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Quick links to online content Annu. Rev. Public Health. 1990. 11:29-37 Copyright © 1990 by Annual Reviews Inc. All rights reserved
TOXICS AND PUBLIC HEALTH IN THE 1990s
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
Norton Nelson** New York University Medical Center, Institute York, New York 10016
of
Environmental Medicine, New
"Toxics" has come to be used as a general term to cover noxious chemicals, particularly those arising in industrialized societies (or those heavily using chemicals, e.g. pesticides). Public health, as a field, has increasingly become aware of and is now actively involved in the role of"toxics" in health injury and the quality of life. The aim of toxicology has always been the prevention of injury; this remains the guiding principle. The emphasis on prevention and finding means of choosing less hazardous ways of working with chemicals (including the development of appropriate regulations and controls) should receive even more emphasis in the next decade. Indeed, the report of the Research Strat egies for the 1990's Committee of the Environmental Protection Agency (EPA) Science Advisory Board (22) uses the theme of prevention as a major thread throughout its proposals for research strategies within EPA. Toxicolo gy will often need the assistance of epidemiology, especially to test the reliability of its "preventive" advice. Toxicology is much changed from what it was several decades ago, when it was primarily a rather routine testing enterprise. Toxicologists now are aware of the immense advances of the past several decades in molecular and cell biology. Toxicologists have developed sufficient sophistication so that the feedback between fundamental scientists and toxicologists serves to advance both fields. Two recent journals, Journal of Biochemical Toxicology and Chemical Research in Toxicology, reflect this interaction. Among the issues that have received a great deal of attention in the last few years are those growing out of the Superfund legislation relating to health and environmental hazards. When the first Superfund legislation was passed, it **Dr. Nelson died 2/4/90, after a fall, two days short of his 80th birthday. To the final hours he was a remarkably active and insightful leader of the field of environmental health, to which he has made so many contributions.
29
0163-7525/90/0510-0029$02.00
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
30
NELSON
was assumed that all was known that needed to be known about the disposal of toxic wastes; namely, that all that was really required was to gather the materials with reasonable regard for their presumed (but often unknown) hazards, bury them in some place, preferably remote, and walk away and hope that all would be well. It has turned out that we did not know many of the things that we needed to know about the safe disposal and secure disposition of chemical wastes. In the Superfund Amendments and Reauthorization Act, much more attention was given to improving means for safe disposal. Unfortunately, the techniques for determining the presence of toxic wastes and their risk assessment for health and ecological effects are still inadequate to distinguish reliably the extent of hazard. An important improvement in the legislation reauthorizing the Act was to direct much more attention and resources to research in these fields. This has led to increased activity and funding within EPA for study and improvements of methods for detection and risk assessment as well as for improved means for disposal of waste. A landmark part of the reauthorization was the enactment of the Superfund health-related program under the National Institute of Environmental Health Sciences; this program calls for university research to improve means for disposal, detection, and risk assessment (The Hatch-Wyden Amendment) (9). This program, now in its third year, provides funding through competitive grants to universities for the development of improved means for detecting and evaluating toxic wastes and for collaborative studies with engineers on means for reducing the amount and toxicity of qazardous wastes. It also provides for ecological studies to improve our understanding of the environ mental effects of hazardous wastes. Although this program is still too young to evaluate its progress, it has been received warmly, and funds have been awarded to nine universities throughout the country, all on a competitive basis. Each such award is linked with collaborative programs with engineer ing and ecological studies as well as studies on hydrogeology relating to possible movement through soils and aquifers. These awards went to universities with some of the most advanced toxico logical programs in the country. As a minimum, it can be predicted that techniques for the detection and evaluation of hazardous materials and their movement in the environment will be improved substantially. As noted, this program includes a novel feature that provides for collaborative work between toxicologists and engineers, particularly chemical engineers, on means for reducing the amount and toxicity of hazardous wastes. Toxicologists and engineers are seeking general processes to minimize the total waste requiring disposal and look for ways to recycle more of the total, ending up with much less toxic material to dispose of with, it is hoped, much less intrinsic toxicity.
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
TOXICS AND PUBLIC HEALTH
31
For now, however, this program can only make a modest dent in the total problem, considering the enormous bulk of waste presently requiring disposal and the extreme variety of wastes that are being d ispos ed , esp ec iall y since many of the wastes will be highly specialized according to the processes and agents i nv olv ed . One of the tools that will contribute in an important way to improving the ability to detect health injury is the advancing technique for detecting even more subtle biochemical changes that can be related to early patterns of injury. These support tools include a number of techniques for detection of early changes that have received the term biomarkers. These biomarkers can include the actual reaction of toxic chemicals or their metabolites with tissue biochemicals. An example of this is the reaction of toxic chemicals with DNA to produce adducts (15), which can be the first stage in the development of malignancy or can, in other instances, simply indicate exposure to a foreign chemical. In other cases, they may represent an altered response of limited duration that, if detected early, serves as an indication of exposure or of the initial stages of disease. Table 1 (6) indicates a spectrum of "indicators" or "markers" of biological response, which could range from the earliest indica tion of exposure of biochemical units, whether intracellular or extracellular, to disease or death. "Biomarkers" for the detection of real or potential injury provide important new tools for the earlier detection of potential injury. Susceptibility often varies widely within human populations. Techniques are emerging that detect individual susceptibility to foreign chemicals (6). The identification and classification of individual susceptibilities, whether from genetic endowment or disease, brings with it some awkward problems in the social use of such p roce dures , not all of which have been resolved at this stage, and means for the safe and fair application of these procedures may be required to guide their application (19). Toxicology, in the sense used here, comprises all of the procedures accessi ble for developing information on the possible or probable hazard of exposure to toxic agents. There are several reasons for linking epidemiological studies with toxicology in the objective of preventing injury. Obviously, the hop e of careful, p re dic tive tox ico lo gica l studies based primarily on laboratory or experimental procedures is to learn of the dangers of possible exposure, the limits of injury, and procedures for avoiding injury or for the development of substitute chemicals before chemicals are put into widespread use. There is always a risk of failing to develop adequate protective approaches, however, and for this reason, epidemiologic follow-ups are of the utmost importance to be sure that the predictions of safety are in fact valid and effective. In addition, epidemiology in some cases may be the only approach for which laboratory studies have not been possible or are suspected of being ineffective. In such cases, the linkage of toxicology through laboratory
32
NELSON Table 1
Continuum from exposure to endpoint. Markers of exposure and/or effects
Exposure
Dose
Effects
Endpoint
Exposure dose
Internal dose
Preclinical response
Disease
Biologically
Biological dose
Clinical effects
effective dose
Surrogate biological dose
Molecular dose
Biological marker
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
Exposure indicator The preferred but not unanimous version of our schematic is as follows:
/' Biological markers � � � Exposure dose � Molecular dose
'" Disease
/'
'"
Surrogate biological markers -> M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
10-9
10-7
10-6
M
10-2
Adapted from Ref. (6).
evaluations with epidemiology can be very important. Toxicology studies in the laboratory can avoid many of the pitfalls of epidemiology in better control of possible confounding factors; however, the techniques suffer from the lack of sensitivity, since the size of the study groups are likely to be small compared to that of possibly exposed groups of humans. Such studies can have a higher specificity than epidemiological studies, in which the exposure of humans under study may not be as well defined as in controlled laboratory studies. Of course, epidemiological studies are optimal in terms of their relevance to humans and do not involve species extrapolations. Table 2 (14) illustrates comparison of the contrasting powers of epidemiol ogy and toxicology. Linkage of the two, wherever applicable, is desirable. Such linkage is now underway in use of some of the more refined "biomarker" endpoints as mentioned above. The promises of these approaches of "molecu lar epidemiology" are still to be fully assessed, but the prospect is very hopeful (15). Occupational diseases are very much still with us. Unfortunately, their extent and prevalence remain inadequately measured. The US continues to need a country-wide system of occupational disease reporting, preferably linked with recording of "sentinel" diseases (Sentinel Health Events, Occupa-
TaXICS AND PUBLIC HEALTH Table 2
33
Toxicology/epidemiology: contrasts
Issue
Toxicology
Epidemiology
Control of variables
Excellent
Poor
Identifying causal factors
Excellent
Poor
Size of population
Limited
Can be very large
Sensitivity
Poor
Poor
Genetic diversity
Normally deliberately narrow
Broad
Intercurrent disease
Controllab le
Not controllable
Study of mechanisms
Easily accessible
Ethical hindrances
Uncertain relevancy
Directly relevant
Unrestricted (except interview)
Severely restricted
Exposure Environment
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
Confounding factors
Diagno stic tests
Nelson (14)
tionally Related)
(18). Part of the problem is the inadequate recognition of
occupational etiologies on the part of the majority of physicians. A number of efforts are underway (including a recent one within the National Academy of Sciences/Institute of Medicine) to encourage wider awareness of occupational diseases by physicians. These are not the first attempts to urge physicians to identify occupational etiologies reliably; however, until there is a nationwide system of mandatory disease reporting, progress seems unlikely. New York State recently developed a statewide system of occupational disease clinics that could substantially improve the situation. A review associ ated with this development places work-related exposures at
3-4% of all
deaths, or between 5000 and 7000 annually in New York State (12). Useful though this statewide study is, a nationwide system for the detection and reporting of occupational disease is the surest way of understanding the substantial extent of impact of occupational disease. As pointed out elsewhere, conceptually occupational disease is almost totally preventable
(13). The techniques that could achieve this would involve
the total enclosure of dangerous processes so the workers would not be exposed. The problem of maintenance of equipment remains a possible source of exposure; here the use of robots under remote control could contribute significantly in filling this gap in the protective pattern. Although there appears not to have been any economic survey made relevant to the issue, it seems quite probable in my opinion that the costs of the "protective boxes" might be substantially less than the costs involved in medical services, medical care, loss of productivity and life, and litigation. In my judgment, the Toxic Substance Control Act, which is intended to control the safety of products, is not as stringent as it should be. Nonetheless,
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
34
NELSON
it is a significant advance over the earlier, near total absence of control. The information required from industry is very sparse indeed, so much so that the final judgment often has to be made on the basis of structure-activity rela tionships alone rather than on the basis of actual toxicological study. The information required under the Toxic Substance Control Act is substantially less complete than guidelines now being developed within the "Common Market" in Europe (5). Improved "structure-activity techniques," especially quantitative structure activity relationships, are needed urgently. The pursuit of reliability in such predictive examinations should be encouraged (10, 11, 17). Such techniques might be especially useful as an aid in the assessment of the hazards of mixtures of chemicals for which current procedures leave much to be desired. Actual exposures of humans normally occur to a mixture of chemicals. Exposure rarely occurs through a single chemical. Another development receiving more attention has to do with the attempt to find test systems that minimize or do not involve the use of vertebrate animals. This is desirable from many standpoints, especially by animal rights advocates. Unquestionably, techniques that use either inanimate or isolated cell systems could replace some, perhaps many, tests on higher animals. One such system is the" Ames" test, which is a bacterial system for the detection of mutations by a relatively simple technique (2). This test has shown reasonably high correlation with the likelihood of the carcinogenicity of genotoxic chemicals, with, however, poor correlation to non-genotoxic che micals (20). Test systems for overall organ response for non-genotoxic endpoints have shown little promise (SGOMSEC) (3). Nevertheless, specific and limited patterns of organ injury can be detected in simplified tests; such approaches show some promise of reducing the need for use of living animals in many test systems. There is a danger that in our concentration on the studies at the molecular and cellular level, we may forget that the human organism is an organized and carefully tuned system of interacting organ functions and overall interaction with homeostatic mechanisms for mutual support and control. Complex organisms such as the human sometimes have to be examined as a complete organism (e.g. in laboratory animals) if important toxic responses are to be identified and their mechanism of action is to be understood. As suggested above, many new tools for toxicological studies are now emerging that can refine our understanding of the mode of injury and the stages through which injury proceeds. These include the increasing knowl edge of the role of receptor systems in toxic responses. An outstanding example of this is the importance of the p450 mixed-function oxidase enzyme system in the detoxification and toxification of foreign chemicals (16).
TaXICS AND PUBLIC HEALTH
35
An example of the attention that the p450 enzyme system is receiving has to do with the very toxic chemical tetrachlorodibenzo dioxin (TCDD), an ex tremely toxic chemical that is a by-product of a number of chemical pro cesses. It was first brought to public and scientific attention during the Vietnam war, when it was identified as a contaminant of 2,4,5T a herbicide then used militarily. TCDD has received extensive study. It is a potent carcinogen in ex perimental animals; and since it is widespread in the human environment, its
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
possible human carcinogenicity is of concern. Although presently there is only limited evidence of human cancer arising from exposure to TCDD, it is the object of extensive study and considerable concern (7). TCDD has the very interesting property that although not proven to be an "initiating" agent through DNA injury, it has been suggested that it produces cancer in experimental animals through what is known as a "promoting" activity; that is, it accelerates the development of cancer by "promoting" the progression of cells, some of which have already been "initiated" to cancer. The mechanisms whereby this "promotion" occurs have excited much interest as both a scientific challenge and a reliable means of carrying out "risk assessment"
(21) for estimating the likelihood of human cancer from exposure
to TCDD. Thus, it has been proposed that the p450s clearly play an important role in this "promotion" of "initiated" cells by dioxin
(16). On the other hand,
there are some who regard TCDD as a complete carcinogen (1). Thus, there is a parallel intensive search for
(a) the means whereby the
enzymes (p450) induced by TCDD aid in conferring its promoting activity, and
(b) how to use its biological and chemical characteristics reliably to
estimate its quantitative cancer risk. Analytical tools for TCDD have been so refined that normal levels of several picogram per gram can now be detected reliably, as can elevated levels found 15 years after exposure in Air Force crewmen who were previously involved in spraying Agent Orange (contain ing 2,4,5T). The same procedures have made it possible to analyze blood from the children with chloracne exposed in the 2,4,5T explosion in Seveso, Italy. The blood samples were carefully preserved from the time of the explosion (1976), when analytical techniques were quite primitive; the high est levels yet seen in humans (up to 30,000 picograms per gram) were found in recent analysis of these preserved samples (4). Research tools used in these studies and others in this newer era of toxicology and public health are of a very sophisticated nature. The study of oncogenes is still far from mature enough to be used routinely in toxicological studies, but that day may be quite close at hand. It appears, for example, that there is some chemical or agent specificity in the kind of oncogene that is activated, which suggests that such studies of the oncogene system can provide additional information perhaps not easily obtainable otherwise
(8).
36
NELSON
In summary, toxicology is steadily maturing as a science and has reached the stage at which it can now make major contributions to fundamental studies of biological patterns of injury. There is widespread and growing interest in toxicology among basic scientists. This pattern can be expected to continue to the advantage both of toxicology and of basic sciences. We are only beginning to apply the new tools and understanding. Major social issues remain to which this improving science and art need to be
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
applied. Legislative and regulatory changes are needed to facilitate the use of these new tools and improved resources to reduce injury and disease. This progress is needed if we are to continue to enjoy the technology to which we owe so many conveniences and pleasures of life. We have not adequately employed these protective and preventive resources to remove these in adequacies, which remain real and dangerous to mankind if uncontrolled.
Literature Cited I. Agency for Toxic Substances and Dis ease Registry (ATSDR). 1989. Toxi cological Profile for 2,3,7,8-Tetra chlorodibenzo-p-Dioxin. US Public Health Service. ATSDRITP-88123 2. Ames, B. N., McCann, J., Yamasaki, E. 1975. Methods for detecting carcino gens and mutagens with the salmonellal mammalian-microsome mutagenicity ·test. Mutat. Res. 31:347-64 3. Bourdeau, P., Somers, E., Richardson, M., Hickman, J. R., eds. 1990. SGOM SEC 4, Short-Term Toxicity Tests for Non-Genotoxic Effects, IPeS Joint Symp. SCOPE. In press 4. Centers for Disease Control. 1988. Preliminary Report: 2,3,7,8-Tetra chlorodibenzo-p-dioxin. Exposure to hu mans-Seveso, Italy. US DHHS, MMWR 37:733 5. Dominguez, G. 1980. Contrasts in Tox ic Substances Identification and Control, European Community 6th Amendment EPA TSCA, Toxic Substances Journal, Vol. I, No. 4, Executive Enterprises Publishing Company 6. Draggan, S., Cohrssen, J. J Morrison, R. E., eds. 1987. Summary Report of the Expert Panel Meeting on Human Health Impacts and their Mitigation. En vironmental Impacts on Human Health, The Agenda for Long-Term Research and Development, ed. S. Draggan, J. J. Cohrssen, R. E. Morrison. New York: Praeger 7. Fingerhut, M. A., Halperin, W. E., Honchar, P. A., Smith, A. B., Groth, D. H., Russell, W. O. 1984. An evalua-
8.
tion of reports of dioxin exposure and soft tissue sarcoma pathology among chemical workers in the United States. Scand. J. Work Environ. Health 10:299-303 Garte, S., Hochwalt, A. E. 1989. Com mentary, Oncogene activation in ex perimental carcinogenesis: The role of carcinogen and tissue specifi ci ty En viron. Health Perspect. 81:29-31 Hatch-Wyden Amendment, Public Law 99-499, Sect. 209 Herndon, W. C., Szentpaly, L. V. 1986. Theore tical model of activation of carcinogenic polycyclic benzenoid aromatic hydrocarbons. Possible new classes of carcinogenic aromatic hydro carbons. J. Mol. Struct. 148: 141 52 Klopman, G., Frierson, M. R., Rosen kranz, H. S. 1985. Computer analysis of toxicological data bases: Mutagenicity of aromatic amines in salmonella tester strains. Environ. Mutat. 7:626-44 Markowitz, S., Landrigan, P. 1989. The magnitude of the occupational disease problem: An investigation in New York State. Toxicol. Indust. Health 5:9-30 Nelson, N. 1981. A personal view of occupational cancer and its prevention. J. Natl. Cancer Inst. 67:227-31 Nelson, N. 1988. Mutual reinforcement between epidemiology and the labora tory in the study of environmental can cer. Ann. NY Acad. Sci. 534:1021-28 Perera, F. P., Santell, R., Poirier, M. C. 1985. Potential methods to monitor hu man populations exposed to carcino gens: Carcinogen-DNA binding as an .
9. 10.
-
II.
12.
.•
13.
14.
IS.
TOXICS AND PUBLIC HEALTH
16.
example. Banbury Report, Vol. 19: Risk Quantitation and Regulatory Policy, ed. D. G. Hoel, R. Merrill, F. P. Perera, pp. 211-23. Cold Spring Harbor Labora tory, Cold Spring, NY Poland, A., Knutson, J. C. 1982. 2,3,7,8 - Tetrachlorodibenzo p - dioxin and related halogenated aromatic hydro carbons: Examination of the mechanism of toxicity. Annu. Rev. Pho.rmacol. Tox icol. 22:517-54 Rouvray, D. H. 1986. Predicting chem istry from topology. Am. Sci. 254:40-47 Rutstein, D. D., Mullan, R. J., Frazier, T. M., Halperin, W. E., Melius, J. M., Sestito, J. P. 1983. Sentinel health events (occupational): A basis for physi cian recognition and public health sur veillance. Am. J. Public Health 73: 1054-l O62 Skolnick, M. 1987. Priority needs in the -
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
17. 18.
19.
37
development of genetic epidemiology. See Ref. 6, p. 29 20. Tennant, R. W., Margolin, B. H., Shel by, M. D., Zeiger, E., Haseman, J. K., Spalding, J., Caspaty, W., Resnick, M., Stasiewicz, S., Anderson, B., Minor, R. 1987. Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236: 933-39 21. Thorslund, T. W. 1987. Quantitative dose-response model for the tumor pro moting activity of TCDD. US En vironmenal Protection Agency, Carcino gen Assessment Group, Appendix, pp. 1-43 22. US Environmental Protection Agency Science Advisory Board. 1988. Future Risk: Research Strategies for the 199Os. Rep. Res. Strategies Committee, SAB EC-88-040, Washington, DC. 19 pp.
Further
Quick links to online content Annu. Rev. Public Health. 1990. 11:29-37 Copyright © 1990 by Annual Reviews Inc. All rights reserved
TOXICS AND PUBLIC HEALTH IN THE 1990s
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
Norton Nelson** New York University Medical Center, Institute York, New York 10016
of
Environmental Medicine, New
"Toxics" has come to be used as a general term to cover noxious chemicals, particularly those arising in industrialized societies (or those heavily using chemicals, e.g. pesticides). Public health, as a field, has increasingly become aware of and is now actively involved in the role of"toxics" in health injury and the quality of life. The aim of toxicology has always been the prevention of injury; this remains the guiding principle. The emphasis on prevention and finding means of choosing less hazardous ways of working with chemicals (including the development of appropriate regulations and controls) should receive even more emphasis in the next decade. Indeed, the report of the Research Strat egies for the 1990's Committee of the Environmental Protection Agency (EPA) Science Advisory Board (22) uses the theme of prevention as a major thread throughout its proposals for research strategies within EPA. Toxicolo gy will often need the assistance of epidemiology, especially to test the reliability of its "preventive" advice. Toxicology is much changed from what it was several decades ago, when it was primarily a rather routine testing enterprise. Toxicologists now are aware of the immense advances of the past several decades in molecular and cell biology. Toxicologists have developed sufficient sophistication so that the feedback between fundamental scientists and toxicologists serves to advance both fields. Two recent journals, Journal of Biochemical Toxicology and Chemical Research in Toxicology, reflect this interaction. Among the issues that have received a great deal of attention in the last few years are those growing out of the Superfund legislation relating to health and environmental hazards. When the first Superfund legislation was passed, it **Dr. Nelson died 2/4/90, after a fall, two days short of his 80th birthday. To the final hours he was a remarkably active and insightful leader of the field of environmental health, to which he has made so many contributions.
29
0163-7525/90/0510-0029$02.00
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
30
NELSON
was assumed that all was known that needed to be known about the disposal of toxic wastes; namely, that all that was really required was to gather the materials with reasonable regard for their presumed (but often unknown) hazards, bury them in some place, preferably remote, and walk away and hope that all would be well. It has turned out that we did not know many of the things that we needed to know about the safe disposal and secure disposition of chemical wastes. In the Superfund Amendments and Reauthorization Act, much more attention was given to improving means for safe disposal. Unfortunately, the techniques for determining the presence of toxic wastes and their risk assessment for health and ecological effects are still inadequate to distinguish reliably the extent of hazard. An important improvement in the legislation reauthorizing the Act was to direct much more attention and resources to research in these fields. This has led to increased activity and funding within EPA for study and improvements of methods for detection and risk assessment as well as for improved means for disposal of waste. A landmark part of the reauthorization was the enactment of the Superfund health-related program under the National Institute of Environmental Health Sciences; this program calls for university research to improve means for disposal, detection, and risk assessment (The Hatch-Wyden Amendment) (9). This program, now in its third year, provides funding through competitive grants to universities for the development of improved means for detecting and evaluating toxic wastes and for collaborative studies with engineers on means for reducing the amount and toxicity of qazardous wastes. It also provides for ecological studies to improve our understanding of the environ mental effects of hazardous wastes. Although this program is still too young to evaluate its progress, it has been received warmly, and funds have been awarded to nine universities throughout the country, all on a competitive basis. Each such award is linked with collaborative programs with engineer ing and ecological studies as well as studies on hydrogeology relating to possible movement through soils and aquifers. These awards went to universities with some of the most advanced toxico logical programs in the country. As a minimum, it can be predicted that techniques for the detection and evaluation of hazardous materials and their movement in the environment will be improved substantially. As noted, this program includes a novel feature that provides for collaborative work between toxicologists and engineers, particularly chemical engineers, on means for reducing the amount and toxicity of hazardous wastes. Toxicologists and engineers are seeking general processes to minimize the total waste requiring disposal and look for ways to recycle more of the total, ending up with much less toxic material to dispose of with, it is hoped, much less intrinsic toxicity.
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
TOXICS AND PUBLIC HEALTH
31
For now, however, this program can only make a modest dent in the total problem, considering the enormous bulk of waste presently requiring disposal and the extreme variety of wastes that are being d ispos ed , esp ec iall y since many of the wastes will be highly specialized according to the processes and agents i nv olv ed . One of the tools that will contribute in an important way to improving the ability to detect health injury is the advancing technique for detecting even more subtle biochemical changes that can be related to early patterns of injury. These support tools include a number of techniques for detection of early changes that have received the term biomarkers. These biomarkers can include the actual reaction of toxic chemicals or their metabolites with tissue biochemicals. An example of this is the reaction of toxic chemicals with DNA to produce adducts (15), which can be the first stage in the development of malignancy or can, in other instances, simply indicate exposure to a foreign chemical. In other cases, they may represent an altered response of limited duration that, if detected early, serves as an indication of exposure or of the initial stages of disease. Table 1 (6) indicates a spectrum of "indicators" or "markers" of biological response, which could range from the earliest indica tion of exposure of biochemical units, whether intracellular or extracellular, to disease or death. "Biomarkers" for the detection of real or potential injury provide important new tools for the earlier detection of potential injury. Susceptibility often varies widely within human populations. Techniques are emerging that detect individual susceptibility to foreign chemicals (6). The identification and classification of individual susceptibilities, whether from genetic endowment or disease, brings with it some awkward problems in the social use of such p roce dures , not all of which have been resolved at this stage, and means for the safe and fair application of these procedures may be required to guide their application (19). Toxicology, in the sense used here, comprises all of the procedures accessi ble for developing information on the possible or probable hazard of exposure to toxic agents. There are several reasons for linking epidemiological studies with toxicology in the objective of preventing injury. Obviously, the hop e of careful, p re dic tive tox ico lo gica l studies based primarily on laboratory or experimental procedures is to learn of the dangers of possible exposure, the limits of injury, and procedures for avoiding injury or for the development of substitute chemicals before chemicals are put into widespread use. There is always a risk of failing to develop adequate protective approaches, however, and for this reason, epidemiologic follow-ups are of the utmost importance to be sure that the predictions of safety are in fact valid and effective. In addition, epidemiology in some cases may be the only approach for which laboratory studies have not been possible or are suspected of being ineffective. In such cases, the linkage of toxicology through laboratory
32
NELSON Table 1
Continuum from exposure to endpoint. Markers of exposure and/or effects
Exposure
Dose
Effects
Endpoint
Exposure dose
Internal dose
Preclinical response
Disease
Biologically
Biological dose
Clinical effects
effective dose
Surrogate biological dose
Molecular dose
Biological marker
Annu. Rev. Public Health 1990.11:29-37. Downloaded from www.annualreviews.org Access provided by University of California - Davis on 02/04/15. For personal use only.
Exposure indicator The preferred but not unanimous version of our schematic is as follows:
/' Biological markers � � � Exposure dose � Molecular dose
'" Disease
/'
'"
Surrogate biological markers -> M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
M
10-9
10-7
10-6
M
10-2
Adapted from Ref. (6).
evaluations with epidemiology can be very important. Toxicology studies in the laboratory can avoid many of the pitfalls of epidemiology in better control of possible confounding factors; however, the techniques suffer from the lack of sensitivity, since the size of the study groups are likely to be small compared to that of possibly exposed groups of humans. Such studies can have a higher specificity than epidemiological studies, in which the exposure of humans under study may not be as well defined as in controlled laboratory studies. Of course, epidemiological studies are optimal in terms of their relevance to humans and do not involve species extrapolations. Table 2 (14) illustrates comparison of the contrasting powers of epidemiol ogy and toxicology. Linkage of the two, wherever applicable, is desirable. Such linkage is now underway in use of some of the more refined "biomarker" endpoints as mentioned above. The promises of these approaches of "molecu lar epidemiology" are still to be fully assessed, but the prospect is very hopeful (15). Occupational diseases are very much still with us. Unfortunately, their extent and prevalence remain inadequately measured. The US continues to need a country-wide system of occupational disease reporting, preferably linked with recording of "sentinel" diseases (Sentinel Health Events, Occupa-
TaXICS AND PUBLIC HEALTH Table 2
33
Toxicology/epidemiology: contrasts
Issue
Toxicology
Epidemiology
Control of variables
Excellent
Poor
Identifying causal factors
Excellent
Poor
Size of population
Limited
Can be very large
Sensitivity
Poor
Poor
Genetic diversity
Normally deliberately narrow
Broad
Intercurrent disease
Controllab le
Not controllable
Study of mechanisms
Easily accessible
Ethical hindrances
Uncertain relevancy
Directly relevant
Unrestricted (except interview)
Severely restricted
Exposure Environment
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Confounding factors
Diagno stic tests
Nelson (14)
tionally Related)
(18). Part of the problem is the inadequate recognition of
occupational etiologies on the part of the majority of physicians. A number of efforts are underway (including a recent one within the National Academy of Sciences/Institute of Medicine) to encourage wider awareness of occupational diseases by physicians. These are not the first attempts to urge physicians to identify occupational etiologies reliably; however, until there is a nationwide system of mandatory disease reporting, progress seems unlikely. New York State recently developed a statewide system of occupational disease clinics that could substantially improve the situation. A review associ ated with this development places work-related exposures at
3-4% of all
deaths, or between 5000 and 7000 annually in New York State (12). Useful though this statewide study is, a nationwide system for the detection and reporting of occupational disease is the surest way of understanding the substantial extent of impact of occupational disease. As pointed out elsewhere, conceptually occupational disease is almost totally preventable
(13). The techniques that could achieve this would involve
the total enclosure of dangerous processes so the workers would not be exposed. The problem of maintenance of equipment remains a possible source of exposure; here the use of robots under remote control could contribute significantly in filling this gap in the protective pattern. Although there appears not to have been any economic survey made relevant to the issue, it seems quite probable in my opinion that the costs of the "protective boxes" might be substantially less than the costs involved in medical services, medical care, loss of productivity and life, and litigation. In my judgment, the Toxic Substance Control Act, which is intended to control the safety of products, is not as stringent as it should be. Nonetheless,
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34
NELSON
it is a significant advance over the earlier, near total absence of control. The information required from industry is very sparse indeed, so much so that the final judgment often has to be made on the basis of structure-activity rela tionships alone rather than on the basis of actual toxicological study. The information required under the Toxic Substance Control Act is substantially less complete than guidelines now being developed within the "Common Market" in Europe (5). Improved "structure-activity techniques," especially quantitative structure activity relationships, are needed urgently. The pursuit of reliability in such predictive examinations should be encouraged (10, 11, 17). Such techniques might be especially useful as an aid in the assessment of the hazards of mixtures of chemicals for which current procedures leave much to be desired. Actual exposures of humans normally occur to a mixture of chemicals. Exposure rarely occurs through a single chemical. Another development receiving more attention has to do with the attempt to find test systems that minimize or do not involve the use of vertebrate animals. This is desirable from many standpoints, especially by animal rights advocates. Unquestionably, techniques that use either inanimate or isolated cell systems could replace some, perhaps many, tests on higher animals. One such system is the" Ames" test, which is a bacterial system for the detection of mutations by a relatively simple technique (2). This test has shown reasonably high correlation with the likelihood of the carcinogenicity of genotoxic chemicals, with, however, poor correlation to non-genotoxic che micals (20). Test systems for overall organ response for non-genotoxic endpoints have shown little promise (SGOMSEC) (3). Nevertheless, specific and limited patterns of organ injury can be detected in simplified tests; such approaches show some promise of reducing the need for use of living animals in many test systems. There is a danger that in our concentration on the studies at the molecular and cellular level, we may forget that the human organism is an organized and carefully tuned system of interacting organ functions and overall interaction with homeostatic mechanisms for mutual support and control. Complex organisms such as the human sometimes have to be examined as a complete organism (e.g. in laboratory animals) if important toxic responses are to be identified and their mechanism of action is to be understood. As suggested above, many new tools for toxicological studies are now emerging that can refine our understanding of the mode of injury and the stages through which injury proceeds. These include the increasing knowl edge of the role of receptor systems in toxic responses. An outstanding example of this is the importance of the p450 mixed-function oxidase enzyme system in the detoxification and toxification of foreign chemicals (16).
TaXICS AND PUBLIC HEALTH
35
An example of the attention that the p450 enzyme system is receiving has to do with the very toxic chemical tetrachlorodibenzo dioxin (TCDD), an ex tremely toxic chemical that is a by-product of a number of chemical pro cesses. It was first brought to public and scientific attention during the Vietnam war, when it was identified as a contaminant of 2,4,5T a herbicide then used militarily. TCDD has received extensive study. It is a potent carcinogen in ex perimental animals; and since it is widespread in the human environment, its
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possible human carcinogenicity is of concern. Although presently there is only limited evidence of human cancer arising from exposure to TCDD, it is the object of extensive study and considerable concern (7). TCDD has the very interesting property that although not proven to be an "initiating" agent through DNA injury, it has been suggested that it produces cancer in experimental animals through what is known as a "promoting" activity; that is, it accelerates the development of cancer by "promoting" the progression of cells, some of which have already been "initiated" to cancer. The mechanisms whereby this "promotion" occurs have excited much interest as both a scientific challenge and a reliable means of carrying out "risk assessment"
(21) for estimating the likelihood of human cancer from exposure
to TCDD. Thus, it has been proposed that the p450s clearly play an important role in this "promotion" of "initiated" cells by dioxin
(16). On the other hand,
there are some who regard TCDD as a complete carcinogen (1). Thus, there is a parallel intensive search for
(a) the means whereby the
enzymes (p450) induced by TCDD aid in conferring its promoting activity, and
(b) how to use its biological and chemical characteristics reliably to
estimate its quantitative cancer risk. Analytical tools for TCDD have been so refined that normal levels of several picogram per gram can now be detected reliably, as can elevated levels found 15 years after exposure in Air Force crewmen who were previously involved in spraying Agent Orange (contain ing 2,4,5T). The same procedures have made it possible to analyze blood from the children with chloracne exposed in the 2,4,5T explosion in Seveso, Italy. The blood samples were carefully preserved from the time of the explosion (1976), when analytical techniques were quite primitive; the high est levels yet seen in humans (up to 30,000 picograms per gram) were found in recent analysis of these preserved samples (4). Research tools used in these studies and others in this newer era of toxicology and public health are of a very sophisticated nature. The study of oncogenes is still far from mature enough to be used routinely in toxicological studies, but that day may be quite close at hand. It appears, for example, that there is some chemical or agent specificity in the kind of oncogene that is activated, which suggests that such studies of the oncogene system can provide additional information perhaps not easily obtainable otherwise
(8).
36
NELSON
In summary, toxicology is steadily maturing as a science and has reached the stage at which it can now make major contributions to fundamental studies of biological patterns of injury. There is widespread and growing interest in toxicology among basic scientists. This pattern can be expected to continue to the advantage both of toxicology and of basic sciences. We are only beginning to apply the new tools and understanding. Major social issues remain to which this improving science and art need to be
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applied. Legislative and regulatory changes are needed to facilitate the use of these new tools and improved resources to reduce injury and disease. This progress is needed if we are to continue to enjoy the technology to which we owe so many conveniences and pleasures of life. We have not adequately employed these protective and preventive resources to remove these in adequacies, which remain real and dangerous to mankind if uncontrolled.
Literature Cited I. Agency for Toxic Substances and Dis ease Registry (ATSDR). 1989. Toxi cological Profile for 2,3,7,8-Tetra chlorodibenzo-p-Dioxin. US Public Health Service. ATSDRITP-88123 2. Ames, B. N., McCann, J., Yamasaki, E. 1975. Methods for detecting carcino gens and mutagens with the salmonellal mammalian-microsome mutagenicity ·test. Mutat. Res. 31:347-64 3. Bourdeau, P., Somers, E., Richardson, M., Hickman, J. R., eds. 1990. SGOM SEC 4, Short-Term Toxicity Tests for Non-Genotoxic Effects, IPeS Joint Symp. SCOPE. In press 4. Centers for Disease Control. 1988. Preliminary Report: 2,3,7,8-Tetra chlorodibenzo-p-dioxin. Exposure to hu mans-Seveso, Italy. US DHHS, MMWR 37:733 5. Dominguez, G. 1980. Contrasts in Tox ic Substances Identification and Control, European Community 6th Amendment EPA TSCA, Toxic Substances Journal, Vol. I, No. 4, Executive Enterprises Publishing Company 6. Draggan, S., Cohrssen, J. J Morrison, R. E., eds. 1987. Summary Report of the Expert Panel Meeting on Human Health Impacts and their Mitigation. En vironmental Impacts on Human Health, The Agenda for Long-Term Research and Development, ed. S. Draggan, J. J. Cohrssen, R. E. Morrison. New York: Praeger 7. Fingerhut, M. A., Halperin, W. E., Honchar, P. A., Smith, A. B., Groth, D. H., Russell, W. O. 1984. An evalua-
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tion of reports of dioxin exposure and soft tissue sarcoma pathology among chemical workers in the United States. Scand. J. Work Environ. Health 10:299-303 Garte, S., Hochwalt, A. E. 1989. Com mentary, Oncogene activation in ex perimental carcinogenesis: The role of carcinogen and tissue specifi ci ty En viron. Health Perspect. 81:29-31 Hatch-Wyden Amendment, Public Law 99-499, Sect. 209 Herndon, W. C., Szentpaly, L. V. 1986. Theore tical model of activation of carcinogenic polycyclic benzenoid aromatic hydrocarbons. Possible new classes of carcinogenic aromatic hydro carbons. J. Mol. Struct. 148: 141 52 Klopman, G., Frierson, M. R., Rosen kranz, H. S. 1985. Computer analysis of toxicological data bases: Mutagenicity of aromatic amines in salmonella tester strains. Environ. Mutat. 7:626-44 Markowitz, S., Landrigan, P. 1989. The magnitude of the occupational disease problem: An investigation in New York State. Toxicol. Indust. Health 5:9-30 Nelson, N. 1981. A personal view of occupational cancer and its prevention. J. Natl. Cancer Inst. 67:227-31 Nelson, N. 1988. Mutual reinforcement between epidemiology and the labora tory in the study of environmental can cer. Ann. NY Acad. Sci. 534:1021-28 Perera, F. P., Santell, R., Poirier, M. C. 1985. Potential methods to monitor hu man populations exposed to carcino gens: Carcinogen-DNA binding as an .
9. 10.
-
II.
12.
.•
13.
14.
IS.
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example. Banbury Report, Vol. 19: Risk Quantitation and Regulatory Policy, ed. D. G. Hoel, R. Merrill, F. P. Perera, pp. 211-23. Cold Spring Harbor Labora tory, Cold Spring, NY Poland, A., Knutson, J. C. 1982. 2,3,7,8 - Tetrachlorodibenzo p - dioxin and related halogenated aromatic hydro carbons: Examination of the mechanism of toxicity. Annu. Rev. Pho.rmacol. Tox icol. 22:517-54 Rouvray, D. H. 1986. Predicting chem istry from topology. Am. Sci. 254:40-47 Rutstein, D. D., Mullan, R. J., Frazier, T. M., Halperin, W. E., Melius, J. M., Sestito, J. P. 1983. Sentinel health events (occupational): A basis for physi cian recognition and public health sur veillance. Am. J. Public Health 73: 1054-l O62 Skolnick, M. 1987. Priority needs in the -
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17. 18.
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37
development of genetic epidemiology. See Ref. 6, p. 29 20. Tennant, R. W., Margolin, B. H., Shel by, M. D., Zeiger, E., Haseman, J. K., Spalding, J., Caspaty, W., Resnick, M., Stasiewicz, S., Anderson, B., Minor, R. 1987. Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236: 933-39 21. Thorslund, T. W. 1987. Quantitative dose-response model for the tumor pro moting activity of TCDD. US En vironmenal Protection Agency, Carcino gen Assessment Group, Appendix, pp. 1-43 22. US Environmental Protection Agency Science Advisory Board. 1988. Future Risk: Research Strategies for the 199Os. Rep. Res. Strategies Committee, SAB EC-88-040, Washington, DC. 19 pp.
