Document DDBOZKKd1LvymXk7rXjMQjE8M

R&S 109994 BIO-MEDICAL.RESEARCH DOCUMENT DESCRIPTION FORM 63 Duplicate .in all cards: --> 68 69 Lfft 76 7ZTW year as-1961- File number [Right justify rNtimerie onlvl Author(s), as Last Name FS (No Punctuation) and coden for journal as JAMA preceeded by one blank space 20 21 -s---x---u---/-'C--o--:--fk--1u--------- 40 41 7778 Sub-Index Code 60 61 62 11 12 13 Title of Report; end with space-hyphen-hyphen-space. Follow with Index Terms separated from each other with comma-space. Avoid other punctuation; do not abbreviate. 12 61 62 2T 22 Psht+a?*- *// 4&te.)c a r /tftfA/ /tfi/tH '{ , ,Z/sr ^-^/y/7- 23 24 Source (Journal, Vol., Number, Pages, Date) 12 /Y/7^ T s 61 62 31 32 Brief Summary 12 10 SUMMARY: 61 62 61 62 63 64 Environmental Health Perspectives Vol. 17, pp. 5--11, 1976 Priorities in the Investigation of Human Health Hazards in the Plastics and Synthetic Rubber Industries by Irving J. Selikoff Experiences in the past decade provide guidance in selecting priorities for invest!* gation of health hazards in chemical industries. Pride of place should be given to the experience of large industrial populations, in part simply because large numbers of people are at risk and in part because such studies are more likely to give reliable answers. This recommendation has further strength when there is community exposure as well. Parenthetically, large populations provide opportunity to study multiple factor interaction; without this, toxic potential of a single agent may be obscured. Second, investigations should be mounted when there is reason for suspicion, as with particular chemical configurations, observed organ toxicity, animal carcinogenicity, unusual clin ical experience ("signal" tumors). It may be added that when agents' have already been used several decades, evaluation of human experience with them is now in order, if only to document absence of toxicity. The same recommendations hold for planned introduc tion of new. agents or widened distribution of existing ones, until we have better infor mation concerning validity of "pretesting" programs. Major advances have been made in epidemiological methods for these investigations. These now allow us to successfully focus on small.defined groups as well as to manage large populations. The Paradox of Rehn In 1895, Rehn reported three cases of cancer of the bladder, among fuchsin dye workers (1). Additional cases of an association between ani line dye exposure and bladder tumors were identified during the next 15 years in Germany and Switzerland. An assumption was projected that the developing chemical industry, with its increasing number of synthetic chemicals new to the human environment, would bring with it a harvest of cancer. This prediction, in the next decades, seemed far from unreasonable when carcinogenicity of literally hundreds of chemi cals in animal test studies was found (2). Yet, by and large, the prophecy was not seen to be fulfilled in the first half of this century. Even until recently, chemically induced cancers in humans have been relatively few and re stricted in type and number, ^-Naphthylamine and benzidine bladder cancer, radium neo- Mount Sinai School of Medicine of the City Uniity of New York, New York, New York 10029. plasms, coal tar skin cancers, sinus and lung cancer with some nickel compounds seemed ex ceptions to the broad spectrum of human con cern. Thus, until recent years, we were faced with something of a paradox; Rehn and his contem poraries had shown that human cancer could result from chemical industry exposure, labora tory studies indicated that agents could be var ied and numerous, yet human experience had not demonstrated this to be a major problem. In recent years, the question has again been put before us in pressing terms. Do experiences with vinyl chloride, bischloromethyl ether, benzene, chromates, etc., demonstrate that the prophecies were really correct, merely prema ture? We do not yet know, but the question is an important one and must be now addressed. Priorities The problem is immense and resources for its consideration scant and limited. From a societal point of view, it is therefore advantageous to October 1976 5 R&S 109996 consider priorities for the utilization of these scarce resources in personnel, facilities, sup port. Experiences in the past decade provide some guidance to. how these might be consid ered (3), and, while they are largely related to U.S. circumstances, the world-wide growth of the plastics and synthetic rubber industry sug gests they mav have broader application as well U). Exposure of Large Industrial Populations The experience of large groups of occupa tionally exposed workers should take pride of place in evaluative studies. First, should an im portant toxic or cancer hazard exist, large num bers of people would be at risk. The identifica tion of such hazards is therefore important sim ply as a matter of public health policy. But, further, such investigations have the added ad vantage of being more likely to provide reliable answers as' to whether or not hazards exist since, in many instances, only the experiences of large groups of people can establish their presence or absence. Indeed, if hazards of rela tively low incidence are present, it might well be impossible to identify them unless we have available the experiences of a sufficiently large number of people. Community Exposure Industrial agents which are also widely dis seminated in the 'Community environment should be given particularly high priority. Ma terials such as beryllium (5), polychlorinated biphenyls (6), lead (7), and asbestos (S) come to mind, albeit not central to the production process. The fact that styrene may leach from the ever-present styrofoam cup container into its contents make this monomer a good candi date for investigation. The experiences of the industrial groups would allow us to evaluate whether or not these agents might be important for the general population and could, in addi tion, teach us something of the sources of envi ronmental contamination. This recommenda tion is made, again, in terms of public health importance of potential human disease. Suspect Agents Sometimes, opportunities exist for investiga tions of agents in which considerations such as those above play a lesser (but not absent!) role. Where leads exist, from any of a variety of sources, it would be unwise not to follow them since there is a greater likelihood of early ac complishment with perhaps minimal allocation of resources. If there be large or moderately large numbers of people exposed, the investiga tion of such possibilities obviously becomes all the more important. Thus, where agents have had biological activ ity already demonstrated, especially in terms of organ toxicity, the full spectrum of their poten tial should be explored, particularly with rela tion to possible carcinogenicity. We might have benefited from such a perspective with vinyl chloride (0), and examples could now include monomers as styrene, halogenated hydrocarbon solvents, and a number of plasticizers. Study of chemical configuration can give ad ditional leads, especially if experience exists suggesting that there may be generalization within classes of chemicals. At the present time, examples would be particular configurations of halogenated ethers, metabolites of known chem ical carcinogens or substituted variants of such chemicals, as 3,3'-dichlorobenzidine. Carcinogenicity in animal models is being widely discussed in relation to its basis for reg ulatory action and control. It would appear ap propriate that it be at least equally utilized for the selection of human populations for study. The predictive value of animal carcinogenicity studies (10,11) might have shortened our lag in recognition of human cancer with vinyl chloride (12) and bischloromethyl ether (13). Not infrequently, limited data relating to hu man experience do not provide firm evidence for the existence of chemical toxicity or carci nogenicity. Nevertheless, such leads require ap propriate extension of studies, in larger popu lations or with alternate epidemiological meth ods. Long Use Where agents have been in use for many dec ades, opportunity exists for evaluation of possi ble health effects; human exposure has already occurred in such circumstances for a period suf ficiently long to determine whether or not dis ease associated with long-term, low-level expo sure will occur. Even if we have no reason to necessarily suspect that hazard exists, the fact that the results of long-term human exposure 6 Environmental Health Perspectives t it * are at hand, and merely have to be gathered and analyzed, provides an opportunity that de serves rather high priority. It might well be that studies of the experiences of such popula tions will result in demonstration that no iden tifiable health hazard has been associated with the exposure. This would be all to the good. It is perhaps equally important to identify agents without hazard, as those with such difficulties, from both scientific and practical points of view. Planned Introduction or Widened Distribution of Agents Where new chemicals are scheduled for intro duction, or for greatly widened distribution, it is reasonable that their potential toxic and car cinogenic effects be questioned prior to such introduction or widened distribution. There will have to be good judgment in selection of agents, however. Where the chemical in question is un likely to involve exposure of more than a very small number of people, in a limited operation, and if it has no resemblance to known carcino genic chemicals and there are no hints from animal or other studies that it represents a hazard, intensive testing might be unwar ranted. On the'other hand, if many people are going to be exposed, and if the chemical is "sus pect," its careful evaluation by all practical means would have to be undertaken. The concept of "pretesting" is very popular at this time. It may have a different meaning, however, for the general public and for scien tists. jMethodological approaches are not yet fixed. I expect that much thought willbe given to this problem'in the next several years and that further guidelines will be established. Methods Toxicological and carcinogenic properties of chemical agents can be investigated in a num ber of ways. These are not mutually exclusive, and while the emphasis given to one or another will vary in specific cases, in general a variety of methods is likely to be useful. The selection of approaches for particular agents and the evaluation of the weight to be given to the re sults of each type of study will require experi enced judgment. Toxicological: Pharmacodynamics Standard industrial toxicological study has a great deal to offer: this has become increas ingly evident in the past several years. The ad dition of modern pharmacodynamics has stead ily widened its scope. Animal Carcinogenicity Similarly, the authority and importance of classical animal carcinogenicity studies still re main central to any program of evaluation of the carcinogenicity of chemical agents. Recent advances in methodology and design have ex tended the importance of such studies (appro priate use of controls; number of species stud ied; lifetime observations; dose-response configurationS; adequate size of exposure groups; im proved facilities; alternate routes of adminis: tration). Evaluation of Bacterial Mutagenicity Models The use of bacterial test systems, such as that of Ames (14), may prove of considerable im portance. At the moment, there remains con siderable need for their validation in terms of animal and human carcinogenicity (15). It is expected that the data that will become avail able within the next two or three years will provide much information on this problem, as well as on its applicability to questions of inter actions of multiple factors to which exposure' may occur concurrently or sequentially. Epidemiological One of the important advances in the past decade has been the considerable progress made in epidemiological approaches to the evaluation of occupational and environmental disease. The next several years will see continued progress in this area and questions derived from epi demiological investigatians will stimulate an-. swers from laboratory studies, and vice versa. Experiences suggest that a variety of epi demiological approaches will be productive, and selection among them will depend upon the problems that are approached and the particu lar circumstances that will then obtain. A considerable difficulty in investigation of environmental and occupational cancer has been the long period of clinical latency (16) between onset of exposure (or, perhaps more accurately, "effective exposure") and the subsequent clini cal appearance of disease. A purely prospective approach to observation of human experience which would start at the present time is often October 1976 i* & !g i1 i* 30 C/> oto <0 <-J0 I t unacceptable, simply in terms of the long time necessary to provide data that would allow ap propriate judgment (17). (There are excep tions: occasionally, skin cancer may occur within a year or a year and a half with particu larly powerful carcinogenic coal tar derivatives; sometimes, chemical-induced leukemia may also have a short induction period.) As an alternative, it has been found that large cohorts can be identified without substan tial selective bias at points of time sufficiently long in the past to allow evaluation of potential long-term toxicity and carcinogenicity. Such a method, retrospective-prospective cohort study (3), is particularly suitable for study of occu pational and environmental hazards. Rare or unusual tumors which might be dubbed "signal'' neoplasms have been found to be of particular interest in identifying environ mental carcinogens. Examples in the past have included asbestos mesothelioma (18,19); an giosarcoma with thorotrast (20), arsenic (21), and vinyl chloride (12) ; nasal and sinus tumors with nickel (22) and among woodworkers .(23). To the present, there has been much insecur ity concerning the reliability and applicability of morbidity studies. It is likely that, with ap propriate care and design, much better use can be made of the vast amount of data available in such records. Methodological advances are needed, but these are in the offing. The classic approach of case-control compari son studies has also been found useful in inves tigation of environmental cancer (24), and it may be that much more extensive use will be made of this method, particularly in industrial circumstances, since the "control cases'' can be suitably matched to the index cases in all re spects other than exposure to the suspect agent. It may even be possible to utilize matched-pair analysis if sufficient large populations are avail able and if environments can be sufficiently well characterized. This has proven a highly success ful method for isolating particular influences from amidst confusing variables (25,26). Epidemiological methods needed for investi gation of community effects of occupational agents are now being developed and such fo cused community studies show great promise. Clear attention was first called to the potential of such investigations by the neighborhood cases of beryllium disease at the end of the 1940's (5) and emphasized by the neighborhood mesotheliomas with asbestos exposure during the 1960's (24,27). Neighborhood populations can be well defined and separated from the gen eral community. Their experiences will give much information concernig the effects of "lowlevel" environmental exposure. Further, recent epidemiological experiences indicate that family contact (conjugal) investigations can be quan titatively designed to provide information not merely to show that conjugal disease is possi ble [which we have known since 1936, with the report of PCB chloracne among family contacts (5)], but that the level of risk can be estab lished and information concerning dose-disease response relationships of the agent in question can be obtained. Cancer registries have, to the present, made but limited contributions to the evaluation of occupational and environmental disease. The utilization of coordinated registry-based data is being reviewed, however, and'it is likely that much better use of their potential will be found in the future. Finally, it is likely that there will be much study of the effects of chemical agents in terms of mutagenicity and teratogenicity and that the relation to potential carcinogenicity will be evaluated. At the present time, the significance of the teratogenic potential of a chemical agent to a risk of carcinogenicity has not been clearly established. It is likely that this will be a fruit ful area for investigation in the future, both in laboratory and epidemiological terms. Birth de fect registries may have an important role to play here. Interaction with focused community studies (see above) is also likely to occur. Multiple Factor Interactions The recent identification of multiple factor interactions in the etiology of human cancer has placed increased emphasis on previous informa tion from laboratory studies (28). Hammond and I consider that investigation of multiple factor interactions should now represent a ma jor perspective in the study of environmental causes of human cancer (29, 39). This is likely to be particularly true in the plastics and synthetic rubber industry, where exposure to a single agent is the exception rather than the rule. This understanding should be a back ground to both epidemiological and laboratory approaches. It has implications, too, in terns of prophylaxis, and control. Sometimes, agents in- R&s 109998 8 Environmental Health Perspectives R&S 109999 large-scale, long-term serial environmental measurements in industry and it' is uncertain whether such agencies should properly do this on a continuing, basis. Industrial management is much more familiar with the details of their production processes and may be considered, moreover, to have a special responsibility for the evaluation of chemical exposures associated with them. Still, the extent and range of envi ronmental measurements is potentially im mense and probably not possible with current industrial hygiene resources. Therefore, thought should be given by industry to the automation of environmental measurements. This is much more than ah engineering prob lem, however. Just as with epidomiological studies, the collection of masses of data, inade quately focused, may present more problems than are resolved. It would be well, therefore, to look to close collaboration between biological and engineering scientists, for the design of environmental surveillance. What we measure will be at least as important as how we meas ure.. Medical Surveillance There is a long tradition of industry partici pation in the medical surveillance of its em ployees. I suggest that it is possible to extend this ongoing system for the detention of toxic and carcinogenic agents in the industrial envi ronment. It would be a matter of little added expense or difficulty to extend currently adopted examination procedures to include tox icological surveillance, since these would necesitate, generally, only additional biochemical studies, possible cytological investigations and x-rays of specific sites (lung). Where particu lar hazards are identified, further additions "'ould be warranted (x-rays of hands with vinyl c iloride exposure, for example). Again, be cause large numbers of examinations would be required, periodically, it is likely that emphasis will be given to automation of examination procedures. A special problem is that of confidentiality. Although statistical results of studies should be available to industry and labor, I suggest that information concerning individuals should be* entirely confidential; there should be (and often is, nowadays) clear separation of the responsi bilities of the medical departments and the per sonnel departments of companies in the rubber and plastics industries. Further Perspectives Backlog of Unstudied Problems Starting shortly before the last World War, continuing through it and in the period since, there has been vast extension of the chemical industry. One need but point to the remarkable growth of the plastics industry to appreciate this (0.1 million tons produced in 1930; 30 mil lion tons in 1970). Comparatively little study of the toxic effects of many of the agents in volved, particularly those observable only after long periods of maturation, was undertaken until the past 5-10 years. Simultaneously, it is necessary to investigate and define toxicity problems associated with current use and cur rent agents. Industry-Labor Cooperation The growing concern and sophistication of labor groups with problems of occupational health and the increasing awareness of such problems in industry sharply raise the question of how these concurrent perspectives can be meshed. In the past, it was sometimes consid ered that the interests of each group was op posed to that of the other, apparently because of the knowledge that industrial health leads to considerable added cost. Such assumptions should no longer be automatically made. Rather, it is in the interest of all concerned to consider and develop close cooperation between industry and labor groups in investigating problems of toxic potential of industrial agents. Both should be involved in the process of con sidering and identifying potential problems, planning and management of the research pro grams, and analysis of the results. This is no longer the prerogative of one or the other, and neither will necessarily be satisfied merely with receiving the conclusions at the end of a study. This work was supported by research grants of the National Institute of Environmental Health Sciences ES 00928 and the American Cancer Society, R-33. REFERENCES 1. Rehn, L. Blasengeschwulste bei Fuchsin Arbeiter, Arch. Klin. Chirugie. 50: 588 (1895). 2. Arcos. J. C., and Argus, M. F. In: Chemical Induc tion of Cancer. Academic Press, New York, 197-1, IIB, pp. 3--1. 10 Environmental Health Perspectives volved will be able to be clearly defined, as the influence of cigarette smoking in the incidence of lung cancer among asbestos-exposed workers (29); at other times, it may be difficult to de cide what the factors are, as with the decrease in the cancer risk among nickel smelter work ers in South Wales, following the modification of smelting processes in 1925 (31). Industry Opportunities Industry has both special responsibilities and special opportunities in the area of environ mental disease and, particularly, environmental cancer. Epidemiological One of the most difficult problems in evaluat ing potential toxicity and/or carcinogenicity of occupational and environmental agents is the fact that identifiable exposed populations are often too small to allow for statistically reliable analysis. This is particularly true when the ef fects being considered have long periods of clinical latency and the populations at risk which meet the requirements of a long period from first exposure are particularly small. It is possible to circumvent this difficulty by coales cence of a number of groups exposed to the same agent, as by combining exposed popula tions in a number of plants in the same indus try, providing industry-wide cohorts. Some times, this can be accomplished by. the use of union records. In 'other instances, cooperation among a number of companies can provide the same opportunity. We have already seen that this can be accomplished in the plastics and rubber industries, and we look forward to the reports of the research groups at the Univer sity of North Carolina and the Harvard School of Public Health (32). Industry records are likely to be particularly valuable in another area, that of exposure of maintenance personnel. As matters now stand, chemical operators are sometimes least exposed to high concentrations of toxic chemical agents. Bather, maintenance personnel, accustomed to dealing with leaks, breakdowns, clean-outs, etc., may be more likely to have excessive exposure. Such individuals are sometime not included in studies of "chemical workers" since they are often separately categorized as steam-fitters, carpenters, electricians, welders, etc. Their identification in industry records would provide a much more exact categorization of potential exposure and facilitate evaluation of their ex perience. In an analogous problem, analysis of the to tal plant population carries the risk of a dilu tion effect. Hazard may be associated with one intermediate chemical among workers em ployed at a single point in the process. Knowl edge of the total process, available to industrial management, allows for appropriate categoriza tion of exposures and associated hazard. In deed,. this concept--vertical analysis of agent use--can extend to delivery and use of raw materials, and the finished product, as well. The episode of Epping jaundice provides a good ex ample (55). Sometimes-very valuable informa tion can be obtained concerning the risk of toxic effects by noting changes in incidence and kind of reaction, over periods of time associated with changes in the production process. The nickel (South Wales) episode has been com mented on. Too, the effect of changes in expo sure levels might also be studied. A particularly valuable opportunity for in dustry lies in its ability to identify those indi viduals who constituted initial exposed groups. It not infrequently happens that agents are in troduced into production and into commerce with no hint of potential toxicity or carcino genicity. Questions in this regard can first be raised decades later. In such instances, it would be particularly valuable to know the long-term experience of those people first exposed to the agent in question. Industry records would be unique. The foregoing implies some reorientation of industry record keeping practices. Employment records in industry are designed for specific purposes and, within these perspectives, are kept for varying periods of time. It will be nec essary in the future to consider the use of these record systems in a somewhat altered form, to include data that will be valuable later in occu pational health terms, and kept for much longer periods of time. Fortunately, computerization of records allows this to be done. Environmental Surveillance It is unlikely that governmental control and surveillance agencies such as the Occupational Safety and Health Administration of the De partment of Labor will be able' to undertake R&S 110000 October 1976 9 * j et-*: s k;t: p** 3. Hammond, E. C., and Selikoff, I. J. Types of pro spective studies needed in cancer research. In: 18. Weiss, A. Pleurakrebs bei lungenasbestose, in vivo morphologisch gesichert. Medizinische 1: 93 (1953). t-... Analytic and Experimental Epidemiology of Can 19. Leicher, F. Primary mesothelioma of peritoneum cer, \V. Nakahara, T. Hirayama, K, Nishioka and in a case of asbestosis. Arch. Gewerbepath. Gewer- H. Sugano, Eds,, University of Tokyo Press, Japan, behyg. 13: 382 (1954). * 1973, pp. 41--19. 20. Swarm, R. L., Miller, E., and Michelitch, H. J. l 4. Levinson, C. Vinyl chloride: a case study of the new Malignant vascular tumors in rabbits injected intra- i * Ft occupational health hazard. International Chemical Workers Federation, Geneva, Switzerland, 1974. p. 107. venouslv colloidal thorium dioxide. Pathol. Micro biol. 25: 27 (1962). 21. Roth, F. Arsen-leber-tumoren (Hemangioendothe- rt i 5. Eisenbud, M., et al. Nonoccupational berylliosis. J. Ind. Hyg. Toxicol. 31: 282 (1949). 6. Schwartz, L. Dermatitis from synthetic resins and liom). 2. Krebsforsch. 61: 468 (1957). 22. Doll, R. Practical steps towards the prevention of bronchial carcinoma. Scot. Med. J. 15: 433 (1970). waxes. Am. J. Pub. Health 26: 586 (1936). 23. Acheson, E. D., et al. Nasal cancer in woodworkers 7. Morbidity and Mortality Weekly Report. Epidemi in the furniture industry. Brit. Med J. 2: 587 (1968). ologic Notes and Reports. Lead Poisoning-Tennes- 24. Newhouse, M. L. and Thompson, H. Mesothelioma i see. Center for Disease Control, Atlanta, Ga., U.S. Department of Health, Education, and Welfare, of pleura and peritoneum following exposure to asbestos in the London area. Brit. J. Ind. Med. 22: i. * March 25, 1976, p. 85. 261 (1965). * ff t1 S. Anderson, H. A., et al. Household-contact asbestos neoplastic risk. Ann. N.Y. Acad. Sci. 271: 311 (1976). 9. Lilis, R., et al. Prevalence of disease among vinyl chloride and polwinvl chloride workers. Ann. N.Y. 25. Hammond, E. C. Smoking in relation to mortality and morbidity. J, Natl Cancer Inst. 32; 1161 (1964). 26. Hammond, E. C., atGarfinckel, L. Aspirin and coronary heart disease: findings of a prospective study. Brit. Med. J. 2: 269 (1975). * * ti Acad. Sci. 246: 22 (1975). 10. Viola, P. L., Bigotti, A, and Caputo, A. Oncogenic 27. Wagner, J. C,, Sleggs, C. A., and Marchand, P. Diffuse pleural mesothelioma and.asbestos exposure \ response of rat skin, lungs and bones to vinyl in the North Western Cape Province Brit. J. Ind. gi chloride. Cancer Res. 31: 516 (1971). Med. 17: 260 (1960). 11. Maltoni, C., and Lefemine, G. Carcinogenicity bio 28. Bittner, J. J. Possible relationship of the estrogenic assays of vinyl chloride--1. Research plan and early results. Environ. Res. 7: 387 (1974). hormones, genetic susceptibility and milk influence in the production of mammary cancer in mice. t 12. Creech, J. L., Jr., and Johnson, M. N. Angiosarcoma of liver in the manufacture of polyvinvl chloride. Cancer Res. 2: 710 (1942). 29. Selikoff, I. J., Hammond, E. C., and Churg, J. l J. Occup. Med. 16: 150 (1974). Asbestos exposure, smoking and neoplasia. J. Amer. 13. Figueroa, W. G., Raskowski, R., and Weiss,- W. Med. Assoc. 204: 106 (1968). Lung cancer in chloromethyl ether workers. N. Engl. 30. Selikoff, I. J. and Hammond, E. C. Multiple risk J. Med. 288: 1096 (1973). 14. Ames, B. N., Lee, F. D., and Durston, W. E. An improved bacterial test system for the detection factors in environmental cancer. In: Persons at High Risk of Cancer. J. F. Fraumeni, Jr., Ed., Academic Press, New York, 1975, pp. 467-484. i i and classification of mutagens and carcinogens 31. Doll, R., Morgan, L. G,, and Speizer, F. E. Cancers Proc. Natl. Acad. Sci. 70: 782 (1973). of the lung and nasal sinuses in nickel workers. 15. McCann, J., et al. Detection of carcinogens as muta Brit. J. Cancer 24: 623 (1970). gens in the 'Salmonella/microsome test: assay of 32. McMichael, A. J., Spirtas, R., and Kupper, L. L. An 300 chemicals. Proc. Natl. Acad. Sci. 72: 5135 epidemiologic study of mortality within a cohort of (1975). rubber workers. J, Occup. Med. 16: 458 (1974). 16. Selikoff, I. J. Recent perspectives in occupational 33. Kopelman, H., et al. The Epping jaundice. Brit. JO cancer. Ambio IV (1): 14 (1975). Med. J. 1: 514 (1966). Bo 17. Selikoff, I. J. and Hammond, E. C. Environmental CO cancer in the year 2000. 7th National Cancer Conf. i Proc., Los Angeles, 1973, pp. 687-696. % o o o i October 1976