INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 27
GUIDELINES ON STUDIES IN ENVIRONMENTAL EPIDEMIOLOGY
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, 1983
The International Programme on Chemical Safety (IPCS) is a
joint venture of the United Nations Environment Programme, the
International Labour Organisation, and the World Health
Organization. The main objective of the IPCS is to carry out and
disseminate evaluations of the effects of chemicals on human health
and the quality of the environment. Supporting activities include
the development of epidemiological, experimental laboratory, and
risk-assessment methods that could produce internationally
comparable results, and the development of manpower in the field of
toxicology. Other activities carried out by the IPCS include the
development of know-how for coping with chemical accidents,
coordination of laboratory testing and epidemiological studies, and
promotion of research on the mechanisms of the biological action of
chemicals.
ISBN 92 4 154087 7
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(c) World Health Organization 1983
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CONTENTS
PREFACE
1. INTRODUCTION
1.1. Interrelationships with toxicological studies
1.2. Design
1.3. Environmental agents and assessment of exposures
1.4. Effects on health
1.5. Organization and conduct
1.6. Analysis and interpretation of results
1.7. Uses of epidemiological information
REFERENCES
2. STUDY DESIGNS
2.1. Introduction
2.2. Preliminary review of state of knowledge
2.3. Descriptive studies and use of existing records
2.3.1. Mortality statistics
2.3.2. Morbidity statistics
2.3.3. Populations at risk
2.3.4. Geographical differences in mortality and morbidity
2.3.5. Time trends
2.3.6. Associations with environmental indices
2.3.7. Case registers
2.3.8. General surveys
2.4. Formulation of hypotheses
2.5. Cross-sectional studies
2.6. Prospective and follow-up studies
2.7. Retrospective cohort studies
2.8. Time-series studies
2.9. Case-control studies
2.10. Controlled exposure studies
2.11. Monitoring and surveillance
REFERENCES
3. ASSESSMENT OF EXPOSURE
3.1. Introduction
3.2. Exposure and dose
3.2.1. Systematic agents
3.2.2. Local exposure
3.2.3. Physical factors
3.3. Combined exposure, physical and chemical
interactions
3.3.1. Same agent, various sources
3.3.2. Various agents, same source
3.3.3. Various agents, various sources
3.3.4. Impurities
3.3.5. Interactions
3.4. Qualitative assessment of exposure
3.5. Environmental assessment of exposure
3.5.1. Quality of data
3.5.2. Monitoring strategy for air pollutants
3.5.2.1 What to sample, how long, how frequently?
3.5.2.2 Representativeness
3.5.3. Monitoring of pollutants in food and water
3.5.3.1 Overall assessment of dietary
intake of toxic elements
3.5.3.2 Indirect assessment of intake
3.5.3.3 Direct assessment of intake
3.5.4. Monitoring of physical factors
3.5.4.1 Noise
3.5.4.2 Vibration
3.5.4.3 Ionizing radiation
3.5.4.4 Non-ionizing radiation
3.6. Personal sampling
3.7. Biological assessment of exposure
3.7.1. Advantages, disadvantages, limitations
3.7.2. Collection for future reference
3.7.3. Index specimens for various pollutants
3.7.4. Example of environmental versus biological
assessment of exposure: inorganic lead
3.7.4.1 Lead in blood (Pb-B)
3.7.4.2 Lead in urine (Pb-U)
3.7.4.3 Lead in faeces (Pb-F)
3.7.4.4 Lead in deciduous teeth (Pb-T)
3.8. Assessment of the subjective environment
3.8.1. Assessment of odour
3.8.2. Assessment of taste
3.8.3. Example of sensory assessment of drinking-water
3.9. Interindividual and intergroup variability in
exposure: population at risk
3.10. Outdoor/indoor exposure
3.11. Time-weighted exposure
REFERENCES
4. HEALTH EFFECTS, THEIR MEASUREMENT AND INTERPRETATION
4.1. Introduction
4.1.1. General comments on effects
4.1.2. General comments on measurements of effects
4.1.2.1 Inter- and intrainstrument variation
4.1.2.2 Inter- and intralaboratory differences
4.1.2.3 Inter- and intraobserver variations
4.2. Mortality and morbidity statistics
4.2.1. Mortality statistics
4.2.2. Routine morbidity statistics
4.3. Cancer
4.3.1. Cancer and environmental factors
4.3.2. Measurements of cancer
4.3.2.1 Incidence and mortality rate
4.3.2.2 Variations of incidence with age
4.3.2.3 Geographical differences
4.3.2.4 Cancer and life-style
4.3.2.5 Cancer in migrants
4.3.2.6 Time trends
4.3.2.7 Correlation studies
4.3.2.8 Hospital data
4.3.2.9 Cancer and occupation
4.3.2.10 Case reports
4.3.2.11 Epidemiological uses of pathological findings
4.4. Respiratory and cardiovascular effects
4.4.1. Symptom questionnaires
4.4.2. Tests of system function
4.4.3. Standardization of methods
4.4.4. Radiographic measurements
4.4.5. Hypersensitivity measurements
4.4.6. Example: Effects of manganese on
respiratory and cardiovascular systems
4.5. Effects on nervous system and organs of sense
4.5.1. Central and peripheral nervous systems
4.5.2. Ear: Effects of sound
4.5.3. Eye and vision
4.6. Behavioural effects
4.6.1. Effects of environmental exposure
4.6.2. Indicators and measurements of effects
4.6.3. Interpretation of data
4.7. Haemopoietic effects
4.7.1. Environmental agents inducing direct toxic
effects in the haematological system
4.7.2. Environmental agents inducing indirect
toxic effects in the haematological system
4.7.3. Measurements and their interpretation
4.7.4. Example: Effects of low lead
concentrations on workers' health
4.8. Effects on the musculoskeletal system and growth
4.8.1. Effects of environmental exposure
4.8.2. Identification of effects
4.8.3. Intrinsic liability
4.8.4. Extraneous influences
4.8.5. Development states
4.8.6. Example: Endemic fluorosis
4.9. Effects on skin
4.9.1. Environmentally caused skin diseases
4.9.2. Epidemiological methods of study
4.10. Reproductive effects
4.10.1. Effects on reproductive organs
4.10.2. Genetic effects
4.10.2.1 Assessment of genetic risks
4.10.3. Fetotoxic effects
4.10.3.1 Measurement of fetotoxic effects
4.10.4. Registries of genetic diseases and
malformations
4.10.5. Example: EEC study of congenital
malformations
4.11. Effects on other major internal organs
4.11.1. Renal system
4.11.1.1 Detection of renal diseases
4.11.2. Bladder
4.11.3. Gastrointestinal tract
4.11.3.1 Oesophagus
4.11.3.2 Stomach and duodenum
4.11.3.3 Intestines
4.11.4. Liver
4.11.5. Pancreas
REFERENCES
5. ORGANIZATION AND CONDUCT OF STUDIES
5.1. Introduction
5.2. Study protocol
5.2.1. Description of problems and hypothesis formulation
5.2.2. Description of methods
5.2.3. Evaluation of institutional-based data sources
5.2.4. Analysis and reporting of data
5.2.5. Resources required
5.2.6. Studies in developing countries
5.3. Ethical and legal considerations
5.3.1. Medical confidentiality
5.4. Time schedule of study
5.4.1. Preparatory phase
5.4.2. Pilot study
5.4.3. Main study
5.5. Composition of the study team
5.5.1. Team leadership and epidemiology
5.5.2. Clinical specialist
5.5.3. Statistical expertise
5.5.4. Environmental scientists
5.5.5. Interviewers and technicians
5.5.6. Support staff
5.5.7. Special considerations for developing countries
5.5.8. Example: Study teams of Itai-Itai disease
and chronic cadmium poisoning
5.6. Implementation of study
5.6.1. Arrangements with local authorities and study population
5.6.2. Picking samples
5.6.2.1 Example: Sampling procedures
5.6.3. Designing recording forms and questionnaires
5.6.4. Planning for control of data and computer programming
5.6.5. Training of personnel
5.6.6. Pilot study
5.6.6.1 Example: Testing of spirometers
and assessment of observer error
5.6.6.2 Example: Assessment of X-ray observer error
5.6.7. Main study
5.6.7.1 Advance contact
5.6.7.2 Interview studies
5.6.7.3 Medical and laboratory examinations
5.6.7.4 Environmental measurements
5.6.7.5 Linkage and evaluation of data
5.6.7.6 Reporting of results
5.6.8. Examples of cohort studies
5.6.8.1 Michigan polybrominated biphenyls study
5.6.8.2 Study on air pollution and
adverse health effects in Bombay
5.6.8.3 Tucson chronic obstructive lung disease study
5.6.8.4 The Tecumseh community health study
5.6.8.5 Late effects of atomic bomb radiation
5.7. International collaborative studies
5.7.1. Study protocol and timetable
5.7.2. Organizational and sampling procedures
5.7.3. Questionnaires
5.7.4. Standardization of measurement instruments
and methods and quality assurance
5.7.5. Reporting forms
REFERENCES
6. ANALYSIS, INTERPRETATION AND REPORTING
6.1. Introduction
6.2. Data preparation
6.2.1. Coding
6.2.2. Key punching
6.2.3. Data monitoring and editing
6.3. Data description (or reduction)
6.3.1. Purpose
6.3.2. Frequency distributions and histograms
6.3.3. Bivariate distributions and scattergrams
6.3.4. Discrete variables and contingency tables
6.3.5. Independent and related data
6.3.6. General points on tables and graphs
6.3.7. Summary statistics and indices
6.3.7.1 Averages
6.3.7.2 Scatter (or dispersion)
6.3.7.3 Morbidity and mortality indices
6.3.7.4 Standardization
6.3.7.5 Proportional mortality
6.3.7.6 Relative risk and attributable risk
6.3.7.7 Concluding remarks about summary
statistics and indices
6.4. Analysis and interpretation
6.4.1. Statistical ideas about the interpretation of data
6.4.2. Errors
6.4.3. Analysing results from cross-sectional studies
6.4.3.1 Qualitative data
6.4.3.2 Quantitative data: response and
explanatory variables
6.4.3.3 Statisticians and computers
6.4.3.4 Analysis of variance
6.4.3.5 Correlations
6.4.3.6 Multiple regression
6.4.3.7 Additive linear models
6.4.3.8 More complicated models
6.4.3.9 Dummy variables
6.4.3.10 Selection of variables
6.4.3.11 Evaluating "goodness of fit"
6.4.3.12 Evaluating the stability of models
6.4.3.13 Predicted normal values
6.4.3.14 Other methods for studying multivariate data
6.4.4. Analysis of data from prospective and
follow-up studies
6.4.4.1 Nomenclature
6.4.4.2 Time as a measured variable
6.4.4.3 Person-years method
6.4.4.4 Modified life-table method
6.4.4.5 Overlap of exposure and observation periods
6.4.4.6 Lagged exposures
6.4.4.7 Measures of latency
6.4.4.8 Some analytical techniques
6.4.5. Analysis of data from case-control studies
6.4.5.1 Relative and absolute risks
6.4.5.2 Relation between prospective and
case-control studies
6.4.5.3 Analysis of stratified samples
6.4.5.4 Analysis of matched samples
6.4.5.5 Effect of ignoring the matching
6.4.5.6 Alternative methods of analysis
6.4.6. Drawing conclusions from analyses
6.5. Reporting
6.5.1. The variety of epidemiological reports
6.5.2. Main scientific report
6.5.2.1 Introduction
6.5.2.2 Methods
6.5.2.3 Results
6.5.2.4 Discussion
6.5.2.5 Abstract
6.5.3. Non-technical reports
REFERENCES
7. USES OF EPIDEMIOLOGICAL INFORMATION
7.1. Introduction
7.2. Communication with the public
7.3. Important features and limitations of epidemiological information
7.4. Standard setting
7.4.1. Factors in standard setting
7.4.2. Interim standards
7.5. Assessment of effectiveness of control measures taken
7.6. Policy of openness
REFERENCES
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 Manager of the International Programme on
Chemical Safety, World Health Organization, Geneva,
Switzerland, in order that they may be included in corrigenda
which will appear in subsequent volumes.
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.
PREFACE
For more than a century, epidemiological studies have
played an important part in investigations on the ways in
which infectious diseases spread through the community. At
the same time, intensive experimental work has resulted, in
many cases, in the identification of the bacterial, viral, or
other biological agents involved and therapeutic, preventive,
and control procedures have been introduced. Epidemiological
studies of biological agents and the effective control of
infectious diseases have paved the way to the use of
epidemiological methods in studying effects of non-biological
agents present in the environment. However, it is generally
more difficult to reach unequivocal conclusions in studies
involving physical and chemical agents than in those involving
biological ones. This is because the various factors involved
in studies of non-biological agents and their interactions are
usually more complex.
The relationship between environmental hazards and the
health of human communities is of growing concern and
increasing interest to governmental and public health
administrators, politicians, and the public. Despite the
substantial efforts made during the past two decades to expand
epidemiological studies on the effects of environmental
agents, there is a paucity of good studies that are useful in
establishing health criteria and a lack of adequate guidance
for the design and execution of studies and for the evaluation
of results. There are numerous papers and published reports
scattered throughout the literature. However, perhaps because
of the rapid development of the subject or of the pressure for
action once a new problem has been recognized, a large
proportion of the studies published to date have suffered from
deficiencies in design, analysis, or interpretation. There is
an urgent need, therefore, for a publication that sets out
appropriate methodology for such studies, which would help
Member States, relevant scientific institutions and individual
research workers to conduct epidemiological studies in a more
correct manner.
The concept of a monograph on the "Guidelines on Studies
in Environmental Epidemiology" was born at the meeting of the
WHO Study Group on Epidemiological Methods for Assessment of
the Effects of Environmental Agents on Human Health convened
in Geneva from 7-13 October 1975. The Study Group considered
that the underlying principles of environmental epidemiology,
particularly with regard to biological agents, had been
sufficiently well established, and that the main problem was
their proper application to the study of the health effects of
physical and chemical agents present in the environment.
The Study Group therefore recommended, among other
proposals, the preparation of a WHO monograph to provide
guidelines on epidemiological methods for assessing the
effects of environmental agents on human health. This
recommendation was unanimously endorsed by the Executive
Board of WHO at its fifty-eighth session in 1976.
In order to fulfil this recommendation, the first meeting
of the editorial group to prepare the monograph was held at
the Medical Research Council Toxicology Unit, St. Bartholomew's
Hospital Medical College, London, on 30 January - 1 February
1978.a The group agreed on the outline of the monograph,
on the tentative list of over 60 contributors or chapter
coordinators, and on the time schedule for preparation of
publication.
The second meeting of the editorial group was held in
London on 26-29 February l980. The group reviewed the first
draft of chapters prepared by coordinators, based on
contributions received, and made suggestions for further
editorial work. It was decided to make clear that the chapters
were not the work of individual coordinators, as the basic
material was being prepared by numerous contributors and
some material was being transposed from one chapter to another
during the course of editing. The chapter coordinators had a
dual role, compiling the chapters from individual contributions,
and also serving both as editors of individual chapters and
members of the editorial group for the monograph as a whole.
The members of the editorial group and all contributors are
shown on pages 14 - 18, respectively. Individual contributions
do not generally appear in their original form, as they have
been merged into various chapters; however, some of them have
been more extensively quoted and appear almost as originally
written.
The editorial group last met for two days at the Institute
of Occupational Medicine in Edinburgh from 20-2l August 1981.
The members of the editorial group were able to consider and
comment on the structure of the individual chapters and on the
volume as a whole. The arrangements for the joint IEA/WHO
workshop on the monograph, which was to take place the
following week during the IXth Scientific Meeting of the IEA,
were also discussed and the work plan for the final editing of
the monograph was agreed upon.
Thirty-eight environmental health scientists, including
six members of the editorial group, attended the joint IEA/WHO
workshop, coming from 16 countries and from the Commission of
-----------------------------------------------------------------
a Professor J. Kostrzewski, then the President of the
International Epidemiological Association (IEA),
participated in this meeting and was elected chairman of
the editorial group. He emphasized the preparedness of
the IEA to offer full technical support to the project.
European Communities. The workshop was held in Edinburgh on
24 August 1981. The members reviewed the drafts of individual
chapters and the monograph as a whole, making valuable comments
and suggestions for improvement. A list of the participants
appears on pages 19 and 21.
The final discussion on the draft of the monograph was held
in Moscow from 30 November - 3 December 1981, attended by a group
of international experts from all WHO regions, five members of
the editorial group, and two WHO staff members. The participants
are shown on pages 22 and 23. This meeting was convened with
the financial assistance of the United Nations Environment
Programme (UNEP) and was hosted by the Centre for International
Projects of the USSR State Committee on Science and Technology
and the A.N. Sysin Institute of General and Communal Hygiene of
the USSR, Moscow, which is also a WHO Collaborating Centre for
for Environmental Health Effects. Comments and proposals made by
this group greatly helped in making the monograph a more cohesive
work.
Thus, a total of 102 experts from 26 Member States were
involved in the preparation of the monograph.
In 1980, WHO, together with UNEP and ILO, launched an
International Programme on Chemical Safety (IPCS) and the present
project has become one of the priority projects within the frame-
work of this new international programme.
Although efforts have been made to avoid inconsistency in
terminology, uniformity has not been possible; indeed, this is
something beyond the scope of the present monograph. However,
within the IPCS, a project is under way to compile internationally
agreed definitions for the terms most frequently used in toxicological
and epidemiological studies. At present, therefore, it is important
to understand that some terms may have various meanings and
implications in different countries or in different scientific
circles and that it may be highly misleading to employ them outside
the national pattern of use or outside the context of a specialized
field, without precise definition. The reader is therefore warned
to be wary of the uncritical transfer of technical terms from one
set of circumstances to another.
The present monograph should serve as a useful guide to
the conduct of epidemiological studies on the effects of
non-biological agents on the health of human communities. An
epidemiological investigation would involve not only
epidemiologists but also other experts (e.g., clinicians,
statisticians, engineers, chemists, and nurses), and the
monograph is intended to address such a broad audience. The
editorial group believes that this publication will pave the
way for future studies.a
The final editing of the monograph was carried out during
1982 by M. Lebowitz and R. Waller, assisted by J. Kostrzewski,
M. Jacobsen, and Y. Hasegawa.
A special tribute should be paid to the late Dr F. Sawicki,
in recognition of his valuable contribution to this monograph,
and his extensive work on environmental factors in relation to
respiratory diseases.
The Editorial Group
* * *
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.
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a For instance, collaborative epidemiological studies on the
health effects of several chemicals being initiated under
the coordination of the WHO Regional Office for Europe
will apply the principles set out in this publication.
The editorial group was aware that a manual on epidemiology
for occupational health was being prepared jointly by the
World Health Organization in Geneva and the WHO Regional
Office for Europe; although the present Monograph has cited
several occupational health studies, it is addressed to
problems in the general population rather than among
specific occupational groups.
GUIDELINES ON STUDIES IN ENVIRONMENTAL EPIDEMIOLOGY
Editorial Groupa
Dr K.P. Duncan, Health and Safety Executive, London, England
(Coordinator for Chapter 7)
Dr M. Greenberg, Health and Safety Executive, London, England
(Coordinator for Chapter 4)
Dr Y. Hasegawa, Environmental Hazards and Food Protection,
Division of Environmental Health, World Health
Organization, Geneva, Switzerland (Secretary)
Professor I.T.T. Higgins, School of Public Health, University
of Michigan, Ann Arbor, Michigan, USA (Coordinator for
Chapter 2)
Dr M. Jacobsen, Institute of Occupational Medicine, Edinburgh,
Scotland (Coordinator for Chapter 6)
Professor J. Kostrzewski, Department of Epidemiology, National
Institute of Hygiene, Warsaw, Poland (Chairman)
Professor P.J. Lawther, MRC Toxicology Unit, Clinical Section,
St. Bartholomew's Hospital Medical College, London, England
Professor M.D. Lebowitz, Division of Respiratory Sciences,
Health Sciences Center, University of Arizona, Tucson,
Arizona, USA (Coordinator for Chapter 5)
Dr I. Shigematsu, Radiation Effects Research Foundation,
Hiroshima, Japan
Mr R. E. Waller, Toxicology and Environmental Protection,
Department of Health and Social Security, London, England
(Coordinator for Chapter 1)
Professor R.L. Zielhuis, University of Amsterdam, Coronel
Laboratorium, Netherlands (Coordinator for Chapter 3)
---------------------------------------------------------------------------
a Professor W.W. Holland and Dr C. du V. Florey, St.
Thomas's Hospital Medical School, London, were initially
the Coordinators for Chapter 4. As they were unable to
continue the work it has been taken over by Dr Greenberg.
The Secretariat wishes to thank Professor Holland and Dr
Florey for their efforts.
GUIDELINES ON STUDIES IN ENVIRONMENTAL EPIDEMIOLOGY
Contributors
Professor M. Alderson, Institute of Cancer Research, Surrey,
England (contributor to section 4.2)
Professor K. Biersteker, Agricultural University, Wageningen,
Netherlands (contributor to Chapter 2)
Professor N.P. Bochkov, Institute of Medical Genetics, Moscow,
USSR (contributor to section 4.10)
Professor D.S. Borgaonkar, North Texas State University,
Denton, Texas, USA (contributor to section 4.10)
Dr N. Breslow, International Agency for Research on Cancer,
Lyon, France (contributor to Chapter 6)
Dr D.G. Clegg, Food Directorate, Department of National Health
and Welfare, Ottawa, Canada (contributor to section 3.5)
Dr J.H. Cummings, Dunn Clinical Nutrition Centre, Addenbrookes
Hospital, Cambridge, England (contributor to section 4.11)
Professor W.J. Eylenbosch, University of Antwerp, Wilrijk,
Belgium (contributor to sections 4.10 and 4.11)
Dr C. Favaretti, Institute of Hygiene, University of Padua,
Italy (contributor to Chapter 7)
Dr A.J. Fox, The City University, London, England (contributor
to Chapter 6)
Mrs M. Fugas, Institute of Medical Research and Occupational
Health, Zagreb, Yugoslavia (contributor to Chapter 3)
Professor J.R. Goldsmith, Ben Gurion University, Beer Sheva,
Israel (contributor to Chapter 3)
Professor B.D. Goldstein, New York University Medical Center,
New York, USA (contributor to section 4.7)
Professor I.F. Goldstein, Columbia University, School of
Public Health, New York, USA (contributor to Chapter 6)
Professor M. Hashimoto, Graduate School of Environmental
Sciences, Tsukuba University, Ibaraki-ken, Japan
(contributor to Chapter 7)
Professor M.W. Higgins, School of Public Health, University of
Michigan, Ann Arbor, Michigan, USA (contributor to section
5.6)
Contributors (contd.)
Dr A.W. Hubbard, Ministry of Agriculture, Fisheries and Food,
London, England (contributor to section 3.5)
Dr A. Jablensky, Division of Mental Health, World Health
Organization, Geneva, Switzerland (contributor to section
4.6)
Dr A. Jakubowski, Institute of Occupational Medicine and Rural
Hygiene, Lublin, Poland (contributor to section 3.5)
Dr H. P. Jammet, Centre for Nuclear Studies,
Fontenay-aux-Roses, France (contributor to section 3.5)
Professor F. Kaloyanova, Institute of Hygiene and Occupational
Health, Sofia, Bulgaria (contributor to Chapter 3)
Professor S.R. Kamat, Department of Chest Medicine, K.E.M.
Hospital, Bombay, India (contributor to sections 4.8 and
5.6)
Dr H. Kato, Radiation Effects Research Foundation, Hiroshima,
Japan (contributor to section 5.6)
Professor L.T. Kurland, Mayo Clinic, Rochester, Minnesota, USA
(contributor to section 4.5)
Dr J.F. Kurtzke, Veterans Administration Hospital, Washington,
DC, USA (contributor to section 4.5)
Dr P.J. Landrigan, National Institute for Occupational Safety
and Health Cincinnati, Ohio, USA (contributor to Chapter 5)
Professor M.F. Lechat, Catholic University of Louvain,
Brussels, Belgium (contributor to section 4.10)
Professor S.R. Leeder, University of Newcastle, New South
Wales, Australia (contributor to section 4.4)
Dr D.T. Mage, Health Effects Research Laboratory,
Environmental Protection Agency, Research Triangle Park,
North Carolina, USA (contributor to Chapter 3)
Dr P.B. Meijer, TNO Research Institute for Environmental
Hygiene, Delft, Netherlands (contributor to Chapter 3)
Dr W.E. Miall, MRC Epidemiology and Medical Care Unit, Harrow,
England (contributor to Chapter 5)
Dr C.S. Muir, International Agency for Research on Cancer,
Lyons, France (contributor to Chapter 2 and section 4.3)
Profesor M. Nikonorow, National Institute of Hygiene, Warsaw,
Poland (contributor to section 3.5)
Contributors (contd.)
Dr B.R. Ordo]ez, Autonomous Metropolitan University, Mexico
City, Mexico (contributor to Chapter 7)
Professor B. Paccagnella, Institute of Hygiene, University of
Padua, Italy (contributor to Chapter 7)
Dr R.F. Packham, Water Research Centre, Medmenham, England
(contributor to section 3.5)
Professor B.S. Pasternack, New York University Medical Center,
New York, USA (contributor to Chapter 6)
Professor W.O. Phoon, University of Singapore, Singapore
(contributor to Chapter 5)
Dr I. Purcell, University of Newcastle, New South Wales,
Australia (contributor to section 4.4)
Professor A.V. Roscin, Central Institute for Advanced Medical
Training, Moscow, USSR (contributor to section 4.7)
Dr M. Saric, Institute for Medical Research and Occupational
Health, Zagreb, Yugoslavia (contributor to section 4.4)
Dr F. Sawicki, National Institute of Hygiene, Warsaw, Poland
(contributor to Chapter 5)
Dr M.A. Schneiderman, National Cancer Institute, Bethesda,
Maryland, USA (contributor to Chapter 2)
Dr I. Shigematsu, Radiation Effects Research Foundation,
Hiroshima, Japan (contributor to section 5.5 and Chapter 7)
Dr C. Silverman, Bureau of Radiological Health, US Food and
Drug Administration, Rockville, Maryland, USA (contributor
to section 3.5)
Professor F.H. Sobels, University of Leiden, Leiden,
Netherlands (contributor to section 4.10)
Dr E. Somers, Environmental Health Directorate, Department of
National Health and Welfare, Ottawa, Canada (contributor
to Chapter 7)
Dr J. H. Stebbings, Jr., Los Alamos Scientific Laboratory, Los
Alamos, New Mexico, USA (contributor to Chapter 6)
Dr A. H. Suter, Occupational Safety and Health Administration,
Department of Labor, Washington, DC, USA (contributor to
section 3.5)
Dr H. Tamashiro, Institute of Public Health, Tokyo, Japan
(contributor to section 5.5 and Chapter 7)
Contributors (contd.)
Dr M.P. van Sprundel, University of Antwerp, Wilrijk, Belgium
(contributor to sections 4.10 and 4.11)
Dr M. Violaki-Paraskeva, Ministry of Social Services, Athens,
Greece (contributor to Chapter 7)
Professor D. Wassermann, The Hebrew University Hadassah
Medical School, Jerusalem, Israel (contributor to Chapter
4)
Professor M. Wassermann, The Hebrew University Hadassah
Medical School, Jerusalem, Israel (contributor to Chapter
4)
Professor W.E. Waters, Community Medicine, Southampton General
Hospital, Southampton, England (contributor to section 5.3)
Dr J.A.C. Weatherall, Office of Population Censuses and
Surveys, London, England (contributor to section 4.10)
Professor P.H.N. Wood, The Arthritis and Rheumatism Council
Epidemiology Research Unit, University of Manchester,
Manchester, England (contributor to section 4.8)
Dr M. Zaphiropoulos, Ministry of Social Services, Athens,
Greece (contributor to Chapter 7)
IEA/WHO JOINT WORKSHOP: MONOGRAPH ON GUIDELINES ON STUDIES IN
ENVIRONMENTAL EPIDEMIOLOGY
Members
Dr E. Bennet, Health and Safety Directorate, Commission of the
European Communities, Luxembourg
Dr S. Beresford, Royal Free Hospital School of Medicine,
London, England
Dr G. W. Brebe, Clinical Epidemiology, National Cancer
Institute, National Institutes of Health, Bethesda,
Maryland, USA
Professor L. Breslow, School of Public Health, University of
California Los Angeles, California, USA
Dr D. Brille, Studies and Research Mission, Ministry of the
Environment, Paris, France
Dr P.G.J. Burney, Department of Community Medicine, St Thomas'
Hospital Medical School, London, England
Miss M. Deane, Epidemiological Studies Section, California State
Department of Health Services, Berkeley, California, USA
Dr A.R. Eltom, Faculty of Medicine, Khartoum, Sudan
Professor W.S. Eylenbosch, Department of Epidemiology and
Social Medicine, University of Antwerp, Wilrijk, Belgium
Professor G.M. Fara, Institute of Hygiene, Milan, Italy
Dr J.J. Feldman, Analysis and Epidemiology, National Center
for Health Statistics, Hyattsville, Maryland, USA
Dr I.F. Goldstein, Environmental Epidemiology Research Unit,
Columbia University, School of Public Health, New York, USA
Dr Y. Hasegawa, Environmental Hazards and Food Protection,
Division of Environmental Health, World Health
Organization, Geneva, Switzerland
Dr N. M. Hanis, Epidemiology Unit, Research and Environmental
Division, Medical Department, Exxon Corporation, E.
Millstone, New Jersey, USA and Cornell University Medical
School, New York, USA
Professor I.T.T. Higgins, School of Public Health, University
of Michigan, Ann Arbor, Michigan, USA
Professor M.W. Higgins, Department of Epidemiology, School of
Public Health, University of Michigan, Ann Arbor,
Michigan, USA
Members (contd.)
Dr M. Hitosugi, Department of Public Health, School of
Medicine, Kitasato University, Sagami-hara City,
Kanagawa-Ken, Japan
Professor A.C. Irwin, Department of Preventive Medicine,
Dalhousie University, Halifax, Nova Scotia, Canada
Dr M. Jacobsen, Institute of Occupational Medicine, Edinburgh,
Scotland
Professor H. Kasuga, Department of Public Health, School of
Medicine, Tokai University, Isehara-Shi, Kanagawa-Ken,
Japan
Dr M. Khogali, Faculty of Medicine, Kuwait University, Safat,
Kuwait
Professor M.A. Klinberg, Department of Preventive and Social
Medicine, Tel-Aviv University School of Medicine, Ramat
Aviv, Israel
Professor J. Kostrzewski, Department of Epidemiology, National
Institute of Hygiene, Warsaw, Poland
Professor L.T. Kurland, Department of Medical Statistics and
Epidemiology, Mayo Clinic, Rochester, Minnesota, USA
Professor R.A. Kurtz, Faculty of Medicine, Kuwait University,
Safat, Kuwait
Professor M. Lebowitz, Division of Respiratory Sciences,
Health Sciences Center, University of Arizona, Tucson,
Arizona, USA
Dr S. Mazumdar, Department of Biostatistics, University of
Pittsburgh, Pittsburgh, Pennsylvania, USA
Dr U. G. Oleru, College of Medicine, University of Lagos,
Lagos, Nigeria
Professor B.S. Pasternack, Department of Environmental
Medicine, New York University, Medical Center, New York,
USA
Professor M.R. Pandey, Thapathali, Katmandu, Nepal
Professor W.O. Phoon, Department of Social Medicine and Public
Health, National University of Singapore, Singapore
Dr M.P. Sprundel, Department of Epidemiology and Social
Medicine, University of Antwerp, Wilrijk, Belgium
Members (contd.)
Professor R. Steele, Department of Community Health and
Epidemiology, Queen's University, Kingston, Ontario, Canada
Dr H. Tamashiro, National Institute for Minamata Disease,
Minamata City, Kumamoto-Ken, Japan
Professor K.W. Tietze, Federal Health Office, Berlin (West)
Dr M. Wahdan, Regional Adviser on Epidemiology, WHO Regional
Office for Eastern Mediterranean, Alexandria, Egypt
Mr R.E. Waller, Toxicology and Environmental Protection,
Department of Health and Social Security, London, England
Professor W. Winkelstein, School of Public Health, University
of California, Berkeley, California, USA
FINAL REVIEW MEETING ON GUIDELINES ON STUDIES IN ENVIRONMENTAL
EPIDEMIOLOGY
Members
Dr L.K.A. Derban, Medical Officer, Volta River Authority,
Accra, Ghana
Dr C. Favaretti, Institute of Hygiene, University of Padua,
Italy
Dr M. Jacobsen, Institute of Occupational Medicine, Edinburgh,
Scotland
Professor S.R. Kamat, Department of Chest Medicine, K.E.M.
Hospital, Bombay, India
Professor J. Kostrzewski, Department of Epidemiology, National
Intitute of Hygiene, Warsaw, Poland (Chairman)
Professor M.D. Lebowitz, Division of Respiratory Sciences,
Health Sciences Center, University of Arizona, Tucson,
Arizona, USA (Co-rapporteur)
Professor A. Massoud, Department of Community, Industrial and
Environmental Medicine, Ain Shams University, Cairo, Egypt
Dr B.R. Ordonez, Environmental Health Programme, Autonomous
Metropolitan University, Mexico City, Mexico
Professor A.V. Roscin, Central Institute for Advanced Medical
Training, Moscow, USSR
Dr I. Shigematsu, Radiation Effects Research Foundation,
Hiroshima, Japan
Academician G.J. Sidorenko, A.N. Sysin Institute of General
and Communal Hygiene, Academy of Medical Sciences of the
USSR, Moscow, USSR (Vice Chairman)
Mr R.E. Waller, Toxicology and Environmental Protection,
Department of Health and Social Security, London, England
(Co-rapporteur)
WHO Secretariat
Dr I. Farkas, Promotion of Environmental Health, WHO Regional
Office for Europe, Copenhagen, Denmark
Dr Y. Hasegawa, Medical Officer, Environmental Hazards and
Food Protection, Division of Environmental Health, WHO,
Geneva, Switzerland (Secretary)
Other participants
Dr I.R. Golubev, Department of Public Health, USSR State
Committee for Science and Technology, Moscow, USSR
Dr Z.P. Grigorievskaya, A.N. Sysin Institute of General and
Communal Hygiene, Moscow, USSR
Dr Y.E. Korneyev, Laboratory of Epidemiological Methods of
Study, A.N. Sysin Institute of General and Communal
Hygiene, Moscow, USSR (Co-rapporteur)
Dr N.N. Litvinov, A.N. Sysin Institute of General and Communal
Hygiene, Moscow, USSR
Dr Y.I. Prokopenko, Department of the Influence of
Environmental Factors of Public Health, A.N. Sysin
Institute of General and Communal Hygiene, Moscow, USSR
Dr Ya.I. Zvinjackovskij, Laboratory of the Influence of
Environmental Factors of Public Health, Marseev Institute
of General and Communical Hygiene, Kiev, USSR
* * *
OTHER REVIEWERS
Dr A. David, Office of Occupational Health, Division of
Noncommunicable Diseases, WHO, Geneva, Switzerland
Mr J. Duppenthaler, Division of Epidemiological Surveillance
and Health Situation and Trend Assessment, WHO, Geneva,
Switzerland
Dr K. Hemminki, Institute of Occupational Health, Helsinki,
Finland
Dr J. Stjernswärd, Cancer, Division of Noncommunicable
Diseases, WHO, Geneva, Switzerland
Dr C. Xintaras, Office of Occupational Health, Division of
Noncommunicable Diseases, WHO, Geneva, Switzerland
1. INTRODUCTION
1.1. Interrelationships with Toxicological Studies
In some respects the present volume is intended to complement
an earlier publication in the Environmental Health Criteria series,
"Principles and methods for evaluating the toxicity of chemicals -
Part I", which dealt with experimental work using mainly animals
and other biological assay systems (WHO, 1978). There are some
parallels between such laboratory studies and epidemiological
investigations of the effects of hazardous substances on human
populations. The object, in each case, is to compare the effects
on groups subjected to different levels of the suspect agent,
always ensuring that the groups are matched as far as possible in
respect of other relevant factors (which may include sex, age,
temperature etc). Much experimental work is indeed done on human
subjects, restricted to doses that will evoke only relatively minor
physiological or biochemical responses that are readily reversible.
The borderline between laboratory experimentation and epidemological
work is not clearly defined. For the present purposes, however,
straight-forward toxicological studies on human beings, in which
the effects of specified doses of suspect agents administered
to small groups of subjects in the laboratory are examined, will
not be considered.
There are extensions of this approach which form a bridge
between laboratory work and that in the general environment, and
some mention should be made of these. Environmental chambers have
been constructed by some research groups, where small numbers of
subjects may spend periods of hours, days, or weeks under closely
controlled conditions. These have application in studies on acute
effects, and have been used, for example, to investigate the
effects of exposure to polluted urban air, drawn in from the
general atmosphere and carrying out control experiments with clean
air (Kerr, 1973). In isolated instances, this approach can be taken
a little further, for example, studies on the effects of lead
intake can be done by controlling the air and/or diet of groups
such as prisoners living in confined conditions (Cole & Lynam,
1973). More generally, however, the investigator cannot control
either the exposure of the subjects or their activities. Advantage
must then be taken of existing contrasts in environmental exposures
to obtain evidence on effects on health. In many cases, both
toxicological and epidemiological data are essential in
establishing sound health criteria and they are complementary to
each other.
1.2. Design
Perhaps as an over-reaction to a number of environmental
"disasters" that have occurred around the world, there has been a
tendency in recent years to carry out epidemiological imvestigations
without first posing any specific questions. There is indeed a
place for exploratory studies, often based on existing routinely
collected data on mortality or morbidity together with general
observations on environmental factors, but further studies
need to be carefully designed to test specific hypotheses. Then
one has to ask:
Who should be studied? Are particular subgroups of the
population at risk? How should control groups be selected?
What should be measured? Can specific agents be
identified? Is there a single pathway (for example, via
inhalation) or have several ways of entry to be considered
simultaneously? How are effects on health to be assessed?
Where has the study to take place? Should geographical
position, altitude, meteorology, etc., be taken into account
in selecting a locality? Are there existing monitoring
stations or sets of data relating to the environmental factors
in question?
When should the study be carried out? Are seasonal
effects likely to be important? Is the available time-span
long enough to provide a satisfactory estimate of long-term
exposures? Should exposures be averaged over months or years,
or are short-term peaks relevant in some cases?
In designing a special investigation or survey in the field of
environmental health, the objects of the exercise must first be
considered carefully. Without advocating a strict cost/benefit
approach to such studies, the question of the amount of time and
money spent in relation to the probable yield of information must
obviously be of importance. At one end of the spectrum, one might
consider monitoring the health records of the whole population, and
linking the information with as many data on environmental factors
as possible. Certainly, the monitoring of national death
statistics and of some aspects of morbidity records is possible,
looking particularly for the emergence of new trends or patterns of
distribution in congenital abnormalities and relatively rare
diseases. The need for this was underlined by the thalidomide
episode and, although the use of therapeutic drugs is not being
considered specifically in the present context, there are many
parallels between present-day enquiries into the safety of drugs
and the conduct of epidemiological studies on environmental agents.
However, to go beyond a broad surveillance such as this, with
enquiries into "health and habits" on a national scale, might be
regarded as an intrusion on personal privacy, apart from the
prohibitive cost. Even so, there is evidence that careful scanning
of linked records maintained on a regional, if not national, scale
can reveal new problems, as in the case of the occurrence of nasal
cancer among furniture makers (Acheson et al., 1967).
In this particular example, suspicions had been aroused by
clinical investigations on a few cases; however often, with a
relatively rare disease the "clustering" of a few cases in one area
or within one small subgroup of the population is sufficient to
give a positive lead on a new environmental hazard. In general,
when there is some indication of adverse effects of a particular
agent, the most effective way to conduct further epidemiological
studies is to concentrate attention on groups of people considered
to be particularly at risk. An example of this for a physical
agent - noise - is the investigation of exposure to "pop" music,
conducted among young college students (Hanson & Fearn, 1975). In
this study, dose-response relationships were examined within the
group selected, but, in general, it may be necessary to include
appropriate control groups, not exposed to the suspect agent.
An alternative approach, still directed towards high-risk
subgroups, is to consider a specific disease or effect, and to
compare the available information on exposures to environmental
agents with those of a control group. This is the "case-control"
type of study that was so successful in the early stages of the
investigation of the role of environmental factors in the
development of lung cancer (Doll & Hill, 1950; Wynder & Graham,
1950).
On wider issues, where the interrelationships between agents
and effects are more diffuse or more tenuous, relatively expensive
general community surveys may be needed, based on random samples of
the population concerned, or of particular age or occupational
groups. This technique has been particularly valuable in studies
on the role of environmental factors in the development of
bronchitis.
The types of survey that have proved to be of value in the
study of the effects of environmental agents are described in
Chapter 2. The dividing lines between them are not always clearly
defined, and there may be advantages in combining several
approaches within a single survey. The choice will depend on the
objects of the study and on the resources available.
1.3. Environmental Agents and Assessment of Exposures
As indicated in the preface, epidemiological methods were
developed initially to investigate the distribution and determinants
of communicable diseases, but their scope has now been widened to
include all aspects of health and wellbeing in relation to
biological or non-biological agents. Much of the discussion that
follows in later chapters on the design, conduct, and analysis of
epidemiological studies could apply to any field of interest, but
the prime concern here is with effects of chemical and physical
agents. The interaction of bacteria, viruses, fungi, yeasts,
protozoa, and higher animal agents or vectors with non-biological
agents is, however, recognized as contributing to human disease.
The term "agent" is a neutral one with no intrinsic implication
of "beneficial" or "adverse" characteristics. Most agents have the
potential for one or other or both of these effects, varying with
the precise nature of the agent, the level and duration of
exposure, and the state of nutrition and other acquired or
inherited characteristics of the subject. Thus, for example, the
chemical agents constituting vitamins and their analogues, that may
serve as essential food factors, are claimed to offer protection
against certain diseases (e.g., vitamin A against carcinogenesis),
or to have severe toxic effects, according to dose, to the state of
nutrition and acquired characteristics of the subject, and to other
agents operating coincidentally.
When studying these chemical and physical agents, it is
necessary to characterize them and to determine their absorption,
concentration in air, water, etc. with careful attention to
precision. For example, when describing a mineral, it is not
enough to give the name, chemical formula, and dose. An adequate
description involves specifying its contaminants, its physical form
(amorphous, crystalline, discrete particulate or fibrous), and
particle size distribution, and sometimes its physicochemical
surface properties. Due consideration has to be given to demo-
graphic and sociocultural factors that may affect the degree of
exposure or uptake as well as to special host characteristics,
including immunological status, before extrapolating the experience
in one population to that of another.
Chemical agents involved in environmental considerations have
been characterized as natural and manufactured organic (but not
living) and inorganic substances occurring in food, air, water,
soil, and other media. While living materials are excluded from
this category, their products are widely distributed in the
environment, in the form of metabolites, cell bodies, or bio-
chemical extracts. Thus, many foodstuffs are infested by, or
require for their synthesis, micro-organisms that are also found in
the wild and may contaminate the general environment.
Physical agents that impinge on man may occur naturally or be
man-made or man-intensified. They include ionizing and non-
ionizing radiation, the latter ranging from ultraviolet through
visible light and infrared to microwave, radio frequency and
extremely low frequency electromagnetic fields. Climatic
conditions of temperature and humidity play important direct and
indirect roles in environmental health. Noise and vibration at the
intensities experienced occupationally are associated with
objective evidence of damage; lesser intensities occurring outside
occupational environments, apart from affecting amenity, are a
source of concern in case they present health hazards.
The assessment of exposures is the most difficult aspect of
epidemiological research on environmental agents, and the one that
requires most careful thought, if any attempt is to be made to
establish "exposure/effect" relationships. For mixtures of
pollutants that are found under actual environmental conditions,
some integrated approach would be required for adequate exposure
assessment. However, such an approach has still to be developed.
The commonest practice is to monitor concentrations or
intensities (in air, water, etc.) at fixed points in order to make
estimates of the exposure of the community being investigated.
Measurements may have to be specially made for each investigation,
but advantage can often be taken of existing monitoring networks.
There has been a rapid expansion of monitoring activities
throughout the world in recent years: many reports have been
written about national and international programmes (Munn, 1973;
Department of the Environment, 1974), and a computer-based record
of current work is maintained in the United States of America
(Whitman, 1975). Although it is possible to monitor environmental
variables continuously at a large number of sites, it is impossible
to use that information in an undigested form in epidemiological
studies in which the health indices are generally crude. Provision
must therefore be made for statistical analyses of the data, once
collected, and, in some schemes operating with automatic
instruments, statistical analysers are incorporated, or the
instruments are "on line" to a central computer. A scheme of this
type in the field of air pollution monitoring has been described by
Lauer & Benson (1974). There is a risk however of becoming
overwhelmed with data from such complex networks and in most
epidemiological studies, it is more important to consider what is
the minimum requirement for a reasonable assessment of exposures
than to collect a vast array of data from which to select a few
figures.
"Personal" monitors may sometimes be applicable. This is
particularly true in assessing exposures to ionizing radiation, as
simple integrating devices (such as film badges) are available. It
is more difficult to measure most other environmental agents with
light portable equipment, but personal samplers for air pollutants,
such as suspended particulate matter and sulfur dioxide, are
available. Even so, the initial cost and maintenance problems
associated with these are at present deterrents to their use in
large-scale epidemiological studies.
For multimedia and non- or less-degradable pollutants, such as
metals and many organochlorine compounds, the biological monitoring
method, namely, the measurement of levels of polllutants in
tissues and fluids, has proved to be a useful tool for exposure
assessment.
Procedures for the assessment of exposures and for their
quality control are described in detail in Chapter 3: in general
the principles involved are meant to apply to any type of
environmental agent, though measurement methods are specific to
the one in question.
1.4. Effects on Health
Physical and chemical agents generated by man's activities
may have various effects on human being. Some substances may not
produce any adverse effects, while others, may be liable, if
exposures are sufficient, to affect such basic phenomena as
growth and development. Sometimes, environmental exposures may
affect host susceptibility or resistance, or produce functional or
prepathological changes. Behaviour may be modified by exposure,
especially to physical agents such as noise, light, and heat. A
wide range of pathological states in different organs may be
induced by exposure to environmental agents, and even death may be
caused or hastened by such exposures.
The starting point for many studies on the effects of
environmental agents has been the examination of existing records
of mortality or morbidity. The interpretation of findings from
these may itself be hazardous, but to determine which effects
should be studied, this retrospective approach is often considered
first.
In most countries, there are well-established systems of
registration of deaths, in which the cause of death is reported
(with varying accuracy) along with the age, date and place of
death, place of usual residence, marital status, occupation, and,
in some cases, additional information that may allow links to be
established with birth registration or other particulars of the
same individual.
Examination of long-term trends in death rates, or of
differences between countries, can occasionally give leads on
suspect environmental agents, but the most fruitful analyses in the
past have been those of local and regional differences in death
rates from specific diseases, within single countries. Thus, an
excess of cancer of the oesophagus could be seen in certain areas
of France, or of bronchitis in the industrial towns of the United
Kingdom, and, in these and many other examples, the findings have
been confirmed and investigated further in carefully designed
epidemiological surveys.
Occupational mortality studies can also be very valuable, but
those based on nationally-collected statistics are difficult to
interpret, since "occupation" may be inadequately described by the
relatives who have to give the information entered on death
certificates. Adelstein (1972) has also drawn attention to the
difficulty in distinguishing occupational risks from those of
"social" origin (notably tobacco smoking) in the more recent
records, and occupational studies are now better done as special
surveys within industries.
Short-term changes in death rates can provide information on a
limited range of agents that are subject to large variations in
intensity over periods of months, weeks, or days, and are
potentially lethal to some sections of the community. Many
diseases spread by bacterial and viral agents fall into this
category, but the main examples among physical and chemical agents
are air pollution and climatic conditions. Tabulations of deaths
on a monthly or weekly basis may be of some value in seeking any
evidence of acute effects of these factors, but ideally daily
tabulations are required, for selected areas containing large
populations.
Death is a crude but clearly defined index of response and it
is the one that has been most widely used in studies of the effects
of environmental agents. Where a small number of otherwise healthy
people die suddenly in one incident, perhaps as the result of an
accidental release of toxic materials in industry, cause and effect
relationships are easily established, but, in the general
community, associations are usually far more tenuous. It is
commonly the weakest sections of the community that are most
sensitive to potentially lethal effects of environmental agents:
the very old, the chronic sick, and the very young. In studies of
acute effects, it may be sufficient to study changes in the total
number of deaths in a given area, but specificity can often be
improved by considering deaths within limited age-ranges or for
certain causes only. Surprisingly, even the effects of major
insults to health may not be immediately obvious, if they impinge
mainly on the very old, among whom death rates are normally
relatively high. In the London fog of December 1952, there were
general indications of an exceptional death rate, such as a
shortage of coffins and flowers for funerals, but it was not until
all the returns of deaths from local registrars were collected
together and scrutinized that it was realized that the number of
deaths during and just after the fog was about 4000 more than would
normally have been expected (Ministry of Health, 1954).
Illness, as defined in various ways in routinely collected
morbidity statistics, can be regarded as a further index of
response. The more it is qualified in terms of age-range and
disease category the better it is, but there are many hazards in
accepting information collected largely for administrative
purposes, because of possible biases. Morbidity data are far more
subject to interference from social factors than mortality data;
weekends and holidays, for example, have little effect on death
rates, but they have a profound effect on consultation rates with
general practitioners and on hospital admissions. Provided these
reservations are borne in mind, it is still possible to make use of
some existing information for epidemiological studies.
The range of indices of effects on health available for use in
specially designed epidemiological surveys is very wide and covers
all organ systems. It is described in detail in Chapter 4 and it
can include death, the onset or prevalence of specific illnesses,
measurements of developmental, behavioural, functional, and
prepathological changes, and biochemical indices. There are,
however, limitations of costs, usage, and acceptability of some of
the tests.
1.5. Organization and Conduct
There are many practical problems to consider in the
organization and conduct of epidemiological studies and the
recommended procedures are described in Chapter 5. Both the level
of study to be conducted (simple to complex) and the resources
required to do it must be considered. As in the rest of the
monograph, studies are described which can be conducted in various
settings in the world. There is often preliminary work to do in
contacting organizations that may be able to provide, or help in
collection of, the health and environmental data, or may merely
need to be made aware of the aims and existence of the survey.
Some advance publicity may be desirable to gain the cooperation of
subjects and, where occupational groups are concerned, discussions
with managements and unions are essential.
Having selected the population required for the study, initial
contacts with individuals may need to be made by letter, prior to
any interview or examination. One of the major difficulties is to
obtain an adequate response from the population selected. Particu-
larly in studies of chronic effects, where contrasts are being
sought between people living in different areas, it is essential to
ensure that failure to contact or to follow up some of the subjects
does not bias the result. The possibility of observer bias must
also be considered. Where a number of observers are engaged in
interviewing or examining subjects in different localities, joint
training sessions are required to ensure uniformity of approach and
it may be necessary to interchange the teams to reduce risk of
bias. Even where objective assessments are being made, for example
with peak flow measurements in surveys of respiratory disease, it
is important to ensure uniformity of procedure and to check
regularly the performance or calibration of the instruments being
used. Careful standardization of methods of measuring the related
environmental agents is also required and, if biological indices of
effects are being used, it may be necessary to ensure that all
these measurements are made in a single laboratory.
The conduct of the field work itself will depend on the nature
of the survey. Surveys can be simple or complex. Subjects may be
seen only by field workers, but preferably by those who know the
community and its culture. Subjects may be asked to come to one of
several bases that might be set up in the areas near where the
subjects live or to a central laboratory or clinic. In surveys
requiring instruments for the measurement of lung function, etc.,
mobile laboratories are sometimes used. Where the subjects are
grouped together, for example in selected schools, offices, or
factories, the survey team will normally visit them there, by prior
arrangement with the authorities concerned. The most labour-
intensive survey, but often the most satisfactory, where the
effects of common environmental agents are being studied on
samples of the general population, is where the field workers
visit the subjects in their own homes.
Ethical problems sometimes arise; for example, if some of the
tests involved are regarded as intrusive. In surveys of exposure
to lead, blood samples may be required and, although there is
relatively little difficulty in taking these with the prior
permission of the subject in the case of adults, problems arise
with children, for parents and others cannot properly give
permission for samples to be taken in this way, if it is not for
the benefit of the child. Apart from this, confidentiality of
all information obtained in surveys must be maintained at all
times, hence it is common practice to exclude names and addresses
at all stages of the preparation and analysis of results, beyond
the original survey form.
1.6. Analysis and Interpretation of Results
In some surveys of modest size and quite often in the case of
studies on acute effects of environmental agents, the findings may
be tabulated manually and/or presented graphically in a straight-
forward manner. More generally, however, the data will be
transcribed on to punched cards, paper tape, or magnetic tape for
analysis by computer. Procedures for the preparation of the data,
and for the analysis and interpretation of findings are described
in detail in Chapter 6, in which the need for the close involvement
of statistical staff throughout the study is stressed.
The statistical analysis of epidemiological studies has been
revolutionized by the application of "package" programmes. These
have been written as general purpose statistical routines and
survey analyses and, although they may be handled by people with
relatively little statistical and computing experience, it is
essential to have expert advice and guidance to avoid misapplying
the techniques or misinterpreting the findings. The more complex
the technique, the more necessary it is to pause to consider the
relevance of the data, and, if possible, to try to provide some
visual presentation of the main features, for example, in the form
of a graph that may be displayed on a screen linked with the
computer, or plotted out on microfilm or by line-printer.
A fundamental point in relation to the control of
environmental pollutants is whether there is any kind of level of
exposure, below which effects of an environmental agent are not
detectable (with the techniques used), but beyond which effects
increase gradually in a defined relationship. A feature such as
this may be extremely difficult to establish, since the effects of
very low levels of exposure cannot be assessed with a degree of
precision great enough to allow much discrimination between
alternative hypotheses.
The greatest risks of mistaken interpretation occur in multiple
regression analysis where attempts are made to assess the extent to
which each of several variables affects some index of health; for
example, the prevalence of respiratory symptoms in a number of
communities may be studied in relation to several different
measures of air pollution, to climatic factors, and to the levels
of cigarette smoking. In such cases, there is a need to consider
whether a linear relationship is appropriate for each of the
variables, but beyond that, if some of those variables included are
correlated with one another (as is likely with measures of air
pollution and climate) then the regression coefficients cannot be
determined with any satisfactory degree of precision, and there is
a serious risk of overestimating the effect of one variable at the
expense of another (McDonald & Schwing, 1973).
Even when a significant correlation is found between an index
of health and one or more environmental factors, the relevance of
this must be considered carefully, for example in terms of
biological plausibility. If the number of observations in a study
is large, a correlation coefficient as low as 0.2 may be
statistically significant, but it would account for only 4% of the
variance in the health index, leaving 96% to be explained some
other way, perhaps in part by environmental factors that were not
measured.a In such cases, it may be necessary to consider
whether the assessments of environmental exposures were adequate,
or whether the overall effect of any environmental factors may have
been trivial in relation to that of other determinants.
Above all, the fact that correlation does not necessarily imply
causation must be recognised. Many unrelated factors exhibit
similar time trends or geographical distributions, and much
supporting evidence is required before there can be any presumption
of causation.
1.7. Uses of Epidemiological Information
The problem of considering whether a statistical association,
observed between indices of health and various chemical and
physical agents in the environment, suggests any cause and effect
relationship, is much more difficult than in the case of classical
epidemiological studies concerned with communicable diseases. The
basic difficulty is that few of the non-biological agents have
unique effects on health, and conversely the effects considered may
often be related to a wide range of factors. Thus, when decisions
have to be made about the need for control of suspect agents,
within industry or in the community at large, many aspects of the
situation may have to be taken into account, such as the strength
and consistency of associations seen in epidemiological studies,
related toxicological and clinical findings, and economic or social
implications of control measures.
Clearly many different disciplines become involved at this
stage and a full discussion is beyond the scope of the present
monograph, but this very important facet, which should involve the
scientist as well as the administrator, is introduced in Chapter 7.
--------------------------------------------------------------------------
a In general terms, the proportion of variance explained by
a regression is r2, where r is the correlation
coefficient; hence r = 1 (perfect agreement), all the
variance is explained: for r = 0.2, r2 = 0.04 (i.e. 4%).
The standard error of a correlation coefficient is
1
approximately -- where n is the number of observations.
n´
1 1
Hence for n = 10000, -- = --- = 0.01 and a coefficient r
n´ 100
in excess of 0.02 would be significant at the 5% level.
REFERENCES
ACHESON, E.D., HADFIELD, E.H., & MACBETH, R.G. (1967) Carci-
noma of the nasal cavity and accessory sinuses in wood-
workers. Lancet, 1: 311-312.
ADELSTEIN, A.M. (1972) Occupational mortality: cancer. Ann.
occup. Hyg., 15: 53-57.
COLE, J.F. & LYNAM, D.R. (1973) ILZRO's research to define
lead's impact on man. In: Environmental aspects of lead,
Luxembourg, Commission of the European Communities, pp.
169-187.
DEPARTMENT OF THE ENVIRONMENT (1974) The monitoring of the
environment in the United Kingdom. London, Her Majesty's
Stationery Office.
DOLL, R. & HILL, A.B. (1950) Smoking and carcinoma of the
lung. Br. med. J., 2: 739.
HANSON, D.R. & FEARN, R.W. (1975) Hearing acuity in young
people exposed to pop music and other noise. Lancet, 2:
203-205.
KERR, H.D. (1973) Diurnal variation of respiratory function
independent of air quality. Experience with an environ-
mentally controlled exposure chamber for human subjects.
Arch. environ. Health, 26: 144-152.
LAUER, G. & BENSON, F.B. (1974) The CHAMP air quality moni-
toring program. In: Proceedings of the International
Symposium, Recent Advances in the Assessment of the Health
Effects of Environmental Pollution (Paris). Luxembourg,
Commission of the European Communities.
MCDONALD, G.C. & SCHWING, R.C. (1973) Instabilities of
regression estimates relating air pollution to mortality.
Technometrics, 15: 463-481.
MINISTRY OF HEALTH (1954) Mortality and morbidity during the
London fog of December 1952. London, Her Majesty's Stationery
Office.
MUNN, R.E. (1973) Global environmental monitoring systems.
Toronto (SCOPE Report 3).
WHITMAN, J. (1975) More on monitoring. Environ. Sci.
Technol., 9: 611.
WYNDER, E.L. & GRAHAM, E.A. (1950) Tobacco smoking as a
possible etiologic factor in bronchiogenic carcinoma. J. Am.
med. Assoc., 143: 329.
WHO (1978) Environmental Health Criteria 6: Principles and
methods for evaluating the toxicity of chemicals. Part I.
Geneva, World Health Organization.
2. STUDY DESIGNS
2.1. Introduction
This chapter is concerned with the type of approach to be used
in an epidemiological study, starting with exploratory investigations,
which may be based on existing mortality or morbidity records, on
general health surveys, or sometimes on quite small-scale clinical
observations, and are aimed at seeking indications of the role of
environmental factors in a particular disease or condition. Such
investigations may be of value in formulating hypotheses that can
be followed up by studies designed specially to test them and,
where appropriate, to try to assess relationships between exposure
and effect in a quantitative manner.
Generally, it is an unusual distribution of disease in a
locality or a particular population that prompts the enquiry (which
could be regarded then as "effect-oriented"), though sometimes
concern arises because of some characteristic of the environment
that is thought, either on toxicological or more general grounds,
to have adverse effects on health ("agent-oriented"). In the
former category, an example is the recent epidemic of a severe
respiratory and generally debilitating disease in Spain (Tabuenca,
1981; Aldridge & Connors, 1982). This affected people over a wide
range of ages in several parts of the country, and it was at first
thought to be due to a respiratory infection. Astute clinical
enquiries concentrating attention on infants in the first instance,
because of their more closely confined environments and more
readily specified diets, revealed that each case was related to the
use of a particular supply of cooking oil that proved to be
chemically contaminated. These initial enquiries constituted the
exploratory study that generated a hypothesis capable of being
tested by both toxicological and epidemiological techniques.
The investigation of long-term effects of exposure to ionizing
radiation, following the 1945 atomic bomb explosions in Japan,
could be regarded as falling in the agent-oriented category. While
immediate effects were disastrous and there was every indication
that survivors would be liable to develop further radiation-induced
illnesses over the years, the exact nature of the effects and the
form of exposure/effect relationships were unknown. A longitudinal
study, in which defined populations were to be followed through to
death, was designed to examine these questions, and this is
referred to in detail in section 5.6.8.5.
In the following sections, some of the more commonly used types
of design in epidemiological studies are described, but it is
essential to stress that they are not alternatives that can be
chosen freely for any given situation. The choice of design
depends primarily on the questions being asked (the objectives of
the study) and on constraints imposed by factors such as resources
available, the time limit within which at least provisional answers
are required, accessibility of the population to be studied, and
ethical considerations. It is vital that a sensible hypothesis,
supported wherever possible by toxicological evidence, is
formulated first and the art of good survey design is to reconcile
conflicts between the ideal and what is possible in a way that will
maximize the acquisition of useful data.
2.2. Preliminary Review of State of Knowledge
The available literature on the clinical features and natural
history of the disease or condition being considered, on what is
known of its causes and distribution in the population, and on
trends with time, should be critically reviewed. Often, there are
conflicting findings between different published studies in the
field of environmental epidemiology and it is important to try to
establish which findings can be regarded as reasonably well-
founded.
At the same time, a review is required of information on all
the relevant environmental factors, including physical and chemical
properties, possible interactions with other agents, and anything
known about their spatial and temporal distribution. Any data
available on toxicological properties from animal experiments or
other biological testing procedures also needs to be examined
carefully.
In some instances, where new problems are encountered suddenly
and immediate action is required, as in the Spanish cooking-oil
problem cited above, or the Seveso accident in which dioxin was
dispersed in the vicinity of a chemical works (see section 7.3),
there may be little prior information on the agents concerned or
their effects, and, in any case, little time to study it. Even so,
it remains vitally important to consider carefully the types of
epidemiological studies that could and should be undertaken. A
false move in the beginning could completely undermine the chances
of yielding results that would contribute to the identification of
causal agents, and to the specification of exposure/effect
relationships.
2.3. Descriptive Studies and Use of Existing Records
Investigations of the general distribution of disease and of
possible environmental determinants on the basis of existing
records are referred to as descriptive studies: they describe the
situation as it exists in the community, without special efforts to
investigate symptoms, physiological functions, or exposures to
particular agents in defined groups. They may be included among
the exploratory investigations mentioned above, but they can
nonetheless be major undertakings in their own right, as in the
case of the construction of the detailed atlases of cancer
mortality that have now been prepared in a number of countries
(Mason et al., 1975; Editorial Committee for the Atlas of Cancer
Mortality in the People's Republic of China, 1979; Japan Health
Promotion Foundation, 1981).
Although past records frequently suffer from lack of
reliability, they also have certain advantages and have been used
not only for descriptive studies but for other types of
epidemiological studies including retrospective studies and case-
control studies (sections 2.7 and 2.9). For example, many of the
diseases and conditions of importance in environmental health
studies, as in the case of a number of cancers, occur many years
after significant exposure has taken place. In these circumtances,
it is usually wise to consider using information about the effects
of past exposures as the basis for providing answers to the
questions of interest.
Another advantage of existing records is economics. In most
situations, it will be found that the length of time required to
gather relevant new data would justify some initial investment of
effort in the study of past records.
There are two further reasons why such an approach should
always be considered. First, environmental hygiene changes with
time; recent exposures are generally at lower levels than those in
the more distant past. The effects of exposure are likely to be
more evident in people exposed to higher levels than in those
exposed to lower levels. If, therefore, the aim is to seek an
answer to a preliminary question as to whether or not there is a
real association between the hazard and the suspected environmental
agent, then attention must be focused initially on so-called "high-
risk" groups who are most likely to demonstrate an effect, if it
exists. The second reason is based on ethical considerations.
Knowing that a group of people has been exposed to a certain toxic
substance, it seems incumbent on society to assess the possible
health effects from such exposures in order to take preventive
action.
2.3.1. Mortality statistics
The routine collection of national mortality data commenced in
a number of countries in the mid-nineteenth century; for example,
since 1837, material has been collected for virtually every death
occurring in the United Kingdom. The World Health Organization
(WHO) has been responsible for sponsoring and encouraging the
collection of accurate mortality statistics throughout the world,
and the majority of developing countries now have some system for
the recording, collection, processing, and production of mortality
data.
All sets of routine data have disadvantages however. The
majority of deaths are certified by the practitioner attending the
patients, or sometimes by an official responsible for investigations
in cases of doubt or of violent or unnatural death, which may
include occupationally-associated disease. Though many systems
suffer from delay in data collection, legal requirements to
register the death and the establishment of registrars responsible
for handling this material usually result in a steady flow of data
into the central processing system. Insofar as autopsy contributes
to accurate diagnosis, varying rates will affect the validity of
comparisons between different countries and different periods
(Moriyama et al., 1966). Diagnostic vogues and differing vigilance
may also introduce bias.
Waldron & Vickerstaff (1977) have reviewed the subject of the
accuracy of diagnoses of fatal conditions and the quality of
certification. Although a clinician may be clear in his own mind
about the diagnosis, he does not always record it on the death
certificate in a way that can be appropriately coded. For a number
of years, it has been recognized that death is commonly the result
of a complex of diseases, and the international system for the
derivation of a single underlying cause of death from a full death
certificate can produce unrealistic statistics. This issue has
been discussed by a number of authors, for example, Alderson
(1976). For all its imperfections, the International Statistical
Classification of Diseases, Injuries and Causes of Death (WHO,
1977) is of great value. It contains definitions and recommendations
together with rules for medical certification, for the clerical
coding of primary causes of death and for quality control.
If death certificates themselves are used for epidemiological
purposes rather than the officially published statistics, then the
person undertaking the coding of cause of death should check his
performance against that of national coding staff. It is possible
to undertake analyses of morbid conditions mentioned on death
certificates apart from the primary cause of death. These can be
of value in studying health service requirements as well as their
relationship with environmental hazards. In some countries (e.g.,
Scotland, Sweden, and the USA) it is considered worth coding all
the conditions mentioned on the death certificates.
2.3.2. Morbidity statistics
A wide range of routine morbidity statistics is now available
in many developed countries. These may include data on abortion,
cancer, congenital abnormalities, hospital inpatients, infectious
diseases, school health, and sickness absence, including accidents
at work and occupational diseases.
WHO plays a major role in the standardization of morbidity
statistics. Various contributions to the World Health Statistics
Quarterly have discussed aspects of the methods required to
collect, analyse, and present material on all aspects of health
care. A general review of this topic has been published by WHO
(1965). Wagner (1976) reviewed 91 projects in 25 European
countries, concerning processed data on patients discharged from
hospital in-patient care. This report provides detailed
information about the capture, coding, and processing of the data
but limited indication of how the output from these systems was
used. A conference of the Commission of the European Community
discussed the relationship between health interview surveys, health
examination surveys, and routinely processed data on hospital
inpatient discharge records; Armitage (l977) indicated the
possibilities of international collaboration and the topics for
which this seemed feasible.
Despite the extensive data base on morbidity in a number of
countries, much care is generally required in using this type of
information, even for exploratory studies in environmental
epidemiology. The records may not provide complete coverage of the
population and there may be many in-built biases, particularly in
relation to socioeconomic class. Thus official sickness/absence
records show large variations in the apparent extent of illness
between different occupations, but these are often connected with
social factors or the amount of physical or mental effort required
in the job rather than with specific hazards precipitating illness.
Data assembled at cancer registries can, however, provide a
valuable supplement to those obtained from mortality records. Each
newly diagnosed case of cancer enters the system and near-complete
coverage of the population has been achieved in many countries.
The techniques involved have been reviewed by McLennan and co-
workers (1978). While both cancer registry and mortality data
suffer from differences in diagnostic standards and practice that
make international comparisons difficult, the former avoids some of
the problems introduced by different treatment regimes in the
interpretation of mortality statistics, and they are particularly
valuable for studies on conditions such as skin cancer that have a
low fatality rate.
2.3.3. Populations at risk
Occasionally, the absolute numbers of deaths or cases of a
particular disease can be of value in establishing relationships
with environmental factors without reference to the size or age
structure of the population at risk. This is particularly true of
rare conditions: for example, the identification of just a few
cases of angiosarcoma of the blood vessels of the liver was
sufficient, coupled with experimental animal studies, to
demonstrate a clear link with occupational exposure to vinyl
chloride. Similarly, clusters of cases of mesothelioma of the
pleura demonstrated links with particular types of fibres
(crocidolite asbestos, among occupational groups in South Africa
and elsewhere, and a local volcanic rock with an unusual fibrous
structure in the case of a village community in Turkey). Also, the
proportion of deaths attributed to a certain cause among all deaths
in a defined group can provide useful clues about environmental
factors, providing that basic data on sex and age are taken into
account (section 6.3.7.5).
More generally, however, detailed information on the size, sex,
and age structure of the population at risk is required for the
proper interpretation of mortality and morbidity statistics. The
calculation of appropriate rates is discussed further in section
6.3.7, and it is necessary here only to stress the importance of
obtaining adequate information on the denominators (the populations
at risk) as well as on the numerators (the numbers of deaths, or
cases of disease).
In most countries, complete censuses of the population are done
at intervals of the order of 10 years, and estimates of changes in
the intervening period are made from records of births, deaths, and
migration. Such records are capable of providing a detailed break-
down by sex and age, not only on the national scale but also for
individual towns and smaller communities within them. Even so,
much care is required in studies confined to small local areas and
it may be necessary to check or supplement the official data, even
to the extent of carrying out an unofficial census. This type of
approach may, in any case, be necessary in countries where census
data are incomplete or where internal migration rates are high.
2.3.4. Geographical differences in mortality and morbidity
Contrasts in appropriately standardized mortality and morbidity
rates (section 6.3.7.3) can be made between countries, or within
countries between groups characterized by their area of residence
or any other qualifier (such as ethnic group) that may be included
on the official records. These characteristics may, to a limited
extent, provide a qualitative guide to exposures to environmental
agents, thus allowing some exploratory studies to be done.
International comparisons are, however, fraught with difficulties,
due to differences in diagnostic practice or other factors. For
example, in the 1950s, mortality from bronchitis was about 25 times
higher in Scandinavia than in the United Kingdom. It was suspected
that this was partly an artifact of definition, and it led to
studies on variations between countries on the certification of
bronchitis and emphysema on death certificates (Fletcher et al.,
1965). In this particular case, it appeared that while differences
in terminology and in rules for assigning cause of death explained
quite a large part of the difference in mortality between the
United Kingdom and other countries, environmental factors probably
also contributed. To pursue this question further, however, it was
necessary to set up specially designed studies (Holland et al.,
1965).
In general, geographical contrasts between areas within a
single country are likely to be less than those between countries,
but they can be more revealing in relation to environmental
influences. Possibly, one of the most exciting intracountry
variations hitherto uncovered is the 30-fold difference in
oesophageal cancer risk for women in different areas along the
Caspian Littoral of Iran where, in the high incidence areas, this
form of cancer, generally rare in females (Kmet & Mahboubi, 1972),
is two to three times commoner than the relatively high incidence
of breast cancer in North American and European women.
It is not only in developing countries that such variations are
to be found. In England, stomach cancer is 50% commoner in
Liverpool than in Oxford. While some of the differences
demonstrated in the recently published maps of cancer morality,
referred to at the beginning of section 2.3, will turn out, when
examined closely, to be due to artefacts, others will prove to be
real and suitable for study.
Some of these contrasts can be linked with differences in
social class distribution between areas, implying effects of broad
environmental factors related to lifestyle, to concentrations of
recent immigrants or ethnic groups or to the selective migration of
relatively fit members of the community in or out of the areas
concerned.
Studies based on routinely collected mortality and morbidity
data usually have to be confined to comparisons based on area of
residence at the time of death or of occurrence of the illness in
question, and this is a limiting factor in studies on chronic
diseases, particularly in countries with high internal migration
rates. However, in the case of migrants between countries,
official records of country of origin are often maintained, and it
is possible to compare the experience of migrants with that of
their compatriots in both the country of origin and that of
subsequent residence. This sheds some light on the relative roles
of environmental and genetic factors in the development of disease.
The migrant exchanges one environment and its associated
exposures for another. If the international differences in various
disease risks observed are due to genetic factors, then incidence
should not be influenced by migration. Yet, as the pioneer studies
of Haenszel & Kurihara (1968) have shown, cancer morbidity and
mortality rates in migrant populations gradually come to approximate
those of the host country.
2.3.5. Time trends
Long-term trends with time in the mortality or morbidity rates
for specific diseases can be of value in indicating possible
effects of environmental factors, though interpretation is
complicated by the effects of improvement in therapeutic treatment,
etc. There has, for example, been a massive decline in mortality
from pulmonary tuberculosis in most developed countries during the
present century. It is difficult however to separate out all the
factors responsible: much of the decline occurred before the
really effective treatment by antibiotics became available, and, to
some extent, it can be attributed to environmental factors in the
broadest sense, i.e., to improved housing and social conditions and
to better medical care generally.
In many countries, the incidence of cancer of the breast, lung,
pancreas, and prostate is rising. It has been suggested, particularly
for lung cancer, that these increases are artefactual, being due to
better diagnosis, changes in classification, etc. (Percy et al.,
1974). While such factors probably have had some influence, it is
very difficult to believe that for an organ as accessible as the
breast they explain more than a small proportion of the observed
increase. The increase in malignant melanoma of the skin, a very
accessible cancer, has been carefully investigated by Magnus (1973)
and others who conclude that the rise is real. In the United
States of America, cancer of the oesophagus has doubled in persons
of Negroid origin, since 1935. Nonetheless, it is worth while
remembering that were it not for tobacco-caused lung cancers, the
overall cancer mortality in the USA for Caucasian males would be
falling and that for Caucasian females, the overall cancer
incidence is falling slowly (Devesa & Silverman, 1978).
When examining trends over an extended period, it is always
important to ensure either that sex/age specific rates are used or
that the data are standardized with respect to age (section
6.3.7.4), since there have been considerable changes in the age-
structure of the population in most countries during recent
decades. Sometimes, contrasts in trends between men and women can
provide clues about the factors responsible, as in the case of lung
cancer, for which death rates began to increase sharply sooner in
men than in women (consistent with an effect of cigarette smoking).
2.3.6. Associations with environmental indices
Apart from the general guidance that can be obtained from the
examination of geographical differences and trends in mortality and
morbidity, it is often possible to use observations on dietary
factors, or on air or water pollution, etc. to carry out further
descriptive studies.
For example, a large number of studies concerned with
associations between mortality and routine observations of urban
air pollution have been reviewed by Holland and co-workers (1979).
While most of these indicate positive correlations with measurements
of pollutants such as smoke, total suspended particulates or sulfur
dioxide, there is probably an interaction with other confounding
factorsa not taken into account, notably tobacco smoking. These
initial studies were however valuable as exploratory ones, leading
to the development of studies designed specifically to test the
hypothesis that exposure to urban air pollution contributes to the
development of chronic respiratory disease.
2.3.7. Case registers
As mentioned in section 2.3.3, it is sometimes possible to
identify environmental agents related to the development of
relatively rare conditions, simply from the clustering of a few
cases in local areas or in particular occupations. It is seldom
possible to recognize associations between common exposures and
common conditions in this way, but one effect-oriented approach is
to establish case registers through hospitals and/or general
practitioners for selected conditions for which there is already
some indication (e.g., an irregular geographical distribution)
that environmental factors may play a part. It may then be
possible, through careful enquiry into domestic and occupational
histories, to identify some common factor that can be followed up
further with additional epidemiological and toxicological
studies.
---------------------------------------------------------------------------
a Defined in section 6.4.5.3.
In developing countries, careful appraisal of a wider range of
cases and their associated histories can, however, help to provide
background information in the absence of comprehensive official
statistics. Even so, with the 3000-5000 people for whom a single
primary health care worker may be responsible, the wide random
fluctuations in morbidity or mortality rates that would be likely
to occur, would have little real meaning, and it would probably be
necessary to assemble information at a district or provincial level
in order to seek evidence of unusual local patterns of disease
(WHO, 1982).
2.3.8. General surveys
While survey techniques, considered in greater detail in
subsequent sections of this chapter, form an essential part of most
of the study designs, in many countries, regular surveys of the
population, made for administrative purposes, can be of value as
exploratory studies in relation to environmental factors. Thus, in
the United Kingdom, there is a General Household Survey that
enquires into family expenditure on foods, etc., and within this,
questions are asked on recent illnesses. There are possibilities
of adding additional questions on matters that may affect health
and, in this way, data have been obtained that could be used in
conjunction with mortality records to demonstrate strong
interrelationships between smoking and occupation and, in turn,
with lung cancer mortality (Office of Population Censuses and
Surveys, 1978). The application of information from other types of
surveys is discussed further in section 4.2.2.
2.4. Formulation of Hypotheses
Studies are most likely to be productive if they are based on
clearly stated hypotheses. These can be developed from the results
of various descriptive studies, as discussed above. Basically,
this is to try to demonstrate an association between carefully
specified effects on health and assessments of exposure to
specified environmental agents. Epidemiological studies cannot by
themselves prove that a particular agent causes a particular health
effect; they may, however, demonstrate quantitatively the strength
of an association between the presence of the agent and the
occurrence of the hypothesized effect. Appropriate statistical
analyses may in turn determine the probability that an association
as strong as that observed might have occurred by chance (section
6.4.1). Whether the correct agent has been identified or whether
the apparent association has arisen artefactually, because of
correlations with exposure to other agents or factors that were not
studied, is a question requiring further epidemiological studies
and, where possible, also toxicological work.
Most investigations in the field of environmental epidemiology
are necessarily of an observational nature, that is, they are
observations based on existing situations. Associations can be
demonstrated most clearly if it is possible to compare groups
exposed to several levels of the agent in question, but, in the
last resort, hypotheses about the exact form of exposure/effect
relationships can be tested effectively in experimental situations,
where the research worker has some control over exposures.
While the working hypothesis must be as simple as possible, it
has to be recognized that causes of ill-health are commonly multi-
factorial, and that the environment, though it comprises many
individual components, acts as an entity, having effects liable to
be greater than the total of those of the components. It may be
that, in the subsequent statistical analysis, a complex variable
can be developed to describe the combined effects of exposures to a
range of different agents as measured within the study (Cassell &
Lebowitz, 1976), but such ideas are difficult to incorporate into
the initial hypotheses.
It may be helpful to view the formulation and testing of
hypotheses in environmental epidemiology as an example of the
essentially iterative process of science, which comprises an
initial (or crude) hypothesis, assembling of data from available
sources or from planned investigations, testing of the validity of
the hypothesis, rejection of the hypothesis leading to its revision
or refinement, and the further assembling of data to test a revised
version.
The main types of study designs in environmental epidemiology
and some of the salient features of each are presented in Table
2.1, and described further in the sections below.
2.5. Cross-sectional Studies
Cross-sectional studies, sometimes called prevalence studies,
provide information on disease frequency (prevalence) at a given
time. Estimates of exposures, and measurements of personal
characteristics and biological effects may be made at the same time
or may be derived from existing records. Thus, for example, an
investigator might pose the question: Are small opacities on a
chest radiograph more often found in welders than in other men (of
the same age)? He might attempt to answer this question by
obtaining 1000 chest radiographs of welders and 1000 chest radio-
graphs of other men. After mixing the films to ensure blinding
with respect to which film was of a welder and which of a non-
welder, the 2000 films would be examined and categorized by two
independent readers and then the changes observed would be
compared, between welders and the non-welders, within 5- or 10-year
age groups. This would be a pure cross-sectional study. In
practice, it is seldom that a cross-sectional study is so precisely
limited with respect to time.
Usually, historical information is collected so that a
retrospective component is included in the study. Thus, information
would be collected on past as well as current smoking habits, an
occupational history would be taken, comprising details of all jobs
held since leaving school, and often residential details of each
community in which the subject had lived, and dietary information
and data on any other present and past exposures of potential
significance would be obtained. On the disease side of the
equation, attempts are often made to establish the time of onset,
mode of development and course of disease, and any relevant
antecedent conditions. Thus, although the information may be
collected at one time, it often refers to events that may have
taken place over a period of years. Hospital records, information
from physicians about past episodes of disease, and any measurements
that may have been made on relevant environmental factors may be
used, if they are likely to contribute useful information to the
study.
(a) Choice of population
Cross-sectional studies are often designed to compare the
prevalence of disease in different places and in different groups
of people according to their measured, assessed, or surmised
exposures. The two most common population types that need to be
considered are: the general population, comprising the whole
community or some segment of it, based on age, sex, and race; and
the occupational group. The former will usually be more
appropriate to the investigation of wider community exposures (air
pollution, water quality and contaminants, effects of hot or cold
weather, neighbourhood pollution from some plant or factory).
Sometimes, the families of workers may be exposed to pollutants of
industrial origin not only because of local emissions, but also
through dust being brought home on the workers' clothes. Many
studies concentrate on the health of children (for example, Golubev
et al., 1979; Dantov et al., 1980); apart from the importance of
this topic in its own right, where concern is primarily with
general environmental agents, the confounding effects of
occupational exposures and of smoking can be minimized in this way.
Among adults, a single occupational group may be chosen for the
investigation of community problems, in order to avoid interference
from specific occupational factors.
Table 2.1. Major features of various study designs in environmental epidemiology
---------------------------------------------------------------------------------------------------------
Study Population Exposure Health effect Confounders Problems Advantages
design are:
---------------------------------------------------------------------------------------------------------
Descrip- Various Records Mortality and Difficult Hard to establish Cheap, useful
tive sub- of past morbidity to sort cause-result and to formulate
study populations measure- statistics, out exposure-effect hypothesis
ments case regist- relationships
ries, etc.
Cross- Community Current Current Usually easy Hard to establish Can be done
sectional or special to measure cause-relation- quickly; can
study groups; ship; current use large popu-
exposed vs. exposure may be lations; can
non-exposed irrelevant to estimate extent
groups current disease of problem
(prevalence)
Prospec- Community Defined at To be deter- Usually easy Expensive and Can estimate
tive or special outset of mined during to measure time consuming; incidence and
study groups; study (can course of exposure cate- relative risk;
exposed vs. change dur- study gories can can study many
non-exposed ing course change; high diseases; can
groups of study) dropout rate infer cause-
result rela-
tionship
Retro- Special Occurred in Occurred in Often Changes in Less expensive
spective groups such past - need past - need difficult exposure/effect and quicker
cohort as occupa- records records of to measure over time of than cohort
study tional groups, of past past diagnosis because of study; need to prospective
patients, measure- and measure- retrospective rely on records study giving
and insured ments ments nature (e.g., that may not be similar
persons past smoking accurate enough response, if
habits) sufficient
past records
are available
---------------------------------------------------------------------------------------------------------
Table 2.1. (contd.)
---------------------------------------------------------------------------------------------------------
Study Population Exposure Health effect Confounders Problems Advantages
design are:
---------------------------------------------------------------------------------------------------------
Time- Large com- Current, Current, Often Many confounding Useful for
series munity with e.g., daily e.g., daily difficult factors, often studies on
study several mil- changes in variations in to sort out, difficult to acute effects
lion people; exposure mortality e.g., effects measure
susceptible of influenza
groups such
as asthmatics
Case- Usually small Occurred Known at Possible to Difficult to Relatively
control groups; in past start eliminate generalize cheap and
study diseased and deter- of study by matching due to small quick; useful
(cases) vs. mined by for them study group; for studying
non-diseased records or some incor- rare diseases
(controls) interview porated biases
Experi- Community Controlled/ To be measured Can be Expensive; Well accepted
mental or special known during course measured; ethical results; strong
(inter- groups of study can be consider- evidence for
vention) controlled by ation study causality
study randomization subjects'
of subjects compliance
required;
drop-outs
Monitor- Community Current Current Difficult Difficult to Cheap when
ing and or special to sort out relate exposure using existing
surveil- groups data with monitoring and
lance effects surveillance
data
---------------------------------------------------------------------------------------------------------
(b) Assessment of exposure and effects on health
The index of occurrence of disease in a cross-sectional study
is prevalence, or the prevalence rate, i.e., the number of persons
in the group who are affected, expressed as a proportion of the
total number in the group. For physiological or biochemical
variables, the average and the distribution are the parameters of
interest (section 6.3.7.1). However, as in the case of exposure,
some assessment of the onset, development, and progression of the
effect may be obtained from judicious questioning; available
information may also be sought from records.
(c) Confounding variables
It is not possible to list all the confounding factors that
need to be considered. These will vary from study to study
according to the condition under investigation and, in many cases,
it may not be possible to avoid confounding factors entirely.
However, it is necessary to ensure that potential confounding
variables are identified at the design stage and that all the
available information on them is recorded. Unless a single sex/age
group is being examined, it may be necessary to ensure that the
contrasting groups that are being selected for study have similar
age and sex distributions, by stratified random sampling. For age,
10-year groups are sufficient for most purposes. Smoking has been
found to be such an important factor in so many of the effects
likely to be investigated, that it should always be recorded. Some
index of social circumstances, number of years of education,
occupation, type and quality of housing, degree of overcrowding and
so on should often be included. Other factors will need to be
considered in certain studies though not necessarily in all. In
short, the appropriate attention to confounding factors can only be
given if the epidemiological and other knowledge about the causation
of the effect of interest is carefully reviewed before and during
the design stage.
(d) Analysis
In many parts of the world, only limited and non-specialized
statistical help may be available for research workers. The
absence of elaborate statistical facilities should not deter would-
be researchers from undertaking prevalence surveys. Full exploitation
of results from such studies may require the application of fairly
complex methods, but important new knowledge about relationships
between environmental factors and indices of health can be
established without sophisticated statistics. The essential
requirements are: attention to the principles of study design
mentioned above; conscientious adherence to protocols and survey
methods (chapter 5); and careful description of the results, as
discussed in section 6.3.
(e) Advantages and disadvantages
A cross-sectional study may provide the answers to many
questions. Thus, this method has been extensively used to compare
the prevalence of respiratory symptoms and levels of lung function
in different groups of people, living in different places and
working in different jobs with various potential levels of
exposure. Prevalence studies have been used to study such diverse
chronic conditions as rheumatoid arthritis, asymptomatic bacteriuria,
diabetes mellitus, hypertension, peptic ulcer, stroke, and coronary
disease. In the occupational setting, cross-sectional studies of
exposure to chemicals, dusts, fumes, and gases have often provided
valuable information to guide decisions on permissible levels of
different substances in the workplace. The threshold limit value
for mercury in the workplace, for example, was initially based on a
cross-sectional study (Neal et al., 1937) and, in the absence of
new relevant data, remained unchanged for 25 years. Cross-
sectional studies were also the basis for standards of cotton dust
in the workplace (Roach & Schilling, 1960).
Thus, despite some difficulties of interpretation, as discussed
below, determination of the prevalence of a disease in groups at a
particular time may give important information required for
preventive action. In any case, a cross-sectional study is a
necessary prerequisite for any longitudinal or prospective study.
Thus, if the incidence of a disease (i.e., the rate of occurrence
of new cases) is to be measured, it is essential to identify persons
who already have the disease in question.
Difficulties may arise because of selection within groups.
Much publicity has been given to the so-called "healthy worker
effect" in occupational health studies, but there is a danger that
this will lead to the underestimation of risk in some cases. How-
ever, this is only one of several population-selection artefacts
that may occur (Fox & Collier, 1976).
It should be noted that certain jobs preferentially attract
persons who may be less fit than the average. In the 1950s, the
attraction to the boot and shoe industry of the tuberculous worker
was noted by Stewart & Hughes (1951). Selection may occur within
occupations. In coalmining, fitter men may work in dustier jobs
where the pay is higher, disabled miners may leave the coalface and
work on haulage or eventually take up lighter jobs on the surface.
Disabled workers may, of course, also leave the industry altogether
and consequently will not be included in a prevalence study. The
impact of these movements may be hard to detect in a cross-
sectional study. Thus, an early study of lung cancer in relation
to chromate manufacture, based on a cross-sectional study (Bidstrup
& Case, 1956), failed to reveal any increased risk of cancer in
relation to chromate exposure, whereas a subsequent prospective
survey revealed an increased risk.
There are important selective factors within local communities
that also have a bearing on the design of cross-sectional studies.
Apart from the "polarization" of different social classes into
different parts of a town, there is a tendency for the less fit to
be left behind in the less favoured areas as others move out. In
the rapidly growing cities in developing countries, new residents
may gather in particular areas, and it has been noted that migrants
into cities are affected more by urban pollution than are the
earlier residents, who may have become adapted to it.
2.6. Prospective and Follow-up Studies
These two types of study may be considered together, though
conceptually they differ to some extent. In prospective studies,
study subjects are observed over a period of time according to the
study protocols that are set out at the start of a study. In a
follow-up of a cross-sectional study, the original findings may be
analysed in greater depth using additional information that has
become available. However, in a follow-up study, unlike a
prospective study that is planned as such from the start, it may
not be possible to follow all of the procedures used during the
cross-sectional study itself. In the discussions that follow,
reference is made only to "typical" prospective studies.
Prospective studies permit the investigator to measure the
rate of development (incidence), the rate of deterioration
(progression or complications), the rate of improvement
(remission), and the rate of mortality of the disease. Repeated
measurements of functions of various organs will reveal how these
are changing over time. Studies of this kind have been carried
out, for example, on chronic respiratory diseases such as chronic
bronchitis, emphysema, and pneumoconiosis, and on hypertension
with particular reference to the factors influencing the level of
blood pressure and its change over time.
(a) Choice of population
Prospective studies can be carried out on the general community
or some special subpopulations. Examples include the Framingham
Heart Study in Massachusetts (Gordon & Kannel, 1970), the Tecumseh
Community Health Study in Michigan (section 5.6.8.4), the Atomic
Bomb Casualty Commission's study of survivors in Hiroshima and
Nagasaki (section 5.6.8.5), the investigation of a number of
diseases by Cochrane and his colleagues in the Rhondda fach and
Vale of Glamorgan (Cochrane, 1960), the studies of air pollution in
New Hampshire by Ferris and his colleagues (1973), in the
Netherlands by Van der Lende and co-workers (1973) and Douglas &
Waller (1966) and the studies of respiratory disease in Arizona
(section 5.6.8.3).
For reasons of economy, prospective studies have often
exploited the potential opportunities of data from occupational or
insured groups, or from rosters of patients who have been treated
in some manner that may possibly raise questions about untoward
side-effects later on. Examples of prospective studies using
occupational groups are the study on British doctors of smoking in
relation to respiratory cancer and other causes of death (Doll &
Peto, 1976), the studies of coronary heart disease such as those of
Stamler and co-workers (1975) and Doyle and co-workers (1957), and
the studies of cardiovascular and respiratory diseases by Fletcher
& Tinker (1961). Prospective studies focusing on patients include
the studies of cancer in children treated by thymus irradiation,
and leukaemia in persons with ankylosing spondylitis treated with
radiotherapy.
The British Pneumoconiosis Field Research on coalminers
provides one of the best illustrations of a prospective study
designed to investigate the influence of occupational exposures on
various respiratory conditions in coal workers (Jacobsen, 1981).
Briefly, a sample of 24 collieries in England, Scotland and Wales
were selected for the study. All the men employed in these
collieries were examined by a respiratory-symptoms questionnaire,
spirometry, anthropometry, and chest radiography on several
occasions over 20-year periods. Dust sampling was carried out in
the coalmines in order to be able to estimate a cumulative dust
exposure for each man. These dust measurements were related to
various indices of disease derived both from the initial cross-
sectional data and from the longitudinal findings. In this way,
the most accurate estimate was made of the influence of coalmine
dust exposure on respiratory conditions (bronchitis, lung function,
pneumoconiosis, and mortality) that is ever likely to be attempted.
The paper by Jacobsen illustrates many of the more interesting
features of this work, and his summary of the way that the study
developed is reproduced in Table 2.2.
(b) Choice of controls (or comparison group)
For prospective studies, either external or internal controls
may be chosen. The general population or a particular segment of
it is often used as an external control. The mortality or
morbidity experienced by members of the population (usually
specific for age, sex, and race) over the period of observation
becomes the standard to which the observed mortality or morbidity
of the cohort is compared. In prospective studies of occupational
groups, the use of the general population as a control group
introduces a bias commonly known as the "healthy worker" effect.
This selection bias appears to be higher for long-term chronic
conditions, such as hypertension and rheumatic heart disease, than
for diseases having a fairly short duration and no early warning
signs, but the effect is detectable also for malignancies,
including respiratory cancer (Fox & Collier, 1976). The ideal
controls would be individuals similar in every respect to the group
under study, except for exposure to the agent of interest. For
example, workers in the same industry or factory, who are not
exposed to the agent in question, often serve as internal controls
for a cohort of workers who have been exposed to the agent.
Measurements of different cumulative exposures for individuals or
subgroups in a cohort constitute the most effective internal
control and lead directly to estimates of exposure/effect
relationships.
(c) Assessment of exposure
In a carefully planned prospective study, exposure is measured
at the start and periodically afterwards. The most appropriate
methods can be used and checks to ensure good quality control can
be incorporated into the design.
(d) Assessment of effects
Since, in prospective studies, the decision on diagnostic
criteria is taken at the start of a study, the investigator has
ample opportunity to specify these with precision and to take due
precautions to ensure that they are applied in a uniform and
standardized manner. Any manifestations that may indicate an
earlier stage in the development of the condition of interest can
also be recorded. Identification and categorization of persons
with disease in a prospective study takes place after they have
been categorized with respect to exposure but the time varies. It
is clearly desirable that, as far as possible, investigators
categorizing the population with respect to disease should not be
aware of the particular exposure category of any subject.
Table 2.2. Progress and development of the pneumoconiosis field researcha
------------------------------------------------------------------------------------------------
1953 1958 1963 1968 1973
------------------------------------------------------------------------------------------------
1st surveys 2nd surveys 3rd surveys 4th surveys 5th surveys
24 collieries 24 collieries 24 collieries 10 collieries 16 collieriesb
31 629 miners 21 849 (69%) 14 888 (47%) 4 077 (13%) 5 709 (18%)
of original group of original group of original group of original groupb
(+477 others from (+8 463 others) (+11 649 others) (+6 311 others) (+5 755 others)
a 25th colliery)
------------------------------------------------------------------------------------------------
a From: Jacobsen (1981).
b Including some ex-miners seen in the "Follow-up" surveys. Complete radiological and dust
exposure data available for 2 600 (8%) of the original group at 10 callieries.
Note: 1. Radiography and interviews on previous occupational history at all surveys.
2. Records of attendance in occupational groups kept throughout.
3. Spirometry, anthropometry, and questionnaire on respiratory symptoms and
smoking habits at 2nd and subsequent surveys.
4. More complex lung function measurements in sample at 4th and 5th surveys.
5. Dust sampling in occupational groups:
1952 With Thermal Precipator.
1965 With Gravimetric Sampler.
6. 1971 Study of mortality in a (56%) sample of men seen at the 1st surveys.
7. 1974 Start of follow-up surveys of survivors in the same sample (miners and ex-miners).
8. 1977 Extension of mortality study to include all (31 629) miners seen at 1st surveys.
(e) Confounding factors
The important point is to consider and record necessary
information on any confounding factors. A review of the
etiological factors should be carried out before starting the study
and a thorough check of the protocol should be made to ensure that
information on important potential confounding factors has not been
omitted.
One particular problem in prospective studies, liable to affect
the assessment of both exposure and effects, is the tendency for
methods to change as technology progresses. Changes may have to be
resisted if bias is to be avoided. At least the effects of such
changes must be investigated in carefully designed comparative
trials.
(f) Exposure/effect
With a carefully performed prospective study it will be
possible to establish relationships between exposure and effect.
If measurements are made early enough in life, a study of this kind
provides perhaps the best estimates of risk based on lifetime
exposures. The study of effects of air pollution on the health of
children carried out by Douglas & Waller (1966) is a good example.
Had this been directed initially at air pollution instead of
ingeniously exploiting a set of data as an afterthought, the
exposures might have been better measured.
(g) Advantages
Prospective studies, if properly conducted, may provide
measures of incidence, estimates of relative risk and inference
about cause/effect relationships with greater confidence than most
other types of epidemiological investigations.
(h) Disadvantages
Prospective studies are usually very expensive and time-
consuming. Loss of study participants in a follow-up is another
serious problem. A follow-up of persons who left an industry can
usually be done only with considerable effort. Changes in the
quantity and quality of exposure over time have to be taken into
account.
2.7. Retrospective Cohort Studies
When data are available from observations and/or measurements
that have been made in the past, it may be possible to design a
study that avoids the long waiting time of a prospective study.
This is often the case in industry, where records may have been
kept of all the departments in which employees have worked and also
of the actual job held since the worker was recruited into the
industry. Examples include the studies of cancer of the urinary
bladder in chemical and rubber workers (Case et al., 1954), cancer
of the lung in smelter workers (Lee & Fraumeni, 1969), cancer of
the respiratory system in chromate workers (Bidstrup & Case, 1956),
and mortality from all causes in miners and millers of asbestos in
Quebec (McDonald et al., 1971). Insured persons often provide a
good opportunity for studies of this kind.
The same principle has been applied for epidemiological studies
concerning side-effects of therapies and diagnostic procedures in
groups of patients. For example, the relation between radiation
and breast cancer has been studied in patients with pulmonary
tuberculosis; patients with tuberculosis, who had been treated with
isoniazid, and mental hospital patients, who had received pheno-
barbital, have both constituted cohorts for the study of possible
relationships between the use of these drugs and the incidence of
bladder cancer.
Sometimes, material collected during the course of a prospective
study may be stored for future analyses, should a hypothesis that
was not included in the original plan subsequently appear worth
investigation. Materials may also be stored for subsequent testing
in the interest of economy. In a study of viral infections in
pregnancy in relation to subsequent congenital malformations, Evans
& Brown (1963) collected and stored sera during pregnancy.
Virological tests were carried out later, if the child was born
with a congenital malformation. Similar methods have been used for
the storage of blood samples for subsequent analysis, should
questions become relevant later in continuing studies of coronary
heart disease. Other samples such as food may also be stored for
subsequent analysis.
(a) Assessment of exposure
Assessment of exposure in a retrospective study is dependent on
the subject's memory and reliable past records. For those who have
died, some information will have to be obtained from a proxy. Its
quality will inevitably be more questionable than that obtained
from the subject himself, and means of checking the validity of
such proxy information should be incorporated into the study
design.
(b) Assessment of effects
Usually reliance will be placed on mortality. Valid morbidity
data were seldom available in the past with a few exceptions from
occupational health studies such as Morris and his colleagues'
study of coronary disease in the transport industry in the l950s
and 1960s (Morris et al., 1966). Many industries are now
collecting morbidity information in a way that should provide
usable diagnostic data (Pell et al., 1978) and, as discussed in
section 2.3.2, various morbidity statistics may be available in
more developed countries.
(c) Confounding factors
Information on factors such as smoking and social class is
often not available from existing records. Sometimes, it is
possible to remedy the gap, but the effort required is time-
consuming, and the reliability of proxy information about those
who have died may be questionable.
(d) Advantages/disadvantages
This approach is generally much less expensive and quicker than
a prospective cohort study. However, as mentioned above, a
retrospective study relies entirely on past records, which usually
do not provide precise information. It is therefore seldom
possible to extract a valid quantitative exposure/effect relation-
ship. Methods may have changed so that past and present exposures
may be hard to combine. Usually a qualitative relationship is all
that is possible (Lee & Fraumeni, 1969). A notable exception is
the study of asbestos miners and millers in Quebec (McDonald &
McDonald, 1971), though even here the study shows the problems
introduced by changes in measurement methods for the asbestos
exposures (Health and Safety Executive, 1979).
2.8. Time-series Studies
When exposure to some environmental hazard varies substantially
over short periods, it may be particularly useful to observe how
this variation affects some biological effect. Ambient temperature
varies from day to day. Does this have any effect on mortality or
morbidity? Does it affect symptomatology or functional capacity?
Thus, a study in which daily temperatures and daily changes in the
number of deaths or cases of illness, or in the values of some
physiological function are compared, might be envisaged. Such
investigations have been used most effectively to study the acute
effects of exposure to air pollution. For example, daily mortality
and hospital admissions data were related to daily concentrations
of smoke and sulfur dioxide and to weather by Martin & Bradley
(1960) and Martin (1964). This type of study is effective only
when it involves large communities of several million people,
presumably because the contribution of air pollution to day-to-day
variations in mortality is relatively small compared with that of
the other factors that determine death or would lead to hospitalization.
Simple procedures for collecting self-recorded information on the
health of bronchitic patients using pocket diaries have also proved
valuable in establishing relationships between exacerbations of
their illness and air pollution (Lawther et al., 1970). There are
advantages in concentrating attention on particularly sensitive
groups in studies of this kind, as mentioned above.
(a) Confounding factors
Many factors influence daily mortality and morbidity. For
example, in studies of the effects of air pollution, temperature,
humidity, and other climatic variables are important as they affect
both air pollution levels and health indices. Either extremely
high or low temperatures may be lethal, thus posing considerable
problems in the analysis and interpretation of effects of pollu-
tion. Epidemics of communicable diseases such as influenza could
be troublesome confounding factors. Ethnic group or sex, major
confounding factors in most epidemiological studies, would not be
great problems in time-series studies, since day-to-day changes in
the relative distributions of these variables among subgroups under
study are likely to be small. However, problems may arise if
studies persist over many years, because the effect of differential
migration may then be considerable.
2.9. Case-control Studies
The focus of a case-control study is on a disease or on some
other condition of health that has already developed. The
questions asked relate to personal characteristics and antecedent
exposures which may be responsible for the condition studied. In
particular, the investigator wishes to determine if the environmental
exposures of those who have the condition of interest differ from
those of persons who do not.
Such studies are relatively cheap and quick, but they depend on
the ability of cases and controls to recall information on past
habits and exposures, often in a quantitative manner, or on the
availability of relevant records.
When the accumulation of cases and controls extends over a
lengthy period, then the data available for study may include a
variety of genetic, immunological, biochemical, virological, and
serological measurements, but apparent differences between cases
and controls may be due to the presence of the disease and cannot
be interpreted as indicating a causal relationship.
Case-control studies can be indicative and economical when the
suspect agent is distributed in say 50-70% of the population, and
the hypothesized effect is relatively rare. On the other hand, if
cases occur frequently in the population being studied and the
suspected agent is only one of several causal factors, then it may
be difficult to establish an association using the case-control
approach. In general, apparent associations in case-control
studies need to be confirmed, in the same as well as in different
settings, before they can be interpreted as indicating a causal
relationship (see also the discussion in section 6.5.6 and Crombie,
1981).
(a) Population for study
By definition a case-control study involves two populations -
cases and controls. The problem is to ensure that the particular
cases and controls that are studied are representative and unbiased
samples from these populations. The majority of case-control
studies have been based on patients in or attending hospitals. For
diseases where most patients have to undergo diagnosis at hospital,
this is obviously a suitable method for identifying cases. It has
been used effectively for studies of many cancers and for other
serious conditions such as cirrhosis of the liver, lupus erythematosis,
and congestive heart failure. However, if most patients do not
have to go to hospital as in the case of, for example, chronic
bronchitis, maturity-onset diabetes, hypertension, etc., then
focusing on hospitalized patients will bias any conclusions.
If patients are to be obtained from hospitals, then all
hospitals in a geographically defined area should be included, so
that comprehensive and unbiased coverage is ensured, for many
hospitals cater for particular segments of the population.
Should all patients with the disease be included or should the
focus be on newly-diagnosed cases? The answer to this may depend
on the condition under study. Chronic long-term disease can
perhaps be adequately studied by considering all cases, but it is
usually recommended to take newly diagnosed cases; their recall is
better and their exposure history is less altered by the presence
of disease.
Patients with conditions of interest may be obtained from other
sources. For example, cancer cases can be drawn from a cancer
registry, birth defect cases from a malformation registry, etc.
Such sources are often more likely to be representative than
patients obtained from a sample of hospitals. Cases of rare fatal
disease have sometimes been identified by writing to all pathologists
in a particular area. Studies on mesothelioma, for example, have
been made in this way (McDonald & McDonald, 1971).
(b) Source of controls
Hospital controls, matched for relevant characteristics, have
often been used. In their early study of smoking and lung cancer,
Doll & Hill (1952) used persons with other cancers as one control
group. They also included a group of hospital patients with
diseases other than cancer who were matched for age, sex, and
hospital as a second control group. Hospital controls are
particularly useful to obtain initial information quickly and
relatively cheaply. Hospital sources of cases and controls, do,
however, introduce considerable difficulties with regard to the
representativeness of all patients with the disease of interest,
and in terms of the controls, the degree to which they are
representative of the general community. Furthermore, response
rates are liable to differ between cases and controls, especially
in those from hospitals. A random or stratified (age, sex) sample
of persons living in the area covered by the hospitals is perhaps
the best source for a control group. There are various ways of
obtaining such a group. A sample might be drawn using city
directory data, tax or electoral rolls, etc. One theoretically
simple, if taxing, way is to draw a domiciliary matched
("neighbourhood") sample. Here, a house is selected in the
neighbourhood of the patient's home and a search is made in a
systematic way, from house to house until a suitable control is
found. In a recent study of bladder cancer, conducted by the US
National Cancer Institute and sponsored by the Food and Drug
Administration, dialing of telephone numbers chosen at random was
used to identify one control group (Hoover & Strasser, 1980).
(c) Measurement of exposure
In most case-control studies, much reliance is usually placed
on past information elicited in a comparable manner from cases and
controls. Occasionally, measurements or records of past exposures
may be available, but, in most cases, it is unlikely that these
will be of comparable quality for cases and controls.
(d) Confounding factors
In a case-control study, these can be dealt with initially by
matching cases and controls in terms of major confounding factors.
"Matching" may refer to pairing individual controls with particular
cases according to the matching factors ("matched pairs"), or it
may refer to arranging that the distributions of the matching
factors among all controls are similar to those found among the
cases, without pairing individual controls with cases. These
design strategies need to be distinguished, because they attract
different approaches in the statistical analyses of results.
It is usually desirable to match for several potentially
confounding characteristics such as age, sex, ethnic groups, and
socioeconomic circumstances. In view of unavoidable differences
in diagnostic precision and entry characteristics, it is also
desirable to match for hospital, in hospital-based studies.
However, it is not possible to study the importance of a
potentially confounding factor in relation to the occurrence of
cases, if that factor has been matched in cases and controls. For
instance, data from a case-control study in which controls were
matched with cases with respect to hospitals, as described above,
would not provide information about the suspected differences
between the hospitals in diagnostic precision or entry characteristics.
It follows therefore that factors which are the subject of
investigation (including so-called "confounders") must never be
matched. Their relative importance and co-associations with
recurrence of cases may however be studied using appropriate
analytical methods, if (unmatched) controls are selected randomly
and provided that correlations between these factors themselves are
not too high. For further details, see section 6.5.4.3.
(e) Advantages and disadvantages
Case-control studies of hospital groups can be carried out
fairly quickly and cheaply. As a first approach to many diseases
about which causation is obscure, such studies are very valuable
for identifying hazards and suggesting hypotheses for more rigorous
testing. The method is particularly useful in studying rare
diseases. The main disadvantages are that bias may be incorporated
into any comparisons, because of greater preoccupation by the
cases than by the controls about the disease under study. Bias can
also arise rather easily because of preconceived ideas on the part
of the investigators. As a case-control study normally deals with
a small group, the wider application of its results has to be made
with caution. Temporal relations as to whether the disease
preceded or followed the exposure may at times be hard to establish
in a case-control study. In a prospective case-control study, loss
of study subjects from the case group may also be a problem.
Furthermore, a case-control study gives only an approximation of
relative or attributable risk.
2.10. Controlled Exposure Studies
The demonstration of prevention of some effect by a well-
designed controlled human exposure study is perhaps the most
convincing way of showing a relationship between cause and effect.
Unfortunately, "experimental" studies often raised insuperable
ethical and practical problems in the past. It has to be
emphasized that any controlled exposure study should be safe, that
any adverse biological changes that may be induced should be
reversible, and that no discomfort (or at most only minimal
discomfort) should be produced. There is also general agreement
about the desirability of informed consent, which may imply
understanding by participants of the study design in some cases
(section 5.3).
Studies of "natural experiments", such as those on
environmental accidents and adverse effects on health that have
ensued, have been a recognized epidemiological approach for a long
time. These include the studies conducted in London, after the
1952 December smog (Ministry of Health, 1954) and those performed
in Hiroshima and Nagasaki on survivors from the atomic bombs
(section 5.6.8.5). These examples have provided a great deal of
useful information on the acute effects of air pollution and on the
health effects of ionizing radiation, respectively.
On a more limited scale, studies of workers before and after
the working shift have provided useful information on the possible
hazards of exposure of the respiratory tract to vegetable and
mineral dusts and various toxic gases. Studying populations before
and after a pollutant has been removed is a reasonable approach to
design, especially when a latency period is part of the design;
certainly an improvement in health would be expected if the
pollutant were causing adverse effects. Sometimes, the
deterioration of the environment following industrial development
may be foreseen and observations may be made to exploit such an
opportunity in the most effective manner. One example of this type
is the pre- and post-studies in relation to the siting of a new
power plant. The possibility that the use of high sulfur fuel has
increased sulfur oxide emissions in some cities, but not in others,
should stimulate the collection of appropriate data in cities where
such changes are anticipated and in control cities where they are
unlikely.
(a) Choice of population
Controlled exposure studies can be based on the general
community or some particular subgroups, such as a specific age
group or occupational group. Such subgroups may be studied by
exploiting some fortuitous change that has divided the population
into the treated and control groups that are needed to test some
hypothesis. One classical example is John Snow's admirable
epidemiological analysis on the natural experiment of cholera
outbreaks in London in the nineteenth century (Snow, 1855). The
study by Harrington and his colleagues on cancer in relation to
asbestos fibres in drinking-water supplied by asbestos cement pipes
to half the households in Connecticut is another model example of
this approach (Harrington et al., 1978).
(b) Exposure, effects, and confounding factors
In controlled exposure studies, the levels of exposure are
known by the investigators. Effects are measured in the course of
study and confounding variables can be identified and controlled.
(c) Advantages/disadvantages
Cause/result and precise exposure/effect relationships can be
obtained. However, a study of this type tends to be costly. The
drop-out rate may be high. As already mentioned, great care must
be given to the ethical problems and the consent of the participants
is required.
2.11. Monitoring and Surveillance
As the network of monitoring stations to measure environmental
pollutants, in particular air pollutants, expands in many countries,
data from these monitoring activities are being increasingly used
for epidemiological studies. However, such monitoring being
primarily for the purpose of pollution control, the data do not
necessarily provide exposure information that is adequate to relate
to the health status of the study population. The use of routine
data for establishing exposure/effect relationships must be made
with great caution (section 3.5).
Assessment of exposure by personal monitoring and biological
monitoring would provide more precise exposure data (sections 3.6
and 3.7), but these methods tend to be expensive.
To relate data from routine monitoring activities to the
information on health effects from a variety of surveillance work,
would need the development of some means of linking records from
different sources.
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3. ASSESSMENT OF EXPOSURE
3.1. Introduction
The validity of studies in the field of environmental
epidemiology depends both on the assessment of exposure and of the
effects on health. Each of these aspects is liable to present
difficulties and uncertainties. Thus, it is important that every-
one involved in the design and conduct of investigations and in the
interpretation of results, has a complete understanding of the
problems. It is the purpose of this chapter to discuss basic
aspects of exposure assessment, in order to improve the quality of
epidemiological studies, and consequently the scientific basis for
control measures. The emphasis is on general population studies,
but exposure assessment is also of major importance in occupational
health studies. The general approach is similar: much of what is
practised in population studies has been markedly influenced by the
practice of exposure assessment in workers. Moreover, for many
environmental agents, occupational exposure may contribute
substantially to the total exposure in some subgroup of the general
population.
The environment may be divided into two types with regard to
exposure assessment: (a) the objective environment, which means
the actual physical, chemical, and social environment as described
by objective measurements such as noise levels in decibels (dB)
and concentration of air polluting: and (b) the subjective
(perceived) environment, as it is perceived by persons who live in
it, e.g., annoyance caused by air pollution or noise, or pleasure
arising from good housing conditions. In this chapter most
sections deal with the objective assessment of exposure; in section
3.8, however, special emphasis will be laid on the assessment of
subjective exposure.
Epidemiological studies may be concerned with scattered
individuals, with groups living or working together, or with
populations in defined areas or countries; in each case appropriate
exposure assessments have to be made. For the present purpose the
environments in which people operate can be considered at the four
following levels:
(a) The domestic or "micro" environment, concerned with the
subject in the home. Exposure may be determined by
personal or family eating habits, cooking facilities,
hobbies, other personal habits (e.g., smoking or
drinking), use of therapeutics, drugs, or cosmetics,
pesticides applied in the home and garden, etc.
(b) The occupational environment. The subject may spend a
large part of his/her life in occupational environments
such as coal mines, steel works, etc., where there may be
specific environmental problems. Periods spent in schools
or other educational establishments might also be
considered under this heading.
(c) The local or community environment. In the immediate area
in which the subject lives he/she may be exposed for example
to ambient air pollution, aircraft and traffic noise, or
drinking water containing particular constituents.
(d) The regional environment. The subject lives in a
particular climatic zone, at a certain geographical
longitude, latitude, and altitude, etc.
A few examples of exposure to the same environmental factor at
various levels of operation are given in Table 3.1.
Table 3.1. Examples of exposure to environmental factors at various levels
of exposure
----------------------------------------------------------------------------
Level of Carbon UV Noise Solvents Ionizing
operation monoxide radiation radiation
----------------------------------------------------------------------------
Micro smoking, therapeu- music, cleaning, medical
or cooking, tics, hammering, hobbies diagnosis
domestic heating gardening, noise from and therapy,
sunbathing neighbours emissions
from struc-
tural
materials
Occupa- traffic laboratory construction workers in x-ray
tional policemen, workers, workers, solvents techni-
metallur- agricul- military manufac- cians;
gical tural service turing, workers
workers workers painters, in nuclear
dry cleaners plants
Local traffic sunlight aircraft, emissions tubercu-
exhaust town from losis mass
traffic industry screening
examination
Regional - high storm, - fallout
altitude, hurricane from atomic
tropics weapons
test,
altitude
----------------------------------------------------------------------------
In assessing individual and group exposure to specific agents,
the contribution from each of these four environmental levels to
the total exposure has to be taken into account; the intensity and
duration of exposure and the coexistence of other hazardous factors
may differ (section 3.3).
3.2. Exposure and Dose
In pharmacological and toxicological studies, the term, dose
is used to indicate the amount administered, and dose-rate to
indicate the dose per unit of time. The unit quantity, and the
frequency and duration of administration determine the total dose
received over a day, a week, or a year. In epidemiology, one often
hesitates to use the term dose, because generally it is only
possible to make an estimate of the actual dose received. There-
fore, the terms, exposure, instead of dose, and exposure/effect
relationships rather than dose/effect relationships are preferred.
The exposure may often be assessed by measuring the concentration
of a substance in air, water etc., or the intensity in the case of
sound or radiation, and some effects may be determined more by the
instantaneous concentration or intensity than by the total dose.
3.2.1. Systemic agents
There are four indices of exposure in the case of agents that
exert an effect after being absorbed into the body:
External exposure in a general sense. This is the
concentration that is present in, for example, food, drinking-water,
or air, in relation to frequency and duration of exposure.
External exposure in a narrow sense - intake. Often the
only data available are concerned with the concentrations of
agents (mg/kg in food, mg/litre in water, mg/m3 in air) and not
the amounts of food, drinking water, and air, to which man is
exposed per unit of time. In medicine, however, the dose
administered is never expressed as the concentration, but as the
amount ingested, injected, or inhaled. In work and sports
physiology, energy consumption is not calculated in concentrations
of oxygen in inhaled and exhaled air, but as the difference between
the amount of oxygen inhaled and exhaled. Therefore, in exposure
assessment, an effort should also be made to measure the
concentration of the agent in its vehicle and the amount of food,
water, and air, consumed by an individual, i.e., the intake. In
most studies reported so far, no endeavour has even been made to
estimate respiratory volume or actual food and water intake. The
oxygen consumption for an adult man (70 kg) at rest is about 0.3
litre/min; the uptake of 1 litre of oxygen requires an intake of
about 25 litres of air; therefore, the respiratory volume/h, at
rest, is about 0.5m3; in moderately heavy work, which can be
sustained during a 8-h working day, the respiratory volume/8 h will
be 8-10m3; for 24 h, the respiratory volume will be 15-20m3.
The energy requirement for a child of 1-3 years is about 420 kJ/kg
body weight, for an adult about 170 kJ/kg body weight; the relative
exposure to a food contaminant per unit of body weight, therefore,
may be higher in children than in adults by a factor of 2-3. The
intake of drinking-water may vary considerably from subject to
subject, consequently the amounts of pollutants ingested through
drinking-water will differ greatly among the subjects.
For particulates in inhaled air, the particle size
distribution determines the fraction that reaches various parts of
the airways, and thus the possibility of local action or pulmonary
absorption will also be determined. Particles with a diameter
> 5 µm tend to be deposited in the nasopharyngotracheal region.
The chemical composition may vary with particle size: carbon,
lead, and sulfates, for example, occur mainly in very fine
particles, generally < 1 µm diameter. The particle size
distribution in occupational exposure may differ greatly from that
in ambient exposure. Fibres of materials such as asbestos, with
very small diameters, tend to follow the air-flow through the
respiratory system and even ones up to some 200 µm in length may
penetrate into the deeper airways.
Highly water-soluble gases, for example sulfur dioxide and
formaldehyde, are trapped by the moist environment of the upper
airways, whereas the less soluble nitrogen dioxide or phosgene
penetrate into the bronchiolar and aveolar regions. Agents in food
also differ in the degree of absorption according to their chemical
composition. The presence of vegetable fibres may produce bulky
gastrointestinal content and increase the speed of passage; the
decreased exposure time might be one of the reasons why the fibre
content of food could have a preventive effect on colonic tumours.
In South Africa, bowel cancer is much rarer in the Bantu peoples
than in the Caucasians; even among the Bantu, intestinal transit
times have been found to be markedly different, probably because of
differences in the fibre content of food (Walker, 1978). Hardness
of drinking water may determine whether elements are leached from
vegetables during cooking or whether their concentration is
increased (Moore et al., 1979).
These examples show that the true intake may differ considerably
from the levels of exposure calculated from concentrations in ambient
air, food, or drinking-water.
Internal exposure - uptake. The agents available for absorption
are usually only partially absorbed into the body: uptake = intake
x (fractional) absorption rate. The degree of absorption varies
widely, for example, in the gastrointestinal tract, methylmercury
is absorbed almost completely, whereas metallic mercury is hardly
absorbed at all. Absorption of lead is higher in an empty stomach
than in a full one, and it is probably higher in children than in
adults.
In the case of inhaled gases or vapours, the concentrations
in both inhaled (Ci) and exhaled (Ce) air must be measured
and multiplied by the respiratory minute volume (V). The uptake
will be (Ci - Ce) x V x t (where t = time). As soon as an
equilibrium has been achieved between uptake and elimination
(such as by biotransformation and excretion), the level of uptake
becomes constant at constant Ci and V. During physical activity,
V increases and equilibrium is achieved earlier than at rest.
Carbon monoxide provides a good example: toxic levels in blood
are achieved earlier during physical activity than at rest, and
sooner in children than in adults.
Exposure at the target organs. In epidemiological studies,
it is usually not possible to measure the concentrations (or
amounts) of agents present at the target organs, for example,
liver, brain, etc., although it is true that determination of the
concentrations (or amount) of cadmium in liver and kidney is
possible by neutron activation analysis (Ellis et al., 1981). The
Task Group on Metal Toxicity (Nordberg, 1976) presented a few
definitions, which not only can be used in metal toxicity studies,
but are also applicable in the study of many other environmental
hazards.
Critical concentration for a cell. This is the concentration
at which an adverse functional change, reversible or irreversible,
occurs in the cell.
Critical organ concentration. This is the mean concentration
in the organ at the time when the most sensitive types of cell
reach the critical concentration.
Critical organ. This term is used for the particular organ
that first attains the critical concentration under specified
circumstances or exposure and for a given population.
Assessment of exposure through biological monitoring or
analysis of samples from specimen banks (section 3.7) may provide
data that approximate the relevant exposure at the target organs
much better than those obtained through environmental monitoring
(section 3.5).
3.2.2. Local exposure
Some agents act on the surface linings of eyes and airways or
on the skin. Oxidants, such as peroxyacetylnitrate (PAN), exert an
irritant effect on the eyes as a function of the number of oxidant
molecules that are absorbed in the eye fluids per unit of time.
Exposure is a function of the ambient concentration of PAN and of
the physical properties of the fluid, such as solubility and
diffusion coefficient. Because the physical properties may be
assumed to be constant, the intensity of exposure will be
determined by the concentration in ambient air and the frequency
and duration of exposure.
Some agents may penetrate the skin; this depends on physio-
chemical properties of the agent, properties of the skin (variable
at different sites in one individual, and variable between
individuals), environmental temperature and humidity, presence of
skin disease, etc.
3.2.3. Physical factors
The considerations under sections 3.2.1. and 3.2.2. apply
mainly to chemical agents, but also apply to compounds with
radioactive properties. However, in the case of physical factors,
for example, noise, vibration, and ultraviolet radiation, the
actual exposure of the subjects has to be assessed as carefully as
possible, using measurements of intensity, frequency, and duration
(section 3.5.4).
3.3. Combined Exposure, Physical and Chemical Interactions
Health effects due to environmental factors are manifested in
various ways (Chapter 4). However, the range of effects is limited
compared with the large variety of chemical and physical factors
that may produce them. To a large extent, health effects are non-
specific; the causative agents can seldom be identified from the
effects manifested. This is the main crux of exposure/health
effect studies.
Simultaneous or consecutive exposure to several agents may
modify risks to health. Nelson (1976) summarized existing data on
the role of the interactions of environmental agents that may
modify biological activity, distinguishing synergism (potentiation),
antagonism, or merely additive effects. Potentiation and
antagonism may be due either to modified toxicokinetics (affecting
internal exposure) or modified toxicodynamics (relating to health
effects).
3.3.1. Same agent, various sources
A well-known example is exposure to noise. In a study in
Japan, Kono and his coworkers (1982) measured total noise exposure
per day as the summation of exposure during work, in the domestic
environment, and while travelling. For housewives, the equivalent
level over 24-h periods (Leq 24) (section 3.5.4.1) was 70.2 dB(A)a
in an industrial area and 67.4 dB(A) in a residential area. As
regards noise exposure in the home, the Leq 24 was higher in
housewives of less than 40 years of age, than in older age groups,
because of different patterns of activity.
3.3.2. Various agents, same source
It is well known that air, food and water carry mixtures of
many environmental agents. In the air pollution situation the
general population may be exposed to a mixture of sulfur dioxide,
sulfuric acid, smoke, sulfates, ozone, oxides of nitrogen,
peroxyacetylnitrate, hydrocarbons, aldehydes, etc. Assessment of
exposure to indicator agents is a valid procedure, provided that
the composition of the pollutants is well known. However, there
has been a considerable change in the composition of pollutants
in urban air and in water supplies in the past few decades,
making it difficult to use any one component as an indicator in
long-term studies.
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a The expression dB(A) is commonly used to refer to the
A-filter frequency weighting, which usually provides the
highest correlation between physical measurements and
subjective evaluations of the loudness of noise, by
modifying the effects of the low and high frequencies with
respect to the medium frequencies (WHO, l980b).
Food may contain a wide range of trace metals (e.g., cobalt,
copper, iron, manganese, selenium, and zinc); however the
proportions may differ from place to place and from time to time.
If only one factor is to be selected for the assessment of
exposure, at least approximate data concerning the composition of
the mixture must be obtained.
In elucidating the so-called "soft water story", i.e., the
observed inverse relation between water hardness and cardio-
vascular mortality, the sum of the calcium and magnesium content of
drinking-water had, until recently, been relied on. However, in
recent years, there have been indications that the magnesium
content might be more relevant than calcium. Generally, with
increasing hardness, the corrosiveness of the water decreases;
however, the ability of hard water to dissolve metals from pipes
is not always less than that of the soft water. The "natural"
relationship between metal concentration and softness of water has
disappeared in the Netherlands in recent decades (Zielhuis &
Haring, 1981). Vos et al. (1978) found higher lead, cadmium, and
zinc (but not copper) concentrations in hard than in soft tap-water
in two adjoining communities; higher lead, cadmium, and zinc levels
in blood were also found in the hard-water town. In addition, hard
water often contains higher concentrations of silicon and lithium.
A valid epidemiological study, therefore, should assess exposure to
a multitude of agents in tap water, which may vary with geographical
areas and with water distribution systems.
In occupational health studies, a relation has been established
between the incidence of lung cancer and exposure to nickel and
chromium compounds and there is evidence that certain medium-
or slightly-soluble compounds of both nickel and chromium are
carcinogenic. If only the total nickel and/or chromium contents of
workroom air are measured, not taking into account individual
compounds, an overestimation of health risk may occur.
3.3.3. Various agents, various sources
The most important example under this heading concerns inter-
actions between tobacco smoking and exposure to environmental
pollutants (particularly by inhalation). For example, it has
been established that the risk of lung cancer in asbestos workers
or uranium miners who smoke is much higher than that in smokers who
are not exposed to asbestos or uranium, or in non-smoking workers;
the risk is not additive, but is more or less multiplicative. In
foundry workers, silicon dioxide dust affects the condition of the
airways and smoking increases its health risk (Kärävä et al.,
1976). Not only the chemical factors should be considered. The
high risk of skin tumours in road-tar workers exposed to the
ultraviolet rays of sunlight is well known.
3.3.4. Impurities
In industry and in chemical applications in the environment,
compounds of commercial quality that may contain up to several
percent of impurities are often used. If trace amounts of such
impurities are responsible for the health risk, then the
exposure/effect relationship of the parent compound is not
representative of the true one. A well known example is the
herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), which
contains trace amounts (< 0.1 mg/kg) of the extremely toxic
2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). Due to dilution
during formulation, the process of application, etc., the final
levels of TCDD in food are usually not detectable, but exposure of
workers may be high enough to cause health effects.
Nitrosamine formation may take place during the production of
some pesticides (e.g., trifluorolin and dinitramine); the
nitrosamine levels in the technical products may occasionally
exceed even 100 mg/kg and therefore become detectable in crops. In
addition, nitrosamines may also be formed owing to reactions
between the pesticides and naturally occurring amines (chemical
interaction, section 3.3.5).
In exposure assessment, therefore, due attention should be paid
to the presence of impurities that may be more toxic than the
parent compounds.
3.3.5. Interactions
Three types of interaction can be distinguished, leading to a
change in the composition of chemical compounds between the point
of emission and the target organs:
- change in the chemical composition and/or physical form
within the environment;
- physical interaction between chemical agents and particulates
within the environment; and
- change in physical and/or chemical composition within the
human body.
Such interactions may essentially change the nature of exposure
and, consequently, the health risk.
Some examples of changes in chemical composition in the
environment are; formation of alkylmercury compounds in sediments
from inorganic mercury compounds; secondary oxidation of sulfur
dioxide to sulfuric acid and sulfates; the build-up of photo-
chemical smog in ambient air. As the chemical reactions in air are
time-dependent, the resultant composition of the mixture may change
over a large distance because of air movements. Furthermore, the
source of emission may also affect the ultimate composition. In a
study from the Netherlands, the ratio of ozone to peroxyacetyl-
nitrate was higher when the main source was automotive exhaust than
when it was the petrochemical industry (Guicherit, 1979).
The Proceedings of the International Workshop on Factors
influencing Metabolism and Toxicity of Metals (Nordberg, 1978)
summarized the present state of knowledge on the interaction of
metals. Among toxic metals, mercury provides a well-known example
of transformation into a more toxic compound, methylmercury, in the
environment. On the contrary, methylation of inorganic arsenic
probably leads to non-toxic organic arsenic compounds, present in
marine food. Within the human body, in the intestines after
ingestion, and in organs after absorption, interaction also may
take place between metals and nutritional factors, either
increasing or decreasing the health risk. At present, only a few
human data are available. However, a number of animal studies
indicate that such interactions might possibly influence human
health risks. Physical agents, e.g., ultraviolet radiation, may
induce changes in the body that affect the subsequent action of
chemical agents.
A low intake of calcium and vitamin D in patients with Itai-
Itai disease (section 5.5.8) may have contributed to high
accumulation of cadmium and to the development of bone changes
associated with high cadmium exposure. Increases in the cadmium/
zinc ratios in blood (or kidney) at higher cadmium exposure may
constitute a more relevant index of exposure than cadmium levels
as such.
In non-occupationally exposed groups, effects of the inter-
action of lead and iron are most often seen in children: iron
deficiency is associated with increased lead levels in the blood,
probably because of increased enteric absorption of lead; more-
over, both iron deficiency and lead overexposure may induce the
same effect - an increase in porphyrin in erythrocytes. A low
nutritional intake of calcium and proteins also may increase lead
absorption. Very probably the intake of selenium counteracts the
toxicity of mercury. In miners exposed to inorganic mercury, a
parallel increase in mercury and selenium levels in the blood has
been demonstrated, suggesting a biological interaction.
Within the body, biotransformation of many organic compounds
takes place, usually mediated by enzymes. Exposure may increase
the production of enzymes (enzyme induction), and thus internal
exposure to the original agent may be changed; in not a few cases,
the parent compound is transformed into metabolites that constitute
the true toxic agents. Assessment of exposure by means of
biological monitoring (section 3.7) also aims at measuring these
relevant metabolites in biological specimens.
Simultaneous exposure to pharmaceuticals may affect the
metabolism of environmental chemicals. In epileptic workers
exposed to DDT and receiving anti-epileptic drugs, the DDT level in
adipose tissue was found to be considerably lower than in non-
epileptic fellow workers. Consecutive exposure to trichloro-
ethylene and alcoholic drinks (after work) may cause skin flushing,
probably because of interference with the metabolic transformation
of ethanol. Industrial exposures may influence the therapeutic
effects of drugs. For example, the anticoagulatory effect of
warfarin may be decreased during exposure to chlorinated
pesticides.
In the gastrointestinal tract, nitrites from food may interact
with secondary amines, and carcinogenic nitrosamines may be formed.
High dietary fat may increase the concentration of bile acids in
the large bowel with subsequent metabolism by bacterial flora to
carcinogens or cocarcinogens; research workers at the International
Agency for Research on Cancer (IARC, 1977) observed differences in
faecal flora between two Scandinavian populations with low and high
risk from carcinoma of the colon.
There also exists physical interaction. A well-known example
is the absorption of gases or vapours on to particulates in air,
thus increasing exposure of the lower airways to agents that might
otherwise have been trapped in the higher airways.
These examples only serve as illustrations and certainly do not
present an exhaustive review. Both in environmental assessment
(section 3.5) and in biological assessment (section 3.7) of
exposure, account must always be taken of the possibility of chemical
or physical interaction, because it may change the nature of health
effects, both qualitatively and quantitatively.
3.4. Qualitative Assessment of Exposure
While the ultimate aim in an epidemiological study should be
the assessment of exposure in quantitative terms, to allow the
derivation of dose/effect relationships, there is a place for
qualitative assessment within exploratory studies, or for the
formulation of hypotheses, as has been discussed in Chapter 2.
In chronic disease studies, it is usually necessary to assess
exposure retrospectively, and since quantitative data are seldom
available for periods extending back for some 40 years or more,
qualitative indices of exposure may have to be used as the
independent variable. In occupational studies, these may be
provided by job histories, together with information on the types
of materials that people in each job might be exposed to, and on
the degree of control that existed in the past. In community
studies, area of residence, information on migration and on ethnic
and racial characteristics may be used as indices, and personal
habits such as smoking, alcohol intake, betelnut chewing,
sunbathing, etc. may provide indicators of exposure to agents of
interest in their own right or as factors interacting with other
environmental pollutants.
3.5. Environmental Assessment of Exposure
The most general method of assessing exposure in quantitative
terms is referred to as environmental monitoring. The definition
of monitoring adopted by the 1974 Intergovernmental Meeting on
Monitoring convened by the UNEP was "the system of continued
observation, measurement, and evaluation for defined purposes"
(WHO, 1975). An International Workshop cosponsored by the
Commission of the European Community (CEC), the US Environmental
Protection Agency (USEPA), and WHO defined the term "environmental
monitoring" as "the systematic collection of environmental samples
for analysis of pollutant concentrations" (Berlin et al., 1979).
In epidemiological studies, the observations must be made in a way
that relates as closely as possible to the exposure of the
population being considered, but they need not necessarily be of a
repetitive or continuous form as required for some other monitoring
purposes.
In designing a monitoring programme, general questions of the
type posed in Chapter 1 have to be considered again, namely:
- what agents need to be studied?
- how long and how often should samples be taken?
- where should samples be drawn from, or instruments located?
- what quality of data is needed?
- which instruments or analytical techniques should be used?
In practice, it is not always possible to meet all these
requirements in a faultless manner because of, for example,
budgetary or technological limitations. However, it should be
emphasized that, if the quality of exposure assessment is below a
certain minimum, the data obtained may be valueless. Many
epidemiological studies, both in occupational and public health,
lack even an adequate qualitative assessment of exposure.
It should be realized, that environmental monitoring, under-
taken to determine whether ambient levels meet legal quality
standards for ambient air, water, occupational environment etc.,
usually does not provide adequate data on exposure for use in
exposure/health-effect studies.
3.5.1. Quality of data
To describe the quality of data, a number of concepts are used,
for example:
- Repeatability: the difference between measurements
carried out at a given time with the same instrument, by
the same person, determining the same property of the same
material.
- Reproducibility: the difference between measurements,
carried out at different times, with different instruments
usually of the same type, by different persons determining
the same property of the same material.
- Precision: the magnitude of the deviations of a series of
measurements, usually expressed as the coefficient of
variation (standard deviation as a percentage of the mean).
- Accuracy: the difference between the measured value and
the true value.
- Resolution: the smallest difference of the measured
property which can still be quantitatively distinguished.
- Time constant and band width: the way an instrument
follows sudden changes in magnitude of the property to be
measured, to be derived from its response to a step
function.
- Detection limit: the smallest measured quantity that can
be distinguished from zero.
The quality is determined both by sampling and by analytical
procedures. In recent years, developments in sampling instruments
and in analytical techniques have been substantial and the quality
of data has improved considerably. Many exposure data, used in
epidemiological studies a few years ago, however, were of a
comparatively low quality. Ferris (1978) presented several
examples of measurement errors in monitoring concentrations of air
pollutants. There have been interferences with measurement: for
bubblers there may be thermal effects (reaction does not take place
if the vehicle is too cold; or there is decay or evaporation, if
it is too hot). Most ambient air monitoring systems for
particulates in Europe have used the standard smoke method - a non-
gravimetric method using light reflectance from a stained filter
paper - the reflectance is calibrated and expressed in terms of
equivalent concentrations of standard smoke. The results cannot
however be taken to be equivalent to those obtained by a high
volume sampler with direct weighing, since refectance/weight
relationships vary widely with the composition of the particulates.
In measuring photochemical oxidants, the quality of the potassium
iodide method, previously used in Los Angeles County, USA and
elsewhere, has been seriously questioned, which places many air
quality data in doubt.
Another recent example is the development in sampling and
analytical techniques for the determination of asbestos fibres.
Before 1964, in the United Kingdom, the commonest instrument was
the thermal precipitator, while in Canada and the USA, most data
were derived from midget impingers. After 1964, membrane filters
were used in the United Kingdom; these allow fibres to be counted
specifically, whereas impingers give general particle counts.
Comparability between particle counts and fibre counts is poor.
Since 1970, personal sampling (section 3.6) has, to a large extent,
replaced static sampling. In 1969, a new method of fibre counting
(eye-piece graticule) was introduced, which increased the fibre
count by a factor of 2-3. This change in sampling and analytical
techniques resulted in 5 times larger fibre counts in 1979 compared
with those in 1970, for the same levels of exposure to chrysotile
fibre (Health & Safety Executive, 1979).
Particularly in health-effects studies over long durations of
exposure, special attention has to be paid to possible changes in
sampling and analytical methods, that may invalidate the
comparability of data; the same applies to the comparison of data
published in the literature.
3.5.2. Monitoring strategy for air pollutants
Reviews on monitoring and/or instrumentation have been
presented by WHO (1976), Stern, ed. (l976), WHO (l977b), the
American Conference of governmental Industrial Hygienists (ACGIH)
(l978), Atherley (l978), NATO/CCMS (l979), and Katz (l980). Before
developing a strategy for the assessment of exposure to ambient air
pollutants, it is important first to evaluate published quantita-
tive or semi-quantitative studies to determine whether there is any
evidence at all of adverse effects on health. Such an exploratory
evaluation may save unnecessary expenditure of time and money, and
moreover, may be essential for a valid design or exposure
assessment.
3.5.2.1. What to sample, how long, how frequently?
In the case of exposure to chemicals, differences in expected
health effects require differences in sampling strategy:
- Irritants: Sampling has to be carried out with high time
resolution: the frequency of peak concentrations may be
more relevant than time-weighted average concentrations.
- Narcotic agents: Sampling may also have to be carried out
with high time resolution, particularly in assessing
occupational exposure at high concentration levels.
- Systemic agents, including teratogens: These agents exert
a toxic action after being absorbed and may cause effects
in the liver, haematopoetic system, kidney, nervous system,
etc. The time resolution of sampling should be geared to
the biological half-livesa of the agent (or its
metabolites) at the target organs (Roach, 1977). For
teratogens, the time of exposure during pregnancy may be
decisive.
- Carcinogens, mutagens: The latent period before health
effects become manifest may have to be counted in years,
or even decades. In most epidemiological studies, the
assessment of exposure is performed retrospectively, and
consequently the assessment is only qualitative or
semi-quantitative. Information on peak concentrations,
however, should not be neglected, because - at least for
some agents - temporary overloading of biological
detoxication systems may open up deviant metabolic
pathways resulting in carcinogenic/mutagenic metabolites.
---------------------------------------------------------------------
a Biological half-life or half-time is the "time required
for the amount of a particular substance in a biological
system to be reduced to one-half of its value by
biological processes when the rate of removal is
approximately exponential" (ISO, l972).
- Agents that may cause pneumoconiosis: Long-term local
deposition of certain chemical compounds in the lungs
results in silicosis, asbestosis, talcosis, etc., in
workers exposed. Average concentrations over months or
over years are particularly relevant for the assessment of
exposure to these compounds.
- Agents that cause asthma, chronic bronchitis, or emphysema
through local action in the airways are usually sampled in
order to obtain the time-weighted average exposures for a
working day (8 h) or for the whole day (ambient exposure,
24 h). However, peak concentrations may be relevant in
some cases, particularly in occupational exposures.
Some agents may exert two or more effects. For instance,
benzene acts as a narcotic agent at high concentrations, and as a
carcinogen, probably at much lower levels; cadmium oxide acts
directly on the airways and is also a systemic kidney poison;
inorganic mercury at high concentrations acts on the airways and,
after absorption, on the brain, whereas, in long-term exposure to
low concentrations effects may be found only on the brain; toluene
diisocyanate and formaldehyde act as irritants in short-term
exposures to high concentrations and as sensitizers in long-term
exposures to low concentrations.
The time resolution has to be adapted to the technological
process in the case of occupational exposures, in order to
characterize those at different phases of production. The basic
considerations, therefore, concern the agent as such, the health
effects under study, and technology. For occupational agents
causing pneumoconiosis, rules for sampling frequency have been
derived, on the basis of the assumption that fluctuations are
caused by stationary stochastic processes (Coenen, 1976, 1977).
Concentrations in ambient air not only depend on the intensity
of emission (often related to season), but also on meteorology.
This variability in concentration should be taken into account,
particularly for agents that exert immediate effects on eyes or
airways, and for those that induce both short-term and long-
term effects. Therefore, both the distribution of concentrations
over time and the toxicodynamics should determine the strategy of
exposure assessment. Larsen (1970) observed that, for many ambient
air pollutants (carbon monoxide, hydrocarbons, nitric oxide,
nitrogen dioxide, oxidants, and sulfur dioxide), the concentration
can be described by a mathematical model with the following
characteristics:
- concentrations are approximately log-normally distributed
for all pollutants in all cities for all averaging times;
- the median concentration (50 percentile for all averaging
times) is proportional to averaging time raised to an
exponent; and
- maximum concentrations are approximately inversely
proportional to averaging time raised to an exponent.
Two parameters may adequately describe exposure over a period
of, say, one year: for example, 50 percentile and 95 or 98
percentile for 1 h or 24 h concentrations. On log-probability
paper, the percentiles follow a straight line. This method of
presentation allows easier interpretation of data than the
corresponding use of geometric average and standard deviation.
This subject has been discussed in greater detail in WHO (1980a).
Ideally, assessment of exposure to these pollutants should be based
on the percentile distributions of averages over 24 h or less, but,
in practice, arithmetic means over months or whole years are often
used as indicators of long-term exposures. Whether the basic
sampling period should be 1 h, 8 h or 24 h depends on the type of
health effects studied. In epidemiological studies, data with
high time resolution, but moderate precision, may be more valuable
than those with high precision, but low time resolution.
3.5.2.2. Representativeness
It is essential to obtain exposure data that are representative
of the exposure of the population at risk (section 3.9). Although
this statement may appear to be self-evident, it still needs to be
re-emphasized. Many studies are based on estimated exposure from
data obtained at monitoring sites selected for regulatory purposes
rather than for estimating the exposure of the population. More-
over, sites tend to be selected at which relatively high
concentrations are expected. Sampling points are often placed at a
much higher level than the human breathing zone. Many sampling
stations are erected at, or near, research institutes for the sake
of convenience. A single site may be assumed to represent a large
area and the number of sites is often limited because of budgetary
restrictions. Modelling techniques are only a partial answer to
the measurement of actual exposure.
If data corresponding to the true exposures are to be obtained,
a monitoring system must be established that is especially designed
for the study. With static sampling, it is possible to measure air
quality at fixed sites. However, even in occupational settings,
people move about and therefore are exposed at various work sites;
exposure may occur in corridors, canteens, offices, or even in the
vicinity of the industry. Non-occupational indoor monitoring has
seldom been carried out. Thus, total exposure is often either
underestimated or the indoor exposure is missed entirely, as for
example in the case of formaldehyde (National Academy of Sciences,
1981). It is an enormous task to derive true time-weighted
exposures by means of static sampling (section 3.11). Two methods
are available for approximating the true exposure more adequately:
personal sampling (section 3.6) and biological monitoring (section
3.7).
3.5.3. Monitoring of pollutants in food and water
The principles discussed in section 3.5.2 for monitoring air
apply equally to the assessment of exposure by ingestion of food
and water. However, the variability in actual exposure is likely
to be much larger in the case of ingestion than in the case of
respiratory exposure, because, in the same ambient or occupational
environment, subjects inhale the same air, but the intake of food,
water, and beverages is purely a personal matter. Consumption of
contaminated food or beverages constitutes a variable part of total
food and water consumption. In addition, cleaning, washing, and
cooking may change the concentration of contaminants considerably.
Therefore, assessment of exposure to contaminants in food and water
has to take into account the individual habits in food preparation
and in the choice of various foods and beverages. Furthermore,
people may consume contaminated food and water that have been
brought from outside, even though local food and water may be
clean. "Ready food" may constitute a mixture from various sources.
Water monitoring can be simple, through the frequent evaluation
of coliform organisms, or more complex, as for trace metals and
organic compounds such as halothane, polychlorinated biphenyls
(PCBs), ketones etc. Some chemical analyses can be performed in
routine laboratories, while others require more specialized
instrumentation, e.g., gas-liquid chromatography/mass spectrometry
equipment (WHO, 1983).
In practice, reliable and representative data are difficult to
obtain, particularly in areas where the population consumes a
heterogeneous diet, where family units are not very uniform, or
where the same element may be distributed throughout many items of
the diet. Within a population, cultural habits and availability
largely affect the choice of food and beverages. Consequently,
many approaches have been adopted with wide differences in accuracy
and representativeness. Overall exposure is a function of
concentration, amount, frequency of intake, and duration. All
dietary studies should be devised to enable such data to be
obtained. In food consumption, the emphasis is placed on long-term
exposure. In such a case, the time resolution and frequency of
sampling may be less important.
Food and beverages may contain chemicals which as such have no
nutritional value:
- intended additives: added to obtain or change certain
qualities, e.g., colouring agents, emulsifiers,
sweeteners; these regulated chemicals will not be
discussed;
- accidental additives: entering food, water, or beverages
from containers, transportation accidents, etc.; and
- incidental additives: present in original raw food or in
water; pesticides, fertilizers, fungi (e.g., aflatoxins),
naturally-occurring chemicals, fall-out, etc. In the case
of breast milk the mammary excretion of pollutants, such
as polychlorinated biphenyls, has to be considered.
Various approaches are being followed in the assessment of
exposure.
3.5.3.1. Overall assessment of dietary intake of toxic elements
Information is collected about the types and quantities of
food/beverages consumed, so that it is representative of national
consumption patterns or those of subgroups within the population.
National data have been obtained by surveys based on:
- The total amount available per person, as an annual
average, from information on the amounts of food and
beverages produced, after adjustment for imports and
exports (FAO, 1971; OECD, 1973). Correction is necessary
for food wastage, subsistence food production, use of food
for animal production, and non-food uses.
- The purchase of food or the amount of food entering a
representative sample of homes in a given week, during
each season of the year (FAO, 1962). This again only
allows calculation of average food purchases, and requires
a knowledge of the wasted amount associated with culinary
preparation and the amount of left-over food.
- Questionnaires, interviewing, or weighing all the food,
beverages, and water being consumed over several days
(Marr, 1971; Haring et al., 1979). This is the only
approach by which information on individual consumption
can be obtained and which therefore provides the most
accurate account. Exposure to specific chemicals can then
be assessed, if data are available on the overall
concentration of the substance under discussion in
foodstuffs and beverages.
In their review of studies on the relationship between organic
chemical contamination of drinking water and cancers, Wilkins et
al. (1979) discussed the pitfalls to avoid in such studies.
Amongst the pitfalls are: the chosen indicator agents (e.g.,
chloroform), which may not necessarily represent potential
carcinogens; non-uniform distribution of contaminants in place and
in time; no data available on levels in past years; routinely-kept
records are not adequate for generating "ideal" exposure data;
aggregate migration data may be an inadequate index of mobility;
classification of individuals on the basis of residence may be
inaccurate with respect to total exposure; considerable individual
variation in water consumption; consumption of bottled water; and
differences between administrative districts and water-distribution
areas. All these pitfalls point to one main difficulty - the
linking of individual exposures to all potential drinking-water
carcinogens over a long period, with medical histories.
In epidemiological studies on relationships between the
hardness of drinking-water and cardiovascular mortality or
morbidity, the composition of mains-water has generally been used
as the indicator of exposure. However, an area may be served by
several water sources, resulting in variable composition. The
Water Research Centre in the United Kingdom has worked out various
mathematical procedures to achieve an estimate of the weighted mean
for the population under study over a certain period (Lacey &
Powell, 1976). Formulae can be applied to a group of important
water determinants, or simply element by element. It may show that
homogeneity exists for one element, but not for another. For the
study of long-term exposure, it would be preferable to define
areas, served by one water plant, with water of a reasonably stable
composition over at least 10 years. Also, changes in water
composition may be taken as a criterion for change in both exposure
and health hazard, as has been done by Crawford et al. (1971).
There is a large variation in water composition according to
source. In the United Kingdom, for instance, the pH was shown to
vary from 3.6 to 7.9 (waters with low pH being more liable to
dissolve material from metal pipes); total hardness (CaCO3) ranged
from 16 to 270 mg/litre, total dissolved solids from 77 to 600
mg/litre and nitrates from 0.5 to 4.0 mg/litre (Packham, 1978). In
recent years, more account has been taken of the composition of
tap-water, particularly the levels of cadmium, copper, lead, and
zinc, which may change between the water mains and the tap,
depending on pH and type and length of the home distribution
system. Haring (1978) has developed a proportional sampler for
tap-water; 5% of the water flowing through the tap is sampled over
a whole week. The consumers are instructed to turn on the sampler
only when water is taken for preparation of food and drinks; this
yields the average intake of water (and pollutants) per household
per week.
In comparing the mortality or morbidity of population groups
from different towns, weighted intakes representative for those
respective populations have to be estimated. This calls for a
number of random samples in each town, increasing with the size of
the population. In the Netherlands, it has been estimated that for
towns of 20 000-50 000 inhabitants, tap-water in about 200 homes
should be sampled to achieve a representative weighted concentration
for metals that are liable to increase in concentration from source
to tap. For pollutants that do not change in concentration, sample
water at the outlet of the water treatment plant can be used
(Zielhuis & Haring, 1981).
3.5.3.2. Indirect assessment of intake
(a) Total diet or market basket studies (composite technique)
Food samples are prepared that are composed of the main
constituents such as cereals, meat, root vegetables etc., based on
national consumption data. They are analysed after normal
preparation and cooking. The mean concentration of toxic elements
in each constituent is measured and an average daily intake can be
calculated for each constituent and for the diet as a whole. Such
studies are repeated for different seasons and in different regions
to reflect local variations in the diet. A number of countries
have based their initial assessment of population exposure on data
obtained from such studies (Ushio & Doguchi, 1977; Dick et al.,
1978). These studies are particularly valuable when elements
(e.g., lead, cadmium) are widely distributed amongst all major food
items, or, as is the case with mercury and arsenic, where bio-
concentration occurs almost exclusively in fish and shellfish.
(b) Selective studies on individual foodstuffs
By measuring concentrations in representative samples of staple
foods, it is possible to use the modal levels found, together with
food consumption data, to calculate average daily intakes. Such an
approach is particularly useful, if the intake is predominantly
influenced by one or two items of food, and where food monitoring
programmes have established an average concentration in a commodity,
e.g., DDT in cereals. The following three groups of consumers may
require special attention (section 3.9): those who have different
patterns of food consumption from ordinary adults (e.g., infants or
the elderly); those whose metabolism is different from ordinary
adults (e.g., infants who normally absorb lead from the gastro-
intestinal tract at a higher rate than adults); and those who are
exposed to an above-average concentration of toxic chemicals in the
diet (e.g., fishermen on tuna boats - methylmercury).
(c) Habit survey (nutrition table method)
A sample is selected within a critical population to obtain
information about the food consumption of extreme consumers. In
the United Kingdom, such an approach has been used to determine the
consumption habits of a critical population by interview; from this
a reference level of consumption of the most extreme consumers is
calculated. This reference level is given as the arithmetic mean
of the consumption rates of a fixed number (usually 30) of the
people at the upper end of the distribution of consumption rates.
Such a reference level has been shown to reflect reasonably the
time-weighted average consumption levels of the most extreme
consumers (Shepherd, 1975), though recent duplicate diet studies
(section 3.5.3.3) have shown that consumption rates determined by
interview are usually an overestimate of actual consumption rates
(Haxton et al., 1979). However, the use of this method enables
consumers to be identified, who are subject to unacceptable
exposure because of their patterns of food consumption, and/or to
increased metabolic susceptibility to the toxic element (section
3.9). In these cases, further direct assessment of exposure must
be undertaken.
3.5.3.3. Direct assessment of intake
The external dose, in a narrower sense, can only be obtained by
the weighing and analysis of a duplicate sample of meals actually
consumed by an individual, including those consumed outside his
home (duplicate portion technique). Practical constraints invariably
limit the application of this approach to the collection of meals
for one or a few weeks from a limited number of subjects. Although
the exercise can be repeated, the demands on individual participants
are quite high and, ideally, the survey should be supervised.
Consequently, such studies are only undertaken if the information
from indirect exposure assessment techniques is such that;
- an average intake is not appreciably lower than the
acceptable or tolerable intake;
- there is a well-defined critical group within the
community; and
- the community is subject to an atypical level of
contamination in the area, in which they live, or in their
food.
In a sense this approach is comparable with the methods of
personal sampling described in section 3.6.
3.5.4. Monitoring of physical factors
3.5.4.1. Noise
Reviews on the assessment of exposure to noise have been
published by Broch (1971), Burns (1973), Persons & Bennett (1974),
Peterson & Gross (1974), Lipscomb (1978), and WHO (l980b).
Noise (i.e., unwanted sound) does not leave a residue; it
dissipates as soon as the vibrating source is discontinued. It is,
however, very pervasive. Environmental assessment of exposure is
possible but not biological assessment.
Noise occurs almost everywhere in a highly-mechanized society.
Occupational exposure to noise is widespread in the production
industry, in transportation, construction, mining, and even in
agriculture. Non-occupational exposure to noise occurs more
extensively in urban than in rural environments. Aircraft are
often regarded as the most annoying source of community noise. In
addition, there is increasing exposure during recreation, e.g.,
from discotheques, shooting, or motorcycling. In remote undeveloped
areas, noise levels are much lower than those in industralized
societies.
Noise is characterized by three basic parameters: frequency,
level (intensity), and duration. The frequency is the number of
oscillations per unit of time, stated in terms of cycles per
second (Hertz). Most common noises contain a complex combination
of frequencies. High frequency noise, in which the energy is
concentrated in a relatively narrow band, is generally more
annoying and damaging to the ear than low frequency broad-band
noise. Noise level, measured in decibels (dB), is perceived as
loudness; the noise level and duration of exposure are closely
correlated with adverse health effects. In exposure assessment, it
is necessary to quantify level (dB) and duration, and to some
extent frequency.
The type of noise should also be distinguished according to the
way it occurs in time. Continuous noise maintains a fairly
steady level over time. Intermittent noise is caused, for
example, by vehicles or aircraft passing by. Impulse or impact
noise (high level, short duration) is generated by two objects
striking together or by a sudden, forceful release of air pressure:
e.g., gunfire, sonic boom, explosions, hammering. The time
resolution of sampling should be geared to these different
characteristics.
One of the easiest, though not the most precise method, is to
use one's own ears. The ear is extemely sensitive and capable of
interpreting sound over a broad range of intensity. In industry
the following estimate is used as a "rule of thumb", on the basis
of being able to understand the spoken language: if loud speech
can be understood at 0.8, 0.45, 0.25, 0.14, or 0.08 m, the noise
level is 65, 70, 75, 80, or 85 dB(A), respectively (footnote to
section 3.3.1). This is an example of assessment of perceived
exposure.
However, instrumentation, such as sound level meters, impulse
noise meters and personal dosimeters (section 3.6) are needed in
order to quantify exposure. Accurate measurements are essential.
All measurements should be conducted and calibrations performed
according to the accepted standards, such as those of the
International Organization for Standardization (ISO). Since
frequency and duration are also essential parameters in the
assessment of exposure, equipment has been devised that incorporates
these characteristics. Some equipment gives direct measurement, as
in the case of frequency weighting networks built into sound level
meters; with other equipment, calculations are required from a
knowledge of the time pattern.
In occupational studies, in addition to a sound level meter, a
work study is needed to calculate the duration of exposure; this
demands a large number of measurements and a close follow-up of the
worker over the entire workshift. However, the recovery of the
temporary auditory threshold shift, caused by exposure to noise
> 80 dB(A), will depend on the noise exposure during commuting, in
the home, or during recreation. In epidemiological studies, the
overall exposure per day should be assessed. More sophisticated
equipment is available that makes use of tape recorders, which can
be taken to a site (workplace, community site); the tapes can
afterwards be analysed in a laboratory, so that a complete history
of noise can be obtained on the site, showing noise level and
spectral characteristics at various times. The noise can then be
described statistically as the amount of time that it exceeds a
certain level (for example, L10 means that the level is exceeded
for 10% of time).
In epidemiological studies on the effects of aircraft noise,
contour noise level lines, computed for areas around an airport can
be used; exposure of the general population can then be expressed
in terms of location of homes (and communities) on this contour
line map.
3.5.4.2. Vibration
Reviews of this topic have been prepared by Dupuis (1969),
Coerman (1970), Guignard & King (1972) (particularly vibration in
aeroplanes) and Wasserman & Taylor (1977).
Vibration is a series of reversals of velocity: both
displacements and accelerations take place. Vibration may be
defined as any sustained oscillating disturbance that is perceived
by the senses (Guignard & King, 1972). Distinction can be made
between deterministic (i.e., the variation can be predicted), non-
deterministic (random), and transient vibration (short-term).
Contact with vibration can be regarded as:
- intended, e.g., during work (or at home), medical
treatment, and nursing; or
- unintended, e.g., as a passenger in cars, aeroplanes,
etc., living in a house situated near factories or busy
traffic routes.
The health effects of vibration on workers are related to the
duration and to the intensity of exposure:
- vibration transferred to the body from tools or machines
through the upper limbs or other parts: local vibration;
and
- vibration transferred from the base, e.g., vibrating
platforms, through muscles and pelvic bones: whole-body
vibration.
From the physical point of view, vibration is a complex
oscillatory movement of a particle or a body with respect to a
given reference point; the movement is transferred in transverse
and longitudinal waves.
The least complicated form is simple vibration, also known as
harmonic vibration, mathematically represented as a sinusoidal
curve. The maximum deflection of a particle from its state of
equilibrium is called the amplitude, measured in cm, mm, or µm.
The overall deflection in both directions, performed by oscillatory
particles in a given time, is called the vibration cycle. The
number of cycles of full vibration per second is called frequency
and is measured in Hertz (Hz).
In practice, vibration is a complex of periodic movements
composed of many sinusoidal curves. Therefore, the amplitude
diagram as a function of time is not sufficient for describing the
number, character, and frequency of its components. The value that
best characterizes vibration is the root-mean-square value (RMS),
because it accounts for both the time and the magnitude of the
amplitude.
In assessing human exposure to vibration, four basic physical
parameters have to be considered, i.e., intensity, frequency,
direction, and duration. In the case of local vibration, the
quantity and direction of forces employed by the operator in
touching the tools or working materials, the position of upper
limbs or the position of the whole body, the type of vibrating
tool, climatic conditions, work methods, and energy consumption
should also be taken into account. In the case of whole-body
vibration, it is necessary to take into account the position of the
body, the direction of vibration, and microclimatic conditions.
Modern apparatus for the measurement of vibration is equipped
with an electronic integration system enabling measurement of
acceleration, velocity, and deflection. Experiments have shown
that the value of RMS of the amplitude is the best characteristic
of vibration in the range of 10-1000 Hz. In order to examine
individual components of a wide-band signal, it is necessary to
perform the analysis of frequency in one-third of an octave.
The measurement of the direction of the penetration of
vibration is of great importance in the case of whole-body
vibration. It is known that the human body is sensitive to
vibration directed parallel to the long-body axis.
In epidemiological studies, it is not necessary to make a
detailed spectral analysis of vibration emitted from various
sources. It is possible to conduct the assessment by measuring a
single parameter - the frequency weighting value of acceleration.
Guignard & King (1972) have presented a review of the
subjective assessment of exposure to vibration.
3.5.4.3. Ionizing radiation
The ionizing radiations to which man is exposed can be electro-
magnetic such as X- or gamma-rays or corpuscular radiation such as
alpha- or beta-rays. Methods for the assessment of exposure have
to be extremely sensitive, because, for ionizing radiation, it is
assumed that a no-adverse-effect-level does not exist.
These radiations can be emitted by radioactive elements
(radionuclides), the presence of which in the environment of man is
likely to lead to exposure. Exposure may occur within all levels
of the environment (domestic, occupational, local, or regional)
(section 3.1). Radon progeny generation from soil, rocks, and
building materials is an example. Thus, it is necessary to assess
the total exposure to the various types of ionizing radiation.
A number of radionuclides are of natural origin and are always
found in the environment; they lead, together with contributions
from cosmic rays, to background radiation. The total background
radiation varies according to altitude and longitude. Other
radionuclides are man-made, especially those derived from the use
of fission reaction as a source of energy, but exposures to
ionizing radiation may occur also from diagnostic and therapeutic
appliances and from some home equipment such as luminous watches.
As with a stable element, a radionuclide is characterized first
by a number of chemical properties, by the physical or physico-
chemical form in which it is found, and finally by its behaviour in
biological media, chiefly its metabolic properties. It also has
particular nuclear characteristics, namely, its disintegration rate
(represented by its radioactive half-life corresponding to the time
necessary for the disintegration of half the atoms present) and the
nature and energy of the emitted radiation.
The human body or some of its tissues or organs may be exposed
to radionuclides in two different ways, namely, externally or
internally.
External exposure may result from radionuclides present in the
environment outside the body. This is especially the case when
irradiation results directly from the source itself such as a
nuclear plant. This kind of exposure is almost exclusively
occupational. In addition, there may be external exposure from
diagnostic or therapeutic X-rays. It chiefly involves X- and
gamma-rays, which are penetrating radiations and therefore likely
to reach tissues lying at a distance from the point of emission.
Internal exposure occurs when radionuclides have been absorbed
by inhalation, ingestion, or percutaneous transfer. It involves
both penetrating gamma-radiation and the much less penetrating
alpha- and beta-radiations. After uptake, the radionuclides may
remain local (e.g., dust inhaled in mines) or may be distributed
throughout the body, according to the normal kinetics of the
element. It is essential to distinguish between the two modes of
exposure, since different methods of measurement and means of
protection apply.
Tissue damage is measured by the energy absorbed at the level
of the tissue, taking into account the type of radiation involved;
it is called "dose equivalent" and used to be expressed in "rem"
but this was replaced in l975 by the joule per kilogram (l rem =
10-2J/kg); more recently the sievert (1 rem = 10m Sv) has come
into use.
In the case of external exposure, many techniques make it
possible to measure the maximum dose equivalent received by the
organism directly from the radiation source itself. This
measurement can be carried out using well-developed and sensitive
techniques: ionization chambers, scintillation counters, thermo-
or photoluminescent dosimeters, etc. Workers likely to be exposed
can be equipped with direct reading personal samplers (but with-out
subsequent chemical analysis) (section 3.6).
In the case of internal exposure, dose equivalents cannot be
measured directly. The methods used consist of assessing exposure
from the evaluation of incorporated activity, derived from the
direct measurement of radioactivity in air, drinking-water, and
various foodstuffs. Many methods are available to determine such
radioactivity either directly on a sample, or after its physical or
chemical treatment, with sensitivities and accuracies that can
seldom be achieved when measuring other hazards.
3.5.4.4. Non-ionizing radiation
Non-ionizing radiation refers to all radiation in the electro-
magnetic spectrum exclusive of the ionizing range. It includes
the various forms of light waves, microwaves, and radiowaves.
It is part of the natural atmospheric background radiation to
which all living things are exposed to a varying degree. As a
result of technological advances in recent decades, man-made
electronic sources have added greatly to the environmental levels
of some forms of non-ionizing radiation in parts of the world.
The health significance of such exposures is related to the
physical characteristics of the radiation, the conditions and
duration of exposure, and the characteristics of the persons at
risk. Reviews on exposure assessment have been prepared by Czerski
and collaborators (1974), Scotto and co-workers (1976), WHO (1979),
and WHO (1981).
Light radiation includes the ultraviolet, visible and
infrared wavelengths of the electromagnetic spectrum. All are
found in various proportions in sunlight. These wavelengths may
also be emitted by man-made products or processes; in the case of
laser devices, the emissions are coherent monochromatic beams of
light.
Exposure is measured as radiant energy. Biological indicators
of human exposure are changes in the eye and skin, the principal
organs that absorb light. Ultraviolet radiation (UVR) is most
important from the standpoint of human health hazards. The UV
spectral range includes three regions (UV-A) extending from near to
far UVR that are referred to as: UV-A (black light region), UV-B
(erythemal range that is believed to be instrumental in producing
skin cancer), and UV-C (germicidal region). UVR is an important
factor essential for the normal functioning of the body: a
deficiency not only leads to specific adverse effects such as
disturbance of the phosphorus/calcium metabolism and rickets, but
there is evidence that it also reduces resistance to chemical
substances (Zabalyeva et al., 1973; Prokopenko, et al., 1981).
By making UVR measurements at specified times in several
locations, quantitative information can be obtained on the
association between solar UVR exposure and cancer of the skin.
This requires assessment of exposure intensities and durations.
Meteorological data combined with interviews on personal habits
(sunbathing, home-treatment, gardening, vitamin consumption, etc.)
may give an approximate estimate of exposure. Ethnic groups may
differ in susceptibility, which is greater in light-skinned races
than in dark-skinned; hereditary predisposition also exists
(xeroderma pigmentosum). A review on ultraviolet radiation has
been published by WHO (1979a).
Visible light from various types of lamps is used for photo-
therapy in hyperbilirubinaemia of the newborn. Combined drug/
light therapies have been developed for certain skin discorders.
Standardized conditions for such therapeutic exposures, including
specific wavelength limits, have not yet been achieved and
exposures are uncertain. Combined exposure to volatile tar
products and sunlight (e.g., among road-workers) has been shown to
lead to synergistic skin effects.
The principal sources of microwave (MW) and radiofrequency
(RF) radiation are electronic devices that generate and transmit
these frequencies. Electromagnetic pollution is becoming world-
wide because of the universal use of radar, heating techniques,
telecommunications, and broadcasting systems. Exposure to MW/RF
fields is generally assessed by the the measurement of average
power density under specified conditions. In the case of some
sources, such as radar, peak power density may also have to be
measured. The principles of measurement, together with a review of
effects on man, have been discussed in a recent WHO publication
(WHO, 1981). Dosimetry is complex and international standardization
of measurement techniques has not yet been reached.
Ultrasound is conventionally included in many non-ionizing
radiation programmes. Ultrasound-emitting devices are used for
therapy and most extensively for diagnostic imaging among various
medical and industrial applications, and in consumer products.
Average output power is measured for two types of ultrasonic
exposures: continuous wave and pulsed. Little is known about the
distribution or absorption of energy in man (WHO, l982b).
Another physical agent that might be considered are power
frequency electric fields (i.e., fields around power cables
operating at high voltage with frequencies in the range 50-60
Hertz). The physical implications of exposures of human beings to
such fields have been discussed in a recent review by Bridges &
Preache (1981).
3.6. Personal Sampling
Environmental monitoring of air (section 3.5.2) has many
drawbacks in procuring true and representative exposure data for
groups of subjects. In recent decades, particularly for the
assessment of occupational exposures, an alternative method has
been introduced: the subject carries a sampling instrument during
the whole (or part) of the working day with the sampling head in
the breathing zone. Within certain limits, sampling time and
frequency during a working day (8 h) can be adjusted to suit the
specific situation; however, monitoring with a high time resolution
is not feasible. Although the air thus monitored is more
representative of the air inhaled, the sampling rate does not
depend on the respiratory volume of the subject; therefore personal
sampling only gives an approximation of the respiratory intake.
The rapid development of personal air sampling instrumentation,
in recent years, has made it possible to monitor a large variety of
workroom air pollutants: metals, solvents, vinyl chloride, etc.
One of the first epidemiological studies in industry based on
personal sampling was performed by Williams et al. (1969) on the
assessment of exposure to lead in an electric accumulator factory.
Personal sampling methods in occupational health were revised by
Meyer (1975) and a review related more particularly to the
assessment of pollutants in the general environment has been
published by the US Environmental Protection Agency (1979).
There are considerable difficulties in using the personal
sampling technique in community health studies. These include:
the large number of subjects involved; at-risk groups may consist
of young children or the elderly; personal contact between the
subjects and the research worker is not as close as it would be in
a factory, and cooperation may not easily be achieved. Azar et al.
(1973) performed a study on lead exposure in taxi-drivers in
various cities in the USA, which showed that, notwithstanding the
difficulties encountered in assessment of exposure to ambient air
pollutants, the use of the personal sampling technique appeared to
be feasible in specific situations. In planning limited scale
epidemiological studies, use of this technique should always be
considered. A review on progress in this field has been published
by the US National Academy of Sciences (1981).
The personal sampling technique not only applies to the
monitoring of air pollution, but a similar approach is used in
assessing exposure to noise (section 3.5.4.1) and ionizing
radiation (section 3.5.4.3). A comparable approach is followed in
the duplicate portion technique of assessing exposure to chemicals
in food (section 3.5.3.3).
3.7. Biological Assessment of Exposure
The biological assessment of exposure is defined as the
systematic collection of human specimens for the determination of
pollutant concentrations (or metabolites). The joint CEC-WHO-EPA
Workshop in l977 distinguished between biological monitoring,
i.e., "a systematic collection for immediate application; analysis
and evaluation would be performed within a period of weeks after
collection" and collection for future reference, i.e., "a
systematic collection and respository of samples for deferred
examination; analysis and evaluation generally will be deferred for
a period of years or even decades following collection" (Berlin et
al., 1979).
Sampling and analysis of faeces may be regarded as a
combination of environmental and biological assessment: the amount
excreted per day reflects ingestion (minus absorption) and
excretion into the gastrointestinal tract, if fractional gastro-
intestinal absorption is low; for some agents (e.g., heavy metals)
both assessment possibilities exist simultaneously. Sampling of
breast milk assesses both the internal exposure of mothers and the
external exposure of infants.
Environmental and biological monitoring are not competitive,
but, depending on the objective of the study, on the environmental
factor(s) under consideration, and on the available expertise and
methods; either or both forms of monitoring may be preferred.
Sometimes a combined approach is required.
A pilot project on the assessment of human exposures to cadmium
and lead by means of biological monitoring has been undertaken as
part of the UNEP/WHO GEMS programmea. The final report (Vahter
et al., 1982) stresses the importance of quality assurance
procedures in this collaborative study. With these established, it
was possible to make valid comparisons of the blood levels of lead
and cadmium among residents in a number of cities around the world.
To avoid occupational factors that might affect the results,
observations were limited to a single group (schoolteachers).
While this project was not in itself part of an epidemiological
study, it provides a valuable example of procedures to be observed
in the biological assesment of exposure.
The method for the assessment of exposure to radiation is quite
different from that for chemicals. Many gamma-emitting radonuclides
can be determined directly by in vivo counting of subjects in a
wholebody counter; with this method it is possible to identify the
organs most affected. Moreover, in most cases chemical contamination
of reagents and apparatus does not influence the measurement. In
addition, unlike chemical contaminants, the elements concerned do
not undergo changes during metabolism, which may alter their
analytical behaviour.
Excreta (notably urine, faeces, and in a few cases, exhaled
air) or tissues taken from autopsy are also used for the biological
assessment of exposure to radiation. Fall-out surveys include
analysis of bone samples for strontium-90 and plutonium and
thyroid samples for iodine-131 and measurement of caesium-137 in
the total body by in vivo counting (UNSCEAR, 1972). Age has to
be taken into account, because both the metabolism of the particular
element and the expected exposure/response relationship may vary
with age. In contrast to the biological assessment of exposure to
chemicals, it is usually necessary to examine large samples, up to
several hundred grams of tissue or excreta, over several days.
-----------------------------------------------------------------------
a GEMS - Global Environmental Monitoring System.
Because of their rapid decay, short-lived radionuclides must be determined
quickly and storage of samples is not possible in such cases. A
review (with many literature sources) on analytical procedures for
biological exposure to radiation has been given by Harley (1979).
3.7.1. Advantages, disadvantages, limitations
In biological monitoring, parameters of internal exposure
(uptake) are measured as the result of external exposure through
ambient air, workroom air, smoking, indoor air pollution, use of
cosmetics, contaminated food and water pollution, etc. Total
exposure, irrespective of the source of pollution, is measured
indirectly. In environmental monitoring for total exposure, on the
other hand, it is necessary to measure simultaneously all sources
of external exposure, together with the duration; this is seldom
possible and may require an enormous input of manpower and money.
Internal exposure is the result of external exposure and of the
characteristics of the subjects exposed. In the case of respiratory
exposure, only concentrations in air are assessed in environmental
monitoring and not respiratory volume, which depends on physical
activity, whereas parameters of internal exposure may increase with
higher physical activity. The health-relevant exposure is much
better assessed in biological monitoring, because the impact on
internal exposure of personal behaviour, choice of foodstuffs,
biological characteristics such as age, sex, interindividual
differences in absorption and metabolism, disease states, and
anthropometry are taken into account. Biological monitoring pin-
points the groups and individuals actually at risk (section 3.9)
and studies may be possible of much larger numbers of subjects
than, for example, with personal exposure monitoring.
In examining biological specimens, measurements can sometimes
be made (in addition to parameters of internal exposure) of
possible health effects, such as changes in blood cells, enzymes,
proteins, lipids, kidney or liver function. In addition, it may be
possible to measure several exposure indices simultaneously, for
example, various metals in blood, hair, urine, or different
solvents in exhaled air.
In recent years, by analogy with environmental quality guides
for air, water, or food, much emphasis has been placed on the
development of biological exposure limits, namely, acceptable
concentrations of agents or metabolites in exhaled air, blood,
urine, etc. In order to fulfil the requirements for establishing
such biological exposure limits, it is necessary to conduct
epidemiological studies on the relationships between environmental
exposure, biological exposure, and health effects.
However, biological monitoring has limitations in comparison
with environmental monitoring. The main drawback is inconvenience
to the subjects; ethical aspects must be considered carefully
before starting such a programme. These may include questions of
inconvenience, health risk, confidentiality of information, and
freedom to refuse participation. Moreover, biological monitoring
can be applied only in the case of compounds that are taken up by
the body. It cannot be applied in the case of several highly
important environmental pollutants that exert their effects
primarily at the point of absorption (for example, sulfur dioxide,
nitrogen dioxide, ozone, and oxidants), or in the case of noise or
ionizing radiation. In general, biological monitoring is not
suitable for registering highly variable exposure, which may
constitute a limitation of this method of monitoring, if systemic
health effects depend on internal peak exposures (very short
biological half-time). In addition, for many chemical agents, not
enough basic data are available to design a biological monitoring
programme.
To sum up, exposure can be estimated in two ways: (a) by
assessing the external (environmental and/or occupational)
exposure, which only approximates the actual external dose; and
(b) by assessing the internal exposure, which approximates the
actual dose at target organs and provides a better estimate than
(a).
The recent publication from the l977 CEC-WHO-EPA Workshop
(Berlin et al., l979), together with those of Zielhuis (1973), and
Aitio and coeditors (1981) present a considerable amount of
information on instrumental, analytical and organizational aspects
of programmes for the assessment of environmental and occupational
exposure by means of biological monitoring.
3.7.2. Collection for future reference
This new approach was also extensively discussed in the CEC-
WHO-EPA Workshop (Berlin et al., 1979) and by Leupke (1979). With
repositories of samples, retrospective studies may be possible to
ascertain whether a pollutant observed in body tissues (or in
environmental samples) at a certain time, already existed in
earlier years, before its occurrence was investigated. Moreover,
with improvements in analytical techniques, it may be possible to
determine concentrations too low to be determined previously. In
some countries such as the United States of America and the Federal
Republic of Germany, pilot schemes are being developed to organize
such repositories. Many problems regarding organization, costs,
storage of various types of specimens, analysis, and evaluation
have still to be solved, before the data can be incorporated in
epidemiological studies. Some work has been done on the freezing
of aliquot diets for the subsequent determination of contaminants,
such as aflatoxins that may have, or later may be shown to have,
carcinogenic properties. In general, however, it should be said
that there is little point in "banking" all kinds of specimens for
the future, unless there is some reasonably well-defined object in
view.
3.7.3. Index specimens for various pollutants
The CEC-WHO-EPA Workshop (Berlin et al., 1979) prepared a
comprehensive table showing major environmental pollutants of
concern from the public health point of view and various human
tissues, organs, and fluids, which might be considered for
collection, either for biological monitoring or for collection for
future reference. A summary is presented in Table 3.2, covering
pollutants and specimens of major importance. The Workshop
concluded that the most important pollutants for which biological
monitoring programmes could be implemented, immediately, in order
to assess exposure of the general population, were: arsenic:
blood, urine, hair; cadmium: blood, urine, faeces, kidney,
liver, and sometimes placenta; chromium: urine; lead: blood,
urine, hair, faeces, kidney, liver, bone, and sometimes placenta;
inorganic mercury: blood, urine, kidney, brain; methylmercury:
blood, brain, hair; organochlorine pesticides: adipose tissue,
blood, milk; pentachlorophenol: urine, polychlorinated biphenyls:
adipose tissue, milk, blood; chlorinated solvents: blood, expired
air, and sometimes urine; benzene: blood, expired air; carbon
monoxide: blood, expired air.
3.7.4. An example of environmental versus biological assessment
of exposure: inorganic lead
The data are mainly based on reviews by Zielhuis (1975),
Nordberg (1976), and WHO (1977a).
The potential contribution of airborne lead to total lead
intake is presented in Fig. 3.1 (WHO 1977a): 6 of the 7 pathways
to man point to ingestion. This clearly indicates that in
epidemiological studies, environmental assessment of exposure will
require an enormous and complicated effort to assess lead levels
through ingestion of dust and soil (through pica) and through
consumption of water, beverages, vegetables, and animal food, as
well as by direct inhalation. Moreover, there are some other
sources that are not included in Fig. 3.1, for example, the use of
certain cosmetics containing lead and the use of lead-glazed ceramics.
Table 3.2. Index specimens to be used in the biological assessment of exposurea
---------------------------------------------------------------------------------------------------------
As Cd Cr F Pb Hg MHgb DDT and Phenoxy PCB, Chlori- Fluori- Non-substi- Alcohols Organo- CO
organo- herbi- PBBc nated nated tuted aliph. phos-
chlorine cides solvents prope- arom. vola- phorus
pesti- llants tile hydro- esters
cides carbons
---------------------------------------------------------------------------------------------------------
Adipose + + 0
tissue
Blood + + + + + + + + + + +
Bone 0 0 + + 0 0 0 0 0 0 0 0 0
Brain + + 0
Expired 0 0 0 0 0 0 0 0 0 0 + + + + 0 +
air
Faeces + + 0 0 0
Hair, + + + 0 0 0
nails
Kidney + + + 0
Liver + + 0
Milk 0 + + 0
Placenta + + 0
Teeth 0 + + 0 0 0 0 0 0 0 0 0
Umbilical
cord blood + + + + + +
Urine + + + + + + 0 + + + + 0
---------------------------------------------------------------------------------------------------------
a From: Berlin et al. (1979).
b methylmercury.
c polychlorinated and polybrominated biphenyls.
+ pollutants and specimens for which there exists sufficient information
to suggest a valid biological monitoring approach.
0 such an approach is not (yet) feasible.
Where lead is used in petrol, it is generally the main
contributor to lead concentrations found in air, which,
consequently, vary sharply with the distance from busy streets and
the amount of automotive traffic on them. Concentrations may also
be elevated around smelters or other local sources (such as scrap-
metal yards).
Lead levels in drinking-water are usually low, except when soft
and/or acidic water flows through lead pipes; this may constitute
a serious health hazard in relation to private water wells, and
also in some public distribution systems. Studies in Glasgow
(Scotland) and in Verviers (Belgium) reported levels of lead up to
2 mg/litre. In exposure assessment, it is important to note water-
drinking habits: water left standing overnight in the pipes
usually contains relatively high lead levels and infant formulae,
morning coffee or tea made with this may be highly contaminated.
Many studies have been carried out measuring intake from food
according to methods discussed in section 3.5.3. Using duplicate
portion techniques, a daily intake of about 80-350 µg/day have been
established for adults (Finland, United Kingdom, USA); higher
levels (up to 500-600 µg/day) have usually been indicated using
composite techniques (Federal Republic of Germany, Italy, Japan).
The washing and processing of food may considerably reduce existing
lead contamination. On the other hand, vegetables cooked in lead-
containing water may take up some from that source. If it is
assumed that foodstuffs with a lead content below detection limits
contain a zero lead level, then the total exposure may be
underestimated.
On the basis of the assumption that 90-95% of orally-ingested
lead is not absorbed in the intestinal tract, intake can also be
measured indirectly from lead levels in the faeces. This method
has been used by Tepper & Levin (1972) who established an intake of
90-150 µg/day in adult females in the United States of America.
A matter for concern may be the lead content of milk,
particularly for infants; human breast milk has been reported to
contain < 5-12 µg/litre, cow's milk, 9 µg/litre; and processed
cow's milk, higher levels than fresh milk. Canning and packaging
may lead to contamination of foods and beverages. Another source
may be wine: it may become a substantial source of exposure in
countries in which the habit is to drink 1-2 litres of wine daily,
as occurs in France and Italy, because of contamination from lead-
containing caps. There are further risks from wines prepared at
home in lead-glazed vessels.
Tobacco smoking has been shown to increase exposure, probably
because of the use of lead-containing pesticides, but, because the
practice of using such pesticides has been abandoned to a large
extent, this source may become less important. A crude estimate of
uptake is 1-5 µg/day from smoking 20 cigarettes/day. However, in
occupational exposure, smoking during work may considerably
increase oral intake, through transfer from contaminated fingers.
Children undoubtedly constitute a group at high risk (section
3.9). Exposure to contaminated soil and dust and to lead-based
paints has been responsible for large epidemics of lead poisoning
in young children, particularly in the USA. This is related mainly
to indoor paint, but may also occur from outdoor paints and dust.
The hands of inner-city children are often more contaminated than
those of suburban children. The presence of lead in the home
environment is related to the socioeconomic and sociocultural
status of the family, and the behaviour of children also affects
exposure through personal hygiene (cleansing hands) or pica
(pathological mouthing). Another source of exposure for young
children is coloured newsprint; coloured pages have been found to
contain lead concentrations of 1140-3170 mg/kg. In section 3.10,
it is shown that occupational exposure of parents may also increase
the exposure of children.
Many epidemiological studies carried out so far have been
concerned with the assessment of exposure of, and possible effects
in, schoolchildren (e.g., 6-14 years of age), apparently because
they can more easily be approached and because the neuropsychological
tests required can be carried out more readily with this age group
than with younger age groups. However, it has been shown repeatedly
that young preschool children (2-4 years of age) have the highest
exposure, because of their behaviour. In Asian populations (and in
those migrating to other countries), cultural habits may increase
exposures, for example, through the use of lead-containing cosmetics.
This short review indicates that, in epidemiological studies on
segments of the general population, environmental assessment of
exposure to lead is an almost impossible task, if it is desired to
achieve a valid estimate of total dose. Even in occupational
studies, in which respiratory exposure is usually predominant,
workroom levels are poorly-related to lead levels in blood.
However, particularly in the last two decades, biological
assessment of exposure (section 3.7) has proved to be of great
value, both in the general and in the occupational environment.
3.7.4.1. Lead in blood (Pb-B)
For long-term steady exposures, blood-lead is a valid indicator
of total exposure over the previous few months. In blood, 90-95%
of lead is located in the erythrocytes. In the case of anaemia,
whole-blood lead levels may underestimate actual exposure; this can
be corrected by means of the haematocrit.
Pb-B levels do not provide direct information on the existence
of health effects. However, they can be used as an estimate of
exposure in exposure/effect relationships. Blood per se is not
the target organ, but, at equilibrium, there is a relationship
between total external exposure, total uptake, and levels in whole
blood and in target organs (the central and peripheral nervous
system, the haemopoetic system, and the kidneys). The duration of
exposure in adults does not affect levels in the blood or in the
target organs. Only the levels in bone (the main site for
deposition) and the aorta increase with duration of exposure and
age.
One method of estimating the lead level in target organs
indirectly is the "provocation test": administration of calcium
disodium edetate (Ca-EDTA) or penicillamine enhances urinary
excretion of lead and, in this way, an estimate can be obtained of
biologically available tissue lead that is not deposited in bone.
Chisolm et al. (1976) established a linear relationship in children
between Pb-B and the logarithmic values of mobile chelatable lead
levels in 24 h urine after administration of lead at 25 mg/kg body
weight. Data from both preschool children and adolescents gave a
common regression line. This important measure of assessment of
internal dose can only be carried out in hospitals and, in any
case, careful consideration must be given to ethical aspects.
3.7.4.2. Lead in urine (Pb-U)
Pb-U levels are also indicative of total exposure, but a normal
rate of lead excretion does not serve as a reliable means of
excluding excessive exposure. Moreover, there are risks of
contamination from clothes, collection vessels, etc. To minimize
the influence of diuresis on the Pb-U level, 24 h samples are
preferred. However, this again limits application to
institutionalized subjects. Measurement of Pb-U levels, therefore,
does not provide a practical method for assessing exposure.
3.7.4.3. Lead in faeces (Pb-F)
Pb-F levels, on the other hand, offer a good estimate of total
oral exposure in adults. The unknown, and probably higher rate of
absorption of lead in young children makes this method less
suitable for exposure assessment in this most important group.
3.7.4.4. Lead in deciduous teeth (Pb-T)
Pb-T and lead levels in hair (Pb-H) are being used increasingly
for estimating integrated long-term exposure. They have the
advantage that samples are easy to procure. Pb-T levels even
indicate exposures of previous years, offering a means of
estimating the history of exposure in children. Deciduous teeth
have been used in studies of the neuropsychological effects of lead
on children (Needleman et al., 1979). Two developments may make it
possible to measure Pb-T levels in situ: the chemical measurement
of lead in enamel biopsies (Brudevold et al., 1977) and X-ray
fluorescence analysis (Shapiro et al., 1978).
Surface contamination of hair has to be removed by careful
washing; it may be very difficult to ensure that measured Pb-H
levels are really due to increased body burden. Routine
application of these methods in exposure assessment has still to
await further research.
Thus, in the present state of the art, biological assessment
of exposure has first of all to be based on measurement of lead
levels in blood. The most reliable method of sampling is by
venepuncture; this demands highly trained personnel, experienced in
taking blood from young children. In some studies, reliance has
been placed on analysis of blood taken by finger-prick. These Pb-B
levels tend to be higher than those measured in venous blood,
partly through contamination from the skin. Only when extreme care
is taken, can similar Pb-B levels be obtained, although even then
capillary samples give higher levels than venous ones (Elwood et
al., 1977).
In the last few years, a simple method has been developed to
identify individuals with probable overexposure to lead. This is
the measurement of zincprotoporphyrin (ZPP) in blood obtained from
a finger- or ear-prick by means of an automated haematofluorimeter.
If, in the case of long-term lead exposure, ZPP is not increased in
comparison with an unexposed control group of the same age and sex,
there is no need to examine for Pb-B. This quick screening method
may save a lot of time and expense.
3.8. Assessment of the Subjective Environment
Two types of environment are distinguished: the "objective"
and the "subjective" (perceived) environment (section 3.1). Where
possible, objective (mostly instrumental) methods should be applied
in the assessment of exposures, but there are some exposures that
may defy objective assessment. Assessment of perceived exposure
differs fundamentally from biological assessment of exposure
(section 3.7), because, in the latter, parameters of internal
exposure are examined, while in the former information is
systematically collected on the subjective response (e.g., to odour
or taste). Because subjective response usually shows wide
interindividual differences in intensity and quality of perception,
exposure assessment has to be based on the response of carefully-
selected groups of subjects, under controlled test conditions.
Although in the case of exposure to noise (section 3.5.4.1)
annoyance reaction may constitute the most important response,
objective methods are widely available for exposure assessment.
The same is true for exposure to oxidants (section 3.5.2.1), that
may have irritation effects.
3.8.1. Assessment of odour
This short survey is based mainly on reviews by Sullivan
(l969), Turk et al. (1974), and the National Academy of Sciences
(l979a). Odorants are chemical compounds; even with sensitive
analytical methods (chromatography, mass spectrometry, etc.)
complete determination and identification of these substances are
often not possible. Physical and chemical determinants of odour
are not yet fully understood. Odours are sensations that have to
be measured as a perceptive human response.
The subjective properties of odour include intensity,
detectability, quality (character), and hedonic tone (pleasant
or unpleasant). Intensity (magnitude of sensation) can be
described in ordinal categorization: faint, moderate, strong, or
possibly with a numerical assignment of magnitude.
Some properties of olfaction can introduce errors into
subjective assessment; adaptation: a rapid decrease of odour
intensity during continuous exposure; recovery: restoration of
olfaction when exposure is removed; habituation: getting used to
the odours, which operates over much larger periods than adaptation
and recovery. Quiet breathing allows only about 3% of odorants to
enter the nose and to contact the olfactory epithelium, whereas
sniffing brings more odorants into contact with these perceptors.
Human sensory responses to individual compounds vary widely and, in
some cases, it may be possible to detect 1 mol of odorant per 109
mol of air. All these characteristics of olfaction require a very
rigid design for the assessment of exposure.
Up to now, a correlation has not been established between a
predicted or measured ambient odour intensity and community odour
annoyance mainly because of: (a) difficulty in obtaining an
unbiased measurement of community odour annoyance; (b) difficulty
in defining an ambient odour intensity level through diffusion
modelling of source odour intensity measurements; and (c)
difficulty in measuring ambient odour intensity, because of
variability in meteorological conditions (Franz, 1980).
3.8.2. Assessment of taste
In general, principles similar to those for odour assessment
apply (Zoeteman, 1978), though it is not the volatile compounds
that are concerned, but the substances dissolved in saliva, which
enter the pores of the taste buds, located on the tongue. The
sense of taste is much less sensitive than that of smell. There
are four classic tastes: sour, salty, bitter, and sweet. Inter-
individual sensitivity may vary up to a thousandfold. Sensitivity
for bitter tastes tends to decrease with age and with smoking.
Many sensations, commonly attributed to taste, are in fact a
combination of taste and odour.
3.8.3. Example of sensory assessment of drinking-water
Zoeteman (1978) conducted a study of sensory assessment of the
chemical composition of drinking-water in the Netherlands. The
purpose was to investigate the suitability of sensory assessment of
water quality as an indicator for the presence of chemical contaminants.
At first, an inquiry was held among a sample of the Dutch population
(n = 3073, 18 years of age and over). In 3.2% and 6.9% of the
subjects the water quality was rated as "offensive" or worse for
odour and for taste, respectively. Water taste proved to be the
main factor in assessment of the sensory quality.
In order to identify the compounds causing bad taste and odour,
20 types of drinking-water (8 of ground water, 5 of drinking-water
from dune filtration, 7 from reservoirs) were collected; a panel of
52 subjects assessed the quality. Because the taste proved to be
more noticeable than odour, sensory assessment was restricted to
taste assessment. The average taste scales clearly differed
between the various types of water. The measured levels of sodium,
calcium, and magnesium salts could not explain the large differences
in taste between various waters. Therefore, organic contaminants
seemed likely to be the cause of the observed differences.
In the 20 types of water, 280 organic substances were detected
(gas chromatographic-mass spectrometer-computer system), but nearly
100 could not be chemically identified. Nearly twice as many
organic compounds were found in drinking-water derived from surface
water, compared with that from ground water. In water derived from
surface water, several taste-impairing compounds could be
identified.
This example merely illustrates the sensory approach in
assessing exposure to organic compounds that have unpleasant
tastes.
3.9. Interindividual and Intergroup Variability in Exposure:
Population at Risk
Individuals vary greatly in exposure and susceptibility to
environmental pollutants. Therefore they should not be treated
like homogeneous groups of experimental animals. Close attention
should be paid to the frequency distribution of exposures, since
this will affect procedures in the statistical analysis (Chapter
6). A common form of distribution is the log-normal. Blood-lead
values, for example, generally follow this pattern, and the median
may then be more appropriate than the arithmetic mean as a central
value for a group. When several groups are being compared in
respect of exposures to environmental pollutants and the
corresponding effects on health, it is important to be able to look
at interindividual as well as intergroup variations in exposures.
As already stated, preschool children are liable to be at
greater risk of exposure to lead than adults living in the same
environment. Furthermore, a mother may act as an external source
of exposure for her child during pregnancy, because of the
transplacental passage of lead and methylmercury, or, during
lactation, more particularly for fat-soluble substances such as
organochlorine pesticides.
Subjects with specific food habits, for instance those
consuming merely macrobiotic foods such as seaweed, or those
consuming marine shellfish, tend to have a high intake of arsenic;
fish eaters may be exposed to a higher level of methylmercury. The
presence of moulds in foodstuffs, producing the highly toxic,
carcinogenic aflatoxin, may also lead to defined groups at risk.
Various groups at risk can also be distinguished with regard to
physical factors, for example, with regard to exposure to ultra-
violet radiation, those with light skin (in comparison with those
with dark skin), and subjects who spend much time outdoors
(fishermen, farmers, etc.).
3.10. Outdoor/Indoor Exposure
In investigating exposure-response relationships in the general
population exposed to air pollutants, the studies have usually been
designed to relate health effects with concentrations in the out-
side air. However, human beings usually spend about 80% of their
time indoors; those particularly at risk (young children, the
elderly, and the chronic sick) spend even more time indoors.
Concentrations of pollutants in the home, at the workplace, or in
public buildings etc., can be quite different from those outdoors.
In recent years, increased attention has been given to pollution
indoors, either in relation to the penetration of pollution from
outside, or to that from sources within the home itself (as from
smoking, heating, or cooking). Reviews have been prepared by
Benson et al. (1972), Henderson et al. (1973), Halpern (1978), WHO
(1979b), and the National Academy of Sciences (1981).
Biersteker (1966) measured the ratio between the concentrations
of sulfur dioxide (SO2) and smoke indoors and outdoors in 60 houses
in Rotterdam, for periods of at least one week. In the average
home, the ratio for SO2 was 0.20 and that for smoke, 0.80. In a
few homes, indoor pollution greatly exceeded outdoor pollution,
apparently because of faulty stoves and chimneys. Biersteker also
established a relation between windspeed (< 1 m/s versus > 6 m/s)
and mortality, which he believed might be due to accidental high
indoor carbon monoxide (CO) concentrations on days of low wind-
speed. Extreme examples of such problems are seen through the use
of coal, wood, or "non-standard" fuels such as dried cow dung for
heating or cooking in poorly constructed dwellings without proper
chimneys. Measurements of smoke and carbon monoxide in such homes
in Nigeria were reported by Sofoluwe (1968), who related cases of
bronchopneumonia among infants to exposure to pollution while on
their mothers' backs or laps during cooking. Fuel burning indoors
has also been demonstrated to lead to chronic bronchitis in Papua,
New Guinea, and Nepal (Anderson, 1979; Pandey et al., 1981).
Clearly, in such circumstances, exposure to pollution indoors is
liable to be vastly greater than that outdoors. Also, exposures to
transient peaks, while close to the fire, are likely to be more
important than those averaged over long periods, but it is
extremely difficult to obtain any proper assessment of them.
Another source of indoor pollution is para-occupational
exposure: workers take pollutants attached to their skin, hair,
clothes, and shoes into their homes. The increased incidence of
mesothelioma in female members of the family who have cleaned
asbestos-polluted workclothes is well known. Watson et al. (1978)
examined 1-6-year-old children of workers at a storage battery
plant, and compared them with as many controls. The levels of lead
in the blood and free erythrocyte porphyrin were higher in the
exposed group, and the workers' homes had much higher lead levels
in the domestic dust.
Jacobson et al. (1978) observed a peculiar source of indoor
pollution with radionuclides. They used thermoluminiscent
dosimeters (TLD) placed in wristbands and worn by members of
families, in each of which one family member had been treated with
iodine-131; in addition they monitored radioactivity in the air at
home. Adults and children received much higher direct exposure to
radiation through their skin than their thyroid; external doses
ranged from 6 to 2220 mrems (60 µSV to 22.2 mSv) and thyroid dose
equivalents from 4 to 1330 mrems (40 µSV to 13.3 mSv). In these
families, childhood exposure could double the risk of developing
thyroid malignancies.
Exposures to radiation of natural origin is generally greater
indoors than outdoors, primarily owing to the emission of the gas
radon from the soil below and from building materials such as
stone, brick, or concrete. This radionuclide decays to solid
materials (generally referred to as radon daughter products) that
become attached to other fine particulate matter in the air, and
concentrations indoors are largely a function of ventilation.
Another pollutant that may be liable to be at higher
concentration indoors than outdoors is formaldehyde, which is
emitted from the urea-formaldehyde resin used in chipboard
furniture, in fabrics, and in the insulating material sometimes
applied to the cavity walls of houses.
Particulates may be at similar levels indoors and outdoors,
though indoor particulates can be quite different in composition,
with contributions from smoking, house dust, aero-allergens, human,
and animal dandruff shedding, consumer products, and furnishings
(National Academy of Sciences, 1981).
The examples above indicate clearly that for a number of air
pollutants, overall human exposures are determined more by
conditions inside individual homes than by those outside. There
are major differences in this respect related to lifestyle, social
conditions, and the structure of buildings, and it is important to
consider the local situation very carefully before embarking on
studies requiring detailed assessments of air pollution exposures.
This topic has been discussed further in a recent WHO document
(l982) and much information on indoor pollution can be found in the
report of an international symposium held in the USA (Spengler et
al., 1982).
3.11. Time-weighted Exposure
While, for some purposes, it may be sufficient to assess the
exposures of defined groups by using average values for the
locality, where more detailed information is required, personal
sampling might be used (section 3.6) or biological monitoring may
be applicable in some cases (section 3.7). An intermediate
approach, however, is to calculate time-weighted averages by noting
the amount of time spent by individuals in different types of
environment and then relating this to concentrations measured in
those environments, using a combination of fixed site or personal
samplers as required.
Fugas (1976, 1977) calculated the time-weighted exposure of a
group of urban dwellers by using time spent and average concentration
in air at various places. She estimated the weighted weekly exposure
(WWE) of urban dwellers living and working in a combination of
situations as shown in Table 3.3.
Table 3.3. Time-weighted exposure (TWE) in urban dwellers
--------------------------------------------------------------
t(h per SO2 Pb Mn
Type of exposure week) Ca Ct C Ct C Ct
--------------------------------------------------------------
Home 110 89 9790 2.5 275 0.04 4.4
Occupation, 42 8 336 0.3 12.6 0.02 0.84
office
Street F 10 600 6000 6.0 60 0.80 8.0
Street B 4 180 720 3.5 14 0.12 0.48
Countryside 2 25 50 0.1 0.2 0.01 0.02
--------------------------------------------------------------
Total 168 16896 361.2 13.74
WWEb 101 2.2 0.08
--------------------------------------------------------------
a C = concentration in µg/m3.
b WWE = weighted weekly exposure in µg/m3.
Five urban dwellers spent an average of 14 h/week outdoors and
2 h/week out of town. The individual weighted weekly exposures (in
µg/m3) depending on the individual exposures in the home and in
the street (no. 5 being a traffic policeman), are given in Table
3.4.
Table 3.4. Individual weighted
weekly exposures (µg/m3) of five
urban dwellers spent an average of
14 h/wk outdoors and 2 h/wk out
of town
-----------------------------------
subject sulfur lead manganese
dioxide
-----------------------------------
1 33 1.0 0.05
2 101 2.2 0.08
3 108 1.5 0.10
4 55 1.0 0.06
5a 177 2.6 0.25
-----------------------------------
a Subject number 5 was a traffic
policeman.
This example shows the large interindividual variations in
exposure that may occur. Moreover, the time spent in the polluted
outdoor environment (streets) was only an average of 14 h in a week
(168 h). These data refer solely to concentrations in air, mostly
measured by means of personal sampling, without taking account of
variations in respiratory volume, in absorption, or in exposure
through food (for lead and manganese). Therefore, although the
time-weighted average concentration through inhalation is better
estimated in this example than in most exposure assessment, it only
improves the measurement of respiratory exposure in the general
sense; the data are still far from giving a measurement of the
actual dose, as such. Biological monitoring of lead and manganese
would have provided indices of total exposure in a far easier way,
including those through food and water.
No fixed rules can be laid down for computing time-weighted
exposures, since the relative importance of the different
contributions varies with the pollutant under consideration, and it
may change also from place to place or from time to time.
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4. HEALTH EFFECTS, THEIR MEASUREMENT AND INTERPRETATION
4.1. Introduction
Historically, much of the information on the effects of
environmental agents on health has come from rather crude counts of
deaths or of clinically-recognized cases of disease, but, with the
passage of time, assessment of symptoms, of specific pathological
conditions, or of biochemical, physiological or neurological
dysfunction has progressed, providing a wealth of tools for the
epidemiologist. Caution is required, however, in proceeding along
such lines for, if the only effect of an agent at a given intensity
is a small change in function, well within the normal physiological
range of variation in an individual, then its importance in
comparison with other factors affecting health must be weighed
carefully. Judgement is required taking into account the duration
of the effects, the number of persons likely to be affected, and
the relative importance of immediate but relatively minor effects
and of long-delayed but more serious ones. In a sense, the
population's health could be an integral index of environmental
quality, and the effects of various environmental agents are
multifactorial (Sidorenko, 1978). Some effects are specific to an
agent, but most are non-specific (Bustueva & Sluchanko, 1979).
In this chapter, the measurement of effects in terms of the
relatively crude, but widely available mortality statistics and
routinely-collected morbidity statistics are discussed in some
detail, followed by a section devoted to one important disease
group (cancer). Techniques available for the more objective
measurement of effects of environmental agents have been arranged
on the basis of anatomical systems, starting with the respiratory
and cardiovascular systems followed by the nervous system and a
section on behavioural effects; though the latter are not strictly
effects on an anatomical system, they are closely associated.
While it is probably true that more measurement techniques have
been developed for the first two systems than for others, the order
in which the systems are discussed does not otherwise imply any
order of their individual importance.
In the study of adverse health effects, the effects under study
must be clearly defined in advance and the terminology employed
must not be confusing.
4.1.1. General comments on effects
A biological effect may be a subjective or objective phenomenon
experienced or measured in the short term or over a long term.
Such phenomena may be ranked in some order or measured on a scale,
if they are graded effects, or simply be registered as "present" or
"absent", as for example with death or cancer morbidity (quantal).
Each measure of health effects depends on the definition of what is
a biological effect. It is risky to generalize beyond any given
definition.
Effects may be described as either "stochastic" or "non-
stochastic". A stochastic effect is one for which the probability
of occurrence, rather than the severity, depends on the absorbed
dose and there may be no threshold. Carcinogenesis asssociated
with ionizing radiation is placed in this category, although it is
possible that a threshold exists for certain other cancer-producing
processes. The non-stochastic effect is one where the severity
varies with the exposure level and for which there may be a
threshold. Damage to the lens of the eye from electromagnetic
radiation constitutes such an effect.
Clinically, an effect may be an acute effect, for example,
chemical pneumonitis following shortly after exposure to a
substantial amount of an irritant, or a chronic effect such as
progressive interstitial pulmonary fibrosis following repeated
exposure to fine particulate allergenic agents, or after intense
exposure to certain fibrogenic dusts, or protracted deposits of
such dusts in the lungs of workers.
However, clinically acute effects may also result following
long-term exposures, for example, epileptic convulsions after long-
term exposure to dieldrin, myocardial infarction in workers
chronically exposed to carbon disulphide, or convulsions and acute
abdominal colic following long-term exposure to lead. On the other
hand, following short-term exposures to asphyxiants such as carbon
monoxide, or histotoxic agents such as nitrogen dioxide, chronic
after-effects may be observed. A special category relates to
sensitizing agents, where repeated exposure to levels that are non-
irritant will be uneventful in a clinical sense, until a degree of
sensitization occurs after which the next dose initiates an acute
clinical response: during the non-symptomatic (prepathological)
phase, the only objective sign may be elicited by serological
studies, though physiological function tests may reveal deficits
that are not yet appreciated by the exposed person.
An agent or combination of agents may induce an effect that can
be readily accepted as being harmful in the short term. Where a
physiological change occurs with no overt clinical benefit or
detriment, then there can be grounds for considerable disagreement
as to the significance to be attached to it. For example, it might
have to be considered whether minor departures from the normal
function might affect the ability to respond to other stresses and
diminish life expectation.
In any population, there will be a range of responses to an
agent with, at the two extremes of distribution, resistant and
susceptible persons; arbitrary cut-off points may define these
sectors. There is usually a number of subsets in a population in
which differing exposure/effect relationships are seen.
Because of differences in susceptibility of populations and
selection factors, exposure/effect relationships derived from one
group should only be used with reservation for other groups.
The terms "susceptible", "vulnerable", "hyperreactive",
"hypersensitive", and "high risk" are often used indiscriminately.
The following are some of the working definitions for these terms:
Susceptibility (vulnerability): The state of being readily
affected or acted upon. In hypersusceptible persons, "normal,
expected" effects occur, but with a lower exposure than in the
majority of the population. Vulnerability can be used inter-
changeably with susceptibility.
Hyperreactivity: In hyperreactive persons, the effects of
the agent are qualitatively those expected, but quantitatively
increased.
Hypersensitivity: To react with "allergic" effects following
reexposure to a certain substance (allergen) after having been
exposed to the same substance.
High risk: The term "risk" can be defined as the expected
frequency of undesirable effects arising from a given exposure to a
pollutant. Thus, the populations at risk are those who have been
exposed specifically to a defined pollutant that may produce a
particular adverse effect.
Susceptibility may be based on physiological factors. For
example, the very young and the very old are relatively vulnerable
to exposure to temperature extremes. Another variety of
susceptibility is associated with a genetically determined
reduction or a virtual absence of important enzymes involved in the
detoxication of compounds, or the repair or reversal of their
effects. Thus glucose-6-phosphate dehydrogenase deficiency renders
persons susceptible to the development of clinical methaemoglobinaemia
following exposure to a range of compounds occurring occupationally
and therapeutically. Exposure to low intensities of environmental
agents may not produce disease but may reduce host resistance
(Litvinov & Prokopenko, 1981).
4.1.2. General comments on measurements of effects
The effect should be defined and measured in as standardized a
manner as possible, whether it is measured using a physical test
(e.g., skin testing and radiography), or is physiologically or
biochemically measured, or some other index of morbidity or
mortality is used.
A number of aspects of measurement need to be considered before
embarking on a study or attempting to evaluate published data. The
results from measurement techniques, such as questionnaires and
function tests, are used with stated criteria to define the health
status of people in the study. The consistency or comparability of
these tools and of the criteria, from area to area or from study to
study, determine whether results can be compared, either as
specific rates or as trends. This, in turn, determines the
replicability of studies and the broader generalizations from
studies. Instruments from one study must be compared with those of
previous studies to maintain standardization. Errors and biases,
which may occur in all techniques, can be minimized with proper
usage, otherwise they may seriously affect the results.
The advantages or disadvantages of techniques or instruments
have to be judged on the basis of (i) acceptability by the study
population; (ii) the accuracy and reliability of the results
obtained using them; and (iii) their ease of use and the
availability of technicians or other persons who can use them.
Instruments for field studies must be simple and robust, with the
necessary supplies and, if possible, electric sources available in
the field.
The sensitivity of the test must be determined, i.e., the
proportion of all persons with a particular characteristic
such as a disease or variation in function that is detected by
the test. Similarly, the specificity needs to be determined,
meaning the proportion of persons lacking a particular
characteristic who are correctly identified by the test. The
purposes of the study will determine the acceptability of the
orders of insensitivity (rate of false positives) and non-
specificity (rate of false negatives). The determination of what
constitutes a true or false positive or negative will depend on the
standard employed, which itself may have been previously validated.
The two measures are related to one another; usually an increase in
sensitivity will mean a decrease in specificity. The degree of
sensitivity and specificity required depends on the objectives of
the study. Each objective will have different needs in terms of
the permissible rate of false positives and false negatives.
Instruments for measurement, whether electronic or mechanical
or in the nature of questionnaires or radiographs, have a number of
characteristics that need to be appreciated, if comparisons are to
be made sequentially within the same study or with other studies.
Some of the characteristics, such as accuracy, precision,
repeatability, and reproducibility, have been explained in
section 3.5.1. Other major characteristics are discussed below.
Reliability is the measure of consistency or reproducibility
and is dependent in particular on accuracy. The validity of a
measurement made by an instrument is determined by the extent to
which it relates to the effect that it is intended to measure. The
reliability of an instrument can be determined by frequent tests in
which everything is the same except the time (test-retest). Some
instruments are or can be set up to obtain measurements of
duplicate samples and results at the same time (split-half
testing); this method is often used in questionnaires where
"identical" questions are used in different parts of the
questionnaire (sections 4.4.1 and 5.6.3). Validity often depends
on the criteria of what is a true characteristic of disease. It
also depends on what is used as the standard. The validity of a
test procedure can often be checked by applying it, along with
other assessments, to a well-defined population.
Some conditions or physiological functions display distinct
cyclical (e.g., diurnal or seasonal) variations, and these must be
taken into account when making measurements related to them.
Effects themselves might also follow a cyclical pattern, as in some
occupational examples in which adverse effects can be more severe
at the beginning of the day's shift or the working week, so that
again the time at which measurements are made becomes critical.
4.1.2.1. Inter- and intrainstrument variation
All instruments have a certain degree of variation in addition
to limitations of accuracy. The instrument may have variations
over time or from place to place due to different circumstances,
such as environmental factors or electrical current, etc.
Questionnaires are also perceived differently in different social
settings. Each instrument has to be evaluated before use and in
any given setting. Changes in barometric pressure, temperature, or
humidity may also affect the functioning of physiological measuring
instruments. Any moveable part of an instrument, or any component
of an instrument may develop defects or change its characteristics
through a variety of causes, which might influence the readings
obtained at different times. The use of standardized protocols and
standardized instruments helps to minimize these problems.
Calibrations and frequent checks are required to examine
intramachine differences: if necessary, adjustments can be made or
correction factors can be determined and applied. The behaviour of
the instrument, such as its consistency or linearity has to be
determined (e.g., section 5.6.6.1). Interinstrument differences
need to be studied carefully, bearing in mind how far such
differences might introduce bias in the particular study in
question. It may sometimes be necessary to set up a special
randomized experiment in which a selected set of subjects
(conveniently research workers) are tested with all the instruments
to be used in a survey and the instruments should be interchanged
with one another during the course of the study in a randomized
manner.
4.1.2.2. Inter- and intralaboratory differences
Quality assurance procedures should be established within a
laboratory and between it and a reference laboratory. Such
procedures include not only analytical quality assurance, but also,
if the study involves biological material, quality assurance during
the sampling and storage of the material. Quality assurance checks
should be carried out before the start of the study as well as
during it.
The use of any instrument will, in part, depend on whether
there are reference values with which results can be compared.
"Normal" will always have to be defined in each study as to whether
that means either an ideal, average, or standard value, or any one
of a dozen other possible definitions.
4.1.2.3. Inter- and intraobserver variations
In any investigation in which there is more than one observer,
technician, or inteviewer, there may be differences between them.
These differences may be due to a large number of factors,
including the way in which tests are applied, information recorded,
or findings interpreted. Interobserver variation must be tested
regularly in a systematic fashion (section 5.6.6.2). An observer
varies in performing and interpreting tests, from time to time and
place to place. Sometimes, this variation can only be measured by
having the observer read a standard test or perform a standard test
at different times, or by evaluating random aliquots of an
observer's work to see if there are differences from time to time
and place to place.
In interviews, though a question may have been asked and an
answer given, the resulting information cannot be immediately
accepted as accurate. Even when independent checks have been
carried out and estimates of error rates produced, caution must be
exercised. There are likely to be errors from: random sampling;
bias from failure to respond or incomplete response; misunder-
standing; memory; inapproriate attempts to quantitate vague or
imprecise notions; deliberate distortion; and recording, coding,
analysis, or retrieval of the results. The sources of error in
interview surveys have been reviewed by Moser & Kalton (l97l),
Bennett & Ritchie (l975), Alderson (l977), and Abramson (l979).
4.2. Mortality and Morbidity Statistics
All sources of data have their advantages and disadvantages,
and their cost/benefit ratios. Existing sources of data are often
the easiest to use, the least costly, and require the least
recourse to subjects. On the other hand, they often lack the
information needed for a thorough examination of the objectives.
Usually, studies, in which existing sources of data are used, are
descriptive in nature, but are retrospective. Such information has
been used in many studies of geographical differences in the
distribution of disease.
4.2.1. Mortality statistics
Some mortality data adequately reflect certain medical
problems. Some conditions have a high mortality rate and death
occurs quickly; thus mortality data for malignant melanoma can
provide fairly accurate quantification of this disease, but such
data would be quite inadequate for quantifying squamous carcinoma
of the skin. Diseases that have a long natural history may be
susceptible to treatment or have a variable mortality: the longer
the natural history, the less indication mortality statistics can
provide about the causative factors in the disease. Though many
conditions create considerable discomfort for patients, this rarely
figures in the mortality data. An extreme example of this is the
common cold which is responsible for virtually no deaths. A more
severe disease is rheumatoid arthritis; again the mortality is so
low that routine mortality data are of limited value in its study.
Many routine data collection systems are relatively inflexible and
there is little facility for introducing new items into the system
and processing these alongside the original data. Flexibility can
only be provided by the special study of additional material
collected independently of the routine health statistics system.
Because of differences in death certification procedures, in
diagnoses, and in coding causes of death, international comparisons
are subject to possible biases. Furthermore, death certificates
usually indicate only the place of residence and the place of
occurrence of the death, thus precluding any estimate of lifelong
exposure that is so critical in the examination of mortality due to
chronic diseases. Death certificates do not contain information on
tobacco smoking, occupational exposures, ethnic groups, and other
host and environmental factors. Without multiple causes of death
coding and autopsies, the cause of death information that is coded
from the death certificate may often be misleading (Moriyama et
al., 1958). Co-morbidity data are rarely available, unless all
causes mentioned on the certificate have been specially coded
(immediate and contributory, as well as underlying). However, the
mortality data for a country can still show very important trends.
An additional dimension is added to mortality statistics when
the data are tabulated according to occupation. In many countries,
census questions have included the occupations of individuals
listed in each household and this can provide a denominator for the
calculation of occupational mortality rates. However, there are
some reservations about this approach: the onset of an
occupationally-induced disease might be associated with a decline
in ability to work and this could result in an individual changing
his job. Since mortality rates are calculated from the terminal
occupation, the true etiology of the disease may not then be
revealed. Occupational mortality statistics, however, provide a
very useful background for the study of occupational disease,
despite doubts about the validity of the data (Alderson, 1972;
Mason et al., l975; Fox, l977).
4.2.2. Routine morbidity statistics
Two indices are used to describe morbidity: incidence and
prevalence. Incidence is the number of newly diagnosed cases of a
disease occurring in a defined population in a defined period of
time. The incidence rate is often expressed as the number of
newly diagnosed cases occurring in 100 000 population in one year.
The second measure, prevalence, is the number of people with a
given disease alive at a point in time (point prevalence) or
over a period of time, say one year (period prevalence).
Again, the prevalence can be expressed as a fraction of the number
of persons in the population at that time: prevalence rate.
In general, morbidity is harder to ascertain than mortality,
but is generally a more sensitive indicator of the health effects
of pollutants. Aspects of the collection of morbidity statistics
have been discussed in various statistical reports (WHO, 1965).
Morbidity data are available in some countries where the
national or local health authorities regularly conduct a health
interview survey or a health examination survey.
(a) Health interview survey
This method involves interviewing a sample of individuals and
asking them questions about their social setting, their recognition
of signs and symptoms of disease, their attitude to sickness and
health, and their contact with health services in the past. It may
be applied to a representative sample of the total population, a
sample drawn from carefully selected locations throughout the
country, or subpopulations chosen by locality, age, occupation, or
other characteristics. The virtue of a health interview survey is
that data from a fairly large sample of respondents may be obtained
with limited expenditure of resources (compared with the use of
medical and other staff to investigate the subjects). In certain
circumstances, this indication of the knowledge, attitudes, and
practices of members of a population may provide a more appropriate
picture of their health care than that derived from other
approaches. In particular, the respondents' answers indicate how
much ill health they perceive, their reactions to this, and the
reported incapacity from the ailment. Perceived ill health may
also be studied in relation to such variables as age, sex,
socioeconomic status, occupational class, smoking and drinking
habits, and ethnic origin. Data may be obtained from subjects by a
variety of methods, such as the use of self-completion
questionnaires, direct interviews, group interviews, or diaries;
as has been mentioned in section 4.1.2, it is important to consider
the reliability and validity of data obtained from such approaches.
(b) Health examination survey
In this type of survey, data are collected by examination and
investigation of the respondents in a sample. Some data will have
to be collected by questioning the subject, but the aim is to cover
quite different issues by direct examination, or to complement any
responses with observations and investigations. It is essential
that the original test results, whether in the form of electro-
cardiographic (ECG) tracings, blood pressure observations,
ventilatory function indices, flow volume curves, or skinfold
thickness measurements, be preserved for study in addition to
diagnoses or judgements based on these results. Certain problems
that may be encountered in this type of survey include the
magnitude of resources required to carry out such a survey and the
fact that gossip about the study may have a marked effect upon the
response rate. By identifying variations from the physiological
and psychological norms, the investigator may be able to quantify
the "morbidity" in a population, which is not recognized by the
subjects themselves or by their families. Even with measurements
such as blood pressure, there is a grey area between normal levels
and those at which treatment is definitely justified.
(c) General practice morbidity data
In the absence of a national or local health interview survey
or health examination survey, it may be appropriate to use
morbidity data from general or family practice as a source of
relevant material. An extensive amount of literature is available
on the organization of medical records in general practice, the
coding of such material, and the use of such data to identify
morbidity in the population; this has been reviewed by Alderson &
Dowie (1979). In addition to considering problems involved in the
measurement of morbidity, the appropriateness of the available
denominator should be considered on the basis of practice size,
which is an essential component in the calculation of morbidity
rates by age and sex. Papers discussing the validity of data
recorded by general practitioners include those by Dawes (l972),
Hannay (l972), Morrell (1972), and Munro & Ratoff (1973).
(d) Hospital morbidity data
Such data are valuable in reference to malignant diseases
(section 4.3.2.8). For many other chronic diseases, hospital
discharge statistics are less useful; for example, where patients
suffer from an acute stroke, there may be strong pressure from the
patient or the family to nurse the patient at home. Hospital
morbidity data may thus not provide an accurate indication of the
load of disease in the community; if an appreciable proportion of
patients are cared for outside the hospital, the statistics will be
unreliable as measures of disease prevalence. Morbidity statistics
from hospital and general practice are biased, because they reflect
the use made of health care rather than the prevalence of
morbidity. Titmuss (1968) commented that the higher income groups
know how to make better use of the health service; they tend to
receive more specialist attention, occupy more beds in better-
equipped and better-staffed hospitals, receive more effective
surgery and better maternal care, and are more likely to get
psychiatric help and psychotherapy than low-income groups. Forsyth
& Logan (1960) indicated a close relationship between the use of
hospitals and the availability of hospital facilities - the more
acute beds in a district, the higher the admission rate and the
longer the length of stay. Vaananen (1970) suggested that
emergency admissions are a reflection of population structure,
whilst planned hospital admissions vary in relation to the
facilities available. Changes in hospital morbidity data may
indicate changes in facilities, rather than any underlying
alteration in the distribution of the disease in the population.
(e) Record linkage studies
The development of a record linkage study has been described by
Acheson (1967) and by Baldwin (1972). Record linkage requires the
construction of a cumulative file of events occurring in the lives
of individual patients. The longitudinal study described by the
Office of Population Censuses and Surveys of England and Wales
(Office of Population Censuses and Surveys, 1973) links birth
registration, domestic migration, overseas emigration, census of
population, notification of cancer, and death registration, for a
l% sample of the total population.
For linking an individual with his health and other relevant
records, a unique identifying marker is required. Some countries
attempt to use unique identification numbers for all or some of
their populations, when operating social security or health service
systems. The use of these numbers can be of considerable help,
even when they are limited to certain categories of persons, for
example, those in active employment.
Absenteeism. Records of leave from work or school due to
specific morbidity may be used to determine the effects of
pollutants on such morbidity. Generally, there is difficulty in
ascertaining the real causes of the absenteeism. This is more
directly related to the day of the week, the season, to epidemics
of some communicable diseases, such as influenza, to some social
event or to behavioural factors.
(f) Occupational morbidity studies
Data on number and duration of episodes of incapacity, in
relation to age, sex and cause of incapacity, have been published
regularly in the United Kingdom. These statistics can be used as
an indication of morbidity in the working population, though
incapacity may be influenced by: occupation; the worker's domestic
environment and access to medical care; selection 'into' and 'out
of' a particular occupation; the financial and social consequences
of declared illness; the completeness of notification; the
unemployment situation; industrial morale; and other subcultural
factors (Alderson, 1967). Specific statistics are produced on
industrial injuries and workers who develop prescribed industrial
diseases, but the general problems of routine statistics apply to
these data.
4.3. Cancer
4.3.1. Cancer and enviromental factors
Within a very broad definition, it may be true that some 80-90%
of cancers can be related to environmental influences, as has been
frequently stated (section 4.3.2.3). In fact, however, only a
relatively small proportion of cancers have as yet been related to
specific agents (Doll & Peto, 1981). The most important factor
identified so far is tobacco smoking, related not only to lung
cancer but also to cancer of other sites, such as the larynx,
buccal cavity, pancreas, and bladder. Excess consumption of
alcohol, when combined with the use of tobacco, increases the risk
of oesophageal and oropharyngeal cancers - frequently in a
multiplicative fashion. Occupational exposures to agents such as
asbestos, tars, radioactive materials, chromates, and products
associated with the refining of nickel also contribute to the
incidence of lung cancer, although their influence is small
compared with that of smoking.
Evidence from migrant and other studies shows that dietary
factors are likely to be of major importance for cancers of the
digestive tract and reproductive organs. Sunlight is an important
cause of malignant melanoma and other skin cancer in the less-
pigmented races. Small numbers of cancers are attributable to
ionizing radiation and chemotherapeutic agents.
4.3.2. Measurements of cancer
4.3.2.1. Incidence and mortality rate
The burden of cancer is measured by the determination of
incidence and mortality rates. When such data are not available,
the relative frequency of the various organs affected as a
proportion of all diagnosed cancers may provide useful information.
Prevalence rate is rarely used. The various sites of cancer are
divided into broad groups in the International Classification of
Diseases (ICD) (WHO, l977) and in the International Classification
of Diseases for Oncology (ICD-0) (WHO, l976).
Incidence data of good quality are available for relatively few
areas in the world (Waterhouse et al., 1982), and few cancer
registries have been in existence for longer than 20 years. The
World Health Organization maintains a data bank of mortality data
of cancer which are periodically analysed (Segi & Kurihara, 1972;
Segi, 1978).
Incidence data on cancer are preferable to the more widely
available mortality figures because mortality is influenced by the
rates of cure, which vary from centre to centre. Nonetheless,
relative frequency data can, if possible sources of bias are
assessed, indicate the likely cancer distribution in a region. The
high levels of nasopharynx cancer, seen in the population of
southern Chinese origin in Singapore, were known from relative
frequency studies long before cancer registration became
established.
4.3.2.2. Variations of incidence with age
Any theory of carcinogenesis must be consistent with observed
age patterns. Cook and collaborators (1969) examined the shape of
the age-incidence curve for many different tumours using data from
eleven different cancer registries; they concluded that epithelial
tumours probably arise from a similar process, part of which would
be continuous exposure to an environmental agent, and that, even if
there is a variation in susceptibility among the population, there
is no indication of a reduction in the relative size of the pool of
susceptibles with age.
Not all cancers behave in the same way and a series of such
age-incidence curves are shown in Fig. 4.1. These different curves
must be explicable in terms of causal factors. The ICD often
aggregates neoplasms with quite different age-distributions, e.g.,
osteosarcoma and chondrosarcoma, hence histology-specific and site-
specific incidence curves may be more informative.
4.3.2.3. Geographical differences
Comparison of data from different parts of the world is subject
to bias. The age-adjusted cancer incidence figures contained in
the Cancer Incidence in Five Continents monographs (UICC, 1970;
Waterhouse et al., 1982) show that the reported incidence of
cancer, taken as a whole, varies between countries by a factor of
around three; when separate anatomical sites are considered, the
difference may be as much as 100-fold. While such extremes are
unusual, for many common sites such as the breast, stomach, and
cervix uteri, risk ratios of 10-30 are observed (Muir, 1975).
Such differences in the geographical ditribution of cancer were
often ascribed to ethnic or genetic factors. Kennaway (1944)
studied primary liver cancer in Bantu in South Africa and Negroes
in the USA, and concluded that "the very high incidence of primary
cancer of the liver found among African negroes does not appear in
US negroes and is therefore not a purely racial character. Hence
the prevalence of this form of cancer in Africa may be due to some
extrinsic factor which should be studied".
Higginson (1960) concluded that these differences were due to
environmental factors. Extending this concept, he examined the
differences in cancer incidence by site reported in the first
volume of Cancer Incidence in Five Continents. Assuming that the
smallest recorded rate represented a level that should be
considered as due to genetic factors, he postulated that the
difference between this rate and the highest observed rate probably
represented those cancers due to exogenous factors. Doll (1967),
Boyland (1967), and Higginson & Muir (1976) have presented further
supportive evidence that most human cancers are due to
environmental causes.
These studies do not imply that genetic factors may not have a
role to play. Skin cancer is clearly influenced by a genetically
determined skin pigmentation, being particularly frequent in
northern Europeans with lightly pigmented skins who have emigrated
to Western Australia. However, objective measurements for
genetically determined susceptibility do not exist for most
cancers.
4.3.2.4. Cancer and lifestyle
Lifestyle is difficult to measure in an objective manner.
Ethnic effects may be involved indirectly through postulated
dietary influence on hormone levels, promoters, and inhibitors.
Some factors, such as age at first pregnancy or age at first
coitus, which are often socially determined, are clearly linked
with breast and cervix uteri cancer risk.
Some religious groups have cancer rates that differ
substantially from those of the general population. Wynder and
co-workers (1959) first reported a lower cancer mortality in a
population of Seventh Day Adventists who neither smoke tobacco nor
drink alcohol and who follow an ovo-lacto-vegetarian diet.
Phillips (1975) has confirmed these findings showing that cancer
death rates in lifetime Adventists, in California, USA, are 50-70%
of those of the general population.
4.3.2.5. Cancer in migrants
It has been reported that the very high incidence of gastric
cancer seen in Japan slowly decreases in Japanese migrants moving
to the USA, but that the incidence of large intestine cancer
increases much more rapidly reaching a level close to that found
among those born in the USA (Haenszel & Kurihara, 1968). Buell
(1973) has also shown that breast cancer morbidity rates in US-
born Japanese approximate to those of the non-Japanese population
of the USA, which could be interpreted as indicating that the
environment - perhaps the diet in the USA - may have manifested its
effect in successive generations to influence hormonal levels and
cancer risk.
4.3.2.6. Time trends
The incidence rates of some cancers are rising, but those of
others are falling over a period of years. The increasing
incidence of cancer of several sites, e.g., the pancreas, has been
interpreted as being due to the introduction of new environmental
agents that are largely unknown at the moment. It has been
relatively easy to link the rise in lung cancer to the increase in
the number of persons smoking cigarettes. Such a link has been
confirmed, for example, by the fact that the decline in the
proportion of physicians in the United Kingdom who smoke has been
followed by a fall in the lung cancer rates in the professional
group.
4.3.2.7. Correlation studies
Correlation techniques based on descriptive data have brought
out statistically significant associations between, for example,
cigarette smoking and lung cancer, spirit consumption and
oesophageal cancer, beer intake and large bowel cancer (Breslow &
Enstrom, 1974). However, by the laws of probability, a certain
number of the correlations that emerge will be due to chance alone
and others may be 'indirect', i.e., linked in some ways to the true
cause. A correlation between coronary heart disease and lung
cancer would merely reflect the fact that both are strongly linked
to cigarette smoking. As, in such studies, the pooled experience
of several populations is contrasted, the effect of intense
exposure within a small segment of a population, say an industry,
would be diluted out (Muir et al., 1976).
However, sizeable international differences in cancer risk are
more likely to be due to the existence of a widespread exposure in
one population compared with another, than to the presence of a
small group at a very high risk. The environmental data available
for use in the correlations are usually of poorer quality than the
cancer incidence figures, and because of the long latent period for
cancer, the correlations should be made using the environmental
data for 10, 20, 30, or 40 years ago and present day cancer
figures. Such historical information on the environment is rarely
obtainable.
Results of correlation studies should never be accepted without
further testing. Failure to demonstrate a correlation probably
indicates that no association exists, though these may fail to
emerge by chance alone.
4.3.2.8. Hospital data
Only a small proportion of patients, thought by the family
doctor to have a malignant disease, are not referred, either on
medical grounds or because of refusal of the patient to attend
hospital. For example, Alderson (1966) found that only 1.1% of 540
patients, dying from malignant disease in a defined population, had
not been referred to hospital. Identification of the presence of
malignant disease is still a problem, but the progress of the
disease is such that deterioration in a patient will usually lead
to hospital referral. Although Heasman & Lipworth (1966) have
demonstrated appreciable discrepancies between clinical and
postmortem diagnoses of patients dying in hospital, hospital
morbidity data may in general provide a good indication of the
distribution of cancer in the population.
4.3.2.9. Cancer and occupation
The Office of Population Census and Surveys of England and
Wales has published data on cancer risk by occupation since the
turn of the century (Office of Population Census and Surveys,
1978).
The frequency of a given occupation - as assessed at the
national census - is compared with the frequency of that occupation
for a given disease on death certificates and a standardized
mortality ratio (SMR) that takes age into account is computed.
Woodworkers, for example, have an excess risk of lung cancer (SMR
113) and of bladder cancer (SMR 145) and teachers a relatively low
risk of lung cancer (SMR 32). The interpretation of such findings
is complex (Gaffey, 1976). Fox & Adelstein (1978) estimated that
perhaps 12% of the excess cancer risk is due to carcinogenic
exposures at work, the remainder to the lifestyle that is
associated with an employment. They base their argument on the
fact that standardization for social class and cigarette smoking
removes, or substantially reduces, the difference in risk and on
the finding that the spouses of those in certain high risk
occupations, for example miners, also have very high risks for
stomach cancer. Thus, while analyses of the type carried out by
the Office of Population Census and Surveys can suggest where
workplace exposure to carcinogens may exist, the presence of such
carcinogens must be established by other methods.
4.3.2.10. Case reports
From time to time, reports are published of a patient or a
small group of patients, who have an unusual cancer and an out-of-
the-way ocupation or exposure: adenocarcinoma of the nasal passages
in furniture manufacturers and bootmakers (Acheson et al., 1968,
1970); adenocarcinoma of the vagina in the daughters of women given
diethylstilboestrol for miscarriage (Herbst et al., 1971);
mesothelioma of the pleura in shipyard workers using asbestos
(Stumphius, 1971). This type of evidence, correlation-based,
usually uncovered by alert clinicians, is unlikely to uncover risks
due to common exposures or to those causing common cancers. Never-
theless, it has resulted in the discovery of human carcinogens.
4.3.2.11. Epidemiological uses of pathological findings
The lack of accuracy of histopathological diagnosis in the
population studied is frequently such as to understate the true
burden of disease. For most tumours, there is a spectrum of
microscopic appearances ranging from marked anaplasia through
various degrees of development and organization, sometimes
differentiating into several patterns. These variations may appear
in different persons or in one block of tumour from a single case.
Attempts have been made, employing concensus diagnosis, to conduct
expert panel readings of sections from patients with mesothelial
tumours meeting agreed criteria (Greenberg & Lloyd-Davies, 1974).
More sophisticated methods have been employed for the diagnosis of
angiosarcoma, using mixed sections, read blind, and recycled for
the study of intraobserver variation (Baxter et al., 1980); this
has lead to reduced interobserver variation, too. Improving
diagnostic accuracy for a special tumour with its attendant
publicity may increase vigilance among non-panel pathologists, so
that an increase in reported cases may include an element of
increased recognition that has to be taken into account in
attempting to determine an increase in true incidence over time.
Further discussions on the contributions of pathology to
epidemiological knowledge are found in the review by Muir (1982).
4.4. Respiratory and Cardiovascular Effects
There has been much confusion in the past over the definition
of "bronchitis" or conditions known variously as chronic non-
specific respiratory disease or chronic obstructive lung disease.
Standardized questionnaires, together with lung function tests,
have played a vital role in establishing a common definition and in
allowing studies of prevalence to be undertaken among occupational
or general population groups in a comparable way throughout the
world. In this way, it has been shown that the dominant factor in
the development of the disease is tobacco smoking. Beyond this,
there are associations between the development of symptoms in adult
life and the earlier occurrence of acute respiratory illnesses.
The effects of environmental agents have been demonstrated in terms
of exposure to urban air pollution (notably by the sulfur
dioxide/particulates complex) and to a wide range of dusts and
fumes in industry.
Equally, investigations of the etiology of cardiovascular
diseases have been greatly aided by the use of questionnaires
together with electrocardiograms (ECGs) and other objective
assessments. In this case, the role of specific environmental
agents is not very clear, but many studies have indicated the
adverse effects of smoking, obesity, and dietary factors, and the
possibly protective effects of exercise on the development of
cardiovascular disease.
In this section, an account is provided of the ways in which
the occurrence of respiratory and cardiovascular disease can be
investigated in order to explore associations with environmental
agents, examining indices that have been developed, methods of
measurement, and interpretation of results.
4.4.1. Symptom questionnaires
One method of determining the environmental agents important in
the development of respiratory and cardiovascular disease has been
the use of standardized questionnaires. This approach, by obtaining
details of respiratory and cardiovascular symptoms, makes it
possible to compare symptom prevalence in groups of individuals
exposed and unexposed to different environmental agents.
The assessment of clinical symptoms is an important technique
in epidemiological surveys, because it can increase the yield of
positive cases of respiratory and cardiovascular disease and act as
an index of disease, measurement errors being different from those
of other methods, such as ECG and lung function tests.
In the construction of symptom questionnaires, it is essential
to formulate precise questions to reduce variations that may result
when different observers ask people about their respiratory or
cardiovascular symptoms. It is necessary to use identical, or at
least very similar, symptom questions to compare data from
different studies. An important advance was the publication, by
the British Medical Research Council's Committee on the Aetiology
of Chronic Bronchitis, of recommended questionnaires for recording
respiratory symptoms, together with instructions for their use
(Medical Research Council's Committee on the Aetiology of Chronic
Bronchitis, 1960; Medical Research Council, 1966, 1976). A similar
advance occurred with the development of the London School of
Hygiene Standardised Cardiovascular Questionnaire (Rose, 1962,
1965). These respiratory and cardiovascular symptom questionnaires
have been translated into different languages and used for surveys
in different countries (Higgins, 1974; Rose et al., 1982). A
recent development was the construction and testing of a standardized
questionnaire for use in respiratory epidemiology by the American
Thoracic Society and the Division of Lung Diseases of the United
States National Heart and Lung Institute (Ferris, 1978).
Self-completed versions of the symptom questionnaires have been
developed to avoid the problem of observer variation, to be used
when personal contact is not practicable, and because they are more
economical than personal interviewing. Epidemiologists have used
this method with various degrees of success to collect information
on respiratory and cardiovascular symptom prevalence. Fletcher &
Tinker (1961) noted that answers on cough, phlegm, dyspnoea, and
smoking habits on a self-completed questionnaire did not always
correspond with those on an interviewer-administered questionnaire.
Furthermore, the self-completed questionnaire was not returned or
was incomplete, in about 25% of the cases under study. This error
rate was only 7% in a group of post office clerks and the
investigators concluded that the self-completed questionnaire might
be particularly useful in persons with a clerical background.
Sharp and coworkers (1965) obtained satisfactory agreement between
the self-completed and the interviewer-administered questionnaires
on respiratory symptoms in an industrial population in Chicago.
Higgins & Keller (1970) used both self-completed and interviewer-
administered respiratory questionnaires successfully in Tecumseh,
Michigan but self-completed questionnaires were not satisfactory in
a survey by Higgins and coworkers (1968) in mining communities in
Marion County, West Virginia.
Lebowitz & Burrows (1976) compared the interviewer-administered
British Medical Research Council and the US National Heart and Lung
Institute respiratory symptom questionnaires with each other and
with a self-administered questionnaire, of their own design, in
Tucson, Arizona. There was a basic 10% agreement between responses
of any two questionnaires for all questions that asked about
symptoms, but less disagreement for more factual questions, such as
those concerning smoking. For questions with similar wording, the
British and USA questionnaires yielded very similar results in
terms of prevalence of responses, relationship to answers on an
independent questionnaire, and interrelationships of positive
responses. The Tucson self-completed questionnaire was a
satisfactory instrument in the population surveyed, detecting more
abnormalities and better delineating cough and phlegm "syndromes"
than the interviewer-administered versions.
Zeiner-Henriksen (1976) sent the London School of Hygiene
cardiovascular questionnaire, by post, to random national samples
in Norway with response rates of around 80%. There were relatively
few missing or incorrect answers and the estimates of mortality
prediction were broadly similar to those in Rose's (1971) follow-up
study of the interviewer-administered version. The evaluation of
these cardiovascular questionnaires by Rose and coworkers (1977)
found the yield of positives for "angina" and "history of possible
infarction" was about twice as high with interviewers than self-
administration, but the positive groups obtained by the two
techniques differed little in their association with electrocardio-
graphic findings or their ability to predict five-year coronary
mortality risk. This suggests self-completion does not produce any
major loss of specificity or dilution with less severe cases.
There is other research that suggests that self-completed
questionnaires can be used successfully to examine the effects of
different environments on the cardiovascular and respiratory
symptoms in migrants and people born in the USA (Krueger et al.,
1970; Reid et al., (1966), in twins in Sweden (Cederlöf et al.,
1966a,b) and in a sample of 37 to 67-year-old people in the United
Kingdom (Dear et al., 1978).
Validity and reproducibility are important criteria in the
assessment of the symptom questionnaires. Reproducibility can be
affected by the changing disease status of individuals or
measurement variability. Interobserver measurement variability in
a study can result in the indiscriminate pooling of heterogeneous
results. It can also produce systematic differences between
studies, so that measurement differences could be mistaken for
differences between populations. Consequently, the method of
administering the questionnaire should be standardized and the
interviewers comparably trained to reduce these systematic
differences.
Checks can be incorporated in the survey to examine inter-
observer reliability. Each observer may be allocated to a randomly
chosen group of subjects with each observer's results analysed
separately for means and standard deviations or their prevalence
estimates. Where practicable, subjects may be examined more than
once, each time by a different observer. Interviewing techniques
can be examined by the playing back of tape recordings.
The reproducibility of the answers to questions about symptoms
for the respiratory and cardiovascular questionnaires has been
studied (Fairbairn et al., 1959; Fletcher et al., 1959; Holland et
al., 1966; Rose, 1968; Zeiner-Henriksen, 1972; Lebowitz & Burrows,
1976). Despite the considerable reproducibility of symptoms on
re-examination, the use of estimates of prevalence based on single
interviews only can cause problems in the interpretation of
results. There is often a substantial proportion of subjects
initially reporting particular symptoms, who do not report these
characteristics on subsequent checks. Therefore, regular
questioning would make it possible to grade the subjects on the
basis of the number of times the subject has been classed as
positive.
To ensure the validity of the symptom questionnaires, the
respiratory and cardiovascular diseases being assessed must be
defined accurately and the symptoms described should be
manifestations of these disease entities. A problem in the
development of stricter diagnostic criteria is that improvements
in specificity (i.e., the yield of a few false positives) may
reduce the sensitivity (the yield of a few false negatives). To
compare the amounts of disease in different populations, it is
essential that the levels of sensitivity and specificity do not
vary from one population to another.
The problem of determining the exact number of false positives
and negatives for symptom questionnaires is complicated by the lack
of a perfect reference test. Therefore, validation must be based
on correlations with different indices of disease, e.g., ECG, FEV,
mortality, each of which is an indirect measure. Holland and co-
workers (1966) have shown answers to questions about respiratory
symptoms to discriminate among persons, categorized on the basis of
more objective measures such as FEV and 1-h sputum volume. Rose
(1971) has examined the relationship between cardiovascular
symptoms, electrocardiographic findings, and coronary heart disease.
ECG findings predicted a higher proportion of cases of coronary
heart disease than symptoms. However, because of a measure of
independence between the ECG and symptom findings, a combination was
more effective than either alone.
Generally, the symptom questionnaires have resulted in an
increased standardization and comparability of results from
different surveys. From an epidemiological perspective they are a
useful technique, because they amplify information from other tests
and may allow the identification of high-risk individuals.
However, in using symptoms questionnaires to compare groups from
different cultures or countries, it is a precaution to ensure the
findings are consistent with other measures of disease such as FEV,
ECG, and mortality.
4.4.2. Tests of system function
There are measurement techniques to assess the effect of
environmental agents on the cardiovascular and respiratory systems.
The major longitudinal studies on the incidence and prevalence of
coronary heart disease such as the Framingham Heart Disease
Epidemiological Study (Kannel, 1976) and the Tecumseh Health Study
(Epstein et al., 1965) have used ECG, blood pressure measurement
and various serum cholesterol determinations. Rose and his
collaborators (l982) describe these epidemiological methods and
other techniques such as chest radiography and the measurement of
heart size.
Holland and coworkers (1979) have reviewed the functional tests
used in the epidemiological study of respiratory disease. These
include the tests that assess airway function during an expiratory
manoeuvre, those that measure airway resistance using a body
plethysmograph, and the closing volume and the frequency dependence
of compliance tests of small airway function. Higgins (1974)
reviewed other tests that can be used to determine the impact of
environmental factors on respiratory function, including cough as
an objective measure, the collection, measurement, and
categorization of sputum, the measurement of morphological changes,
and chest radiography. Lebowitz (1981) reviewed other techniques
used to study both acute and chronic effects on health of air
pollution.
There are important criteria to be considered in the selection
and interpretation of a particular test to determine the effect of
the environment on cardiovascular and respiratory function. These
include the following:
(a) The test should be appropriate to the problem under study.
Some tests are able to determine functional abnormality
while others are more able to assess the specific site of
functional disturbance. If a study can be done only with
expensive and complex equipment, the investigators must
balance the relative importance of the problem against the
cost factors.
(b) Does the test measure one or more aspects of system
functioning, e.g., does it examine a specific physio-
logical quantity or a combination of functions? For
example, Bouhuys (1971) states that, to test the
hypothesis that the early stages of sarcoidosis are
characterized by increased stiffness of the lungs, the
static recoil curves of the lungs should be measured. A
less specific test would be to measure lung compliance, as
factors other than lung stiffness are involved in the
test.
(c) To what extent is the test able to distinguish normal from
abnormal functioning? Tests that depend on a forced
exhalation are the most frequently used in respiratory
epidemiology. PEFR (peak expiratory flow rate), FEV
(forced expiratory volume), and airway resistance can be
used to assess impaired lung function. However, these
tests cannot be used to determine specific diseases, and
may not be sensitive to small changes that can start in
the peripheral airways. The other indices of respiratory
function that involve reductions in expiratory flow rates
at 50% and 25% of vital capacity are more sensitive
indicators of early airways disease (Ingram & O'Cain,
1971). McFadden & Linden (1972) found that measurements
of mid-expiratory flow rate were reduced in heavy smokers
in whom FEV, airway resistance, and the maximum expiratory
flow rate were normal. Leeder and coworkers (1974) have
demonstrated that changes in maximum expiratory flow rates
at low lung volumes show greater differences between
normal and asthmatic children than FEV or PEFR. The tests
of small airway function are important since expiratory
flow rates at high lung volumes may be normal, but
measures of closing volume and frequency dependence of
compliance may reveal early functional abnormality. In a
study by Buist and coworkers (1973), an estimate of
nitrogen closing volume was found to be a more sensitive
test for distinguishing normal from abnormal individuals
than FEV, or expiratory flow rates. However, the closing
volume test involves a problem with reproducibility
(Martin et al., 1973). The PEFR is considered a useful
adjunct to clinical studies, but is not recommended
otherwise (Ferris, 1978). Ferris (1978) then concluded
that tests other than spirometry and, occasionally, in
occupational studies, the diffusion capacity/total lung
capacity ratio (DLco), are impractical and unnecessary in
epidemiological studies.
(d) The degree to which the test has been standardized, the
observer and instrument measurement variability assessed,
the relationship studied of the measure to variables such
as age, sex, and height and whether it can be administered
to large numbers of people, are further important
considerations in the selection of an epidemiological
test. Some of these points are discussed below in section
4.4.3.
4.4.3. Standardization of methods
The standardization of methods and criteria for defining
disease is essential to facilitate comparisons between different
studies. The pooling of data increases confidence concerning
the relationship of environmental risk factors in the development
of cardiovascular and respiratory diseases. The Epidemiology
Standardization Project (Ferris, 1978) was a major undertaking to
standardize tests of pulmonary function and chest radiographs for
epidemiological use in addition to a questionnaire on respiratory
symptoms. Evidence of the advantage of standardization was
reported by the Pooling Project Research Group (1978) who pooled
data from a number of major independent longitudinal studies of
risk factors such as serum cholesterol, blood pressure, smoking
habits, relative weight, and ECG abnormalities in the incidence of
major coronary illness.
Blackburn (1965) and Rose and his collaborators (1982) have
described a classification system, now in a revised form and known
as the Minnesota Code 1982, from which it is possible to evaluate
ECG measurements according to exact dimensional criteria, and which
has been used extensively in the earlier form in epidemiological
surveys. Schwartz & Hill (1972) examined the problem of
standardization for cholesterol analysis, as different laboratories
use different methods of extraction of cholesterol from serum and
of isolation of cholesterol, and different types of colour
reaction.
Comparability of results is affected if different investigators
use different methods. Problems occur if different investigators
use different numbers of practice and test trials and examine
different quantitative aspects of the measures of cardiovascular
and respiratory function. The British Medical Research Council
(Medical Research Council, 1966) recommended the use of three
technically satisfactory exhalations after two practice trials in
the forced expiratory manoeuvre. Tager and coworkers (1976) have
compared the three largest and the three last of five forced
expiratory manoeuvres and recommended that five forced exhalations
should be made and the three largest recorded. Epidemiological
studies based on a single measurement of blood pressure may give an
erroneous representation of the prevalence of hypertension (Armitage
et al., 1966; Carey et al., 1976; Hart, 1970). The mean value
derived from single measurements taken at relatively lengthy
intervals corresponds more closely to the subject's general level of
blood pressure than do single readings (Armitage et al., 1966;
Armitage & Rose, 1966).
The ability of the cardiovascular or respiratory test to detect
functional abnormality can be influenced by changes in diagnostic
criteria. For example, Rose & Blackburn (1968) state that the
definition of myocardial infarction to persons with Minnesota Code
1:1 (extensive Q/QS changes) may reduce the prevalence to well below
1%, even in countries where the incidence is high.
In blood pressure measurement using a sphygmomanometer, potential
sources of variability include variable size of cuff and deflation
speeds and observer preferences for certain terminal digits,
usually 0 or 5 (Rose et al., 1964). There have been several
studies (Blackburn, 1965; Higgins et al., 1965) of observer
variations in the coding of electrocardio-grams by the Minnesota
Code. If the interobserver and interinstrument variations are
substantial, the small difference observed between the
subpopulations being studied may lie within this range. To
eliminate these influences, which can confound the interpretation
of results, it is advisable to use random-zero sphygmomanometers
and standardization of the sound at which the blood pressure levels
are recorded.
Intrasubject variability can be affected by various factors
including age, sex, seasonal and diurnal variation, stress, genetic
characteristics, and drugs. Blood pressure readings can be
influenced as well by the time of day, amount of rest, physical
strain, and pain or excitement that precedes the measurement (Bevan
et al., 1969). Rose and his coworkers (1982) state that meals,
glucose administration, smoking, and heavy physical exercise in the
two hours preceding the ECG recording can influence the measurement.
The PEFR, FEV, and FVC (maximum expiratory volume with maximum
effort to full inspiration) can vary with season (Morgan et al.,
1964) and time of day (Guberan et al., 1969). Green and coworkers
(1974), in a study of the variability of maximum expiratory flow
volume curves found that flows above 70% of vital capacity varied
substantially between individuals, which was attributed to the
degree of individual efforts. There is some variability in
measures taken at low lung volumes owing to failure to reach the
same minimal lung volume on repeated efforts (Black et al., 1974).
The precise criteria for distinguishing normal from abnormal
functioning are complicated by the relationship of cardiovascular
and respiratory variables to age, sex, and other factors. Techniques
have been developed to overcome the problem of controlling for these
confounding effects. Ferris (1978) discussed such techniques for
respiratory tests. For blood pressure measurement (Tyroler, 1977),
these included the use of standardized blood pressure scores referred
to a common age and of age-specific standard deviations from the
means for that stratum, which is the most comonly used and reported
method for the adjustment of blood pressure for major age, sex, and
ethnic origin effects. Black and collaborators (1974) and Knudson
and coworkers (1976a,b) have determined "normal" values for the
expiratory flow volume curve at selected lung volumes. Although
they provide prediction equations based on height, age, and sex,
intrasubject variability in performance can reduce the ability of
the measure of expiratory volume to distinguish normal from abnormal
functioning.
4.4.4. Radiographic measurements
The epidemiological use of radiography has made considerable
advances, especially in developing methods for studying dust
diseases of the lung. Historically, schemes devised were related
to the diagnosis and classification of severity of disability for a
few specific diseases. The current concept is that observers
should describe and quantify the opacities observed in the chest
radiograph, rather than interpret these findings. Although changes
are considered to lie on a continuum, the ILO International
Classification of Radiographs of pneumoconioses provides a means
for the systematic recording and ranking, in a simple reproducible
way, of radiographic changes in the chest produced by dust (ILO,
1980). It provides a text and a set of standard films that define
the limits of normality and guide the film reader in the
classification and quantification of radiographic features. A full
plate posteroanterior film is required and the technical desiderata
for radiographic technique and reading conditions are specified.
Each film has to be read by several trained and quality controlled
readers. The derivation of a final score for the film is still a
matter for discussion (Fox, 1975), as is the sequential study of a
series of films (Reger et al., 1973). Nevertheless, valuable use
of the scheme has been made in epidemiological studies of coal-
miners for dust standard setting (Jacobsen, 1972) and it has been
used for studies in other industries as for example by the
Employment Medical Advisory Service, 1973 (asbestos), by Lloyd-
Davies, 1971 (foundries), and by Fox and co-workers, 1975
(potteries). It has been possible to detect interaction between
the occupational environment and the cigarette smoking habit.
On the other hand, radiographic signs of obstructive lung
diseases and their relation to morphology have not been very useful
nor have they been standardized (Higgins, 1974). Chest radiographs
can be used to obtain total lung capacity (TLC), but TLC is not a
critical epidemiological measurement (Ferris, 1978). Chest radio-
graphs are still a major tool for appraising the possibility of
lung cancer.
4.4.5. Hypersensitivity measurements
Immunological reactions are functional changes that can be
environmentally induced (Litvinov & Prokopenko, 1981). Immediate
hypersensitivity (IgE mediated) responses may be associated
directly or indirectly with air pollutants or smoking (Lebowitz,
1981). It is hypothesized that particulates of the size that
impact on the nasal pharyngeal area, or some gases such as sulfur
dioxide, may release mediators through a variety of pathways.
These mediators may lead to an asthmatic type reaction, that is
generally acute, but may be associated with chronic effects. There
are various skin tests for immediate hypersensitivity, including
those that use histamine or non-specific antigens. There are also
serological tests for IgE. Responses to skin tests have been used
as an intervening variate in the study of air pollution effects
(van der Lende, 1969). The tests are easy to administer and
measure, the standard protocols have been developed and studies
have been performed examining immediate hypersensitivity responses
to various environmental antigens (Pepys, 1968). Various B and T
cell immune mechanisms may be appropriately studied in chronic
obstructive pulmonary disease responses to environmental agents.
Bronchial challenge is another method by which the role of
immediate hypersensitivity and bronchoconstriction is assessed.
Standard protocols for challenges with spirometric measurements
before and after challenge have been formulated, such as for
histamine (van der Lende et al., 1973).
4.4.6. Example: Effects of manganese on the respiratory and
cardiovascular systemsa
Saric and colleagues (1975, 1977a, 1977b) studied the effects
of manganese aerosols in and around a ferro-maganese alloy smelter
in Yugoslavia that has been operating since before 1940. The
hypotheses were that the exposed workers and the community
population experienced more acute respiratory diseases, especially
pneumonia and bronchitis, and the exposed workers would show some
neurological signs and increased blood pressure. Unexposed control
workers and populations were used for comparisons. Ambient sulfur
dioxide, sulfate, and respirable manganese concentrations were
sampled within the factory, at five sites around the factory, and
at a control point, 25 km distant. Sulfur dioxide was low every-
where with an annual mean of 13-27 µg/m3 and a maximum of 47-122
µg/m3, and sulfate was about 9.9-13.9 µg/m3. Mean concentrations
of manganese were 0.3-20.4 µg/m3 in the plant (400 workers) and
0.002-0.302 µg/m3 in the control plants (about 800 workers).
Zones around the plant had annual mean manganese concentrations of
0.236-0.39 µg/m3 (8 700 people), 0.164-0.243 µg/m3 (17 100 people),
0.042-0.099 µg/m3 (5 300 people) and the manganese levels at the
control point were 0.024-0.04l µg/m3.
A retrospective study of work absenteeism due to pneumonia and
bronchitis from workers' medical files showed an increase in
incidence rates correlated with exposure. The British Medical
Research Council questionnaire (Medical Research Council, 1966), a
neurological questionnaire, spirometry, and blood pressure
measurements were used in the cross-sectional study of workers.
There was more chronic respiratory disease in exposed smokers
compared with unexposed smokers, but not in exposed non-smokers.
Spirometric results were lower in those exposed for more than
ten years. Neurological signs occurred in 16.8% of exposed workers
and less than 6% of controls, but clinical manganism was not
present in any group. Diastolic blood pressure was also higher in
exposed workers than controls. A prospective study of town
inhabitants using data available from the local chest clinic,
showed increased incidences of acute bronchitis and peribronchitis,
but not of pneumonia, related to the zone of residence. Children
under age 4 years were especially affected. School children and
their families were studied with spirometry and acute disease
questionnaires (as carried out by Shy et al., 1970). Those in the
exposed town showed a tendency towards lower spirometric values and
had a higher incidence of acute respiratory disease.
4.5. Effects on Nervous System and Organs of Sense
4.5.1. Central and peripheral nervous systems
Disorders of the nervous system are mediated by alteration in
structure or function of the various components of the central
nervous system, the motor and sensory portions of the peripheral
nervous system as well as functional and organic disorders of the
autonomic system. Environmental agents may act directly on the
nervous system or the injury may be mediated by circulatory
disturbance or by vascular accident.
-------------------------------------------------------------------
a Based on the contribution from Dr M. Saric, Institute of
Medical Research and Occupational Health, Zagreb, Yugoslavia.
Some signs may be observed clinically including alterations in
aim and sensation. Disorders of the autonomic system may be
manifested as functional disturbances of the cardiovascular system
(e.g., cardiac arrhythmia and vasospasticity). Vasospasticity can
be expressed clinically by signs of skin pallor and coldness. In
practice, while it is occasionally possible to observe the effects
mediated by a single lesion of a particular part of the central
nervous system, complex disorders may occur involving symptomatic
and behavioural changes that are gross enough to be detectable on
clinical examination or more subtle changes that require
electrophysiological examination and sophisticated behavioural
investigation for their detection.
Friedlander & Hearne (1980) reviewed available neurological
examination methods used for epidemiological studies including:
electroencephalography (EEG) for studies on styrene and mixed
solvents; nerve conduction velocity measurements for styrene and
mixed solvents; sensory nerve conduction velocity measurements
for mixed solvents; measurements of slow nerve fibres conduction
velocity for lead and trichloroethane; electromyography (EMG)
for trichloroethane, 2-hexanone (methylbutyl ketone), mixed
solvents and lead; electroneuromyography for mixed solvents;
specific questionnaires for chlordecone (Kepone) (tremor,
nervousness), methylmercury (paraesthesia), trichloroethane
(headache, nervousness) and maganese (tremor and other symptoms).
The neurological methods used for an epidemiological study of
employed workers exposed to lead and of controls (Baloh et al.,
1979) included clinical neurological examinations, oculomotor
function tests, nerve conduction studies and auditory measurements.
The clinical neurological examination, though known not to be
sensitive for detecting the early effects of increased lead
absorption, was carried out primarily to exclude confounding
conditions. The neurologist was required to pay special attention
to early signs of peripheral neuropathy. Oculomotor function tests
were carried out to make precise measurements of the extraocular
muscles and their brain control system. The test battery included
tests of saccadic and smooth pursuit and optokinetic nystagmus.
Nerve conduction studies included fast and slow motor conduction
velocities in ulnar and peroneal nerves and sensory latencies of
ulnar and sural nerves. Environmental and skin temperatures were
carefully controlled during these examinations. Under standard
acoustic conditions, a battery of tests was carried out to
determine the magnitude of hearing loss and to differentiate the
sites of lesion.
In a survey of shoe and leather workers exposed to solvents, a
very high prevalence of polyneuropathy was observed in persons,
supposedly normal according to clinical examination of muscle tone,
tendon reflexes, muscle wasting and normal sensation, when compared
with a control population (Buiatti et al., 1978). Electromyography
was carried out using needle electrodes and motor conduction
velocity was measured in the median and lateral popliteal nerves.
Conduction velocity was considered to be in the pathological range,
when it was lower than the 95% confidence limits for values in the
normal control population of the same age. For an electromyo-
graphical diagnosis of polyneuropathy, the presence of spontaneous
activity, polyphasia, and irregular potentials and a reduced
interference pattern were considered, as well as alteration in the
size of motor responses and sensory action potentials. Examining
motor nerve maximum conduction velocity, the authors observed not
only that maximum conduction velocity fell with age, but that
exposure to solvents increased the physiological lowering with age.
When analysing the decrease in maximum conduction velocity as a
function of age in the group of workers not considered to have
polyneuropathy, it was possible to differentiate between them and
the normal control population. However, it was not a reliable
criterion for the diagnosis of polyneuropathy, when taken in
isolation. These methods are not always considered suitable for
field work. The use of surface electrodes is more socially
advantageous than needle electrodes.
EMG and EEG have also been used for epidemiological studies of
exposures to organophosphorus compounds (Roberts, 1979; Duffy &
Burchfield, 1980).
With regard to the effects of physical factors, some
neurological tests have been used. In an epidemiological study of
vibration white finger (Pelmear et al., 1975), the objective tests
used included depth test aesthesiometry, two point discrimination
and the vibrotactile threshold. In another epidemiological
study on effects of vibration, Vaskevich (1978) employed
electroaesthesiometry to measure impairment of electrotactile
sensation and elevation of pain threshold as well as reflex
response times. He discussed other methods of measurement and how
they might be used for discriminating between the various sites in
the nervous system for the functional lesion. A range of electro-
physiological tests exists for sensory motor nerve conduction and
for the study of motor power and physiological and adventitious
movement of eyes and limbs. However, electroneurophysiologists
will not always agree on the battery of tests required or on their
interpretation.
4.5.2. Ear: Effects of sound
The study of the prevalence and degree of hearing loss lend
themselves to field studies employing screening audiometers or
diagnostic audiometers and the provision of transportable sound-
insulated booths. National and international standards have been
set for virtually all aspects of hearing monitoring. These
standards range from the specification for the design and operation
of audiometers and the practice of audiometry, to calibration and
testing of calibration, designs for headphones and their testing,
and for the design and performance of acoustic booths. Over the
past decade, there have been a number of changes in these standards.
Therefore, before embarking on an audiometric study, it would be
wise to refer to the appropriate national institute responsible for
standard setting or to the International Organization for
Standardization (ISO). Taking such standards into consideration,
it is possible to design methods suitable for epidemiological audio-
metric studies (Health and Safety Executive, 1978). Where
appropriate, further laboratory tests may be employed to pinpoint
the site of the lesion and to quantify the order of disability
(Baloh et al., 1979).
An example employing mobile facilities on a large scale, but
with relatively unsophisticated means of analysis, is given in an
occupational noise surveillance study in Austria involving 165 000
tests (Raber, 1973). Facilities have now been developed for the
direct recording of audiograms on tape or disc systems and for
their filing in a minicomputer for easier data handling and
subsequent analysis.
Apart from sound energy, neurotoxic agents may affect
perceptive hearing and balance, including lead and carbon monoxide,
as may barotrauma and electrical energy. Agents that produce
obstructive chronic inflamatory lesions in the nasopharynx may lead
to conductive disorders of hearing and disorders of balance. The
investigation of non-conductive deafness is a laboratory activity
as is the investigation of disorders of balance.
4.5.3. Eye and vision
Environmental and occupational eye diseases include: (a)
irritation of the cornea and conjunctiva (acute or chronic) from a
variety of gases, fumes, and dusts (e.g., bromine, chlorine
dioxide, hydrogen sulfide) leading to discomfort and temporary
visual impairment from coloured haloes; (b) corneal dystrophy, for
example, from occupational exposure to coaltar pitch, leading to
deformation of the cornea, keratoconus, and progressive
astigmatism; (c) staining of the cornea, by quinones and other
organic compounds, which may be intense enough to impair vision and
affect colour vision; (d) lens changes because of deposition of
metal or alteration of the lens material producing a range of
opacities (e.g., due to ultraviolet and infrared light) from
asymptomatic to blinding cataract formation; (e) retinal injury
which may be asymptomatic or, where the fovea is affected, lead to
a loss of central vision and fine discriminations; (f) optic
neuritis (e.g., due to alcohol or tobacco), with effects ranging
from peripheral field loss to total blindness; (g) visual cortical
atrophy, from alkylmercurial compounds, with various degrees of
visual impairment; (h) derangement of accommodation, due to some
organic compounds; (i) diplopia, due to carbon monoxide, methyl
chloride, or alkyltin compounds; (j) visual field constriction,
associated with exposure to carbon disulphide, carbon monoxide, or
ethyl glycol; and (k) nystagmus, due to poor illumination.
One of the earliest effects on the eyes demonstrated on the
victims from the atomic bomb explosions in Hiroshima and Nagasaki,
was the occurrence of lenticular opacities. A small number of
well-developed cataracts have been observed, but for the most part,
the lesions have consisted of a posterior lenticular sheen or of
small subcapsular plaques that do not interfere with vision (Finch
& Moriyama, 1980).
Eye strain, in numbers of persons affected, is the most
prominent condition. Even where refractive errors are absent or
have been corrected, it may occur under circumstances because of
lighting of inadequate intensity, poor contrast, glare, imperfect
visual presentation often compounded by psychological factors
including management deficiencies. Although it does not threaten
vision, it makes demands on nervous energy and may lead to
symptomatic complaints of headaches of various degrees of
intensity; there may also be signs of conjunctival irritation.
The study of organic lesions of the eye necessitates the
services of a clinical ophthalmologist: the apparatus required and
the conditions of examination do not lend themselves readily to
field study. Simple near and distant vision tests may be used,
which are designed to determine the ability to discriminate objects
that subtend particular angles at the eye. They have been designed
to deal with the literate and the non-literate, but it is necessary
to standardize the lighting and other conditions under which they
are carried out. Relatively easy tests exist for stereoscopic
vision and colour appreciation that commend themselves for field
use; however, their execution and interpretation may be difficult.
Transportable and portable instruments have been designed to
provide a battery of tests of visual functions under standardized
conditions for screening purposes. The study of visual fields has
been a time-consuming exercise, and current developments are
restricted to the clinic.
Any attempt to measure the effect of environment on functional
or organic disease in particular populations, unless the excesses
are extreme or the lesions are peculiar, requires that their
incidence or prevalence rate in a control population be determined.
For example, with the limited evidence on human exposure to the
electromagnetic spectrum, it is not possible to state an exposure/
response relationship for the appearance of lenticular opacities
from cataracts, nor to determine whether the disease of the eye is
commoner in exposed populations. However, contributions to the
determination of the prevalence of common eye disorders have been
made in a study, known as the HANES study, of a population of some
10 000 persons, using a symptom questionnaire and a standardized
ophthalmological examination (US National Health and Nutrition
Examination Survey, 1972; US Department of Health, Education and
Welfare, 1973). To test the hypothesis that radiant energy (sun-
light) was an important causal factor in the development of
cataracts, Hiller and collaborators (1977) used data from the HANES
study and from a group of blindness registries in the USA, and
related prevalences to average annual sunlight hours in each
geographical area, taking non-cataract disease as controls. A
technique for studying exposed and controlled persons employing two
ophthalmologists to minimize observer bias is given by Elofsson and
co-workers (1980) together with a protocol for ophthalmological
investigation.
4.6. Behavioural Effects
4.6.1. Effects of environmental exposure
The effects on mental health of environmental agents fall into
three broad categories. The first includes effects that are
directly attributable to structural or functional damage to the
central nervous system (CNS), such as those resulting from carbon
monoxide or carbon disulfide poisoning. The second category
includes effects that arise as a generalized behavioural (or
psychosocial) response of the individual to a physiological
impairment caused by a noxious factor, for example, the syndrome of
irritability, depression, and loss of interest in a person who has
developed a chronic lung disease following long-term exposure to
industrial dusts.
A classical epidemiological precedent was the study of the
etiology of pellagra (Goldberger, 1914), in which environmental
causes of what had been previously considered an endogenous
disease, were revealed by epidemiological mapping of the cases of
pellagra psychosis and the distribution of dietary patterns in the
population.
For the best results in applying epidemiological methods it is
necessary to be familiar with the clinical manifestations of CNS
responses to exogenous insults, and with the individual's ways of
coping with impairment. These responses, constituting the first of
the above categories, have been described as 'exogenous reaction
types' (Bonhoeffer, 1909), or as 'psychoorganic syndromes'
(Bleuler, 1951), and can be presented as shown in Table 4.1.
Table 4.1. Clinical manifestations of organic damage to the
central nervous system (CNS)
-------------------------------------------------------------------
Predominantly
CNS response Generalized Focal
Acute Confused states1 Epileptic seizures,
Other neurological
manifestations
-------------------------------------------------------------------
Chronic Korsakov-type psychosis2 Frontal lobe syndrome3
Dementia4 Temporal lobe syndrome5
Parietal lobe syndrome6
-------------------------------------------------------------------
1 Disorientation, excitement or stupor, incoherent speech,
hallucinations, acute anxiety or euphoria.
2 Memory disturbance, confabulations.
3 Personality change, loss of control over own behaviour.
4 Loss of learning ability, intellectual deterioration, apathy,
social withdrawal.
5 Language difficulties, apraxia, emotional instability.
6 Reading difficulties, arithmetic difficulties, disturbance of
body image.
The scheme in Table 4.1 does not exhaust the great variety of
clinical manifestations of organic damage to the central nervous
system, but the conditions listed are characteristic examples.
Distinctions between acute/chronic, and generalized/focal, are
never quite clearcut, and many transitional phenomena may occur
between them.
The second category of mental health effects, as mentioned
above, comprises a wide variety of behavioural responses of a
predominantly neurotic or emotional type, often accompanied by
characteristic physiological dysfunctions (psychosomatic
reactions). Such responses may arise, either under the influence
of unpleasant or stressful environmental stimuli (e.g., noise), or
as a behavioural (symbolic) overlay of physical impairment. In
both cases, they are mediated by the previous experience,
attitudes, and coping skills of the personality, as well as by the
social environment.
Until recently, knowledge about the mental health effects of
environmental agents was derived mainly from clinical studies,
following short- or long-term exposure to agents, such as lead,
mercury, organic mercury compounds, manganese, thallium, methyl-
bromide, tetraethyl lead, and carbon monoxide. A synthesis of such
knowledge has been provided by Lishman (1978). Many behavioural
toxicology studies have been focused on the effects of heavy metals
or chemicals that are common in industry, such as petroleum
distillates, jet fuel (Knave et al., 1978), organic solvents
(Hänninen et al., 1976; Lindström, 1973), and carbon disulfide
(Hänninen, 1971). A review of recent research in such areas is
provided by Horvath (1976). Environmental pollutants of a physical
nature have also been the subject of studies, for example, the
investigations of the mental health effects of aircraft noise
around airports (Gattoni & Tarnopolsky, 1973; Jenkins et al., 1979;
Shepherd, 1974).
4.6.2. Indicators and measurements of effects
The epidemiological approach requires suitable indicators and
the application of some standardized measurement of effects, though
cruder methods based on clinical records and hospital admission
data have been of use as well (Edmonds et al., 1979). The indicators
of behavioural effects of noxious environment agents fall into two
broad groups as shown in Table 4.2.
Psychological tests have proved to be effective in the dectection
and assessment of organic brain damage, and relatively simple
techniques, such as Raven's progressive matrices and vocabulary and
memory tests, can be both reliable and practical in field studies
involving the screening of a large number of individuals. A
concise guide to the most widely-used psychometric tests is included
in Lishman's review (1978).
Table 4.2. Indicators of behavioural effects of noxious
environmental agents
--------------------------------------------------------------------
Indicators Examples of methods of measurement
--------------------------------------------------------------------
1. Measures of psychological Psychological and psychophysiological
and psychophysiological tests (e.g., performance, verbal,
functioning learning tests; skin conductance
changes in response to standard
stimuli)
2. Measures of mental state Psychological and psychiatric
and behaviour screening questionnaires;
standardized psychiatric interviews
--------------------------------------------------------------------
Note: Neurological effects must be clarified first, using methods
previously described (section 4.5)
Instruments, used in the standardized assessment of mental
state and behaviour, fall into two groups:
(a) Screening instruments
Most of these are relatively short questionnaires that can be
self-administered or used as an interview by a research assistant,
for example, the General Health Questionnaire (GHQ) developed by
Goldberg (1972), which is now available in several languages. In a
modified form, this has been used in several WHO coordinated cross-
cultural psychiatric studies. The scoring of the "yes/no" responses
of the subject to a number of questions is simple, and cut-off
points are provided for the sorting of respondents into a group of
likely cases of psychological disorder and a group of likely non-
cases. The GHQ and other similar instruments are not diagnostic
tests, in the sense that they do not lead to a subclassification of
the detected cases into diagnostic categories. Therefore, their
great usefulness is as first-stage screening tools for the
selection of affected individuals for more detailed investigation.
(b) Mental state and psychosocial functioning assessment tools
These include the Present State Examination (PSE), which has
been the main assessment tool in major cross-cultural studies of
functional psychoses (WHO, 1974; WHO, 1979a) and is available in 19
different languages. The PSE is a structured interview guide based
on clinical concepts, and has been designed for use by psychiatrists,
who receive brief special training before applying the instrument
in research projects. It can be used to elicit and record
information about the presence or absence of 140 clinical symptoms
the operational definitions of which are provided in a glossary
(Wing et al., 1974). This information can be processed by a
computer diagnostic program (CATEGO) which produces a standard
diagnostic classification of cases. The PSE exists also in a
shorter version, the administration of which in an interview can
take 10-45 min (depending on the number of symptoms present) and
can be applied by interviewers who are not psychiatrists, provided
that they receive the special training required. Although the PSE
provides systematic coverage of all major areas of psychopathology,
it was not specifically designed for the study of organic brain
syndromes. It is necessary to combine the PSE interview with the
application of some simple tests for organic brain damage, if such
pathology is suspected among the population studied.
Among other instruments available for epidemiological research
is the Disability Assessment Schedule (DAS) developed by the World
Health Organization for standardized recording of information about
disturbances in social behaviour and adjustment. This is a semi-
structured interview that can be used as a complement to the PSE
and can be applied by a social worker or a research assistant.
4.6.3. Interpretation of data
Adequate consideration should be given to procedures necessary
for achieving and sustaining a high level of interobserver and
intraobserver reliability of the assessment of psychological and
behavioural variables (section 4.1.2).
Interaction effects are often the rule in behavioural research,
and these should be taken into account, both in the design of the
study and in data analyses (Cooper & Morgan, 1973). The mental
health effects of environmental agents will be influenced not only
by the length and intensity of exposure, but also by factors such
as age, sex, previous personality, learning, and social experience,
and various individual levels of susceptibility. Therefore, the
question of the selection of a control population is a more complex
one when behavioural effects are studied. However, the recognition
of many interacting factors must not lead to an unnecessary
proliferation of items in the research instruments as this would
make a meaningful analysis of the data collected impossible.
4.7. Haemopoietic Effects
The haematological system is affected by many environmental
agents, both chemical and physical. These environmental agents can
be loosely grouped under the following two headings, reflecting
their relative involvement in the haematological system in
toxicological action.
4.7.1. Environmental agents inducing direct toxic effects in the
haematological system
These include agents such as benzene and ionizing radiation
affecting haemopoietic precursor cells. In a recent retrospective
evaluation of the occupational history of patients with acute non-
lymphoblastic leukaemia in conjunction with cytogenetic findings,
it was suggested that perhaps 50% of such leukaemias had been
caused by environmental agents (Mitelman et al., 1978); though this
claim awaits confirmation. A number of environmental agents
directly affect circulating red cells. Inhalation of relatively
low levels of arsine (AsH3) induces acute haemolysis, which is
frequently fatal.
Methaemoglobinaemia is produced by certain aromatic hydro-
carbons, including aniline dyes and sulfonamide derivatives.
Alteration in the ability of haemoglobin to bind or release oxygen
is a potential mechanism of toxicity of environmental agents.
Chemicals with oxidizing properties can induce Heinz body
haemolytic anaemias. There are a number of inherited abnormalities
of red cell function that increase individual susceptibility to
environmental agents, producing methaemoglobinaemia or Heinz body
haemolytic anaemias. These include unstable haemoglobinopathies,
such as methaemoglobin reductase deficiency and glucose-6-phosphate
dehydrogenase (G-6-PD) deficiency. The latter is relatively common
in a mild form, possibly associated with systemic protection
against malaria. There are, however, more severe variants of G-6-
PD deficiency in which exacerbations due to environmental agents
could have potentially grave consequences.
Many environmental agents also affect immunoglobulins
circulating in the blood that are important in sensitization,
allergic reactivity, and general host resistance.
4.7.2. Environmental agents inducing indirect toxic effects in the
haematological system
The haemopoietic system may be indirectly affected by almost
any chronic disease state. For instance, environmental processes
producing chronic lung disease may lead to secondary polycythaemia,
while those causing chronic renal disease will generally result in
anaemia. An elevated granulocyte count is the usual response to
acute injury of any organ system. There are also agents that have
direct effects on the haematological system, but exert their
principal toxicity in other organs. An example is lead: the
anaemia and relatively specific changes in haem metabolism are of
diagnostic value and provide insight into certain mechanisms of
effect. However, the more important signs of dysfunction occur in
the central and peripheral nervous system, varying with age at
exposure and the nature and exposure levels of the lead compounds.
4.7.3. Measurements and their interpretation
Blood cells are one of the most accessible human tissues, and
therefore relatively more is known about these cells, both in terms
of understanding basic biomolecular processes as well as associating
changes in this system with disease processes. The information
obtainable from laboratory evaluation of blood cells is pertinent
both to disorders of the haematological system and to diseases
primarily affecting many other organs in which blood cell changes
occur as secondary manifestations. Its accessibility, at no
significant risk to the subject, makes it possible to include
fairly simple examination of mature blood cells in population
studies. Recent advances in medical technology have resulted in
improved ability to perform routine haematological studies that are
reproducible, rapid, and inexpensive. Thus, many formerly highly-
specialized laboratory procedures may be used now in epidemiological
studies.
The obvious haematological laboratory tests for use in
epidemiological studies are the standard procedures usually covered
by the term "complete blood count". There is a wide range of
"normal" values for most blood elements. The counts cited as
abnormal also vary greatly among laboratories. Unless particular
care, such as the analytical quality assurance procedures, is
taken, the use of routine blood counts can be an insensitive means
of detecting small but real differences between populations due to
differences in exposure to environmental agents.
For population studies of circulating erythrocytes, where
complex automated equipment is not available, the microhaematocrit
performed on approximately 0.1 ml of blood in a capillary
centrifuge is probably preferable to the spectrophotometric
determination of haemoglobin levels and certainly preferable to the
manual red cell count. One of the more recent advances in
automated cell counting is the use of machinery to perform
differential white cell counts. Though it is still too soon to
gauge the relative effectiveness of this procedure, accurate
differentials, in conjunction with a total leukocyte count, may be
of value in studying populations for the effects of environmental
pollutants. For instance, lymphocytopenia is known to be a
consequence of benzene exposure and there are suggestions that
lymphocyte levels may be affected by such diverse situations as
polybrominated biphenyl toxicity and zinc deficiency.
Modern instrumentation has also been developed for the rapid
evaluation of other specific haematological parameters of more
limited application. Two excellent recent examples are instruments
of use in the study of lead absorption and neonatal
hyperbilirubinaemia. A single drop of blood placed on a filter
paper, is then automatically inserted into a compact light-weight
fixed florometer providing an immediate digital read out of zinc
protoporphyrin, free erythrocyte protoporphyrin, and erythrocyte
protoporphyrin levels. These species of protoporphyrin are
increased following lead absorption and should therefore be an
excellent tool for population studies of inorganic lead effects
(Eisinger et al., 1978). For the interpretation of the results, a
knowledge of the chemobiokinetics of lead is essential. An
instrument, which depends on specific fluorescence, measures free
bilirubin in minute amounts of neonatal blood. A widely-adopted,
relatively simple and reproducible assay might make possible the
type of comparison studies that would lead to identification of
environmental factors involved in neonatal hyperbilirubinaemia.
4.7.4. Example: Effects of low lead concentrations on workers, healtha
Studies of low-intensity exposures to lead have been conducted
in the USSR on male and female solderers and on unexposed female
controls. The solderers were generally (64%) exposed to levels of
lead below 0.01 mg/m3 (the USSR maximum permissible level); 95%
-------------------------------------------------------------------
a Based on the contribution from Professor A.V. Roscin,
Order of Lenin Central Institute for Advanced Medical
Training, Moscow, USSR.
of samples were below 0.02 mg/m3. Lead on the skin ranged from
0.043 mg/100 cm2 (before work) to 0.057 mg/100 cm2 (after work),
and lead on the clothes averaged 0.22 mg/100 cm2. It was estimated
that intake by ingestion and absorption through any external
surface was less than that by inhalation and all three intake modes
at work were less than lead intake from food (0.3 mg/day).
To determine the possible effects of the exposure to lead,
various haematological and biochemical indices were measured. The
results showed disturbances of porphyrin metabolism and changes in
enzyme activity, protein fractions of blood serum, liver function,
and blood cell production. This indicates that exposure to
relatively low concentrations of lead, i.e., levels less than the
established health standard, produced a complex of haematomorpho-
logical and biochemical changes, which must be regarded as early
signs of effects of lead.
After termination of the lead exposure, the previous bio-
chemical and haematological deviations in the women workers tended
to return to normal, and the porphyrin metabolism and other indices
investigated showed normal values.
4.8. Effects on the Musculoskeletal System and Growth
4.8.1. Effects of environmental exposure
Only rarely do musculoskeletal disorders have a fatal out-
come and so virtually all studies are of morbidity, in terms of
disturbance of, or interference with, normal structure and
function. Apart from certain occupational disorders, the most
important target to be considered is bone. Physical development
may be affected by exposures to some chemicals.
Some of the reported environmental effects on the musculo-
skeletal system are summarized as follows (in most cases the
association is related to extreme occupational or accidental
exposures rather than to those that would normally be encountered
in the general environment): ionizing radiation, specifically
bone-seeking isotopes, may lead to bone necrosis or bone sarcoma
(as with strontium); ultraviolet radiation may precipitate
systemic lupus, through activation of lysosomal enzymes;
electrical shock, in which trauma may lead to cervical disc
degeneration; ultrasonics, which may lead to bone necrosis;
extremes of barometric pressure may, due to gas embolism, lead
to aseptic necrosis (head of the humerus and femur) in caisson
disease and related conditions; thermal sensitivity has been
associated with Raynaud's syndrome and aggravation of rheumatic
syndromes; vibration may lead to Raynaud's syndrome, carpal
decalcification, occasional soft tissue injury (bursitis, muscle
atrophy, Dupuytren's contacture), or arthrosis (especially in
elbow); fluoride exposure, skeletal fluorosis; iron exposure,
siderosis progressing to spinal osteoporosis, destructive lesions,
and arthropathy (especially in hands) as seen in Bantus; lead
exposure, gout associated with lead poisoning; arsenic exposure,
osteoarthropathy; cadmium exposure, secondary osteomalacia
resulting from renal damage; vinyl chloride exposure, osteolysis;
asbestos exposure, hypertrophic osteoarthropathy with pulmonary
disease; phosphorus exposure, bone necrosis (phossy jaw); poly-
chlorinated biphenyls (PCBs) exposure, diminished growth in boys
who had consumed rice oil contaminated with PCBs (Yoshimura, 1971)
and smaller babies than normal, born to mothers with this disease
(Yamaguchi et al., 1971).
4.8.2. Identification of effects
Many musculoskeletal disorders are diagnostically vague; they
usually lack a specific feature or diagnostic test and may as a
result be heterogeneous, with similar effects resulting from
different causes. The methods for detection have not been very
well developed. It is necessary to be alert to the array of
syndromes that may be encountered, but systematic searches are
cumbersome. By adopting a screening approach, it is possible to
limit consideration to three features, though each unfortunately
poses its own problems. The first, pain and weakness, can be
elicited by questionnaires, but with all the attendant difficulties
of behavioural phenomena related to subjective experience. The
second, functional changes, can be elicited by physical
examinations and functional tests, many of which are tests of other
systems, as musculoskeletal changes may be secondary (see above).
The third, structural changes particularly in bone, if they
call for radiographic detection, raise ethical problems about
radiation exposure as well as requiring technological sophistication
(i.e., X-ray equipment, film processing facilities, etc.) and
greater expense. For example, epiphysial deposition of lead (lead
line) may be detected in children by radiography. The epidemiological
use of radiography in the study of bone pathology, where small areas
of rarefaction or reaction to necrosis feature, merits the same
scrupulous attention to the establishment of reading standards, the
training of quality control readers, and the improvement of film
techniques, as in the case of chest radiography. Deformities such
as lordosis and kyphosis of the spine and limitation of movement of
joints may be measured objectively in a standard manner (Russe &
Gerhardt, 1975).
Indirect measures, such as incidence of disability or absence
statistics, lack specificity as they are associated with multiple
factors, as are population prevalence rates (Bennett & Burch,
1968a,b). Standardized epidemiological methods, diagnostic
techniques, and serological studies for rheumatic diseases have
been discussed by Bennett & Wood (1968).
4.8.3. Intrinsic liability
Biological and genetical factors contribute to variation
between individuals in their susceptibility to outside influences.
Differences in disease experience related to age and sex are very
evident, though most of these have still not been accounted for.
Human leukocyte antigens (HLA) and haemoglobinopathies of SS and SC
genotypes have been associated with several musculoskeletal
disorders in recent years. Other conditions such as spondylolis-
thesis may predispose individuals to the development of severe
musculoskeletal changes like an incapacitating back symptom (Wood,
1972).
4.8.4. Extraneous influences
The influence of very general and non-specific aspects of
the individual's surroundings and highly particular disturbances
of those circumstances may be confounding. This is very evident
with geographical variations; uncertainty arises about the
relative importance of ethnicity (cultural or genetic), lifestyle,
and specific agents in particular environments, such as minerals
in the water supply. The ubiquity of many rheumatic disorders
also gives rise to problems. Thus, the suggestion arises that
the frequency of a well-recognized existing disorder may be
increased in certain environmental circumstances. As in other
situations, the occurrence of graded variation rather than
discontinuous experience tends to blunt the precision of analysis
and to make establishment of a causal relationship more difficult.
4.8.5. Development states
In the case of studies of development, subjects may be
categorized in terms of weight/height relationships. Some
population studies are facilitated by not requiring persons
to remove footwear, in which case allowance requires to be made
for this artefact. Posture during measurement also requires to
be standardized. Alternatively, skin thickness may be measured
at standard sites using spring-loaded standardized calipers
(Billewicz et al., 1962).
Biological age standards and sexual development indices have
been determined for clinical use: they may be adapted for
epidemiological purposes. Studies of childhood physical
development as influenced by the environment have been conducted in
the USSR (Melekhina & Bustueva, 1979) and in Poland (Pilawska,
1979). In studying the effects of pollutants on growth and
nutrition, ethnic and cultural factors should be carefully taken
into account (Chandra, 1981).
4.8.6. Example : Endemic fluorosisa
For a number of years, signs and symptoms of endemic fluorosis
had been noted to occur in residents of several areas in India
(e.g., Punjab, Andhra Pradesh, Karnataka). Several epidemiological
studies were carried out in clusters of villages where the
population was affected. There was a high incidence of dental
mottling (50-70%) in those who had skeletal fluorosis. These
subjects had joint pains, muscle wasting, and developed severe bone
deformities, including sclerosis, kyphosis, and calcification, seen
on X-ray. Nerve compression, with signs of radiculomyelopathy, was
found on examination. The epidemiological studies showed higher
rates in males than in females, in areas with sandy soil and where
the summer water source was well water. Blood and urine samples
yielded high levels of fluoride - 6 mg/litre and up to 20 mg/litre
respectively (normal levelsb are only traces in blood and less than 1
mg/litre in urine). Some bone specimens had levels up to 7 g/litre
(the normal rangeb was less than 300 mg/litre). The water samples
obtained from the community had levels up to 14 mg/litre (Siddiqui,
1955; Singh et al., 1961; Singh & Jolly, 1962).
4.9. Effects on Skin
4.9.1. Environmentally-caused skin diseases
Diseases of the skin, except skin cancer, are rarely life-
threatening, though they can be a considerable annoyance, either in
terms of effects on an individual or in terms of the number of
persons that may be affected. The effects observed may result from
the direct local action of the agent or may be mediated as part of
a systemic disorder. In their causation, host factors such as
idiosyncracy, hyperreactivity, and hypersensitivity may play a
role.
Adverse effects observed following exposure to physical and
chemical agents include the following: unwanted pigmentation or
loss of pigmentation; premature ageing with alteration of
subepithelial connective tissue; inflammation, necrosis and
atrophy; eczematous dermatitis, photoactinic sensitization; skin
cancer (basal cell carcinoma, epithelioma and malignant melanoma),
precancerous skin conditions and similar conditions of the mucose
of the buccal cavity; acne; drying; maceration; hair loss or
dystrophy of scalp hair and alteration of body hair; and disorders
of the nails.
Infections with microorganisms may complicate these conditions
by aggravating a local skin lesion or by inducing adverse effects
mediated by immunological mechanisms at distant sites.
The agents associated with the disorders may be part of the
general environment or may be found in foods, drugs, cosmetics,
other consumer products, or occupationally. In the general
environment, ultraviolet light is responsible for skin cancers
among lightly pigmented inhabitants of sunny climates (section
4.3.2.3). Other portions of the electromagnetic spectrum, found
within the general environment, do not play a significant role in
the causation of skin disorders, unless there is a personal
idiosyncracy or sensitization by chemicals. Low relative humidity
and cold, again in association with personal susceptibility are
responsible for dry scaly erythematous lesions on exposed areas
(chapping). Cold on its own can produce injury on fingers and toes
(chilblains) and other exposed parts.
-------------------------------------------------------------------
a Based on the contribution of Professor S.R. Kamat, K.E.M.
Hospital, Bombay, India.
b Provided by the National Institute of Occupational Health,
Ahmedabad, India.
Food additives, drugs, and cosmetics have been responsible for
skin eruptions produced by relatively simple local sensitization as
well as photo- and actinosensitization. Additives that enhance the
keeping quality, or other performance, of foodstuffs have been
responsible for outbreaks of dermatitis. Colouring agents such as
tartrazine, used in drug formulae and foodstuffs, have produced
sensitization. Several materials used for cosmetic purposes may be
allergens, including orris root, bergamot, wool alcohol, parabens,
and eosin dyes.
Through occupation, a person may be exposed to a range of
irritant, sensitizing, and carcinogenic agents. For example,
coaltar materials have the potential for all three effects, with the
sensitization also extending to photosensitivity. Among the more
interesting recently-observed materials is vinyl chloride which, in
addition to its other systemic effects, is associated with scleroderma-
like skin lesions accompanied by micro-vascular changes (Maricq et
al., 1976). Excessive exposure to ionizing radiation is associated
with acute inflammatory effects, which may be followed by atrophic
changes and skin tumours. Ultraviolet light in substantial dosages,
which may be incidental to a process like welding or constitute the
essence of a process for the polymerization of resins, can be
phototoxic or photoallergic (WHO, 1979b). Formaldedehyde is also a
skin sensitizer through industrial as well as domestic exposures
(Gupta et al., 1982).
Predisposing conditions that render persons hypersusceptible
to environmental agents include the atopic diathesis, which
predisposes to sensitization, and inherited conditions. Xeroderma
pigmentosum, a recessive autosomal disease in which there is
absence of enzymes involved in DNA repair, renders persons
excessively sensitive to ultraviolet light and leads to a very high
frequency of skin cancer. Linking skin eruptions with systemic
disease is a hereditary form of photosensitivity reported among
North and South American Indians. This appears to be an autosomal
dominant state leading to pleomorphic light eruptions, which become
secondarily infected with nephritogenic organisms to form a hazard
for the individual.
Errors of porphyrin metabolism, where crises may be provoked by
drugs or ultraviolet light, are also important conditions in
certain populations and individuals. Malnutrition commonly
presenting with multiple deficiencies is associated with cutaneous
and mucosal dystrophy.
4.9.2. Epidemiological methods of study
Dermatological examinations are essentially clinical, but they
are susceptible to a standardized approach with a protocol designed
for ease of subsequent analysis. Thus, for example, a substantial
number of persons inadvertently exposed to polybrominated biphenyls
(PBBs) were subject to a range of investigations including a
detailed scrutiny of finger nails and toenails, scalp hair, body
hair, general skin lesions, acne, and lesions of the oral cavity
(Selikoff & Anderson, 1979). Studies on skin cancer have been
discussed in section 4.3.2.
The use of patch testing is primarily a clinical procedure; for
practical reasons, it may have limited application in field
studies. In population studies, it is common to discover a higher
prevalence of disease than is reported by spontaneous complaint.
Thus, while the use of general practice records and hospital
outpatient records may be of value for the study of skin cancer, an
assessment of the full burden of other skin lesions depends on a
systematic study of the population at risk and a carefully matched
control population.
4.10. Reproductive Effects
4.10.1. Effects on reproductive organs
A wide variety of environmental factors act directly on the
gonads, or indirectly by interfering with the complex regulatory
mechanisms of sexual and reproductive functions. Physical agents
most often mentioned in relation to genetic disorders include
ionizing radiation, non-ionizing electromagnetic waves, vibrations,
and high temperatures. The chemicals most likely to produce
genital disorders are heavy metals and organic solvents.
(a) Female
The only common and easily detectable index in women, that can
be asked for by questionnaire, is the occurrence of menstrual
disorders such as dysmenorrhoea, oligomenorrhoea, or amenorrhoea.
Other more complex assessments are not suitable for epidemiological
studies.
(b) Male
Symptoms of decreased libido and functional disorders can be
revealed by simple questionning, but are not specific enough to be
of much value. Testosterone blood levels yield more information
about hormonal production. Routine spermiograms for the early
assessment of the influence of environmental agents on reproductive
function are not suitable for environmental studies.
4.10.2. Genetic effects
Environmental factors such as ionizing radiation and some
chemical compounds may induce changes in human germ and somatic
cells. Evaluation of mutagenic effects in these cells should be
made separately, as methods of study for the two types of cells
differ significantly.
Mutagenic agents may induce different kinds of damage in the
genetic material. Methods for the detection of chemical mutagens
have been described by Hollaender (1971-1976), Hollaender & de
Serres (1978), and Kilbey and coworkers (1977). The time between
the origin of a mutation and its manifestation depends on its mode
of inheritance.
Mutations may be responsible for a sizeable fraction of
spontaneous abortions, congenital malformations, and mental and
physical defects, and it has been advised that sentinel diseases
known to be genetically determined or due to a mutation should be
monitored in human populations. Those recognizable at birth will
probably be picked up by a birth-defect recording system (section
4.10.4). Others, which develop later, will need to be detected by
other means - possibly notification, or the detection of "new"
cases, when they start to attend medical institutions - primary
care centres or hospitals.
The evaluation of mutagenic effects in germ cells under the
influence of environmental factors involves a comparison of
frequencies of gene and chromosome diseases in the control and
exposed groups. The most complete investigations of the genetic
effects of ionizing radiation have been carried out on the
population of Hiroshima and Nagasaki, exposed during atomic
bombing (Neel et al., 1974). In the progeny of persons
surviving after the explosion of atomic bombs, there were no
noticeable changes in the proportion of sexes (recessive lethal
mutations in X-chromosome), in the frequency of chromosome
diseases, or in the mortality rate (section 5.6.8.5). In the
USSR, the frequency of spontaneous abortions is regarded as a
major index of mutational impairments (Bochkov, 1971). Shandala
& Zvinjackovskij (1981) reported an increase in the frequency of
spontaneous abortions in relation to the level of ambient air
pollution.
Many chemicals may induce chromosome aberrations in somatic
cells. These include vinyl chloride monomer (Funes-Cravioto et
al., 1975; Purchase et al., 1978), and a number of other industrial
chemicals and drugs (Evans & Lloyd, 1978).
4.10.2.1. Assessment of genetic risks
Few methods are at present available to assess the presence of
mutagenic agents in the human body (Sobels, 1977). Ehrenberg and
co-workers (1977 a,b) have developed a method to estimate the
frequency of induced mutations by determining the degree of electro-
philic substitution of proteins as haemoglobin in the exposed
persons. In a study by Strauss & Albertini (1977), an autoradio-
graphic method was reported for the detection of 6-thioguanine-
resistant lymphocytes. The method should have the advantage of
being capable of detecting somatic cell mutations in vivo.
Another approach to assessing the presence of mutagenic agents
in the human body consists of testing samples of blood or urine
with sensitive microbial assay systems (Legator et al., 1978).
Mutagenic activity has also been assessed using human faeces and
breast milk. Indications for chromosome breakage activity can be
obtained in short-term lymphocyte cultures from peripheral blood
samples. These aberration yields in somatic cells cannot be
correlated, however, with the frequencies of translocations to be
expected in the germ cells. Other indicators for genetic activity
concern sister-chromatid exchanges in peripheral blood cells and
morphological abnormalities of spermatozoa (for the latter, see
Wyrobeck & Bruce, 1978). Thus, an increase in the proportion of
abnormal sperm atozoa has been observed in direct relation to the
degree of cigarette smoking (Viczian, 1969). Epidemiological
surveys relating heritable damage in man to exposure to chemical
mutagens have not yielded statistically convincing results, except,
perhaps, in the case of cigarette smoking (Mau & Netter, 1974).
4.10.3. Fetotoxic effects
Some substances absorbed by the mother pass across the
placenta, but others do not. The substances transported into the
fetus are not necessarily distributed within the fetal tissues in a
similar way to that in the mother's tissues. It is possible that a
substance administered to the mother or entering her blood stream
is not of a sufficient dosage itself to harm the fetus, but
metabolites developed during the elimination of a substance from
the mother may pass across the placenta and be harmful to the fetus
(Longo, 1980). Adverse effects on the fetus must be distinguished
from adverse effects on the germ cells, before fertilization. A
symposium, reported by Boué (1976), reviewed the knowledge, up to
that date, on this subject.
In order to interpret data about fetal toxicity, it is
desirable to measure the reproductive efficiency of couples
(Levine et al., 1980) and the number of spontaneous miscarriages as
distinct from abortions. The difficulties in the field of
reproductive epidemiology are well reviewed by Buffler (1978) and
Erickson (1978) and available methods have been reviewed by Hemminki
et al. (1983) and Leck (1978). All show the necessity of collecting
reliable data about exposure to substances that might be toxic to
the fetus.
4.10.3.1. Measurement of fetotoxic effects
To make a quantitative study of fetal loss, the pregnant women
must first be identified at an early stage of her pregnancy.
Loss of fetuses in the first trimester is difficult to quantify
because, in many women, irregularity of the menses may confuse the
identification of early pregnancy. Loss in the third month is more
easily recognised, because of the menstrual bleeding periods that
will have been missed, and it is more likely that the pregnancy has
been reported to a doctor. However, the chance that miscarriage
can occur without the women noting the event or receiving medical
care is high. It is likely that women observe and report
spontaneous abortions very individually, which makes interview
studies on these abortions liable to bias. Even though notes on
early spontaneous abortions are not found in medical records, it is
advisable, for confirmation of data, to consult such sources in
studies on spontaneous abortions (Hemminki et al., 1983).
Legal abortions may obscure attempts to measure spontaneous
fetal loss and means for counting the effect of this group should
be provided if early fetal loss is to be studied accurately. The
loss of a fetus may not be a matter of the mother's problems alone.
An abnormal fetus is frequently aborted (Alberman, 1976). Thus, to
measure abnormalities of aborted fetuses involves obtaining the
fetus for subsequent examination. Loss rates and the proportions
with specified abnormalities may be measured and analysed by
various factors, such as drug usage, substances used in employment,
food, water, and other environmental influences that may affect the
health of the fetus.
During the second trimester, there are three main types of
fetal loss: spontaneous loss, abortions (legal and quasi-legal) of
an unwanted child, and legal termination after the diagnosis of an
abnormal child. Again, discrimination among these three groups is
essential, if the toxic effects are to be distinguished from the
chromosomal effects. Although very difficult, attempts should be
made to examine dead fetuses from all three sources in order to
determine the number malformed, so that those in which genetic
damage is present may be distinguished from those where toxic
damage to the fetus has occurred in utero.
In the third trimester (after about 24 weeks), premature labour
or legal or quasi-legal termination is quite likely to result in
the delivery of a live baby and problems arise in many countries as
to whether the fetus from a termination is to be registered as a
live baby. Dead fetuses must be examined to distinguish between
those with chromosomal anomalies and those with other anomalies.
The latter should also be distinguished from those who have been
injured during the birth process or during antenatal examinations.
Occasionally, a fetus damaged during the intrauterine period may
not show damage till later in childhood.
If there are sufficiently rare malformations, retrospective
examination of the environmental factors prevailing during
pregnancy may help to identify a causal agent (Bakketeig, 1978).
This was done successfully in demonstrating the association of
thalidomide in pregnancy with gross limb malformations in the
offspring (Lenz, 1962).
Longitudinal studies of pregnancies with detailed case
histories give a good picture of toxic effects, though many years
may have passed by the time the data have been collected and
processed. Often, such studies indicate 'significant' effects but
lack replicate observation, thus necessitating other investigations
(Rumeau-Rouquette et al., 1978). To overcome this problem, in a
longitudinal study of l4 774 women who gave birth in 2l clinics in
the Fereral Republic of Germany between 1964 and 1972, data was
analysed in two sets so that the second set could be used to
corroborate or refute the findings in the first set (Deutsche
Forschungsgemein-schaft, 1977). The study involved recording many
details about normal pregnancies in order to obtain data on the
relatively few pregnancies that ended in spontaneous abortion, or
where the baby was born with anomalies.
An alternative strategy involves collecting data from mothers
of abnormal babies and from a control mother who has had a normal
baby (Saxen et al., 1974; Greenberg et al., 1977). If data are
recorded routinely for all pregnancies, the records can be examined
for mothers of abnormal babies and for a matched control mother;
such a procedure would substantially reduce the risk of bias being
introduced by the outcome of the pregnancy.
Transplacental carcinogenesis studies in human beings have to
date only conclusively established one such process, involving the
administration of diethylstilbestrol in high doses to mothers in
the first trimester whose daughters presented with the rare tumour
of adenocarcinoma of the vagina at 14-22 years of age (Herbst &
Scully, 1970).
The testing of a hypothesis that a given environmental factor
is causing malformations is probably demonstrated most convincingly
by a study in which the factor in question is excluded from some of
the mothers, i.e., a selective avoidance trial. When the incidence
of an abnormality is less than 5%, such a trial would need to be
extensive before a significant difference between mothers excluded
from, and mothers exposed to, the factor is demonstrated. However,
when women in such a study are at a known and high risk of having
abnormal babies, an avoidance trial can be used without using
control mothers, as was done by Nevin & Merrett (1975). They
studied mothers who had already given birth to infants with central
nervous system anomalies and who abstained from eating potatoes
during subsequent pregnancies and found that the avoidance of
potato eating did not reduce the risk of giving birth to infants
with these anomalies.
4.10.4. Registries of genetic diseases and malformations
Registration of spontaneous abortions, birth defects, and
perinatal deaths might not always reflect genetic effects, because
these events take place as a result of changes in the hereditary
structures in gametes as well as from a number of other non-genetic
causes.
Only a few programmes have so far developed genetic registries
on a wide scale with a defined population. For instance, genetic
disorders in the population are included in the Birth Defects
Registry (established in 1952) developed in British Columbia,
Canada. Originally concerned with the delivery of medical
services, it includes the provision of incidence and prevalence
statistics on handicapping illnesses in all age groups, and
provides a basis for surveillance, and genetic counselling. It has
attempted to ascertain and document all relevant cases in British
Columbia, though registration is not mandatory. Some data are
provided on certain genetic conditions such as cleft lip and per
palate, clubfoot, and Down's Syndrome. There were 1.42 liveborn
1000 live births with Down's Syndrome.
Borgaonkar and his co-workers at North Texas State University,
USA, established an International Registry of Abnormal Karyotypes -
later called Repository of Chromosomal Variants and Anomalies
(Borgaonkar, 1980; Borgaonkar et al., 1982). They contacted all
established cytogenetic laboratories around the world and have an
open-door recruitment policy. With the support of the World Health
Organization, they distributed several cumulative listings of the
Repository. The most recent, the Ninth Listing, has data from 140
contributors on about 200 000 cases. The modes of ascertainment of
cases and the total number of cases studied are included in the
report. All types of variations and anomalies are systematically
arranged in a format used earlier in preparing a catalogue of
chromosomal variants and anomalies - Chromosomal Variation in Man.
By analysing data in the Repository and the catalogue, it has been
possible to draw some conclusions about the origin of certain
chromosomal disorders.
Some specific types of new chromosomal mutations are almost
always "environmentally" induced. The ring chromosomes and
isochromosomes have been reported more than 600 times in the
Repository and there are about 500 more published cases. An
examination of the origin of these cases shows that with few
exceptions almost all the cases are new mutations; that is, the
parents, when examined, have been found to have normal chromosomes.
Most of the examples are also "genetic lethals" in that they do not
reproduce. Early death does not seem to be a characteristic of
these individuals. Almost all the cases come to attention because
of the medical problems that the individual encounters, including
developmental and maturational anomalies. Very few cases are
detected in general population surveys. Use of the Repository in
developing uniform growth patterns and syndrome delineation has
been well documented (Mulcahy, 1978).
The use of cytogenetic approaches in the monitoring of
industrial workers has been defined, presumably with systematic
development of registries. Records prior to and during employment
can provide data for assessment of the genetic effect of the
occupational exposure (Kilian et al., 1975).
Registries of birth defects exist in a number of countries.
For example, in Finland, there is a registry of all congenital
malformations reported from all hospital deliveries, with
registration of the various environmental factors involved. This
data base has been used for a study of the relationships between
solvent exposure of fathers and mothers and congenital abnormalities
of the nervous system (Holmberg & Nurminen, 1980).
The following European Economic Community (EEC) study of
congenital malformations provides an example of an international
collaborative study on their registration.
4.10.5. Example: EEC study of congenital malformationsa
In 1974, the Committee of Medical and Public Health Research of
the EEC decided to promote, as its concerted action, an international
cooperative study on the registration of congenital malformations.
After a feasibility study conducted in 1975 and 1976, the
Concerted Action on Congenital Abnormalities and Multiple Births
was established in February 1978. The study is supervized by a
steering committee whose members are nominated by the participating
member countries. Initially, 15 study areas were proposed within 9
countries (Belgium, Denmark, France, Federal Republic of Germany,
Italy, Ireland, Luxembourg, Netherlands, and the United Kingdom).
In 1979, the participation of Greece with an additional area was
approved. The Concerted Action Project in Registration of
Congenital Abormalities and Twins has received the acronym -
EUROCAT.
The long-term objective of this study is to test the
feasibility of carrying out epidemiological surveillance in the
countries of the EEC, taking surveillance of congenital
abnormalities and multiple births as an example.
The specific objectives of the study are:
(a) To set up, within each selected area in each country, a
population-based register of congenital abnormalities and
multiple deliveries. In order to achieve full recording,
ideally the outcome of each conception in women resident in
the defined area should be known. This involves searching for
congenital malformations, and biochemical and chromosomal
anomalies in aborted fetuses, in live and stillborn infants,
in dead children, and during childhood. Babies from multiple
deliveries should be recorded at birth.
(b) To study the methods of data collection in each centre,
to evaluate the effects of these in biasing the data
collected, and to propose and test ways to circumvent these
difficulties.
(c) To monitor the incidence rates reported in different
population groups at different times in order to identify
possible etiological factors.
(d) To create, in each country, an area where reporting is
reliable, so that base line rates are available for use in
calibrating any national warning system established for the
detection of adverse environmental influences by allowing the
interpretation of a reported increasing rate.
--------------------------------------------------------------------------
a Based on the contribution from Professor M.F. Lechat,
Catholic University of Louvain, Brussels, Belgium, with
the help of Dr J.A.C. Weatherall, Office of Population
Censuses and Surveys, London, England.
(e) To evaluate the effectiveness and efficiency of screening
programmes and preventive measures.
(f) To provide a well-documented set of individuals recorded
in a defined population for further specific studies, such as
follow-up studies of cases with specified malformations, in
order to compare the results of different treatment regimens.
(g) To establish the means by which multiple births can be
efficiently registered at birth and how information can be
collected that will make possible the reliable and cheap
recording of zygosity.
A feasibility study showed that considerable variations existed
in the recording of malformations in different countries and in the
collection of morbidity and mortality statistics and of other
relevant epidemiological data concerning children, both in the
definitions used and in the methods of processing of the data. To
ensure valid comparability of the data, it was decided to concentrate
first on well-defined geographical areas in each country where
studies could be performed.
The study has concentrated, at the start, on recording malformed
infants at birth. Special studies are being undertaken to measure
the efficiency of the reporting of cases among the births to women
living in each area. As soon as good birth coverage is achieved,
the observations will be extended to the recording of all the
abnormalities found in the children born in the area during their
childhood. Those discovered in spontaneously- and legally-aborted
fetuses will be recorded as well. By 1980, the recording of
multiple births was being carried out in only a few areas, but
other areas will start to record multiple births, when the methods
for recording zygosity have been established in each area.
4.11. Effects on Other Major Internal Organs
Environmental factors may have beneficial or harmful effects on
internal organs. The gastrointestinal system, especially, receives
beneficial essential metals and other minerals from the environment.
On the other hand, some metals and many other chemical compounds
are hazardous to these organs, if concentrations are sufficiently
high.
4.11.1. Renal system
Renal damage can be caused by many chemical compounds or
physical factors. Depending on the kind and concentration of
noxious agents, and the intensity and duration of exposure, an be
caused by nephrotoxic products such as mercury, chromium, arsenic,
and ethylene glycol.
Subacute and chronic renal diseases are caused by a wide
variety of environmental factors and can generally be related to
either glomerular or tubular injury. Nephrotoxic agents may lead
to a quantitative alteration in the filtration rate or to
qualitative changes in the filtration pattern by influencing
glomerular permeability. Inorganic mercury, cadmium, potassium
perchlorate, and different chelating agents increase glomerular
permeability. Hydrocarbon solvents and pertroleum products may
produce antiglomerular basement-membrane-mediated glomerulone-
phritis (Van Der Laan, 1980).
The most common type of chronic renal impairment of toxic
origin is tubular injury with suppression of tubular reabsorption.
Proximal tubular damage is produced by all the nephrotoxic heavy
metals such as lead, mercury, cadmium, uranium, and bismuth. X-
radiation produces renal disorders, mainly of the tubular type.
4.11.1.1. Detection of renal diseases
Most tests suitable for epidemiological studies do not yield
much information about the specific causes of renal dysfunction,
but they provide a crude measure of the degree of renal damage.
The early stages of renal damage are seldom accompanied by
symptoms. Thus, questionnaires are useless in the early detection
of renal impairment, and laboratory tests are imperative.
(a) Functional change
One of the simplest tests is the assessment of renal
concentrating capacity by measuring urinary specific gravity after
a period of restricted fluid intake. Results can be biased by the
presence of glucose, proteins or other substances in the urine or
by extrarenal factors such as hypertension or a low-protein diet.
(b) Test for urinary sediment
Analysis of urinary sediment may indicate generalized kidney
damage as for instance the number of epithelial cells excreted in
the urine. The presence of even microscopic haematuria must evoke
the possibility of cancer of the urinary tract, especially in high-
risk groups.
(c) Test for glomerular function
Except under certain physiological conditions characterized by
a temporarily increased output of proteins, normal urine contains
only small amounts of proteins. Significant proteinuria is always
pathological and generally reflects glomerular dysfunction
characterized by a high relative molecular mass protein output.
The appearance of low relative molecular mass proteins in the urine
must be interpreted as a sign of tubular damage. Proteinuria is
considered an early sign of renal injury, preceding other signs
such as aminoaciduria or glycosuria. These tests can be used in
epidemiological surveys.
(d) Test for tubular function
All substances excreted or reabsorbed in the tubular area can
be used as indices of tubular function. Normal phenosulfon-
phthalein (PSP) and para-aminohippurate secretion tests indicate
tubular functional integrity. In general the performance of
clearance tests requires a clinical setting and therefore they are
not useful in masssurveys for renal dysfunction. However, if
comparison is made with urinary creatinine, ambulant clearance
testing can be carried out, as was done for example by Nogawa et
al. (l980).
A Fanconi-like syndrome of glucosuria, phosphaturia, and
aminoaciduria is precipitated by most heavy metal intoxications.
Ammonium ion excretion after acid loading may serve as an indicator
of distal tubular function. Renal tubular damage in persons with
excessive cadmium intake is accompanied by an increase in urinary
excretion of beta-2-microglobulin. Nowadays, quantitative
immunological methods for the measurement of beta-2-microglobulin
(Evrin et al., l97l) and retinol-binding proteins (Bernard et al.,
l982) in urine are available and these methods facilitate the
detection of tubular dysfunction. The methods of diagnosing
cadmium-induced proteinuria have been reviewed by Piscator (l982).
Quantitative protein excretion should be relied on in preference to
simple paper tests (Lauwerys et al., 1979; Roels et al., 1981).
Various other factors involved in the effects of cadmium on renal
function have been reported (Friberg et al., 1974; Tsuchiya, 1979;
Commission of the European Communities, 1982).
(e) Tests for enzymuria
Disruption of kidney cells by nephrotoxic agents results in the
release of specific renal enzymes in the lumen of the nephron.
Enzymes present in both serum and kidney tissue can often be
distinguished from each other as isoenzymes and separated by
electrophoresis. Since the enzyme patterns of the different parts
of the nephron are well characterized, study of enzymuria often
makes it possible to localize the injury (for example, a rise in
urinary acid phosphatase (EC 3.1.3.2) indicates glomerular lesions,
while an increase in alkaline phosphatase (EC 3.1.3.1) suggests
proximal tubular damage).
Distal tubular injury gives rise to the appearance of lactate
dehydrogenase (EC 1.1.1.27) or carbonic anhydrase (EC 4.2.1.1) in
the urine. Other enzymes, not found in serum, appear in urine
after toxic renal damage as, for instance, beta- N-acetylgucosamin-
idase (EC 3.2.1.30), glycine amidinotransferase (EC 2.6.1.4), etc.
Aminopeptidase-activity (EC 3.4.11.1) increase occurs in many
pathological conditions of the kidney, especially in the case of
tubular lesions induced by many chemicals. Enzymuria is a highly
sensitive and specific criterion for the early assessment of renal
damage and precedes any other symptom either functional or
morphological. The usefulness of the assessment of enzymuria in
epidemiological surveys is limited by its high cost and the need
for specialized laboratories.
4.11.2. Bladder
Bladder cancer is a known hazard in many industries resulting
principally from exposure to carcinogenic amines. Screening for
early tumour development may be done by the determination of
urinary beta-glucuronidase (EC 3.2.1.3l), or by cytodiagnosis of
tumour cells exfoliated in the urine. The second method, however,
requires a high degree of skill and experience for reliable
diagnosis, but it has been accepted as a good screening method.
4.11.3. Gastrointestinal tract
The gastrointestinal tract is particularly susceptible to
environmentally-determined disease, because it is the first system
in contact with chemicals contained in food and drink. In addition,
through the liver and biliary system, the gut provides a route for
the excretion of toxic chemicals, drugs, and products of metabolism.
There are many tests available for the detection of existing
gastrointestinal diseases and some for the identification of
persons at risk of them. Not all of the tests are suitable for use
on an epidemiological scale, because they involve sophisticated
equipment, significant doses of radiation, or are so labour-
intensive as to be uneconomic. The methods mentioned below are the
minimum necessary for the identification of these diseases. All
are fully described in standard texts (Russell, 1978; Sleisinger &
Fordtran, 1978; Bateson & Bouchier, 1982). These text books also
contain information concerning other more detailed tests, suitable
for use in smaller groups of people, provided adequate resources are
available.
4.11.3.1. Oesophagus
Cancer is the main environmentally-determined disease of the
oesophagus. It can be detected readily by a combination of a
clinical history and either X-ray or fibroptic endoscopy.
Endoscopy has been found acceptable, on a population basis, in Iran
(Crespi et al., 1979), where precursor inflammatory changes were
detected in the oesophagus, often in quite young subjects. In
China, X-ray examination is widely used to screen populations at
risk (Coordinating Group, 1975). Exfoliative cytology of the
oesophagus is also a valuable screening test for oesophageal
neoplasms. Only a simple apparatus is needed to obtain the sample,
although a trained cytologist must look at the specimen. The test
is positive in 70-94% of cases with 1-2% false positives.
4.11.3.2. Stomach and duodenum
Gastric cancer is amongst the world's commonest fatal
malignancies. It may be detected best by X-ray, which is the most
accurate simple screening test for established disease. Fibroptic
endoscopy is also a useful diagnostic procedure and may be
essential in distinguishing large gastric ulcers from malignant
ulcers. In these situations, multiple biopsies must be made;
80-90% of malignancies are detected in this way. Much effort,
especially in Japan, has gone into the detection of early stages of
gastric malignancy in an effort to prevent this disease. Population
screening by X-ray has been widely used (Nagayo & Yokoyama, 1974).
Exfoliative cytology is also useful and can be performed by a
medical assistant. Gastric lavage is carried out, usually with
chymotrypsin, on fasting patients and the whole test requires only
a small stomach tube, syringe, and centrifuge. Accuracy of
diagnosis of 90% has been claimed for proved tumours with only 1-2%
false positive (Brandborg, 1978).
4.11.3.3. Intestines
The small bowel plays a vital role in digestion and absorption,
but few environmental causes of small bowel diseases are known. On
the other hand, in many industralized countries the large bowel is
one of the major sites of cancer.
The simplest and most widely applicable test for large bowel
disease is examination of the faeces. Depending on the cooperation
of the population under study, anything from a random sample of
stool to a full 5-day collection can be made. Stool samples have
been collected from randomly selected members of the public in
studies of the etiology of large bowel cancer (International Agency
for Research on Cancer; Intestinal Microecology Group, 1977).
These were used for the measurement of faecal bile acid
concentrations and faecal microflora studies. Also valuable is
the stool test for occult blood. In the early detection of bowel
cancer, this test, if done under properly controlled dietary
conditions, can be organized for a very large number of people.
4.11.4. Liver
Hepatic tumours, particularly primary tumours, often produce no
change in standard function tests. They may be demonstrated by any
of a number of radioisotopic scans now available, but all involve
considerable doses of isotope. Hepatic ultrasonography offers a
useful non-invasive alternative and computerized axial tomography
scanning may also prove to be a valuable alternative, although
expensive. Serum alpha 1-fetoprotein appears in the blood of
patients with primary hepatic tumours. The proportion of positives
varies from 30-80% depending on the area under investigation.
A great number of tests of hepatic function are available and
should be tailored to the particular objective of any epidemiological
study. Standard texts on the subjects should be consulted (Schiff,
1975; Sherlock, 1975). Some of these tests are simple and accurate
while others require great resources and are inherently dangerous.
Examination of the urine can be most useful in liver disease.
The presence of conjugated bilirubin or urobilinogen is often an
early index of disease. Faecal examination is much less useful.
Serum tests of liver function are widely available and easy to
perform. These include bilirubin, aspartate (EC 2.6.1.1) and other
aminotransferases (EC 2.6.1), gamma-glutamyltransferase (EC
2.3.2.2), alkaline phosphatase (EC 3.1.3.1), 5'-nucleotidase (EC
3.1.3.5), serum proteins, blood cholesterol and ammonia.
4.11.5. Pancreas
Pancreatic cancer and pancreatitis have been often implicated
to be related to environmental factors such as smoking and intake
of alcohol and coffee (Wynder et al, 1973; Lin & Kessler, 1981;
MacMahon et al., 1981).
However, the pancreas is one of the least accessible internal
organs and is thus difficult to investigate. No simple tests for
epidemiological study are available, though some pancreatic
function tests may be used (Mottaleb et al., 1973; Mitchell et al.,
1977) and indirect evidence of pancreatic disease may also be
obtained from determination of serum amylase and lipase levels.
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