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%i ESTIMATES OP THE FRACTION OF CANCER IN THE UNITED STATES RELATED TO OCCUPATIONAL FACTORS Prepared by: National Cancer Institute National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health Contributors (alphabetical order): Kenneth Bridbord, M.D., NIOSH Pierre Decoufle, Se.D., NCI Joseph F. Fraumeni, Jr., M.D./ NCI David 6. Hoel, Ph.D., NIEHS Robert N. Hoover, M.O., Sc.D., NCI David P. Sail, M.D., Ph.D., NIEHS, Director Umberto Saffiotti, M.D., NCI Marvin A. Schneiderman, Ph.D., NCI Arthur C.Ufcton, fc.p., NCI, Director Contributor to the Appendix: Nicholas Day, Ph.D., NCI, IARC September 15, 1978 APOOO12387 This statement addresses the question: "What is the best esti mate of the fraction of cancer incidence (or deaths) in the United States that is reasonable to attribute to occupational ^exposure in the present# and in the forseeable future?" Previously published estimates of this fraction have been as low as 1% to 5% for past data [reviews by Higginson (1-3)# Wynder and Gori (4)# and Doll (5)] and as high as 10% to 15% [see the discussion by Cole (6)]. All these estimates are somewhat speculative and several were seriously incomplete or deficient. Most are now out of date. If recent evi dence is considered and if the full consequences of occupational exposures in the present and recent past are taken into account, estimates of at least 20% appear much more reasonable# and may even be conservative. These estimates refer to the near term and the future. Four Pitfalls Four general problems confound attempts to answer this question. (a) Incomplete data. .Few industries have been investigated adequately for evaluating the possible occurrence of occupationally related cancers. Because of the insensitivity of epidemiologic sur veys and various difficulties in conducting them (7)# only agents and industrial processes which lead to rather large excess incidences have been identified to date. The International Agency for Research on Cancar (ZARC) has an ongoing program to review data on chemicals for potential carcinogenic effects. To date# some 358 chemicals and industrial processess have been reviewed. According to a recent 1 AP000I2388 exposures which started one or more decades in the past. Accurate numerical assessment is further complicated by the strong dependence of cancer incidence upon age and upon duration of exposure. Even in cases where and excess risk is detected within one or two decades, this dependence on age implies that most of the attribut able cancers will not occur until later in the life span of the exposed workers, perhaps as much as 40 or 50 years after the first exposure. It is difficult^to trace anyone for so long a time, and those epidemiological studies which do not follow people for a full lifetime are likely to underestimate lifetime risks. Mast in dustrial-epidemiologic studies have not (and probably could not) fol low a working population to its extinction. This problem is dis cussed in more detail in the Appendix, but a numerical example illustrates its importance. For many types of cancer, incidence increases approximately as the fourth or the fifth power of age (10}; hence the cumulative number of cancers occurring in a popula tion over a lifetime increases as the fifth or sixth power of age. If exposure to a carcinogen results in a constant multiplicative increase in risk at all ages, -then the number of cancers occurring in an exposed group will similarly increase as the fifth or sixth power of age. Thus, for example, the number of attributable cancers occurring by age 50 would be only about one-fifth or one-sixth of that expected by age 70. For this reason epidemiological studies often enumerate only a small fraction of the total excess cancers attributable to an agent. Any overall assessment of the importance of occupational carcinogenesis should take this into account. 4. APOOb12389 In 1976, Higginson and Muir (2) again sstimated the impact of environmental factors in human oancer. They stated, again with few supporting details: "Although occupational cancers recognized so far provide some of the most satisfactory data for identifying external agents, the absolute number of cancers due to occupational exposures would appear to be relatively small, probably 1% to 3% of all cancers." - In 1977, Wynder and Gori (4) presented estimates of the "percent of cancer incidence in the United States attributable to specific environmental factors." It would appear from Figure 1 in their paper that their median estimates for ths fraction of cancers at tributable to occupational factors were 41 for men and 2% for women. Their explanation for these estimates was: "The data presently svailable are, at best, educated estimates of the relationship between specific cancers and specific occupational groups. Cole et al. (56) suggested that 20% of bladder cancers occurring in males in the Boston area are related to occupational exposure. In certain counties of New Jersey, the in creased risk for this cancer appeared to be high among workers in certain bhemical industries. Bailar {personal communication) estimated that the occupa tional contribution to total cancer Incidence in males lies between 1 and 5%, -and a similar estimate was made by Nelson (personal communication) General estimates of the percentage of all human cancers related to occupational exposure range between 1 and 10%. How ever/ identification of specific high-risk groups, hazardous exposurs levtls, and relatsd oancer inci dence rates is yet to be determined." in addition to the error of "one-effect, one-cause" thinking pointed out above, their reliance on "educated estimates," "personal communi cations," and "general estimates" makes the resulting conclusions tenuous. And again, of course, no attempt was mads to estimate future consequences of past exposures. 6 AP000I2390 In 1977, Doll (5) published a survey of the importance of environmental faotors in human cancer in the U.K. Ee indicated his belief that occupational factors were of relatively small im portance, but did not make a numerical estimate* In 1977, Cole (6) estimated the fraction of cancer that is occupationally-induced to be less than 15% for men and less than 5% for women. Be explained the basis for these estimates as follows: "I estimated that the occupationally-induced burden was less than 15% for men and less than 5% for women. The major causes of cancer deaths art cancers of the lung, the breast and the colon; and these are largely or totally non-occupationally induced. Lung cancer is 90% cigarette-smoking-induced; breast cancer is probably not at all occupationally induced; there may be some, probably small, occupational component in cancer of the rectum. Other sites such as cervix or ovary have a negligible occupational component, if any. The above listed sites account for about half of the cancer deaths. For other sites, it is diffi cult to assess the occupational component. However, even an 'occupationally-related' cancer like bladder cancer can be attributed directly to occupational exposures only about 25% of the time. With half the cancer essentially non-occupationally induced, and half the cancers occupationally-induced less than 25% of the time, a reasonable estimate seemed to be 15% for males." This argument also assumes that a cancer which is related to a non- occupational factor cannot also be occupationally related. Cole's statement of the basis for his estimates makes it obvious that all these estimates contain a large element of uncertainty. We conclude that the statement that no more than 1% to 5% of cancers in the United States are attributable to occupational factors is based on partial use of current knowledge, reflects the one-cause one-effect fallacy--and is not particularly useful for estimating 7 AP000I2391 future risks. It is not even a correct reflection of the published estimates, which range up to 10% (4) or 15% (6) Re-formulating the Question Another defect of the studies summarized above is that they may deal with an inappropriate question. Most appear to have been at tempting to provide estimates of the fraction of present-day cancer incidence that is attributable to occupational exposures in the past, to agents that have already been demonstrated to be carcino genic. However, such a question is of limited interest because the most important consequences of exposures in the recent past will not be manifested until some time in the future. The question that needs to be addressed is "What is the likely contribution of presentday occupational exposures to future cancer incidence?" An answer to this question must be somewhat speculative, because we do not know which of the chemicals in the present-day workplace will be identified sometime in the future as causing cancer. Accordingly, to provide a basis for making appropriate estimates, ve will first attempt to estimate the contribution, of occupational exposures to known carcino gens in the recent past to present and future cancer incidence. It is not particularly helpful merely to speculate about the possible ex istence of hazardous chemicals in present-day workplaces. Asbestos as a Well-Studied Example The consequences of occupational exposure to asbestos in the United States have only begun to be recognized in the recent past (12-14). It has been estimated* (11} that between 6 and 11 million * Several authors of this report were responsible for preparing these estimates. AP00012392 workers have been exposed to asbestos in the U.S. since the beginning of World War II. Of that total# approximately 1.5 to 2.5 million are presently employed. Probably a million have already died, while the remainder--between 5.5 and 7.5 million workers--were formerly employed An environments with significant asbestos exposure, including the survivors among the 4.5 million who worked in shipyards during the 1940's. Of these and other asbestos workers, approximately 4 mil lion are believed to have had heavy exposure to asbestos (11) Epidemiological studies of workers (13-15) have indicated that, of heavily exposed workers who have already died, 20-25 percent have died of lung cancer, 7-10 percent of pleural or peritoneal meso thelioma, and 8-9 percent of gastrointestinal cancers, adding up to a total of 35-44%. These figures may be underestimates of lifetime cancer risks, because most of these workers have not been followed to the end of their life span. Of the 4 million heavily exposed workers, at least 1.6 million are thus expected to die of the asbestos--related cancers listed above. [In the absence of exposure to asbestos, about 0.35 million (8-9 per cent) would have been expected to die of cancers at these sites.} Assuming that the excess risk to the remaining less heavily exposed workers is one-quarter of that to the heavily exposed workers (an assumption suggested by the data in ref. 16), the total number of cancers attributable to asbestos in the less-heavily exposed group would be expected to be in the range 0.4 to 0.7 million, raising the total to 2.0 to 2.3 million. Since most of these cancers will be manifested over a period of 30-35 years, the expected average number $ AP00012393 of cancer deaths associated with asbestos per year in that period will be between 58,000 to 75,000.* Such numbers would comprise 13-18% of all cancer deaths expected in the united States in the forseeable future (assuming that total cancer deaths increase to 400,000 to 450,000 per year). Three features of these estimates deserve emphasis: 1. Although most of the exposure to asbestos has been in the past, most of the predicted effects are expected to be in the future. An estimate of the present-day numbers of cancers attributable to asbestos would undoubtedly be smaller. 2. A large fraction of the asbestos-related cancers are also related to smoking (lung and esophagus} or are in the gastro-intestinal tract (esophagus, stomach, and colon), where cancers are usually assumed to be not occupationally related (1,4,5,6). Hence, if the old one-effect, one-cause approach were used, the occupational origin of most of the asbestos-related cancers would be overlooked and they might be attributed to other or "unknown" factors. 3. Although the frequency of asbestos-related cancers is already substantial and is probably increasing rapidly, it has not yet been detected by examination of gross trends in cancer incidence (or mortality) in the general population. There are several reasons for this: (a) two of the major types of asbestos-related cancer, pleural and peritoneal mesothelioma, are not classified as such in the national health statistics, but are usually listed as lung cancers or as various abdominal cancers, respectively; (b) most asbestos-related lung cancers are also smoking-related, ^ Selikoff (15) made an estimate of 50,000 per year, exclusive of the added cases that would come among the less heavily exposed group. 10 AP00012394 so that if one thinks one has the full explanation for the rise in lung cancer incidence in smoking, it is likely that no other causes will be looked for; (c) any increase in asbestos-related cancers of the stomach and colon would be masked by the other long-term trends in cancer incidence at these sites (down in the stomach* probably up in the colon)? these long-term trends are usually attributed to dietary or unknown factors. Perhaps the most important lesson to be learned from the asbestos story is that a major public health disaster can develop while its early manifestations are lost by being attributed to other factors. This would support the argument that the earlier estimates for in dustrially related cancers may be deceptively low--having left out such information as the asbestos situation has now brought to our attention. 11 APOO012395' Comparison of Risks due to Asbestos with those due to Five Other High-Exposure Substances Zn Table 2 we have tabulated data on carcinogenic risks associated with exposure to five other substances to which there is large-scale occupational exposure, for comparison with corres ponding data on asbestos. The tabulation is similar to that pre sented in ref. 17, but incorporates more recent data where avail able, and is limited to the substances and cancer sites for which the best data *re available on both exposure and relative risks. The first three columns in Table 2 list the agent, the affected organs, and the observed risk ratios (&} (from Table 1 in ref. 7). The fourth column lists the age-adjusted incidence (I) of cancer at the sites in question in U.S. males (from data * presented in the Third National Cancer Survey, ref. 19) The figures tabulated are the age-adjusted incidences in males over 20 years of age, because most occupational exposure starts at around that age. The fifth column lists the estimated number of workers (N) exposed to the chemical in 1972-74 (from ref. 18, derived from the National Occupational Hazard Survey, ref. 20) The notes to Table 2 give further information about each chemical, including summaries of data from the most definitive studies of each, and references to excess cancers at sites other than those listed in the Table. The last column in Table 2 lists values of the quantity (R-l)NI. This is the average number of excess cancers that would 12 j AP00012396 be expected to occur in a population of size N, subject to a site-specific risk R tines that in the general population. Although these figures are crude projections of the numbers of excess cancers to be expected in the exposed workers, they are unlikely to be precise estimates of future cancer mortality, for several reasons. Perhaps the most important reason is that they are pro jections of the numbers of excess cancers in only one cohort of N workers. Because of turnovers in the workforce, the number of exposed workers and ex-workers subject to excess caneers at any one time will be several times larger than N. If, for example, the total number of workers who have ever been exposed to a substance is, say, 5 times the number currently exposed, then the figures in Table 2 would underestimate the potential effects by a factor of 5. It is primarily for this reason that the data for asbestos in Table 2 underestimate the expected future mortality from asbestos-related cancers by a factor of 4-5. Because the data for the other substances in Table 2 were derived in the same way as those for asbestos, they may likewise underestimate the number of cancers attributable to these substances. The other major assumption that is necessary before the figures in Table 2 can be used as predictions of future cancer 13 AP00012397 mortality is that the relative risks K would remain the same as those reported in the published studies throughout the workers1 lives, even if exposures ceased. The basis for this assumption is discussed in Appendix A, where both observational and theoretical reasons for assuming conatancey of R are put forward. In any case several of the studies from which the figures in Table 2 are derived reported average risks over a substantial fraction of the workers' lives. Several other factors complicate the interpretation of the figures in Table 2, including the potential consequences of simultaneous or sequential exposure to other carcinogens or modifying factors. One reason why Table 2 may overestimate numbers of tumor cancers is that some of the workers presently exposed may have less exposure than the workers from whom the risk ratios R were originally derived. For these reasons, the figures should not be interpreted as precise estimates of future cancers, but it is reasonable to compare them with the data derived by the same method for asbestosrelated cancers. At the least, the *data sfu*mmarized in Table 2 show that the five other agents together pose hazards similar to or greater than those posed by asbestos. The sum of the best projections (see notes to Table 2) for the five compounds is about 33,000 cancers per year, versus 13,900 for asbestos. In presenting this comparisont it should be emphasized that the former figure lncludez only the primary sites of action. Inclusion of ex pected excess cancers at other sites would increase the 14 AP00012398 estimates substantially. It should be re-eaphasized that many of the cancers con* sidered here as attributable to occupational exposure would simultaneously be attributable to other factors, especially smoking. They are "attributable to" occupational exposure in the sense that most of them would not have occurred in the ab sence of exposure, so that they could have been prevented by prevention of occupational exposure. Other Known and Potential Risks In addition to the five major agents listed in Table 2, a number of other agents and industrial processes are known or suspected to pose carcinogenic risks to exposed workers. We omitted from Table 2 several agents listed as occupational Carcinogens in refs. ?, 8 and 17, because we had difficulty matching data on relative risks to data on the number of workers exposed. These agents include cadmium, coal tar pitch volatiles, hematite, and vinyl chloride. The data we used on the number of workers exposed to carcinogenic -petroleum fractions are probably conservative,. - The* IARC (8) has already reviewed 221 agents identified as capable of inducing cancer in experimental animals. Although some occupational exposure is known to occur for most of these chemicals, epidemiological and case studies of their possible association with cancer in humans were lacking or were judged to be "inconclusive." Other carcinogens have been reported in the literature. To date only a very small proportion 15 AP00012399 of all the chemicals in use have been tested for carcinogenicity. Table 3 lists a number of occupational groups that have been shown to be at increased risk of cancer at specific sites, without specific causative agents having been identified. Al-< though risks ratios are available in most of these cases, the imprecision of information on the numbers of workers in the jobs concerned prevented us from making estimates about the number of cancers to be anticipated. In addition to chemical carcinogens, occupational exposure to radiation is known to be a significant cause of cancer in U.S. workers. Groups at risk include radiologists, uranium miners, workers in the nuclear industry, military personnel exposed to radiation from nuclear explosions and to nuclear weapons, air crews, and persons working at high altitudes. Persons working outdoors such as farm workers and fishermen are subject to in creased risks of skin cancer associated with solar radiation. We have not attempted to make numerical estimates of expected cancer incidence in these occupations although many millions of workers are at presumptive risk. Consequences of Present-Day Exposures She estimates of potential excess cancer mortality that are listed in Table 2 are projections of the future consequences of past exposures. The estimates of risk ratios listed in Table 2 are derived from studies published between 1947 and 1978, mostly since 1966 (7). The estimated numbers of workers exposed are derived from a survey in 1972-74 (20). The anticipated excess 16 AP000t24OO cancer incidences are those expected to be observed in the next three decades, and could exceed those currently occurring and attributable to the agents in question. There is evidence that occupational exposure to several of these agents has been reduced since the studies developing the risk estimates were published. Exposure to asbestos, benzene, coke oven emissions and vinyl chloride has been limited (although not eliminated) by recent OS&A regulations* There is also evidence, however, that not all the major occupational carcinogens have been eliminated* Of the agents in Table 2, there is today widespread exposure to arsenic, chromium, nickel, and many petroleum products* Most of the excess risks referenced in Table 3 remain uncontrolled because the causative agents have not been identified. A number of important occupa tional groups (such as agricultural field workers) have not been adequately surveyed for excess cancer risks. Only a handful of the 221 chemicals found positive in experimental animals and reviewed by the XARC (8) have been regulated as carcinogens in -the '&; workplace. Among those not regulated are a number of syn thetic organic chemicals to which there is widespread occupational exposure, but which have not been in production for long enough periods for excess risks to have been identified by epidemological studies. For public policy purposes, it would be very desirable to make numerical estimates of the potential consequences of presentday exposure to carcinogens in the workplace. Such estimates 17 APOOO12401 would, however, require numerical data on the extent and intensity of exposure, and on dose-response relationships in experimental animals. If sufficient data were available, pre diction of future consequences would require quantitative extra polation from animal responses to man. In our view, existing methods for such extrapolation leave enough questions open con cerning their precision so as to make us unwilling to attempt large scale estimates -- particularly in the absence of exposure data. Bence, we can say nothing firm about the magnitude of future risks attributable to the unquantified present-day ex posures . There is no evidence, however, that these risks are sub stantially less than the risks resulting from exposures in the recent past. Although several of the most Important known car cinogens have been controlled, others have not; many carcinogenic and potentially carcinogenic chemicals are still present in D.S. workplaces; the total volume of synthetic organic chemicals produced in the U.S. continues to.increase rapidly. If only one of the thousands of chemicals introduced into commerce in the past 30 years .proves to be as hazardous as asbestos, this could suffice to maintain comparable rates of occupationally-related - cancer for decades into the future. In our view, any complacency about the future consequences of present-day exposure to un characterized chemicals would be unjustified. 18 AP00012402 Two Alternative Approaches Other ways can ha used to estimate the possible contribution of occupational exposures to human cancer incidence. Although none, to our knowledge, has been used formally and quantitatively, at least two have been used informally to argue that occupa tionally-related cancers cannot be numerically important. The first approach is to analyze trends in total cancer incidence (or mortality) in the U.S. population. The argument is made that if occupational factors were important causes of cancer, then total cancer incidence vhould be increasing rapidly, reflecting the rapid increase in the number and amount of synthetic organic chemicals produced in recent decades. In fact (the argument runs), the continued increase in cancer incidence and mortality is almost solely due to increases in lung cancer and other smoking-related cancers. If the "smoking -related" cancers are subtracted from the total, the argument is that the overall trend is constant or even slightly decreasing. There are several fallacies in this argument: 1. Most of the increase in production of synthetic organic chemicals is too recent to be reflected in current cancer statistics. 2. The increase in production of synthetics (some of which are potential carcinogens) in the period 1940-1960 may well have been offset by reductions in the intensity of exposure to other I chemicals, resulting from improvements in industrial controls stimulated, in part, by government regulation. Exposure to several major carcinogens has been reduced substantially in recent years. Exposure to other potential carcinogens (such as carbon tetra chloride) was reduced earlier, to reduce other types of toxic / 19 AP00012403 hazard. The predicted consequence of reduction in exposure to "old" carcinogens and increase in exposure to "new" carcinogens is consistent with what is observed: an increase in cancer at sone sites and a decrease at others. 3. To subtract all the "smoking-related" cancers from the total is sophistry, because at least two of the sites in question are precisely those in which "occupationally-related" cancers are best recognized. Many of the smoking-related cancers should be simultaneously attributable to occupational factors. On a per-capita basis smoking among adults is declining and this should result in a decline in the smoking-related cancers -- but none of this is factored in when all "smoking-related" cancers are removed from the total. If the smoking-related cancers are not subtracted, total age-adjusted cancer incidence in the U.S. is increasing at more than 1% per annum (37). 4. Not all of the smoking-related cancers, i.e. those in the lung, pancreas, and bladder, are attributable to smoking. Sven if a liberal figure:is used for attributable risk, the frac tion of lung cancer incidence not attributable to smoking is increasing and total cancers possibly industrially related have been increasing more rapidly in the last several years than in the two decades from 1950 to 1970 (38 ). 5. As pointed out earlier, the major public health impact of asbestos-related cancer is just beginning to he re flected in overall cancer statistics, despite 37 years of heavy exposure. One should hardly expect more recent additions to have shown a great effect already. 20 AP00012404 A second approach is to compare cancer incidence in men and women. To the extent that exposure to chemical carcinogens occurred in occupations in which most workers are (or were) saler this should be reflected in differences in overall cancer incidence (and trends in incidence) in the two sexes. This argument would tend to support the concept of industrial risk. .The predicted difference is in fact observed: age-adjusted cancer incidence is greater in males than in females at every common site except the gall bladder and thyroid (19). In par ticular, incidence is much higher in males than in females in the key occupationally related sites: lung, liver, bladder, kidney, hematopoetic and lymphatic system and perhaps stomach and pan creas (19). Nonetheless, there are some flaws in this argument, too. Not only male workers have substantial exposure to carcinogens. Although male workers doubtless predominate in chemical manu facturing and heavy industry, women have long been employed in large numbers in light industry where there is substantial ex posure to certain carcinogens, e.g. the radium dial painters. The fraction of occupationally related cancers in women may increase in future years due to increased employment of women in jobs where they are exposed to carcinogens. . Even housewives have greater occupational exposure to some potential carcinogens than typical working men.* * We regard the home as a workplace, even if it does not fall within the jurisdiction of OSHA. 21 AP00012405 It would clearly be valuable to snake a rigorous comparison between employed and never employed women, but such a study would be difficult to conduct and interpret because of the many con founding variables. In our view, there is nothing in the gross cancer statistics for the U.S. population which is inconsistent with the hypothesis that up to 20-40% of all cancers are (or will be in the next several decades) attributable to occupational factors Relation between Occupational and Other Contributing Factors These estimates do not diminish the importance of other contributing factors to cancer risk such as smoking, diet, and perhaps urban-rural differences. While much of the data on occupational cancer risk considered in this paper does not specifically consider factors such as smoking (except for asbestos) and diet, it is also fair to state that the prevailing body of data linking smoking and diet with cancer risk do not adequately consider the contribution of exposure to occupational carcinogens. This is largely because the avaii&ble scientific methodologies do not facilitate, adequate consideration of all contributing factors in any single study or approach. Until recently most scientists did not take into account the multiple etiologies and the multi-stage nature of cancer. In retrospect, it is likely that cancer risk is a function of multiple interacting factors. Past assessments, unfortunately, generally failed to consider adequately one of the most important, and preventable, risk factor, exposure to carcinogenic agentsiin the workplace. 22 AP00012406 Opportunities for Prevention The estimates of cancer attributable to occupational ex posure given here should be viewed as pointing up the oppor tunities that exist to prevent disease in future generations* The causes of cancer sure multiple, with more than one factor con tributing to cancer risk. In such a situation, any percentage accounting of contributing causes to cancer well exceeds 100%. To prevent cancer, one must concentrate on causative factors that can be reduced so that we can decrease the burden of disease in future generations. It has been argued that present day asbestos workers are at lower risk than earlier workers. Opportunities to reduce risks and subsequent disease in other occupations are at hand. Summary and Conclusions 1. The estimates that only 1% to 5% of total cancers in the United States are attributable to occupational factors have not been scientifically documented and have little meaning for estimating even short-term future risks. 2. Host'cancers have multiple causes: it is a reduction ist error and not in keeping with current theories of cancer causation to attempt to assign each cancer to an exclusive single cause. 3. Because cancer incidence is strongly dependent on age and upon duration of exposure, and because most cancer occur late in life, many industrial epidemiological studies detect only a small fraction of cancers (i.e. those developing early). 23 AP000I2407 4. Past exposure to asbestos is expected to result in up to 2 million excess cancer deaths in the next three decades: this would correspond to roughly 13-18% of the total cancer mortal ity expected in that period. 5. Reasonable projections of the future consequences of past exposure to established carcinogens suggests that at least five of them may be comparable in their total effects to asbestos. 6. These projections suggest that occupationally related cancers may comprise as much as 20% or more of total cancer mortality in forthcoming decades. Asbestos alone will probably contribute up to 13-18%, and the data in Table 2 suggest at least 10%-20% more. These data do not include effects of radiation/ nor effect^a number of other known chemical carcinogens. 7. Although exposure to some of the more important occu pational carcinogens has been reduced in recent years/ there are still many unregulated carcinogens in the U.S. workplaces; a number of occupations are characterized by excess cancer risks which have not yet been attributed to specific agents. 8. There no sbund reason to assume that the future consequences of present-day exposure to carcinogens in the work place will be less than those of exposure in the recent past. 9. Patterns and trends in total cancer incidence (and mortality) in the U.S. are consistent with the hypothesis that occupationally-related cancers comprise a substantial and in creasing fraction of total cancer incidence. 24 AP000I2408 10. The conclusion that a substantial fraction of cancers in the United States are occupationally related is not inconsistent with conclusions that substantial fraction of cancers are also associated with other factors, such as cigarette smoking and diet. 11. Occupationally-related cancers offer important oppor tunities for prevention* 25 AP00012409 references 1. HIGGINSON, J. 1969. Present trends in cancer epidemiology. Proc. caned. Cancer Congr. 6:40-75. 2. HIGGINSON/ J., and MtJIR C.S. 1976. The role of epidemiology in elucidating the importance of environmental factors in human cancer. Cancer Detection and Prevention 1:79-105. 3. HIGGINSON/ J. 1976. A hazardous society? Individual versus community responsibility in cancer prevention. Amer. J. Publ. Health 66:359-366. 4. WYNDER, E.L., and GORIr G.B. 1977. Guest Editorial: Contribu tion of the environment to cancer incidence: an epidemio logical exercise. J. Nat. Cancer Inst. 56:825-832. 5. DOLL, R. 1977. Strategy for detection of cancer hazards to man. Nature 265:589-596. 6. COLE/ P. 1977. Cancer and occupation: Status and needs of epidemiologic research. Cancer 39:1788-1791 (Discussion on pp. 1807-1808). 7. COLE, P., and GOLDMAN, M.B. 1975. Occupation. Pp. 167-184 In Persons at High Risk of Cancer (J.F. Fraumeni, Jr., ed.) Academic Press, New York. 8. 9. TOMATIS, L., AGTHE, C., BARTSCH, H., HUFF, J., MONTESANO, R., SARACCI, R., WALKER, E.# and WILBOURN, J. 1978. Evaluation of the carcinogenicity of chemicals: A review of the IARC Monograph Programme (1971-77). Can. Res. 38:877-885. * SELIKOFF, I.J., HAMMOND, E-C-', and CTURG, J. 1968. Asbestos exposure* smoking and neoplasia. J. Amer. Med. Assoc. 204:106-112. 10. ARMXTAGE, P., and DOLL, R. 1961. Stochastic models for carcino genesis. Proc. 4th Berkeley Symposium on Mathematical Statistics and Probability, Vol. 4:19-38.University of California Press# Berkeley. 11. U.S. DEPARTMENT OF HEALTH, EDUCATION AND WELFARE. 1978. Statemene of Secretary Joseph A. Califano, Jr. April 26# 1978. 12. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. 1977. Monographs on the Assessment of Carcinogenic Risks of Chemicals to Man. vol. 14*Aabestos. (Appendix A# pp. 82-84). yon, France. 26 AP000I2410 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. SELIROFF, I.J. 1978. Paper presented at meeting of the New York Academy of Science, June 1978* SELIXOFF, I.J. 1978. Oral testimony at public hearings on OSHA generic cancer policy# June 1, 1978. SELIXOFF, I.J., and HAMMOND, E.C, 1978. Asbestos-associated disease in United States shipyards. CA 28:67-99. MENCK, H, and HENDERSON, B.E. 1976. Occupational differences in rates of lung cancer. J. Occup. Med. 18:797-801. LASSITER, D.V. 1976. In Occupational Carcinogenesis (eds. U. Saffiotti and J. Wagoner). Ann. N.Y. Acad. Sci. 271: 40-48. BRIDBORD# X. 1978. New Horizons in occupational medicine. National Institute of Occupational Safety and Health# Rockville# Maryland. NATIONAL CANCER INSTITUTE. 1975. Third National Cancer Survey: Incidence data. Nat. Cancer Inst. Monogr. 41:1-454. (S.J. Cutler and J.L. Young# Jr.# eds.). NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH. 1977. National Occupational Hazard Survey. Vol. III. Survey Analysis and Supplemental Tables. DREW (NIOSH) Publica tion No. 78-114. Cincinnati# Ohio. LEE, A.M. and FRAUMENI, J.F., JR. 1969. Arsenic and respira tory cancer in men: An occupational study. J. Nat. Cancer Inst. 42:1046-1052. INFANTE, P.F.# RINSXY, R.A., WAGONER# J.V., and YOUNG, R.J. 1977. Leukemia in benzene workers. Lancet:76-78# July 9# 1977. ' ROCKETTS, H.'E.'1977. Cause Specific Mortality of Coal Miners. J.'Occup. MSd. 19:795-801. LI, F.P., FRAUMENX# J.7., JR.# MANTEL, N. and MILLER# R.W. 1969. Cancer mortality among chemists. J. Nat. Cancer Inst. 43:1159-1164. KOSKELA, RXXTA-SISXO, HERNBERG# XARAVA, R.# JAKVINEN, E. and NURXNEN# H. 1976. A mortality study of foundry workers. Scan. J. Work Environ. Health 2:suppl. 1# 73-89. GIBSON, E.S.# MARTIN# R.H., and LOCKINGTON# J.N. 1977. Lung cancer mortality in a steal foundry. J. Occup. Med. 19: 807-812. 27 AP000124II 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. MOSS, E. and lee, W.R. 1974. Occurranca of oral and pharyngeal cancers in textile workers. Brit. J. Znd. Med. 31:224-232. LLOYD, J.W., DECOUFLE, P.r and SALVIN, L.G. 1977. Unusual mortality experience of printing pressmen. J. Occup. Med. 19:543-550. WAGONER, J.K., MILLER, R.W., LUNDIN, F.E., JR., FRAUMENI, J.F., JR., and BAIJ, M.E. 1963. Unusual cancer mortality among a group of underground metal miners. Mew Engl. J. Med. 269:284-289. REDMOND, C.K., STROBINO, B.R. and CYPESS, R.H. 1976. Cancer experience among coke by-product workers. In Occupational Carcinogenesis. (Eds. U. Saffiotti and J. Wagoner) Ann. N.Y. Acad. Sci. 271:102-115. LEMON, R.A. , LEE, J.S., WAGONER, J.K. and BLEJER, H-P. 1976. Cancer mortality among cadmium production workers. In Occupational Carcinogenesis. (Eds. U. Saffiotti and J. Wagoner.) Ann. N.Y. Acad. Sci. 271:274-279. COOPER, W.c. 1976. Cancer mortality patterns in the lead in dustry. In Occupational Carcinogenesis. (Eds. U. Saffiotti and J. Wagoner.) Ann N.Y. Acad. Sci. 171:250-259. MONSON, R.R., and NAKANO, K.x. 1976. Mortality among rubber workers: I. White male union employees in Akron, Ohio. Amer. J. Epidemiol. 103:284-296. PEDERSEN, E., HOGETVEIT, A.C., and ANDERSEN, A. 1973. Cancer of respiratory organs among workers at a nickel refinery in Norway. Int. J. Cancer 12:32-41. DOLL, R., MORGAN, L.G., and SP2ISER, F.E. 1970. Cancers of the lung and nasal siiiuses in nickel workers. Brit. J. Cancer 24:623^632'. ENTERLINE, P.E. 1974. Respiratory cancer among chromate workers. J.Occup. Med. 16:523-526. SCHNEIDERMAN, M. 1978. Statement prepared for OSHA hearings. SCHNEIDERMAN, M. 1978. Supplementary statement prepared for OSHA hearings. ACHESON, E.D. 1976. Nasal cancer in the furniture and boot and shoe manufacturing industries. Prev. Med. 5:295-315. BRXNTON, L.A. 1977. A death certificate analysis of nasal cancsr among furniture workers in North Carolina. Cancer Res. 37:3473-3474. w* - 28 AP006I2412 41. AKSOY, M. et al. 1974. Leukemia in shoe workers chronically exposed to benzene. Blood 44s637-841. 42. NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH. 1975. Criteria for a recommended standard: occupational exposure to inorganic arsenic. National Institute for Occupational Safety and Health. BEW Publication No. (NIOSH) 75*149. Rockville/ Maryland. 29 AP00012413 TABLE 1 CHEMICALS OR INDUSTRIAL PROCESSES ASSOCIATED WITH CANCER INDUCTION IN MAN (Derived from ref. 8, with addition of data on worker exposure from ref. 19i sic also footnotes to Table 3.) Chemical or Industrial Process Aflatoxins 4-Aainobiphenyl Arsenic compounds Asbestos Auramine Manufacture) Benzene Benzidine Bis(chlorosthyl) ether Cadmium using industries (? cadmium oxide) Main Type of Exposure* Target Organs in Man Main Route of Exposure . Estimated No. of Workers Exposed in U.S. Environmental, occupational0 Occupational Occupational, medicinal, en vironmental Occupational Occupational Occupational Occupational Occupational Liver Bladder Skin, lung, liver c Lung, pleu ral cavity, g.i. tract Bladder \ Hemato poietic system Bladder Lung Oral, inha lation6 Inhalation, kin, oral Inhalation, skin, oral Inhalation, oral Inhalation, skin, oral Inhalation, akin Inhalation, akin, oral Inhalation d 100 1,500,000g 1,600,000 d 1,900,000 2,200 d Occupational Pro strate, lung Inhalation, oral 1,400,000 30 AP00012414 Chemical or Industrial Process Main Type of exposure* Chlorampheni col Medicinal Chloromethyl ethyl ether Chromium (chro mate producing industries) Cyclophospha mide Diethylstilbestrol Haematite mining Isopropyl oil Melphalan Occupational Occupational Medicinal Medicinal Occupational Occupational Medicinal Mustard gas 2-Naphthyldftine ickel (oxides) Chlornaphasine Oxymethelone Phenaeetin Occupational ' Occupational Occupational Medicinal Medicinal Medicinal Target Organs in Man Main Acute of Exposure15' Estimated No of Markers Exposed in U, Hemato poietic system Lung Oral, injec tion .Inhalation d d Lung, nasal cavities^ Inhalation Bladder Uterus, vagina Lung Oral, Injec tion Oral Inhalation 1,500,000 (chromium oxides) d _______d 19,000 Kasai cavi ty, larynx Hemato poietic system .. . Lung# * larynx Bladder Xasal cavi ty, lung Bladder Inhalation Oral, injec tion Inhalation Inhalation, skin, oral Inhalation Oral d d ________ d 1,000 l,4 00,00(f _______d Liver Kidney Oral Oral ________d _________d 31 APOOOf24f 5 TABLE 2 REPOSTED RISKS ASSOCIATED HITE OCCUPATIONAL EXPOSUREi COMPARISON BETWEEN ASBESTOS AND FIVE OTHER HIGH-EXPOSURE SUBSTANCES Chemical Substance Affected Organs Risk Ratio (RJ** Age-adjusted Incidence per 100,000 .Males >20 yre (I)b Estimated No of Workers Currently Exposed (N)c (R-l)NI Asbestos Asbestos Asbestos Asbestos Asbestos Arsenic Bentene Chromium Nickel (oxides) Petroleum fractions (including aromatics) Lung, pleural and peritoneal esothelia Lung, pleural and peritoneal esothelia Esophagus Stomach Colon/rectum Respiratory" tract Leukemia Respiratory tract Respiratory tract Lung 1.5-12 6.6a 2.74 1.7d 1.6* 3-8 2-5* 5-9 5-10 (2-33) 116 116 9.4 26.2 85 131 17.9 131 131 116 1,600,000 900-19,000 1,600,000 10,400 1,600,000 1,600,000 1,600,000 l,300,000g 2,000,000 1,500,000 1,400,000 3,900,000f 250 400 BOO ,900-14,000 350-1400 ,900-16,000 ,300-16,500 9,100 * Fro rtf. 7 unless otherwise stated: D Fran ref. 18 c Fron ref. 17r derived from ref. 19 * Fron Table 3 in ref. 15 * From ref. 21 * Freni ref. 16: see notes below 9 Proa ref. 42 see also detailed notes below. 33 AP000124I6 NOTES TO TABLE 2 The figures for risk ratios listed in the table are drawn from the tabulation by Cole and Goldman (ref. 7) The notes below provide further data drawn from the principal published references for each substance. ASBESTOS Number of workers potentially exposed: About 1,600,000 Bisk Ratios: 1.5 - 12 for lung, pleural and peritoneal me80thelia Projected number of excess cancers per year: 13,900 Prom the studies of Selikoff (ref. 15) the relative risk for lung cancer among asbestos-insulation workers in the U.S. is about 6.6, which accounts for about 20% of their deaths. A further 7% of cases are due to mesotheliomas which otherwise occur rarely. Applying the 6.6-fold increase in lung cancer to 1.6 million exposed workers yeilds 10,400 excess cases with roughly another one third or-3,500 due to mesothelioma for a total of 13,900 eases p^r year. Provisional projections for excess' cancers in the respiratory tract, based upon the observed relative risks in Selikoff1s study (15) are given in Table 2. ARSENIC Number of workers potentially exposed: about 1,500,000 Risk Ratios: 3-8 for respiratory tract cancers Projected number of excess cancers per year: 7,300 In 1969 Lee and Fraumeni (ref. 21) evaluated the mortality experience of 8,047 white male smelter workers exposed to arsenic 34 - AP00012417 trioxide during 1938 to 1963. Smelter workers were found to have a three-fold excess in mortality from all respiratory cancer compared to a statewide population control group. About half of those in the study population were exposed to 'arsenic less than 10 years. Of those exposed for at least 15 years and followed another 25 years, the relative risk for respiratory cancer was 4.7. If this excess can be applied to the approximately 1,500,000 workers exposed to arsenic, it is projected that about 7,300 excess, lung cancers each year may occur. It should be noted that the cancer risk from exposure to arsenic may be influenced by exposures to other occupational chemicals, such as sulfur dioxide. Exposure to arsenic has also been associated with excess cancers of the skin and liver (7): these sites are not considered here. BENZENE Number of workers potentially exposed: about 2,000,000 Risk Ratios: About 5 for leukemia Projected number of excess cancers per year: 1,400 A study by Infante, Rinsky, Wagoner and Young (ref. 22) examined the mortality experience of workers exposed to benzene from 1940 to 1949. A significant 5-fold excess risk of death from all leukemias was observed compared to controls (7 observed vs. about 1.4 expected). This study represents an understatement of risk since the 25% lost to followup in the study population were regarded as alive in the statistical analysis. These data are consistent with numerous case reports of leukemia deaths AP000I 2418 among workers exposed to benzene. Based on these figures and an estimated occupationally-exposed population of about 2 million# it is projected that about 1,400 excess leukemia cases may occur due to benzene exposure on the job. CHROMIUM (Trioxide and other hexavalent chromium compounds) Number of workers potentially exposed: about 1,500,000 Risk Ratios: 3-40 for nasal cavity and sinus, lung and larynx Projected number of excess cancers per year: 7,900 Enterline (36) noted that the overall SMR for respiratory cancer in a group of 1,200 chromate workers, ages 20-64, who were working some time between January 1, 1937 and December 31, 1940 and who were born after 1889 was 942.6. SMRs decreased steadily over the observational period from a high of 2909.1 in the interval from 1941-45 to a low of 474.7 in 1956-60. From the above, it would seem that a reasonable estimate of the risk ratio for all respiratory cancers among workers exposed to chromium would be at least 5 and perhaps as high as 9. Assuming that an overall . .. V- `` risk of 5 can be-applied to the approximately 1.5 million exposed workers, it is estimated that about 7,900 excess cancer cases might occur each year. NICKEL (Oxides) Number of workers potentially exposed: about 1,400,000 Risk ratio: 5-10 for respiratory tract projected number of excess cancers per year: 7,300 A Norwegian study by Pedersen et al. in 1973 (34) observed an overall excess respiratory cancer increase of 5.6 fold among 36 AP00012419 nearly 2,000 men exposed to nickel. The highest risk (risk ratio of 14.0) was observed in men first employed before 1930 and followed for at least 40 years. Assuming that an overall risk ratio of abo.ut 5 for all respiratory cancers can be applied to the approximately 1,400,000 workers estimated exposed to nickel, it is projected that about 7,300 excess respiratory cancers, excluding nasal cancer, will occur each year. Studies by Doll (35) document the dramatic decrease in risk from respiratory cancer when positive action has been taken to reduce occupational exposure to nickel. Exposure to nickel compounds is also associat ed with excess cancers of the nasal sinuses (7): these cancers are not considered here. PETROLEUM PRODUCTS, INCLUDING AROMATIC HYDROCARBONS Number of workers potentially ..exposed: about 3,900,000 Risk ratios: 2-33 for lung cancer Projected number of excess cancers per year: 9,100 The carcinogenic properties-of petroleum products, especially polynuclear aromatic hydorearbona (PNHs) have been well stud ied. Lung cancer risk ratios in the range of 2 to 33 have been observed for coke oven end gas workers in the U.S., England, and Japan exposed to PBNs which are contained in petroleum products (Doll, Lloyd, Kawai, Xalzumdar, Redmond). Excess lung cancer risk rates have also been observed for roofers in the U.S. (Hammond). Less well appreciated is the fact that many other occupational groups are exposed to aromatic hydrocarbons, including poly nuclear aromatics; these groups include mechanics, electricians, and workers in the printing industry* (Menck and Henderson ref. AP00012420 16). The risk ratios for lung cancer in these groups range from about 2 to 4. The number of workers estimated to be ex posed to aromatic hydrocarbons, including polynuclear aromatics, is about 3,900,000. Assuming that an overall lung cancer risk ratio of 3 can be applied to these workers, it is estimated that about 9,100 excess lung cancer deaths each year might occur in this group. 38 AP066t242f TABLE 3. OCCUPATIONAL GROUPS IN WHICH EXCESS CANCER INCIDENCE BAS BEEN REPORTED WITHOUT IDENTIFICATION OF A SPECIFIC ETIOLOGIC AGENT Occupational Groups Coal Miners Chemists Foundry Workers Textile Workers Printing Pressmen (newspaper) Metal Miners Coke byproduct Workers Cadmium Production Workers Rubber industry Processing Tire Building Tire Curing ' Furniture Workers Shoe Workers Leather Workers Cancer Site(s) Stomach / Pancreas, lymphomas Lung Mouth and pharynx Mouth and pharynx Lung Large intestine. pancreas Lung, prostate Percent Excess Reported 40 64 79 50-150 77 125 200 181 312 135 248 Stomach# leukemia Bladder-# v. Brain Lung Nasal cavity and sinuses Nasal cavity and sinuses, leukemia Bladder 80 140 e 90 61 300-400 700 100 150 Ref. 23 24 25,26 27 28 29 30 31 33 33 33 39 39,40 41 7 Note: With the possible exception of the lung cancers and leukemias, there is no overlap between the excess cancers listed in this table and Table 2. 39 APOOO12422 APPENDIX A ESTIMATION OP LIFETIME RISKS FOLLOWING OCCUPATIONAL EXPOSURE A major part of the preceding paper concern the prediction of lifetime risk following occupational exposure to carcinogens during all or part of a working life. The estimates were derived assuming that relative risks remain constant for the rest of the lifetime, the esti mated values for the relative risks being derived from cohorts with their own particular distributions of age, and both age at, and dura tion since first exposure. The purpose of this Appendix is to show that the assumption of constancy of relative risk has a reasonable basis. Both relevant epidemiological data and the predictions of mathematical models of carcinogenesis will be considered. Epidemiological data from four types of exposure are discussed: asbestos, nickel, radiation, and cigarette smoking. The latter two are not primarily occupational exposures, but they provide the two examples best studies with regard to evolution of risk after exposure. For cigarette smoking, the incidence of lung cancer increases with the daily amount' smoked (either linearly or perhaps quadratically) and with the fourth power of duration of smoking, for current smokers. On stopping smoking the incidence does not further increase, but re mains approximately constant with age until it approaches that of non-smokers after some 20 years (Doll and Pete 1976) The relative risk therefore falls within fiva yaars of stopping smoking, as shown in Figure la. For radiation, leukemia behaves differently from tumors of epi thelial origin. Following a singla course of radiation treatment for APOOOt 2423 ankylosing spondylitis (Smith and Doll 1978), the relative risk for leukemia rises rapidly, reaching a peak within 3-5 years, then decreases to become inappreciable some 12-15 years after exposure (Figure lb). The relative risks for epithelial tumors of heavily exposed organs, however, remain low until 10 years-after exposure, then rise and remain on a plateau for the remainder of the observa tion period (Figure lc). Other epidemiological data on risks from irradiation show simi lar behavior for leukemia (A-bomb survivors) and for breast cancer (A-bomb survivors, women given radiation treatment for tuberculosis or post-partum mastitis) The two examples just given provide the two extreme possibilities, continually elevated risk following exposure of very limited duration, or a rapid fall in risk following cessation of a long lasting exposure. Asbestos and nickel provide two examples of occupational expo sures where cohorts have been followed over an extended period of time. Asbestos causes lung cancer, eancer of the gastrointestinal tract, and mesotheliomas (Selikoff and Hammond 1978). Among a cohort wove than two thirds of whom had been exposed for less than two years (Mewhouse and'Berry), the incidence of mesotheliomas increased with increasing rapidity until the limit of the observation period, 35 years after first exposure (Figure Id). Conversion of these Inci dence figures into corresponding values for relative risk is not helpful due to the rarity of the non-occupationally related disease. However, the absolute risk, as given by the incidence figure, shows no sign of leveling off even thirty years after cessation of external exposure. Extrapolation of the incidence curve to higher age groups A-2 AP0b6l2424 would seem justified, to give an estimate of 8-10% of deaths due to mesothelioma predicted in the group under study (Newhouse and Berry 1976). For cancer of the lung the data have not been presented in such clear fashion, but all studies indicate an increase in relative risk for the period more than twenty years after start of exposure com pared to 10-19 years after start of exposure. Assumption of a con stant relative risk would appear to be conservative (Selikoff and Bammond 1978; Peto et al. 1977; Newhouse and Barry 1976; Knox et al. 1968) . For nickel, the main carcinogenic hazard for the cohort from Wales appears to have been removed from the environment around 1930 (Dollt Matthews and Morgan 1977). Nevertheless, there has been no indication that the relative risk for either lung cancer or for can cer of the nasal sinuses has fallen over the decades following the reduction in hazard (Doll at al. 1970,1977) up to the most recently reported follow-up ending in 1971. Similarly in the Norwegian study r(Federsen 1973), the great reduction in expsoure to dust and fumes since 1950 is. not reflected in any reduction in relative risk. In terestingly, the values for the relative risk (average over follow up to 1971 in both cases) for the Welsh cohorts exposed before 1930 and the Norwegian cohort exposed before 1950 were similar, approxi mately 10-fold. One would conclude from these two examples of occupational exposure that the'epithelial tumors induced behave more like epithelial tumors related to radiation than to those related to cigarstte smok ing. Exposure to the aromatic amines would seem similar with risk %* AP00012425 among the exposed not falling two decased after removal from the workplace of the known carcinogens, but in this situation the replacements for the carcinogens may themselves have been carcino genic (Fox and Collier 1976). The different types of behavior described above can be devised from the widely accepted multi-stage theory of carcinogenesis, where a cancer is assumed to arise from a single cell which then passes through a series of stages, the last of which leads irreversibly to a clinically apparent tumor. With k stages, and with probabilities of transition constant over age, one would predict the age-specific incidence to increase with age to be (k-1) power, as is observed for most epithelial tumors with k 5 or 6 (Whittamore 1977; Cook, Doll and Fellingham 1969). Now suppose that an external carcinogen, as in an industrial exposure, begins to operate at time t^, and then is removed at time t2. If cancer is a multi-stage process, then the effect on the inci dence of the target organ cancer, and on the relative risk, will de pend on which stage in the process is primarily effected. If the initial stage is .affected then we expect the relative risk at time t (t>t2) to be of the forms RttJ - 1 + c td - + (1 - t2/t)k-1l where c is proportional to the dose. R(t) is shown graphically for various values of and t2 in Figure 2a. The approximate con stancy of the relative risk over time for a range of values of t^ and t2 is apparent, similar to the behavior for epithelial tumors after irradiation, and probably similar to the affects of asbestos and nickel. AP00012426 If the penultimate stage is affected/ the behavior is different/ the relative risk at time t (t>t2) being given by 1 + (t2/t)*"^ (tj/t)*kl , i.e. decreasing rapidly after cessation of exposure, as in Figure 2b. Cigarette smoking related lung cancer gives an example of this type of behavior* For mesotheliomas/ where because of the low spontaneous inci dence relative risk calculations are of little value, a multi-stage model (with K - 3) has been successfully fitted to both animal data and data from 35 years of follow-up of a cohort (Newhouse and Berry 1976). The multi-stage model appears to give a coherent picture of the evolution of risk after exposure during a limited interval which is consistent with available epidemiological data, at least for epi thelial tumors which comprise the great majority of occupationally related cancers. These data, taken together with the implication of the model, give support to the assumption on which many of the numeri cal estimates of the paper are based, and justify extrapolation of relative risk values.obtained from industrially exposed cohorts to the remaining lifetime of the cohort. 1-5 APOOO12427 REFERENCES COOK, P.J., DOLL, R., and FELLINGHAM, S.A. 1969. A mathematical model for the age distribution of cancer in man. int. J. Can. 4:93-112 DOLL, R., MORGAN, L.G., and SPEIZER, P. 1970. Cancers of the lung and nasal sinuses in nickel workers. Brit.-J. Can. 24:623632 DOLL, R., and PETO, R. 1976. Mortality in relation to smoking: 20 years-' observation on male British doctors. Brit. Med. J. 2:1525-1536 DOLL, R., MATHEWS, J.D., and MORGAN, L.G. 1977. Cancers of the lung and nasal sinuses in nickel workers: A reassessment of the period of risk. Brit. J. Indust. Med. 34:102-105 FOX, A.J., and COLLIER, P.F. 1976. A survey of occupational can cer in the rubber and cablemaking industries: Analysis of deaths occurring in 1972-74. Brit. J. Indust. Med. 33:249264 KNOX, J.F., HOLMES, S., DOLL, R., and HILL, I.D. 1968. Mortality from lung cancer and other causes among workers in an asbestos textile factory. Brit. J. Indust. Med. 25:293-303 NEWHOUSE, M.L., and BERRY, G. 1976. Predictions of mortality from mesothelial tumors in asbestos factory workers. Brit. J. Indust. . Med. 33:147-151 PEDERSEN, E., HOGETVEIT, A.C., and ANDERSEN, A. 1973. Cancer of respiratory organs among workers at a Nickel refinery in Norway. Int. J. Can. 12:32-41 v. - PETO, J., DOLL-, -ft., HOWARD, W.V., KINLEN, L.J., and LEWXNSBOH, H.C. 1977.' A'mortality study among workers in an English asbestos factory. Brit. J. Indust. Med. 34:169-173 SELIKOFF, I.J., and HAMMOND, E.C. 1976. Asbestos-associated disease in United States Shipyeard. Can. 28(2):87-99 SMITH, P.G. and DOLL, R. 1978. Age and time dependent changes in the rates of radiation induced cancers in patients with ankylos ing spondylitis following a single course of x-ray treatment. Presented at the International Atomic Energy Agency Symposium on Late Biological Effects of Ionizing Radiation, Vienna, March 13-17 WHITTEMORE, A.S. 1977. The age distribution of human cancer for carcinogenic exposures of varying intensity. Am. J. Epld. 106(5)$418-432 A-6 AP00012428 LEGENDS FOR FIGURES 1. a. Incidence rate of lung cancer as a percent of rate at time of stopping. b. Risk for leukemia following Irradiation for ankylosing spondylitis. Left hand vertical axis shows scale for relative risk* right hand vertical axis shows absolute excess number/10^ population per year. c. Risk for tumors of the heavily Irradiated sites, following Irradiation for ankylosing spondylitis. Vertical axes as In 1b. d. Incidence of mesothellomata, expressed as cumulative number observed, in years since first exposure to asbestos. Expected Incidence obtained from a Weibull model with Risk c (t-w)* where c, w and k are constant (as given In the figure) and t the time since first exposure. 2. Evaluation of risk after exposure of limited duration as predicted by a multi-stage model of carcinogenesis. e. First stage effected by the exposure, b. Penultimate stage effected by the exposure. r AP00012429 'FIGURE 1A PERCENT OF RATE AT TIME OF STOPPING 1000.. Continuing cigarettes smokers cigarette smokers I w \ 0 5 10 15 20 Years since stopping FIGURE IB A-8 AP000I2430 FIGURE 1C FIGURE ID 45 A-fr AP000I243I FIRST STAGE EFFECTED EXPOSURE BEGINS AT AGE 20 Evolution of Relative Risk After Limited Exposure, Expressed as Percent of Relative Risk Associated with Exposure Through Age 70 A-10 APOOO12432