonary dust deposits was described by DeVries & 
Meijer (1968).  The technique was especially developed for the 
study of pneumoconiosis in workers employed in industries 
processing these minerals.  In this procedure, the oxides are 
converted, under heating, into water-soluble sulfates by fumes of 
sulfuric acid, after which the corresponding sulfates are 
identified by staining reactions. 

3.  SOURCES OF ENVIRONMENTAL POLLUTION

3.1.  Natural Occurrence

    Titanium is the ninth most abundant element in the earth's 
crust.  It is widely distributed and occurs at an average 
concentration of 4400 mg/kg (Mason, 1966).  It is usually found 
in the form of stable minerals, e.g., the end products of the 
weathering of basic rocks, principally ilmenite and rutile, and 
in the form of impurities or dispersions in many aluminosilicates 
(Vinogradov, 1959).  Owing to its great affinity for oxygen and 
other elements, titanium does not exist in the metallic state in 
nature.  A variable amount of titanium occurs in unweathered 
particles of clay, in amphibole, laepidomelane, and micas (Joffe & 
Pugh, 1934).  The most common titanium minerals are ilmenite 
(TiFeO3), which can contain a maximum concentration of titanium 
dioxide (TiO2) of 530 g/kg, and rutile, which is 100% titanium 
dioxide.  Titanium-bearing minerals such as anatase and brookite 
are associated with ilmenite and rutile.  Other titanium minerals 
are known which are locally abundant in some deposits, but have not 
been used commercially.  These include sphene (CaTiSiO5), 
pyrophanite (MnTiO3), and perovskite (CaTiSiO5) (Stamper, 1970). 

    Both rock and sand deposits contain titanium minerals of 
economic importance.  Some sand deposits containing less than 1% 
of titanium dioxide are commercially workable, if the principal 
titanium mineral is rutile.  Titanium also occurs to a lesser 
degree in rocks such as brookite, anatase, and in feldspars, micas, 
biotites, and others in the form of isomorphic impurities.  Rutile, 
ilmenite, brookite, and other common titanium minerals accumulate 
in sedimentary rocks and sometimes in certain soils as the end 
products of metamorphism of titanium-containing minerals and rocks. 
It is present in the form of titanium(IV) compounds; the rarer 
oxidation form of titanium(III) is also known in certain iron 
minerals as are complex titanium(IV) compounds (Vinogradov 1959; 
Stamper, 1970).  Titanium levels in coal and oil have been reported 
to average 500 and 0.1 mg/kg, respectively (Bertine & Goldberg, 
1971). 

3.2.  Industrial Production

    Titanium is mined commercially from rock and sand deposits by 
open-pit and dredging operations.  Mechanical beneficiation methods 
are used for concentrating the major minerals, ilmenite and rutile. 
The production of elemental titanium is a comparatively difficult 
process since titanium in the molten state has a great affinity for 
oxygen, nitrogen, and moisture in the air, as well as for carbon 
and most refractory materials.  The principal method for the 
commercial production of titanium sponge metal is the Kroll 
process, which involves the reduction of titanium tetrachloride 
with magnesium metal in an inert atmosphere.  Present commercial 
production by this method yields a titanium alloy of 99.5% purity 
that differs in hardness and strength from the pure titanium metal 
prepared from the thermal decomposition of titanium iodide (TiI4). 
Titanium metal powder is usually produced by reaction of the metal 

with hydrogen; the resulting brittle titanium hydride is then 
crushed before heating in a vacuum to remove the hydrogen (Stamper, 
1970). 

    Titanium dioxide of pigment quality is made by two distinct 
processes.  In the sulfate process (Stamper, 1970; Katari et al., 
1977), ground ilmenite or titanium slag is dissolved in sulfuric 
acid, reducing the iron present to the ferrous state.  The 
titanium dioxide is then precipitated by hydrolysis together with 
part of the iron in the form of hydrated iron sulfates (copperas).  
The precipitated titanium dioxide is calcined at 900-1000C, 
treated by proprietary finishing processes, and ground to pigment 
size.  In the chloride process (Katari et al., 1977), titanium 
tetrachloride is oxidized with air or oxygen and the resulting 
titanium dioxide calcined at approximately 500-600C to remove 
residual chlorine and any hydrogen chloride that may have formed in 
the reaction.  Aluminium chloride is added to the titanium 
tetrachloride to assure that virtually all of the titanium is 
oxidized in the rutile crystalline form.  After calcination, the 
titanium dioxide is treated by proprietary finishing processes as 
in the sulfate process. 

    There are about 30 commercially available grades of pure 
titanium and alloys.  Elements in titanium alloys fall into two 
categories, i.e., those that strengthen and stabilize the alpha or 
room temperature modification, and those that strengthen the beta 
or high temperature modification.  An alloy containing 6% aluminium 
and 4% vanadium comprises almost 50% of the total mill products 
used.  Other alloys used widely include those containing either, 8% 
aluminium, 1% each of molybdenum, and vanadium, or 5% aluminium and 
2.5% tin.  Further aspects of the procedures dealing with the 
preparation and refining of titanium dioxide, titanium metal 
powder, and alloys have been dealt with in various monographs 
(Stamper, 1970; CEC, 1974; Katari et al., 1977). 

    The total world production of titanium concentrates in 1979 was 
3.49 million tonnes of ilmenite (including leucoxene), 0.36 million 
tonnes of rutile, and 0.77 million tonnes of titaniferrous slag 
(Lynd & Hough, 1980).  The approximate amount of titanium produced 
can be estimated knowing that rutile is 100% titanium dioxide and 
ilmenite has a theoretical maximum content of titanium dioxide of 
53% (Stamper, 1970).  Four countries together produced over 85% of 
the global production of ilmenite, i.e., Australia (33%), Norway 
(24%), USA (17%), and USSR (12%).  Australia produced 77% of the 
total known world production (359 000 tonnes) of rutile. 
Practically all of the titaniferrous slag is produced by Canada 
(61.4%) and South Africa (38.5%) (Lynd & Hough, 1980).  The world 
production figures for titanium concentrates are given in Table 2. 

Table 2.  World production of titanium concentrates in 1979
(Values expressed in short tonnes = 907 kg)a
------------------------------------------------------------------
Country        Ilmenite            Rutile        Titaniferrous
               and leucoxene                     slag
------------------------------------------------------------------
Australia      1 280 646           305 773

Brazil         20 000              400

Canada                                           525 840

Finland        145 000

India          165 000             10 000

Japan                                            200

Malaysia       206 000

Norway         903 576

Portugal       200

Sierra Leoneb                      11 000

South Africab                      46 000        330 000

Sri Lanka      39 000              15 000

USA            639 292             Wc

USSRb          450 000             10 000
------------------------------------------------------------------
World total    3 848 714           398 173       856 040
------------------------------------------------------------------
a From:  Lynd & Hough (1980).
b Estimated.
c W = witheld company proprietary data.


    The recovery of titanium from secondary sources has so far been 
very modest, probably not exceeding 1% of the total production. 
However, it is likely to increase in the future.  It has been 
calculated that the world demand for titanium in the year 2000 will 
range between 2.1 and 4.5 million tonnes.  An estimate of ilmenite 
and rutile reserves is given in Table 3. 

Table 3.  Estimated world reserves of ilmenite and rutilea
------------------------------------------------------------------
Country                      Million short tonnesb
------------------------------------------------------------------
                    Ilmenite  Titanium     Rutile   Titanium
                              equivalent            equivalent
------------------------------------------------------------------
Australia           20        5            4.0      2.0

Canada              100       25           0.5      0.250

India               60        15           0.1      0.050

Norway              120       30           -        -

Sierra Leone        -         -            3.0      1.50

Sri Lanka           5         1            0.3      0.150

United Arab         40        10           -        -
Republic        
[Egypt]

USA                 100       25           0.5      0.250

USSR                100       25           0.3      0.150

Otherc              25        6            -        -
------------------------------------------------------------------
a From: Stamper (1970).
b US short tonne = 907 kg.
c Includes Brazil, China, Finland, Japan, Malaysia, Spain.

3.3.  Uses of Titanium 

    Titanium, used as a construction material, is usually in the 
form of alloys, most of which have higher strength than pure 
titanium and enhanced corrosion resistance.  About 95% of the 
titanium metal consumed in the USA is for aerospace applications, 
including aircraft and space craft.  The remainder is used in the 
chemical and electrochemical processing industries, for handling 
some of the most corrosive processes, and in marine and ordnance 
applications. 

    Titanium is used in the paper pulp industry, because of its 
excellent resistance to organic acids, sulfides, and strong 
bleaches. It is also used in tubing, and in liners for vessels etc. 
in the production of nitric acid and acetaldehyde.  The first 
large-scale industrial application of titanium was in the aluminium 
anodizing industry, where the metal supporting racks were made 
almost exclusively of titanium.  Platinized titanium anodes are 
used in electroplating with gold, platinum, copper, silver, and 
other metals of high purity.  Similar anodes are used in cathodic 
protection systems of ships, harbour installations, water heaters, 
and cleaning lines in the production of stainless steel strip. 

Another still expanding use of titanium metal is in surgical 
implant materials and prostheses. 

    Titanium dioxide (TiO2) is by far the most important titanium 
compound.  Because of its extreme whiteness and brightness, as well 
as its high index of refraction, titanium dioxide is extensively 
used as a white pigment primarily in surface coatings such as 
paints, lacquers, and enamels.  It is estimated that over half of 
all non-permanent white or light-coloured surface coatings include 
a titanium dioxide level of 0.1-0.3 kg/litre.  Over 17% of titanium 
dioxide is used in paper coatings or as paper fillers to improve 
opacity, brightness, and printability.  The third largest and 
apparently fastest growing application of titanium dioxide is in 
the plastics industry, because of its resistance to degradation by 
ultraviolet light, high refractive index, whiteness, and chemical 
inertness (Stamper, 1970). 

    In addition, titanium dioxide is used in ceramic capacitors and 
electromechanical transducers, welding-rod coatings, and in the 
production of glass fibres.  Miscellaneous applications of titanium 
dioxide pigment and other titanium compounds include the production 
of floor coverings, mainly of the synthetic resin types, rubber 
tyres, porcelain enamels, inks, wall coverings, artificial leather, 
oilcloth, upholstery materials, and other coated fabrics.  Titanium 
dioxide is also used in the production of titanium carbides. 

    To a much lesser extent, titanium dioxide is used as a colour 
additive in the confectionery (Lorenz & Maga, 1973), food (Bone, 
1967), and dairy industries (Kosikowski & Brown, 1969), as a 
potential additive for bread flours, replacing the normally used 
flour-bleaching agents (Lorenz & Maga, 1973), as a clouding agent 
for incorporation in dry beverage mixes (Carlson et al., 1972), and 
in tobacco wrapping (Detert & Buchholz, 1971). 

    Another commercially important compound is titanium 
tetrachloride (TiCl4).  It is primarily an intermediate in the 
production of titanium metal and pigments.  It is also a component 
of Ziegler catalysts used for the low pressure polymerization of 
ethylene, propylene, and other hydrocarbons.  Titanium tetrachloride 
is also widely employed as the intermediate raw material for the 
production of most organic titanium compounds, such as alkyl esters 
of titanium, alkyl titanates, other titanium esters, and butyl 
titanate (Feld & Cowe, 1965), which are used as cross-linking 
agents and catalysts. 

    Titanium trichloride (TiCl3) is used for polymerization
catalysts and as a colouring agent in molasses.  It is prepared by 
reducing titanium tetrachloride.  Some of the most common 
applications of titanium and its compounds are listed in Table 4. 

Table 4.  Some main applications of titanium and its compounds
-------------------------------------------------------------------
Compounds               Use
-------------------------------------------------------------------
titanium (Ti)           in alloys, aerospace, chemical processing
                        industries

titanium dioxide        pigments, paints, lacquers, printing,
(TiO2)                  ceramics, as food additive, drug and
                        cosmetic applications

titanium tetrachloride  polymerization (Ziegler type) catalyst,
(TiCl4)                 starting material for most organic 
                        compounds
                          
titanium trichloride    polymerization catalyst
(TiCl3)                   
                                                       
titanium carbide (TiC)  structural metals, alloys      
                                                              
organic titanium        cross-linking agents, catalysts
compounds
-------------------------------------------------------------------

3.4.  Disposal of Wastes

    The mining and concentration of titanium and the production of 
titanium dioxide generate large quantities of wastes.  Disposal of 
these wastes and especially those generated by titanium pigment 
production is an important environmental problem for the industry. 
The waste also contains weak sulfuric acid.  Large amounts of such 
processing wastes are dumped into the sea or river water (Peschiera 
& Freiherr, 1968; Elik, 1969; Fader, 1972; Weber, 1972; Hfele, 
1974; Walsh, 1974; Katari et al., 1977).  In the mining and 
beneficiation processes of ilmenite and in the production of 
titanium dioxide pigment, air pollutants are generated and sulfur 
dioxide and particulate matter containing titanium are emitted 
(Katari et al., 1977).  Incineration of titanium-containing 
products such as paper, plastics, inks, and painted wood may 
contribute to the pollution of the air by titanium, which may 
subsequently enter the soil. 

4.  ENVIRONMENTAL LEVELS AND EXPOSURES

4.1.  Levels in Air, Soil, Water, and Other Media

4.1.1.  Air

    Titanium concentrations in urban air are mainly below 0.1 g/m3 
and are still lower in rural air (Tabor & Warren, 1958; McMullen et 
al., 1970; US Environmental Protection Agency, 1973; Giauque et al.,
1974).  Concentrations exceeding 1.0 g/m3 have occasionally been
reported in urban air and especially in industrialized areas (Japan 
Environmental Sanitation Centre, 1967; National Air Pollution 
Control Administration, 1969; Dams et al., 1970; US Environmental 
Protection Agency, 1973). 

    Tabor & Warren (1958), employing a semi-quantitative 
spectrographic method, studied the distribution of a number of 
metals including titanium in the atmosphere of several American 
cities.  In 754 samples examined, detectable amounts of titanium 
(0.01 g/m3) were not found in 23.3% of the samples, medium 
concentrations (0.01-0.1 g/m3) were found in 71.4%, and high 
concentrations (0.1-0.3 g/m3) in 5.3% of the samples.  The 
combustion of coal and oil results in a discharge of trace amounts 
of several elements, including titanium, into the atmosphere.  The 
principal sites of fossil fuel consumption are in the mid-latitudes 
of the Northern Hemisphere.  Consequently, as was pointed out by 
Bertine & Goldberg (1971), the contribution to the titanium 
concentrations in air and natural waters will be most evident at 
these latitudes.  Average concentrations of titanium of 500 mg/kg 
in coal and 0.1 mg/m3 in oil, have been reported. 

    Johansson (1974) determined the variation of titanium abundance 
with particle size in aerosols from North Florida, sampled near to 
the ground by a 5-stage cascade impactor in mainly unpolluted 
inland and coastal locations.  The 32 separate size distributions 
were determined by proton-induced X-ray emission spectroscopy. 
Since titanium coheres with iron in most samples, and the ratios 
found were constant and close to the geochemical average of the 
ratios of these elements in soils, it was suggested that titanium 
had originated mainly from a soil source (yielding particles of 1 
m).  For the smallest particles (0.25 m), there was an indication 
of elevated titanium/iron ratios that might arise from an 
additional source of small particle titanium. 

4.1.2.  Soils and sediments

    Though titanium is ubiquitous in its geographical distribution, 
regional levels vary considerably according to conditions such as 
weathering, fallout from consumption of fossil fuels, and 
incineration of refuse.  Sandy soils, e.g., sand, bog, loess, and 
calcareous soils contain less titanium than heavy clay soils. 
According to an extensive review by Vinogradov (1959) of titanium 
values in soils from various parts of the world (e.g., Robinson, 
1914; Tamm, 1925, 1930/1931); Agatomoff, 1928; Askew, 1930; Malac, 
1931; Hirai & Buichiro, 1937; Ivanova & Koposov, 1937; Salminen, 

1938; Lee, 1941; Monier-Williams, 1950), the average concentration 
in soil appears to be below 5 g/kg.  However, some soils contain 
titanium dioxide at a concentration of about 10-100 g/kg. 

    Grabarov (1970) found that the titanium content of soils in 
Kazakhstan, USSR, ranged from 2 to 7 g/kg but that only 10-50 mg/kg 
was in a readily soluble form.  Hussain & Islam (1971) measured 
titanium in soil, silt, and clay fractions of a number of soils 
from the Barind tract in Bangladesh.  The mean titanium dioxide 
content in the soils ranged from 6 to 12 g/kg with an average 
value of 8 g/kg.  The content in the clay fraction was higher than 
that in the silt fraction, with these soils showing signs of the 
development of argillic horizons. 

    Soils in the vicinity of power and incineration plants and 
industrial discharges may be enriched in heavy metals and trace 
elements.  Klein & Russel (1973) reported that soils around a coal-
burning power plant contained higher levels of trace metals than 
surrounding areas.  The average level of titanium in soils in the 
vicinity of this power plant was 92 mg/kg compared with a back-
ground level of 56 mg/kg.  The enriched area covered 300 km2 with 
the enrichment confined to the upper 2 cm of soil. 

4.1.3.  Water

    The concentration of titanium in water depends on both the 
amount of titanium dissolved in the water and on the quantity of 
titanium particles dispersed in the water.  Titanium has been 
reported in all samples from 15 rivers in the USA and Canada in 
concentrations ranging from 2 to 107 g/litre (Durum & Haffty, 
1961).  Durfor & Becker (1964) found titanium in 81% of 42 
municipal water supplies in the USA at a mean concentration of 
2.1 g/litre with a range of 0.5-15 g/litre. 

    Titanium levels in sea water have been reported to range from 
1 to 9 g/litre (Bowen, 1966; Mason, 1966).  Titanium was found in 
21% of the 24 samples collected along the entire coast of 
California, USA, the two highest concentrations being 0.7 g/litre 
and 0.9 g/litre (Silvey 1967).  Ishibashi (1966) reported the 
distribution of 50 elements in sea water with levels of titanium 
averaging 0.65 g/litre. 

    In studies by Hallsworth & Adams (1973), the heavy metal 
content of rainfall ash was compared with that of the fly ash from 
several power stations in the East Midlands of the United Kingdom. 
Levels of titanium in rainfall, which ranged from 6 to 7.8 g/kg of 
residues were roughly comparable with levels of titanium in the fly 
ash, which ranged from 3.6 to 7.5 g/kg. 

4.1.4.  Plants

    Titanium, like aluminium, is found in relatively abundant 
quantities in the lithosphere and in soils, but is poorly absorbed 
and retained by plants (Underwood, 1977).  Average titanium levels 
of approximately 1 mg/kg have been reported for a wide variety of 

plants (Bertrand & Voronca-Spirt, 1929a, 1929b).  It has been 
suggested that levels in herbage samples are indicators of soil 
contamination (Barlow et al., 1960).  Mitchell (1957) reported mean 
levels of titanium of 1.8 mg/kg (dry weight) in red clover (range 
0.7-3.8 mg/kg) and 2.0 mg/kg in ryegrass (range 0.9-4.6 mg/kg) 
grown on different soils.  In Kazakhstan, grain crops absorbed 
titanium levels of 50-100 g/ha and legumes 123-398 g/ha from soil 
containing levels of titanium of 1.2-7 mg/kg (Grabarov, 1970).  
More titanium was found in maple and elm leaves than in the leaves 
of other plants while the content of titanium in brush was 50-820 
mg/kg. 

4.1.5.  Food

    Large variations in the concentrations of titanium in different 
types of foods have been demonstrated.  Schroeder et al. (1963) 
found whole grains, some vegetables and fruits, and common fish 
meat contained little or no detectable titanium (level of 
sensitivity = 0.025 mg/kg for tissues and 0.01 mg/kg for other 
materials) while higher levels ranging from 1.76 to 2.42 mg/kg wet 
weight were found in milled grains, butter, corn oil, corn-oil 
margarine, and lettuce.  Wheat flour from the USA and Japan was 
found to contain 0.41 and 0.99 mg/kg (wet weight), respectively; 
corn oil and corn-oil margarine levels were 0.83 and 1.80 mg/kg 
(wet weight), respectively.  In a study by Asmaeva & Il'vickij 
(1969), levels of titanium in grains were related to the region of 
growth and climatic conditions. 

    Though titanium is poorly absorbed and retained by both animals 
and plants (Monier-Williams, 1950; Underwood, 1977), higher 
concentrations of titanium can potentially occur in food crops in 
localized areas as a result of soil contamination by:  fly ash 
fallout (Hallsworth & Adams, 1973; Klein & Russel, 1973; Capes et 
al., 1974); industrial contamination (Tarabrin, 1970); and use of 
industrial, household, and sewage residues for the fertilization of 
vegetable plots (Lescenko et al., 1972).  Some algae are able to 
accumulate titanium up to 10 000 times and possess the potential to 
introduce large quantities into the food chain (Schroeder et al., 
1963). 

    High concentrations of titanium in food, especially cheese, can 
arise from the use of titanium dioxide as a whitener in the 
manufacture of mozzarella cheese (Kosikowski & Brown, 1969; Leone, 
1973).  Titanium is also used in the production of niva and Edam 
cheese to accelerate aging and improve quality (Palo, 1966, 1967). 

4.2.  Occupational Exposure

    Nearly all exposures to titanium are to dusts, though 
some exposure to fume and vapour occurs in handling titanium 
tetrachloride.  Occupational exposure to titanium mainly occurs in 
the mining and production of the metal, and in the production and 
processing of titanium dioxide and carbide.  During the extraction 
and recovery of titanium from its major ores such as ilmenite and 
rutile, the atmospheric concentrations of the ores may reach 

levels commonly regarded as the maximum permissible for inert or 
nuisance dusts.  In the preparation of raw materials, i.e., 
crushing, grinding, mixing, and sieving of rutile concentrates and 
technical grade titanium dioxide - the concentration of dust 
depends on the humidity of the air and on the materials treated. 
According to Kokorev et al. (1960), the dust concentration in the 
air of crushing rooms, containers, and transporters, amounted to 4-
6 mg/m3.  Considerable concentrations of titanium tetrachloride 
vapour were found in the chlorine department.  In some other 
departments, such as the crushing and classification departments, 
the concentration of titanium dust (titanium-rich slag containing 
about 70% titanium dioxide) may reach 30-50 mg/m3. 

    Exposure to titanium and its compounds occurs not only in the 
production of metallic titanium, but also in processes in which it 
is used.  According to Mezenceva et al. (1963), in the production of 
hard alloys, the dust concentration in the air during the sieving 
of titanium carbide ranged from 20.3 to 40.2 mg/m3, while in the 
process of carbonization, it amounted to 22 mg/m3. 

    Skurko & Brahnova (1973) reported high concentrations of 
titanium dust in the breathing zone of workers employed in the 
manufacture of titanium hydride.  High mean concentrations up to 
500 mg/m3 were found in the hydrogenation shop, manual handling, 
screening, and packaging of the powder.  Cleaning of the retort 
resulted in a mean concentration of 210 mg/m3. 

4.3.  Cosmetic and Medical Uses

    A variety of drug and cosmetic applications for titanium 
dioxide exist based primarily on its effectiveness:  as a short-wave 
ultraviolet sunscreen (Vickers, 1967; MacLeod & Frain-Bell, 1971); 
in the treatment of herpes simplex (Scott, 1969; Shuster 1971) and 
photosensitive cheilitis (Rich et al., 1971); in dermatological and 
cosmetic formulations (Rudowska, 1967; Miller & Gilmore, 1971); as 
an anti-acne ointment (Fuga, 1967) and an anti-inflammatory 
ointment for gums and oral mucosas (Lakovska et al., 1971); in 
removal, by tattooing, of facial haemangiomas (Hage, 1967); and in 
a variety of tablet-coating formulations (Lindberg & Jonsson, 1972; 
Hortobagyi, 1973). 

    Mention should be made of the increasing use of titanium in 
metal plates, pins, nuts, and bolts in contact with various tissues 
(Beder & Eade, 1956; Beder et al., 1957). 

4.4.  Estimate of Exposure of Man through Environmental Media

    Food is the principal source of exposure to titanium for man. 
This is obvious from the concentrations of titanium in food, water, 
and air (sections 4.1.1-4.1.5).  As titanium has not been proved to 
be an essential element for man and is not very noxious, only a few 
dietary intake and balance studies have been undertaken.  Recent 
studies are not available and the results from earlier studies are 
not always very representative. 

    Because of the variations in diet, as well as the variations 
in total food consumption in different parts of the world (Hamilton 
& Minski, 1972/1973), it is very difficult to estimate the daily 
intake of titanium.  Typical American diets were estimated by 
Schroeder et al. (1963) to provide approximately 300 g of titanium 
daily. Tipton et al. (1966) reported the 30-day mean total American 
dietary titanium intakes of two individuals to be 370 and 410 
g/day.  The daily titanium intake for two men (23 and 25 years 
old), over a period of 50 weeks, was reported by Tipton et al. 
(1969) to be 750  80 g and 2000  400 g, respectively.  The 
dietary content of titanium was measured from estimated (i.e., not 
weighed) duplicates of every ingested item.  Hamilton & Minski 
(1972/1973) reported a daily intake of about 800 g from the United 
Kingdom and ICRP (1959) arrived at an estimate of 540 g.  The 
daily intake of titanium from drinking-water is usually very low, 
probably below 5 g/day. 

    Outside occupational settings, the amount of titanium absorbed 
via the lungs is of little significance in relation to the intake 
from food, and the intake by inhalation is less than 1% of the 
total intake.  Assuming a respiratory volume of 15 m3/day, the 
intake would vary from almost none to 4.5 g with an average of 
about 0.75 g, but it can be expected that only one-third or less 
of the inspired titanium is retained in the lungs (Schroeder et 
al., 1963).  Woolrich (1973), basing his estimates on surveys in 
four American cities, calculated the daily intake from air to be 
approximately 3.8 g of titanium assuming that 20 m3 air per day 
is respired, with a maximum concentration of 0.19 g/m3. 

    In the working environment, where the air concentration may 
reach several mg/m3, exposure through inhalation is of greater 
importance.  Data on pulmonary retention as well as absorption of 
swallowed particles are insufficient to make any estimate of the 
exposure in various occupational environments.  However, several 
autopsy studies on workers occupationally exposed to titanium 
dioxide dust have shown the presence of titanium in the lungs in 
concentrations clearly exceeding those found in the lungs of 
unexposed subjects (Schmitz-Moorman et al., 1964; Elo et al., 1972; 
Ophus et al., 1979). 

5.  CHEMOBIOKINETICS AND METABOLISM

5.1.  Absorption, Distribution, and Excretion

5.1.1.  Animal studies

    Data on the absorption of titanium compounds are very limited 
and very little quantitative information is available with regard 
to absorption by inhalation.  Ingested titanium is apparently 
absorbed from the gastrointestinal tract (Schroeder et al., 1964) 
but there is little information regarding the extent of absorption, 
and comparative studies using different titanium compounds have not 
been made.  Lloyd et al. (1955) tested the suitability of titanium 
dioxide as a marker for digestibility.  The recovery of only 92% of 
the titanium dioxide fed to rats at a dietary level of 2.5 g/kg 
remained largely unexplained.  The minute absorption of titanium 
from the gastrointestinal tract was demonstrated in a study in 
which mice were given 44Ti intragastrically (without marker).  The 
whole body count after 24 h did not exceed the background level 
(Thomas & Archuleta, 1980). A comparison of organ contents of 44Ti
after oral and intravenous administration of the isotope (3 Ci), 
indicated a gastrointestinal absorption of less than 5% in lambs 
(Miller et al., 1976).  When male and female rats were fed a diet 
containing titanium dioxide (100 g/kg) for a period of about 32 
days, a significant retention of titanium of 0.06 and 0.11 mg/kg 
wet weight was found only in the muscles; no retention was observed 
in the liver, spleen, kidney, bone, plasma, or erythrocytes (West & 
Wyzan, 1963).  The same authors administered 5 g of titanium dioxide 
to 5 male adult volunteers on 3 consecutive days.  This did not 
cause any significant increase in the urinary content of titanium. 

    The clearance of titanium dioxide from the lungs was studied in 
rats after inhalation of 15 or 100 mg/m3.  The average median 
aerodynamic diameter of the titanium dioxide particles was 1.48 m. 
After a single exposure, about 40-45% of the deposited particles 
were cleared from the lung in 25 days.  At 15 mg/m3, 0.7% was found 
in the hilar lymph nodes indicating penetration of titanium dioxide 
particles from alveoli into the lymphatic system and partial 
clearance by the lymphatic route.  The clearance rate was similar 
after intra-tracheal administration of titanium dioxide.  At an 
exposure of 100 mg/m3, the clearance rate decreased drastically 
(Ferin & Feldstein, 1978).  Elo et al. (1972) demonstrated the 
presence of titanium dioxide in the lymphatic systems of 3 workers 
employed in processing titanium dioxide pigments. 

    The distribution of titanium in the organs of mice following 
the administration of a tetravalent, soluble titanium salt 
(titanium potassium oxalate) in drinking-water at a concentration 
of 5 mg/litre was reported from a life span study by Schroeder et 
al. (1964).  The results were compared with organ concentrations in 
control mice fed drinking-water without the addition of titanium, 
and in wild field mice (Table 5).  Organs of treated and wild 
animals displayed concentrations of roughly the same order of 
magnitude, whereas untreated mice showed lower levels, the 
differences being more pronounced in males. 

Table 5.  Titanium concentrations in the organs of mice given 
titanium in the drinking-water at 5 mg/litre throughout the life 
span (values in mg/kg wet weight)a
-------------------------------------------------------------------
                    No.   Heart  Lung  Spleen  Liver  Kidney
-------------------------------------------------------------------
Treated mice

      Male          41    8.80   4.81  6.83    1.81   2.86
      Female        37    4.10   1.66  3.70    2.05   2.89

Untreated mice

        Male        31    0.34   0.13  0.94    0.38   0.33
        Female      51    1.08   0.66  1.10    0.67   0.55

Wild field mice     9     6.93   3.03  -       4.10   1.03
-------------------------------------------------------------------
a From:  Schroeder et al. (1964).


    Following intravenous injection of rats with 50 mg of titanium 
dioxide (250 mg/kg body weight), there was an exponential 
disappearance rate with only about 30% remaining after 10 min. 
After intravenous injection of 250 mg/kg body weight of titanium 
dioxide in rats, about 70% of the injected dose was detected in the 
liver, 5 min after administration, and almost 80%, 15 min after 
injection.  The highest concentration was found in the liver 
followed by the spleen after 6 h, whereas, after 24 h, the highest 
concentration was found in the celiac lymph nodes, which filter the 
lymph from the liver.  One year after the injection, the highest 
concentrations were still found in these lymph nodes (Huggins & 
Froehlich, 1966). 


5.1.2.  Human studies

    Little information is available on the absorption of titanium 
compounds by man.  With respect to absorption by inhalation, there 
is evidence showing that titanium containing particles in the air 
are in the upper respirable size range (Johansson, 1974).  The 
titanium retained in the peripheral part of the lungs does not seem 
to account for the observed titanium levels in lung tissue 
(Schroeder et al., 1963).  Experiments on rats suggest that 
titanium may be taken up by the lungs from the blood.  On the basis 
of rather rough calculations, Schroeder et al. (1963) concluded 
that a third or less of the inspired titanium may be retained in 
the lungs. 

    Few studies have been reported on the absorption of titanium 
from the gastrointestinal tract in man.  Perry & Perry (1959) 
reported a mean concentration of 10 g/litre in pooled urine 
indicating absorption; however, the extent of the absorption is not 
known.  Accepting this amount in the urine, and assuming a daily 
intake of 300 g of titanium, Schroeder et al. (1963) calculated 
that about 3% of the dietary dose would be absorbed. 

    Wide variations in titanium levels in different organs in man 
have been found, the lungs frequently containing the highest 
amount.  Hamilton et al. (1972/1973) using X-ray fluorescence found 
concentrations of 3.7 mg/kg wet weight in the lung and 0.8 mg/kg in 
the brain, demonstrating that titanium passes the blood-brain 
barrier.  Earlier, Tipton & Cook (1963) and Schroeder et al. (1963) 
had also found that concentrations in lung tissue were higher than 
in other human tissues.  In a male worker not occupationally exposed 
to metals, the highest concentration was found in the hilar lymph 
nodes (150 mg/kg dry weight) followed by the lung (33 mg/kg dry 
weight) (Teraoka, 1980).  Comparison of tissue levels of titanium 
between American subjects and people from other geographical areas 
showed similar high concentrations in pulmonary tissues (Perry et 
al., 1962). 

    In the study by Schroeder et al. (1963), accumulation of 
titanium started in the lung after the third decade and did not 
occur in the kidney, skin, or aorta.  Infant kidneys contained 
several times the adult concentration of titanium (Tipton & Cook, 
1963). 

    Metal and mineral concentrations in the lungs of West Virginian 
bituminous coal miners were studied by Crable et al. (1967, 1968). 
The mean concentration of titanium, among other metallic 
constituents, in the lungs of 26 miners (with 23-50 years service) 
was 119 mg/kg dry weight compared with a normal level of 19 mg/kg. 
Rthig & Wehran (1972) found concentrations of titanium in the 
lungs of patients with silicosis ranging from 4 to 24.3 mg/kg. 
Levels in the lymph nodes ranged from 12.2 to 120 mg/kg.  The 
average titanium concentration rose with increasing severity of 
silicosis, the concentration of titanium in the hilar lymph nodes 
being much higher than that found in the lungs. 

    A mean titanium concentration in blood of 0.07 mg/litre was 
reported by Hamilton et al. (1972/1973), not much different from 
the 0.02-0.03 mg/litre previously reported by Maillard & Ettori 
(1936a; 1936b).  A somewhat higher mean level of 0.1230.005 
mg/litre was found in 20 healthy subjects, 20-43 years of age, by 
Mozajceva (1970).  Timakin et al. (1967) reported a mean level of 
0.0540.002 mg/litre in the serum of 200 healthy persons from the 
USSR. Smysljaeva et al. (1971) determined the distribution of 
titanium in the blood of children in the age range of 1-14 years. 
They found a ratio of 2:3 between erythrocytes and plasma; this 
ratio decreased slightly with age.  The range of the ratios was 
0.5-1. 

    Titanium was qualitatively detected in leukocytes, using 
electron probe microanalysis (Carroll & Tullis, 1968).  There are 
some indications that titanium levels in the blood may change in a 
variety of diseased states (Bredihin & Soroka, 1969; Kas'janenko & 
Kul'skaja, 1969; Mozajceva, 1970; Alhimov et al., 1971). 

    Schroeder et al. (1963) demonstrated the presence of titanium 
in the tissues of newborn infants, indicating that titanium passes 
the placenta.  The fact that titanium was not detectable in all 
fetuses may reflect the sensitivity of the analytical methods used; 
however, Scanlon (1975) interpreted this finding as evidence of 
titanium not being an essential element for man. 

    Most of ingested titanium is eliminated unabsorbed with the 
faeces.  Under normal circumstances, titanium is excreted with the 
urine probably at a rate of about 10 g/litre (Perry & Perry, 1959; 
Schroeder et al., 1963).  Higher urinary excretion levels of 0.41 
and 0.46 mg/litre have been reported in two adults (Tipton et al., 
1966).  Other routes of excretion are not known. 

5.1.3.  Biological half-life

    Few attempts have been made to calculate the biological half-
life of titanium in man or experimental animals.  The lung is 
considered to be the primary target organ in man and the residence 
time of titanium dioxide in the lung has been regarded as long 
(ICRP, 1959).  In one report, the biological half-life of titanium 
in man was calculated to be 320 days (ICRP, 1959).  Following the 
intraperitoneal and intravenous administration of 44Ti in mice, a 
mean biological half-life of 640 days was calculated.  On the basis 
of experience with the biological half-life of uranium dioxide in 
rats, monkeys, and dogs, the authors speculated that the whole-body 
retention of titanium in man may be even longer than the reported 
640 days in mice (Thomas & Archuleta, 1980). 

6.  EFFECTS ON ANIMALS

6.1.  Acute Toxicity

    When administered to rats as a single intraperitoneal injection 
of 25 mg (139-156 mg/kg body weight) (Sethi et al., 1973) or an 
intravenous injection of 250 mg/kg body weight (Huggins & 
Froehlich, 1966), titanium dioxide behaved as an inert substance. 

    Studies on titanates suspended in corn oil revealed that the 
intraperitoneal LD50 for rats was 3.0 g/kg body weight for barium 
titanate, 2.2 g/kg body weight for bismuth titanate, 5.3 g/kg for 
calcium titanate, and 2.0 g/kg for lead titanate.  The corresponding 
oral LD50 was more than 12 g/kg body weight (Brown & Mastromatteo, 
1962). 

    Titanium dioxide (TiO2) has been used as inert dust particles 
in lung clearance studies on animals (Ferin 1971a, 1971b, 1972; 
Ferin & Leach, 1973).  Observations made 2 months after 
intratracheal injection of titanium dioxide (20 mg/animal) in rats 
did not reveal any reactions other than non-specific responses to 
dust particles (Gthe & Swensson, 1970). 

    Short-term exposure of guinea-pigs to titanium dioxide aerosol 
did not induce any inflammatory response; the number of leukocytes 
and macrophages remained normal, whereas dusts with a toxic 
potential, such as the dioxides of silicon (SiO2) and manganese 
(MnO2) caused an increase in the number of leukocytes (Rylander et 
al., 1979).  The biological inertness of titanium dioxide was 
further demonstrated in that it did not exert any demonstrable 
effect on the viability of alveolar macrophages (Mtt & Arstila, 
1975); moreover, titanium dioxide did not cause fibroblasts to 
produce hydroxyproline indicating a lack of fibrogenicity 
(Heppleston, 1971).  When the synthesis of collagen increases, the 
level of proline hydroxylase (EC 1.14.11.2) in lung tissue 
increases.  This was shown to occur in rats a few weeks after 
exposure to silica (Halme et al., 1970).  In a study by Zitting & 
Skytt (1979), a suspension containing 50 mg of titanium dioxide 
dust in 0.5 ml saline was administered to rats by pipetting into 
the pharynx.  This did not result in increased levels of proline 
hydroxylase.   In vitro haemolysis of erythrocytes has been 
suggested as a model for the biological activity of dusts (Macnab & 
Harrington, 1967).  It was, however, noted that while rutile 
pigments did not have any haemolytic effect  in vitro, the anatase 
pigments as well as a mixture of anatase and rutile did exhibit 
such an effect (Zitting & Skytt, 1979).  The reasons for 
differences in the effects of rutile and anatase dusts could not be 
explained, but the report points to the importance of studying 
titanium dioxide pigments in relation to their type of crystal 
lattice. 

    Inhalation of titanium tetrachloride (aerosols of its 
hydrolitic products, i.e., titanium compounds and hydrogen 
chloride) caused a higher death rate and more rapid development of 
lung oedema in mice than inhalation of an equivalent concentration 
of hydrogen chloride (Mel'nikova, 1958; Mezenceva et al., 1963; 
Mogilevskaja, 1973).  This higher toxicity appears to be associated 
with the adsorption of hydrogen chloride on particles of hydrated 
titanium oxide which penetrate to the deeper parts of the lung not 
usually reached by the highly soluble hydrogen chloride.  Particles 
containing intermediate products of titanium tetrachloride 
hydrolysis are deposited in the alveoli, where hydrolysis continues 
causing additional damage to the lung tissue. 

    Similar effects were observed in mice and rats by Sanockij 
(1961).  Titanium tetrachloride also caused purulent conjunctivitis 
and corneal opacity in rabbit eyes. 

6.2.  Subacute Toxicity

    The general inertness of titanium metal has been demonstrated 
in various implantation studies.  Beder & Eade (1956) studied the 
effects of discs of titanium metal implanted in the muscle tissue 
of dogs and left  in situ for 7 months.  The tolerance of soft 
tissue and bone to contact with titanium was illustrated by lack of 
irritation, normality of wound-healing and the encapsulation of the 
metal by fibrous tissue.  Similar inertness and lack of response in 
the bone tissue of dogs was reported by Beder et al. (1957), 120-
180 days after the plating and fixation of fractures using titanium 
plates. 

    Studies on the intratracheal injection of 400 mg of titanium 
dioxide in rabbits and observation after 3 months did not reveal 
any reactions other than non-specific responses to dust particles, 
such as an increase in numbers of phagocytes (Dale, 1973). 
Intratracheal instillation of a total dose of 75 mg of barium 
tetratitanate suspended in saline (50 g/litre), given in 3 weekly 
doses to guinea-pigs did not induce any signs of fibrotic reaction, 
up to 12 months after administration (Pratt et al., 1953).  Similar 
results were achieved by Wozniak et al. (1976), who gave rats 50 mg 
of titanium dioxide intratracheally.  No fibrosis was found in the 
lungs after 3 months. 

    A fibrotic effect on eosinophilic infiltration was noted in 
guinea-pigs (Lenzi, 1936) following repeated titanium dioxide 
inhalation over various time intervals ranging from 5 days to 4 
months.  The dose administered was not reported but the compound 
used was characterized as "pure". 

    A single intratracheal injection of a suspension of 50 mg of 
metallic titanium dust or titanium dioxide dust was administered to 
5-7 rats.  Sacrifice of some animals after 6 months and sacrifice 
of the remaining animals, which had been injected a second time, 
after 11 months did not reveal any nodular processes or 
interstitial sclerosis.  Minor effects on the lungs after the 
second injection were limited to some lympho-histiocytic reaction 

around the particles (Mogilevskaja, 1956).  In another study 
Mogilevskaja, (1961) administered 50 mg of a titanium concentrate 
(ilmenite) intratracheally to 8 rats and sacrificed the animals 
after 5 and 7 months.  She found slight fibrogenic activity in the 
lungs.  The ilmenite contained silica (SiO2) at 15-20 g/kg, 
aluminium(III)oxide (Al2O3) at 5-35 g/kg, iron(II)oxide (FeO) at 
270-320 g/kg, and iron(III)oxide (Fe2O3) at 170-230 g/kg. 

    Schlipkter et al. (1971) administered 48 mg of titanium 
dioxide and 2 mg of quartz (particle size, 5 m) intratracheally 
to 60 rats.  Thirty of the rats were injected subcutaneously every 
8 weeks with 2 ml of a solution of poly-vinylpyridine-N-oxide 
(PVNO) (20 g/litre).  When sacrificed after 12 months, the animals 
treated with only the titanium-silica dust showed advanced 
fibrosis, whereas the PVNO-treated rats were found to have an inert 
deposition of dust in the lungs and lymph nodes without any sign of 
fibrosis.  The hydroxyproline content of the lungs in PVNO-treated 
animals did not differ significantly from that in rats treated with 
only titanium dioxide but was lower than that in rats given 
titanium-silica dust.  As PVNO inhibits silica (SiO2) specifically, 
the fibrogenic activity was likely to be due to the quartz added to 
the titanium dioxide. 

    Inhalation studies using needle-like potassium octatitanate 
fibres (average length 6.7 m, diameter 0.2 m) in doses ranging 
from 2.9 to 41.8 x 106 fibres (5 m in length) per litre for 3 
months (6 h daily) induced a dose-related fibrosis in rats, 
hamsters, and guinea-pigs, 15-24 months later (Lee et al., 1981).  
A dose-related fibrosis was also noted in rats receiving titanium 
phosphate fibres (length 10-20 m, diameter 0.2-0.3 m) 
intratracheally.  The titanium phosphate fibre is a man-made fibre 
that has a potential use for replacing asbestos in various 
applications (Gross et al., 1977). 

    Intratracheal administration of 50 mg of titanium nitride (TiN) 
to rats was reported to induce a weak fibrogenic effect after 6 
months (Brahnova & Samsonov, 1970).  The oxyproline content of the 
lungs of rats exposed to titanium hydride (TiH2) dust was 
increased, but the increase was only about 16-20% of that induced 
by silica.  These effects were accompanied by dystrophic changes in 
the myocardium, liver, and kidneys (Skurko & Brahnova, 1973) as 
well as biochemical changes that, according to the authors, 
indicated abnormalities in protein metabolism (Brahnova & Skurko, 
1973).  Brahnova (1969) compared the effects on animals of different 
dusts containing transition metal borides or carbides, including 
those of titanium, over a 1-12 month period with respect to their 
electron structure.  An elevated fibrogenic action and pronounced 
dystrophy of the liver, kidneys, and sometimes of the myocardium 
were found to occur to a greater extent with the borides than with 
the carbides. 

    A group of 10 male and 10 female rats was given N.F. grade 
titanium dioxide in the diet at 100 g/kg, for 30-34 days.  A second 
group did not receive the titanium dioxide.  All animals remained 
healthy and behaved normally.  Weight gain and food intake were 
comparable for the 2 groups.  No relevant gross pathology was 
observed at autopsy (West & Wyzan, 1963). 

    Three groups of 2 dogs each, were respectively given 0.05, 0.1, 
and 0.15 g of titanium dioxide, orally.  Every 5 days, the dose was 
increased by the original amount.  One dog out of each group was 
kept for 1 month, the other, for 2 months.  No toxic effects were 
seen with regard to haematology, gross pathology, and histopathology. 
Three dogs received weekly subcutaneous injections of a suspension 
of titanium dioxide in oil; the initial dose of 500 mg was raised 
progressively to 3 g over 7 weeks.  The 3 dogs survived without 
adverse effects.  A fourth dog, which initially received 250 mg/kg 
rising to 2 g/kg body weight, died, but death, according to the 
author, was not causally connected with the administration of 
titanium dioxide (Vernetti-Blina, 1928). 

6.3.  Long-term Toxicity

    Schroeder et al. (1964) administered titanium potassium 
oxalate, at a concentration of 5 mg/litre, in the drinking-water of 
Swiss Charles River mice, from weaning to natural death.  The 
control group consisted of 88 female and 61 male mice compared with 
53 female and 54 male mice in the treated group.  The survival rate 
after 18 months was 75% females and 50% males for the control 
animals, and 70% females and 40% males for the treated group.  The 
body weights of the animals in the titanium-fed group were higher 
than those in the control group. 

    Two guinea-pigs, 2 rabbits, 2 cats, and 1 dog were fed 
technical grade titanium dioxide for 390 days.  The dog received 9 
g/day, the rabbits and cats, 3 g/day, and the guinea-pigs, 0.6 
g/day.  Two additional cats received 3 g titanium dioxide daily for 
175 and 300 days, respectively.  Adverse effects were not seen in 
any of the animals and histopathological examination did not reveal 
any abnormalities (Lehman & Herget, 1927). 

    Christie et al. (1963) did not find any evidence of pathological 
response in the lungs of rats that had inhaled titanium dioxide 
dust (air concentrations in the range of 10-328 million particles 
per cubic foot) 4 times daily, 5 days per week for periods up to 13 
months, followed by a 7-month period of fresh air.  The inhalation 
of titanium dioxide did not affect the weight of the rats. 

6.4.  Mutagenicity

    Evidence of mutagenic activity of titanium or its compounds 
is scant.  Levan (1945) described cytological reactions induced in 
the stems of  Allium cepa by a large variety of inorganic salt 
solutions.  Titanium salts induced sticky chromosomes manifested by 
the formation of anaphase bridges.  Titanium tetrachloride has been 
claimed to be non-mutagenic (Hsie et al., 1979).  Some titanium 

compounds have been tested using the "rec-assay" with  Bacillus 
 subtilis.  The following compounds were found to be negative in the 
"rec-assay":  titanium tetrachloride (TiCl4), titanium trichloride 
(TiCl3), titanium boride (TiB2), titanium carbide (TiC), titanium 
fluoride (TiF4), and titanium dioxide (TiO2) (Kada et al., 1980). 

6.5.  Carcinogenicity

    Few studies have been carried out on the carcinogenicity of 
titanium and its compounds. 

    Furst (1971) reported that titanium metal (pure powder of at 
least 200 mesh) injected intramuscularly in 6 monthly doses, each 
of 6 mg in 0.2 ml trioctanoin, induced 2 fibrosarcomas in 25 male 
and 25 female Fisher-344 inbred rats and lymphosarcomas in 3 out of 
25 males.  Fibrosarcomas or lymphomas were not seen in the controls 
given trioctanoin alone.  Treated rats survived up to 820 days and 
controls up to 935 days. 

    When a suspension of lead titanate in saline (10 g/litre) was 
administered intratracheally to 6 guinea-pigs (0.3 ml, once every 3 
months) for a total of 6 injections, it did not give rise to 
tumours (Steffee & Baetjer, 1965). 

    In the longevity study by Schroeder et al. (1964), described in 
section 6.3, the mice receiving titanium throughout their life-time 
did not show any increase in the tumour incidence compared with the 
control mice. 

    Titanocene, a laboratory experimental compound, was shown 
to be carcinogenic, when suspended in trioctanoin and injected 
intramuscularly into Fischer-344 rats, once a month, to give a 
total administered dose of 200 mg.  Fibrosarcomas developed in the 
thigh muscle at the site of injection.  In addition, some of the 
treated animals developed hepatomas and malignant lymphomas of the 
spleen.  The control compound, titanium dioxide was reported to 
have induced only 3 fibrosarcomas in 3 out of 50 rats.  Details of 
the study were not reported (Furst & Haro, 1969). 

    It has recently been shown that metallocene dichlorides, 
(C5H5)2MCl2, where M = titanium, vanadium, molybdenum, or nobium, 
exhibit cancerostatic activity against the Ehrlich ascites tumour 
system in mice, and that treatment with such metals has lead to 
total cures.  According to Kpf-Maier & Kpf (1980), the mechanism 
behind the cancerostatic effect of titanocene dichloride is not 
known.  The antitumor activity has been investigated in mice, using 
single intraperitoneal injections of titanocene dihalides at doses 
ranging from 10 to 240 mg/kg body weight.  Survival times without 
manifestations of tumours, were significantly longer in treated, 
than in control animals (Kpf-Maier et al., 1980a, 1980b; Kpf-
Maier & Krahl, 1981). 

    On the basis of available data, titanium has generally been 
considered to belong to the group of metals of low carcinogenicity 
(Sunderman, 1978; Radding & Furst, 1980; Valentin & Schaller, 
1980). 

6.6.  Teratogenicity and Effects on Reproduction

    Schroeder & Mitchener (1971) studied the toxic effects of 
titanium on the reproduction of mice and rats.  Breeding mice of the 
Charles Rivers CD strain and rats of the Long-Evans BLUE: (LE) 
strain were exposed in separate studies to titanium in the form of 
a soluble salt in the drinking-water (concentration 5 mg Ti/litre).  
Each group was carried through 3 generations.  The data on rats are 
summarized in Table 6. 

Table 6. Results of a 3-generation study on rats receiving titanium 
in the drinking-watera
----------------------------------------------------------------------------
            Number   Average  M/F    Maternal  Dead     Young   Runts  No.
            litters  litters  ratio  deaths    litters  deaths         rats
----------------------------------------------------------------------------
F1
generation
control     10       11.4     1.14   0         0        0       0      114
titanium    11       9.4      1.43   0         0        1       23     103
----------------------------------------------------------------------------
F2
generation
control     10       11.3     1.10   0         0        0       1      113
titanium    16       10.9     0.99   1         0        24      14     174
----------------------------------------------------------------------------
F3
generation
control     11       11.0     1.06   0         0        1       0      121
titanium    2        8.0      0.60   0         0        0       6      16
----------------------------------------------------------------------------
a From: Schroeder & Mitchener (1971).

    In rats, the titanium was toxic with a marked reduction in the 
numbers of animals surviving to the third generation, only 2 
litters appearing in this generation.  The male/female ratio was 
progressively reduced.  The controls continued to breed for 4 
generations with few deaths and runts occurring. 

7.  EFFECTS ON MAN - CLINICAL AND EPIDEMIOLOGICAL STUDIES

7.1.  Clinical Studies

    Elo et al. (1972) examined lung specimens from 3 factory 
workers employed for 9 years in processing titanium dioxide 
pigments.  Significantly higher titanium levels were found in the 
lungs of these patients compared with lung specimens from a general 
autopsy population.  Deposits in pulmonary interstitium were 
associated with cell destruction and slight fibrosis.  Titanium 
dioxide was found in the lymphatic system, suggesting that it was 
cleared via this route.  Electron-microscopic studies revealed 
titanium dioxide particles within lysosomes of the alveolar 
macrophages.  It was suggested that industrially processed titanium 
dioxide, either alone or in conjunction with other compounds such 
as silica, may behave as a mild pulmonary irritant.  Using X-ray 
microanalytical light and electron-microscopic methods, open lung 
biopsy samples and sputum specimens from 3 former workers exposed 
to titanium dioxide were studied by the same investigators.  These 
studies revealed that, in addition to titanium, the alveolar 
macrophages contained small amounts of silicon, aluminium, iron, 
and potassium.  As industrial titanium dioxide is mostly coated with 
various other elements such as aluminum and silicon, and because 
these substances were localized in different structures of the 
lung, it was postulated that the weak fibrogenic effect was exerted 
by silica or silicon compounds rather than by the titanium dioxide 
(Mtt & Arstila, 1975). 

    Autopsy studies on workers exposed to titanium dust have 
generally corroborated experimental animal studies showing that 
titanium dioxide dust does not exert any fibrogenic effect on lung 
tissues.  Extensive titanium dioxide deposits were found in the 
lungs of a worker who had been exposed to titanium dioxide dust for 
15 years.  However, no inflammatory or fibrotic changes could be seen
(Schmitz-Moorman et al., 1964).  In a more recent autopsy study on 
a 55-year old man who had been exposed to titanium dioxide, the 
crystal modification was taken into consideration.  The methods 
used included scanning and transmission electron microscopy, 
electron X-ray diffractometry, and atomic absorption spectroscopy.  
Considerable deposits of rutile were found, but there were not any 
signs of fibrotic changes (Ophus et al., 1979).  Husten (1959) 
reported fibrosis in a worker who had been exposed in the hard 
metal industry.  The study is quoted as an indication of a possible 
fibrogenic effect of titanium (American Conference of Governmental 
Industrial Hygienists, 1973).  However, this worker had been exposed 
to other elements more likely to be responsible for the fibrosis, a 
feature occasionally seen in workers in the hard metal industry 
(Parkes, 1974; Konietzko et al., 1980). 

    Accidental exposure to titanium tetrachloride (TiCl4) fumes 
was described by Heimendinger & Klotz (1956).  Splashing with 
titanium tetrachloride at 100 C and inhalation of fumes of titanic 
acid and titanic oxychloride led to surface skin burns with 
scarring.  The mucosa of the pharynx, vocal cords, and trachea was 
markedly congested with cicatrization and laryngeal stenosis as 

late sequelae.  Histology showed titanium dioxide phagocytosed in the 
lungs.  Larger dust deposits were associated with small areas of 
focal emphysema, but no specific lesion was seen.  Lawson (1961) 
reported 3 cases of accidental exposure to titanium tetrachloride 
liquid, which was then washed off.  Contact with water resulted in 
severe burns due to the exothermic reaction between titanium 
tetra chloride and water.  Later sequelae were pigmentation and 
scarring.  Nine other mild cases showed less severe burns, without 
subsequent permanent skin changes.  However, contact with a 10% 
solution of titanium tetrachloride can cause second and third 
degree burns in man (Mogilevskaja, 1973), and precautions have to 
be taken in handling titanium tetrachloride to protect occupationally-
exposed workers (Kokorev et al., 1960; American Conference of 
Governmental Industrial Hygienists, 1973). 

    The lack of toxicity of titanium and its compounds in contact 
with the skin has been demonstrated by its use in the therapy of 
skin disorders.  Titanium compounds (salicylate, peroxide, oxides, 
tannate) have been used for many skin disorders (Ereaux, 1955). 
During the Second World War, a protective film of cream containing 
titanium dioxide was used on exposed parts of the body to prevent 
flash burns (Fairhall, 1969).  Dribr (1941) has described its 
innocuous use as a constituent of cosmetic preparations. 

    Titanium is accepted as a biocompatible implant material in 
orthopaedics, oral surgery, and neurosurgery.  It has extremely 
high corrosion resistance and does not cause adverse tissue 
reaction (Williams & Adams, 1976; Palmer et al., 1979; Solar et 
al., 1979; Schroeder et al., 1981).  Small amounts of titanium may 
occasionally be found in tissues adjacent to the implant (Laing et 
al., 1967; Meachim & Williams, 1973).  The mechanism of the release 
of titanium is not well understood as it seems to be unrelated to 
wear processes (Williams & Adams, 1976; Solar et al., 1979).  No 
harmful effects have been reported to follow such a release of 
titanium from implants.  Harmful immunological reactions to 
titanium have not been demonstrated (Lyell, 1979; Brun & Hunziker, 
1980). 

7.2.  Epidemiological Studies

    Epidemiological surveys have focused, almost exclusively, on 
the possible fibrogenicity of titanium dioxide dusts.  An early 
study conducted by Vernetti-Blina (1928) on men exposed to titanium 
dust for prolonged periods did not reveal any sign of abnormality 
in the clinical, radiological, or blood picture.  Uragoda & Pinto 
(1972) investigated the health of 136 workers in an ilmenite 
extracting plant, in Sri Lanka.  The workers were exposed to a 
number of minerals, the principal ores of which were ilmenite, 
rutile, and zircon.  The prevalence of changes in the chest radio-
graphs did not differ between the workers and a reference group 
drawn from the general population.  Furthermore, Moschinski et al. 
(1959) did not detect any fibrosis in titanium dioxide-exposed 
workers. 

    Daum et al. (1977) studied 207 workers exposed to titanium 
dioxide in a plant producing the dioxide from ilmenite ore using 
the sulfate process.  Ninety per cent of the workers had been 
exposed for 20 years or more.  Spirometry revealed obstruction of 
the airways in 47%, but pneumoconiotic changes in the chest 
radiographs were "relatively few and unrelated to the respiratory 
abnormalities observed".  It was pointed out by the authors, and by 
Parkes (1977), that the sulfate process may cause irritation of the 
upper respiratory tract, and that this probably caused the 
abnormalities found in the study, rather than the titanium dioxide 
dust. 

    In a survey of workers in factories manufacturing titanium 
tetrachloride, Kokorev et al. (1960) found a significant number of 
damaged respiratory pathways (hyperaemia, thinning of mucosa, toxic 
bronchitis).  The author considered these effects were caused by 
titanium tetrachloride and the products of its hydrolysis. 

8.  EVALUATION OF HEALTH RISKS TO MAN

    There is no evidence indicating that titanium is an essential 
element for man or animals.  According to available data on the 
toxicity of titanium and titanium compounds and their presence in 
various environmental media, there is no reason to believe that 
exposure to titanium would constitute any health risks for the 
general population.  Studies on titanium alloys, used in implants, 
do not indicate any adverse local effects on tissues, suggesting 
that titanium is a biologically compatible element. 

    Accidental exposure to titanium tetrachloride constitutes a 
hazard in industrial settings, as contact with either the substance 
or the fumes emitted will cause burns. 

    Occupational exposure to titanium dioxide occurs frequently 
and the level of exposure may be high.  Studies on experimental 
animals, clinical studies including autopsies, as well as some 
epidemiological surveys on exposed working populations have shown 
convincingly that titanium dioxide is biologically inert and does 
not possess fibrogenic characteristics.  This has been corroborated 
by  in vitro investigations, where, however, different titanium 
dioxide dusts were shown to have various degrees of haemolytic 
activity, rutile being practically inert and anatase having a 
measurable haemolytic activity.  This emphasizes the importance of 
considering titanium dioxide dusts of different composition and 
mineralogical structure separately, always stating clearly the 
characteristics of a tested compound. 

    In studies where fibrosis has been reported in association with 
exposure to titanium dioxide dusts, the etiological relationship 
has not been convincingly proved.  Moreover, in these studies 
concomitant exposure to other elements such as silica seems to 
offer a more likely explanation of the fibrosis than the titanium 
dioxide itself. 

    Other titanium compounds, such as the hydride, carbide, and 
boride, may have fibrogenic properties according to experimental 
animal studies.  Man-made fibres such as potassium octatitanate or 
titanium phosphate fibres are also fibrogenic in laboratory 
animals. 

    Available data do not suggest that titanium or titanium 
compounds induce any mutagenic or teratogenic effects.  However, 
few studies on these aspects have been made.  Intramuscular 
injection of powdered titanium metal has induced fibrosarcomas and 
lymphosarcomas in rats.  Titanocene, an organotitanium compound, 
has induced fibrosarcomas in rats.  Available data on the 
carcinogenicity of titanium in man do not indicate any such effect, 
and adverse immunological reactions to titanium have not been 
reported. 

    It is not possible from the available data to establish dose-
effect or dose-response relationships for any effect associated 
with exposure to titanium or its compounds.  Thus no quantitative 
assessment of the human health risk from exposure to titanium or 
titanium compounds in occupational or non-occupational 
environmental situations can be made. 



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    See Also:
       Toxicological Abbreviations