Document qk8yY6d31xpbenwLMqZ1vz4gE

AIHC AMERICAN INDUSTRIAL HEALTH COUNCIL 1075 CENTRAL PARK AVENUE SCARSDALE, NEW YORK 10583 (914) 72*1492 November 1978 At the suggestion of the Steering Committee of the American Industrial Health Council# the following documents are enclosed for your informations 1) Reply to the "Estimates of the Fraction of Cancer in the United States Attributable to Occupational Factors" (October 23# 1978) 2) "Estimates of the Fraction of Cancer in the United States Related to occupational Factors" prepared by the National Cancer Institute# National Institute of Environmental Health Sciences# National Institute for Occupational Safety and Health (September 15# 1978) 3) Draft Summary of "Estimates of the Fraction of Cancer Incidence in the United States Attributable to Occupational Factors" prepared by the National Cancer Institute and National Institute of Environmental Health Sciences (September 11# 1978). AP00008850 AIHC AMERICAN INDUSTRIAL HEALTH COUNCIL 1075 CENTRAL PARK AV0-1UE SCARSDALE, NEW YORK 10583 (914) 725-1492 A Reply to: "Estimates of the Fraction of Cancer in the United States Attributable to Occupational Factors" (September 15, 1978) October 23, 1978 AP00008851 Table of Contents Introduction Critical Review of Methods Used in Estimates Paper to Predict Cancer Mortality Due to Occupation Use of Inapplicable Risk Ratios Use of Inappropriate Estimates of the Exposed Population Paulty Use of Incidence Rates to Estimate Mortality Attributable Risk Confused with Associated Risk Summary Appendices: Appendix A - Asbestos appendix B -- National OccupationalHazard Survey Appendix C - Arsenic Appendix D - Chromium Appendix E - Nickel Appendix P -- Petroleum Distillates Appendix G - Benzene Appendix H - Vinyl Chloride Appendix I * Comments on EstimatesPaperAppendix A 1 5 6 8 9 11 12 A-l B--1 C-l D-l E-l F-l G-l H-l 1-1 AP00008852 Introduction The American Industrial Health Council (AXRC) has reviewed the recently released government paper "Estimates of the Fraction of Cancer in the Onited States Related to Occu pational Factors" whleh was filed in the OSKA post hearing record-on September 15, 1978 (referred to hereafter as "Esti mates Paper") This document predicts a massive Increase in estimated cancer incidence and mortality due to occupational exposures. While recognizing that oceupationally-ralated can cers' do occur and that this incidence must be reduced, AIBC be- 1 lieves scientific evidence does not support the contention that the magnitude of the problem even approaches the projections made in the Estimates Paper. She following analysis by the AIHC presents documented examples to demonstrate the questionable logic used in the Esti mates Paper* In this Reply, AIBC discusses the methodology used in the Estimates Paper and examines specific contentions of the Estimates Paper for asbestos, arsenic, chromium and polynuclear aromatic hydrocarbons plus the basic epidemiology concepts used in the Paper, A complete detailed discussion of the Estimates Paper is presented in Appendices to this Reply, To make this analysis, it was necessary to try to reconstruct the statistieal manipulations performed through review bf the Paper's souree references. This analysis revealed selective use of data, whieh was often outdated and of questionable scientific validity. -- r* * -1- AP00008853 In preparing the Estimates Paper, asbestos has been ehosen as the keystone for its argument* Asbestos is an attrac tive example for a document such as this; it is universally accept ed as a carcinogen; many studies exist; excess mortality has been documented; and there is a high level of public and political awareness of its health hazards* Hany of these same characteris tics make it an unusual carcinogan. The document does not mention, for instance, that no other industrial carcinogen is suspected of so many deaths, nor that such other carcinogens are unlikely to exist currently without our knowledge* Data available from both the Surveillance Epidemiology and End Results Program (SEER) of the National Cancer Institute and the Third National Cancer Sur vey (TNCS) belie the projections* of an asbestos epidemic contained in the Estimates Paper* Zf the Paper is correct, our country should at present be experiencing a marked increase of mesothelioma (the marker disease for asbestos), and it is not. As described more fully in the attached Appendix A, using the methodology set out in the Estimates Paper itself, one would project a present-day mesothelioma incidenca of at least 5,000-9,000 annually (using some very conservative assumptions) and possibly as high as 10,000 or more* In fact, SEER data indicate that the national annual in cidence is less than 1,000* Zn predicting enormeue future mortality from aabastoa, the Estimates Paper (a) overestimates the number of people in the previously heavily exposed WW ZZ cohort still alive since mortal ity has baen occurring for many years due to many causes; (b) dis- -2- AP00008854 regard* the fact that asbestos exposure has baen declining by both number of workers and by degree of exposure in recant years; and (e) ignores any changes in smoking habits, expeeially among asbestos workers, that should have important effects on reducing Asbestos mortality. Although specific calculations for the asbes tos case study are presented in Appendix A, some of the faulty logie followed in this example has baen noted here since the Esti mates Paper advocates extending these principles to other carcino gens* Significant errors in estimation of cancers attributabla to occupational causes were made for many of the other hazards considered. In the case of arsenie, populations at risk were exaggerated by ignoring significant changes in indus trial applications. The Estimates Paper failed to mention the fact that certain major industries no longer use arsenic in their processes. This matter had been addressed only recently by OS BA in its inorganic arsenic rulemaking. OSHA's own con clusion on this issue does not support the Estimates Paper's inflated number of workers at risk from exposure to arsenie. The Estimates Paper indicates that l.S million workers art currently exposed to some form of chromium compounds, with the elaar implication that all of these workers are at signifi cant risk. The rafaranca cited in the Paper refers to workers whose exposure may be only inferred or potential rather than actual. Furthermore, among the 1.5 million exposed workers, N20SH indicates a sizeable number of these persons are exposed -3- AP00008855 1 to chromium compounds not considered to bo carcinogenic. Horo again, the Estimates Paper appears to be less than scientifically . objective. To estimate the lung cancers attributable to Polynu clear Aromatic Hydrocarbons (PNA) exposure, the Estimates Paper applies the relative risk of various cohorts of coke oven and gas workers to a vide variety of workers potentially exposed to PNA's in other industries. The exposures in other indus tries, however, are very different from the exposures of eoke oven and gas workers. Extrapolation between industries there fore is inappropriate and misleading. It is AZHC's position that whenever a confirmed or high ly probable cause of eancer ie found in the workplace* there is good and sufficient reason to take prompt and stringent protec tive action. The scientific evaluation of the risks involved, however, must be thorough and sound. When estimates such as those in the Estimates Paper are made on the basis of unsound methods, erroneous data and an unsciantific analysis, AXHC feels it is necessary to try to put the record straight. That is the purpose of this Reply. AP00008856 CRITICAL REVIEW OF METHODS USED IK ESTIMATES PAPER TO PREDICT CANCER MORTALITY DUS TO OCCUPATION The Estimates Paper purports to prediet the number of deaths from cancer likely to occur in the future# due to past and present industrial exposure to carcinogens. The pre diction is based on the following formulation:. Annual Excess Deaths Due To Occupation Age-Standardised (Risk Ratio - 1) x Cause-Specific x Exposed Incidence Rate Population Obviously, any errors in determining risk ratios, representa tive rates# or of population at risk will result in a multipli cation of those errors*' In fact, serious errors have been made in determining all three multipliers# and these errors have .yielded exaggerated estimates of excess mortality due to occupational exposures* Specifically# the estimates have the following major problems* Risk ratios inapplicable to recent workplace conditions were used* Inflated estimates were made of the exposed population* 1972 estimates of numbers of po tentially exposed workers were taken as the number of workers currently and actually exposed* , The concept of attributable risk was confused with associated risk# ignoring the risk of such cancers in unexposed workers and ignoring -5- AP00008857 other risk factors. Age-standardized rates based on spacifie age-sex distributions were applied to large cohorts whose age and sex distribution is entirely unknown. Incidence rates were used as equivalent to aortality without adjustment for sur vival or competing causes of death. * * ... Use of Inapplicable Risk Ratios In the appendix of this Reply, we have examined in more detail the problems with specific estimates relating to risks from particular substances*. In the Estimates Paper, risk ratios generally ara taken from studies of workers exposed in the 1920's - 1950's. Workplace conditions for known esreinogens, and for a great many other chemicals also, have, however, improved considerably since then. Applying a risk factor associated with heavy exposure to workers no longer subject to heavy exposure must grossly overestimate the risk to the worker. In his asbes tos studies, Selikoff acknowledges that it is probably reasonable 1/ to conclude that "cancer risk varies directly with exposure." Exposures have been much lower in recent years yet no adjustment * is made for this. 1/ Selikoff, I. J. and Hanmond, E. C. "Multiple Risk Factors in Environmental Cancer", Persons at High Risk of Cancer, at 467-483, 1975. t AP00008858 The Estimates Paper's treatment of arsenie is a good Illustration of this point. The risk ratios used to assess the. risk of exposure to arsenie by the Estimates Paper Is 4.7*- This risk ratio* derived frpm the Lee and Fraumeni study,*" was found by the authors in only one cohort of persons who worked during the early process days. Zn a second cohort in the same study* exposures of at least IS years duration, but later in tine, yielded a risk ratio of 3*7; 10*14 year exposures.gave a risk, ratio of 2.3. All of these risk ratios, however, are based on conditions considerably worse than those that have existed for the past 15 years. The authors acknowledge a "gradient in pro portion to the degree of exposure." Bowever* the Estimates Paper utilises the highest figure evetr reported, whereas even the lower reported risk ratios are undoubtedly too high to apply to workers exposed within the last 15 years. The risk ratio of 5 used in the ehromium estimate is similarly inappropriate because the studies conducted were largely based on data from the 1930*s and 1940's from old chromate-producing plants. In a recent report (1978) of chrome pigment workers by Davies, no excess risk was seen among persons with "low exposures* in two factories (exposure dates 1932*1954 and 1948*1967). Nor was excess risk found over all exposure strata in a cohort of workers employed during 1955-1967. 1/ Reference 21-The Estimates Paper. 2/ Davies, J. H. "Lung*Cancer Mortality of Workers Making Chrome Pigments*, The Lancet, at 384, 1978. -7 - AP00008859 The risk ratio of 6.2 used in the nickel category is exaggerated. a 1977 study by Doll ^ a reassessment of ths study referenced in ths Estimates Paper# states that the six-fold excess found was confined to persons, exposed before 1930 and that no significant excess of lung or nasal cancer vas seen among persons first exposed during the period 19301944# after process changes had been implemented. Css of Inappropriate Estimates of the Exposed Population The exposed population figures used in the Estimates Paper (with the exception of asbestos and arsenic) are based on the National Occupational Baxard Survey (NOBS) document publish ed in 1977. This survey did not"measure levels of exposure and# in fact# included actual# potential# or inferred exposures as veil as part-time exposures. In the case of chromium# for ex ample, only 16% of the 1.5 million workers considered as poten tially exposed by NOBS were full-time workers. (Definition of full-time was at least 4 hours per day.) la addition# not all of the 1.5 million workers in the chromium oxides industry were potentially exposed to hexavalent chromium compounds# the only ehromium compounds which have been found tb be car cinogenic. The same problem occurs with the nickel estimates. 1/ Doll# A.# Mathews# J. D.# Morgan# L. G.# "Cancers of the Dung and Nasal Sinuses in Nickel Workers: A Reassess ment of the Period of Risk*# Brit. J. of Industr. Med. 1977 34*102-105, -------------- -B- T i j f AP00008860 The risks refer to persons engaged in nickel refining (and as stated earlierf they pertain to a tine when exposures were nuch heavier}* The estimated number of workers currently^posed as reported in the Estimates Paper, however, includes many jobs in addition to those involving nickel refining. With respeet to asbestos, the numbers are apparently a combination of an estimate of 4.5 million WW II shipyard workers by Dr. Selikoff and an estimate of 3.5-6.5 million ex posed workers based on some unidentified factor of work force turnover applied to NOBS data. All attempts to ascertain docu mentation for the figures contained in the estimates Paper have proven fruitless. With respect to arsenic, the exposed population figure of 1.5 million is based on 1964 data cited in the 1975 NIOSH Cri teria Document. OSHA's own Inflationary Impact Statement on In organic Arsenic rejected that outdated number. OSHA concluded that of an exposed population of 660,000 a "large number" work in areas where exposures are "very low or non-existent." Faulty Use of Incidence Rates to Estimate Mortality Table 2 of the Estimates Paper is used to predict future cancer mortality. In using incidence rates instead of mortality rates, an incorrect assumption is made: namely, that all persons who are diagnosed with caneer subsequently die with cancer as the underlying cause. This clearly is not the ease. Many cancer patients die eventually of ether causes. -9- AP00008861 Za contrast to tho incidence ratal given in Table 2, . 1970 mortality ratas for males over age 20 for neoplasms ace given below. Age-Adjusted Incidence, 1969-70 Mortality per 100/000 Rate/ Males/ 1970 Males. 20 years* */ 20 years* */ % Excess Incidence Over Mortality Lung Esophagus _ Stomach Colon/rectum Respiratory Tract Leukemia 116 9.4 26.2 85 131 17.9 88 32 7 34 16 64 37. 130 94 40 12 49 ^/Source* Third National Cancer Survey. **/ Source: Vital Statistics of the united States 1970-Vol XIMortality/ at 1-197, 6-17. Zt can be seen that incidence rates are considerably higher than mortality rates. While cancer incidence itself is tragic, using th highar incidence rates as though equivalent to mortality rates is inappropriate and greatly compounds error. In addition, the Estimates Paper ignores important tem poral changes in mortality rates. For example/ stomach eanesr death rates have been steadily decreasing, lung cancer deaths have been steadily increasing. Such changes, along with other factors,'make it Impossible to project a decade, or several de cades ahead. The use Of mortality rates or the use of ineidenee rates with adjustment for survival and competing causes of mortal ity would have been a more accurate way to estimate deaths. Fur- -i j t *\ - 10 - AP00008862 - ther, *9* and sex distribution of exposed cohorts were never considered in the Estinstes Paper, thereby rendering invalid the use of age-standardized rates to predict mortality in the totally un specified cohort* Attributable Risk Confused With Associated Risk _v__ __________ ____ _ Presumably, a key question is "what fraction of-deaths could be prevented by reduction of industrial.exposure?" To follow the logic of the Estimates Paper, Worker 1, in group of 10 men, who previously worked in asbestos application and uranium mining and smoked, would have his death attributed to each of several factors. Suppose each of the other nine men in the group had known work histories as outlined in the table below. All died of.lung cancer* Worker 1 2 3 4' 5 6 7 8 9 10 Smoker + + + Asbestos + 4* + 4* Uranium 4* + + Deaths attributable to smoking Deaths attributable to asbestos Deaths attributable to uranium 5 3 Total deaths 14 If we accept the Estimates Paper logic, we would then conclude that smoking accounted for 60% of deaths, asbestos for SOI, and - 11 - AP00008863 * uranium for 30%. We now have "attributed" 140% of deaths and have not yet taken into account genetie susceptibility* diet* or exposure to any other carcinogens. Thus* under the methodology of the Estimates Paper* a double or triple accounting for each death will occur because a person is tallied as dying more than once if he is potentially exposed* for instance* to both asbestos and uranium. The error of double or triple accounting is magnified by use of NOBS-databecause a high proportion of workers listed as exposed are only part-time or only inferentially or potentially exposed. Zn feet* the NOHS estimated 4.38 billion potential exposures among 38.2 million workers. This gives an average of 115 potential exposures per worker (including a sizeable*number of clerical and other office workers). Clearly* one cannot assume.each death is attri butable to each of 115 different exposures. The survey data con tained in the NOHS report were not meant to be used in the manner presented in the Estimates Paper. Summary AIHC analysis demonstrates that the Estimates Paper* in the haste to complete and release the document* has Ignored basie principles of sound epidemiological and biostatistieal practice. The Estimates Paper through such practices has come to unscientific end highly speculative conclusions. By selecting high risk ratios applicable to a small group of highly exposed workers* by inflating estimates of workers actually exposed* by - 12 - i; f; i r r t}' i t; n i\ * i! i i! i AP00008864 confuting incidence with mortality, by neglecting age and eex distribution of worker cohorts and by confusing attributable risk with statistical association, the Estimates Paper arrives at a speculative conclusion concerning the probabilities of an Imminent cancer epidemic due to occupational causes. This con clusion cannot be supported by national cancer statistics of the National Cancer Institute itself. - 13 - AP00008865 n if if y'_ it tf 4' it if APPENDICES d 4 d d 3 3 I L !'( ;-1 ft. I I AP00008866 APPENDIX A Comments On Estimates Paper With Regard To Asbestos . Summary --An analysis of the Estimates Paper regarding the inci dence.of lung cancer related to exposure to asbestos.shows that the projected increase is of an order of aagnltude greater than ean be supported by the data. Using data from, the National Can cer Institute's SEEP Program (Surveillance, Epidemiology and End Results) for the incidence of mesothelioma (a marker tumor for asbestos related lung eancer) approximately 950 cases oecur anually in the U.S. She Estimates Paper would predict as a minimum 5,000-9,000 deaths annually from mesothelioma in the World War II shipyard workers alone. This estimate is far afield from current experience and data, underscoring the logical and methodological flaws in the Estimates Paper. Both the risk faetors utilised and the population assumed to be at risk are greatly exaggerated. Testing The Logic of the Estimates Paper Against the Available Data To illustrate the unscientific approach used to obtain the projections in the Estimates Paper, the treatment of asbestos, the "well-studied example", is worthy of some attention. Mesothelioma, a rare tumor In the general population, is eommraonly found in heavily-exposed asbestos groups. Thus, it is known as a marker or identifier tumor for cohorts at increased A-l r AP00008867 1/ risk because of heavy exposure to asbestos. Following the Logic of the estimates Paper As a check against the accuracy of the predictions in the Estimates Paper# It may be useful to estimate, how many marker mesotheliomas would have been predicted for the U.S. in 1976#. using the reasoning and figures in the Estimates Paper which statess ."It has been estimated that between 8 and 11 million workers heve been exposed to asbestos in the u.s. since the beginning of World War It. Probably a million have already died# while the remainder -- between 5.5 and 7*5 million workers -- were formerly employed in environments with significant asbestos exposure# including the survivors among the 4.5 million who worked in shipyard's during the 1940*1* Of these and othsr asbestos workers# approximately 4 million are believed to have had heavy ex posure to asbestos." (Estimates Paper at 8-9.) Continuing with our testing of the logic of the Estimates Paper# let ua consider the 4*5 million WW II shipyard workers and au ppose the probable million who have already died came entirely fr dm that group# leaving an estimated 3.5 million ww II shipyard workers alive in 1978. This is a very conservative allocation of the "probable million dead#" since of the 7-10 million'exposed siice the beginning of WW II and still alive in 1978 (8 to 11 million# minus one million dead# according to the Estimates Paper) 1/ Sea# e.c.* Blot et al# "Lung Cancer After Employment in tEe Shipyards During World war II# The Wew England Journal of Medicine# September 21# 1978, at 520-6237 Hoover and Fraumeni, co-authors of the article, are also contributors to the Estimates Paper. A-2 1 I jr I I v 1 I I I l I I f, f f \ l f l AP00008868 we-have allocated all deaths to tha group with*the earliest - exposure* thus Baking it nore difficult to find current "asbestos-deaths" Bow aany of the 4 million who are "believed to have had heavy exposure to asbestos" should be allooated to the-3.5 million, surviving WW 11 shipyard workers? Since the document estimated 7 to 10 million surviving workers have.been exposed to asbestos sinee the beginning of WW it* it follows-that 4/10 - to 4/7 of surviving workers have had "heavy exposure." Since much of the "heavy exposure" took piece during WW II, s conserva tive allocation (conservative again in the sense of.making it more difficult to find current "asbestos-deaths") would assign heavy exposure to only 4/10 to i/7 of the already conservative 3.5 million. Thus* we have the following tablet Table A--1 Conservative Allocation of Surviving WW .II Shipyard workers to Heavily Exposed Category ._^ Range for Total Exposed and Alive 1978 Total Beavily Exposed Surviving WW II Shipyard Workers BeavilyExposed Less BeavilyExposed Total 7*000*000 4*000*000 2*000*000 1*500*000 3*500*000 10*000*000 4*000*000 1*400*000 2*100*000 3*500*000 Therefore* a conservatively low estimate of heavilyexposed surviving WW II shipyard workers would be between 1.4 and 2.0 million. Virtually all of these WW II workers would havs been in their mid-fifties or older by 1976. A-3 AP00008869 According to figures published by the U.5. Bureau of _the_*nsus (Statistical Abstract of the United States? 1949) . . approximately one in three workers in the civilian labor force -daring W? II was female* To allow for the fact, that age-specific., mortality rates are higher for males than females*.the female pro-, portion in the surviving WW II shipyard work force will be in creased from an initial one-third to 40%. Using the figures. . .. published by the national Center for Health statistics ("Vital . -Statistics Rsport" Advance Report* Final Mortality Statistics* 1976* DHEW Publication HO* (PSS) 78-1120* Vol* 26* Ho. 12*... Supplement (2)* March 30* 1978) we see the following age and eex specific death ratess Table A-2 Whita Aqa-Sax--Speciflc Death Rates* 1976 ____________ - 1976 Death Rates per 1000 Population Ace Group Hales Females___ 55-64 19.2 9.2 65+ 67.1 45.8 !: h i In 1976* in the 55 and over age groups* slightly.over 50% of the males were 65 and over* while over 56% of the females were 6$ and over* Therefore* we allocate 50% of the surviving 1/ If one were to assume* contrary to this assumption* that fewer women end more men were exposed* one would expect* because of the differences between the sexes in life ex pectancy and smoking patterns* a shorter-lived cohort with a greater number of deaths in 1976. A-4 AP00008870 WW XX males to each of th two age groups in Table Ar2mnd 45% . : ** and 55% to the 55*64 and 654- female age groups, .respectively.; .The following calculations can now be made* .T. Table A-3 Sax/Age Group Males Female Total Deaths from WWII Shipyard Workers -- 1976 White p.S. Age-Sex Specific Rates - * _____ ;; Alive at beginning off 1976 Deaths in 1976 55-64 1,050,000 630,000 1,680,000 654 1,050,000 770,000 1,820,000 55-64/;. '654 Total. 20,160 5,985 70,455 35,266 90,615 41,251 26,145 105,721 131,866 For example, if 60% of the surviving WW XX shipyard work* ers are males, and 50% of those are 654, we get 3,500,000 X .6 X *5 1,050,000 in the 654 ag group at the beginning o 1976. (Recall that to be conservative we have not allowed any deaths, in 1977.) Apply ing the age-sex specific death rate of 67*1 per thousand from Table A-2, we get 1,050 x 67.1 - 70,455 deaths. Bow many mesothelioma deaths should there have been, if the conjectures in the Estimates Paper apply? According to the references cited In the Estimates Paper (e.c.* (15) and Ntvhouse and Berry in Appendix A) the latency period is long enough for the *7-10 percent" of deaths to be due to pleural or peritoneal mesotheliomas. Recall from Table A-l the conservative allocation of past heavy asbestos exposure to the surviving WW XX shipyard A-5 AP0000887I cohort* If 2*000,000 wort heavily exposed (derived from the assumption of 7,800,000 surviving in 1978), it follows that of t*1* 131,866 deaths, 4/7 will have been from the heavily-exposed group (since 4/7 of the surviving 3,500,000, or. 2,000,000 were.: - heavily exposed). Thus at least 7% of the ((4/7).x 131,866 - 75,352)!deaths among the heavily-exposed group (.07 x ?5*,352 m 5,275) will have been due to mesothelioma. ' The document assumed that* "the excess risk to the remaining less heavily exposed workers is one-quarter of that to the heavily exposed workers." -r Applying the 1/4 excess risk, we get (3/7) x 131,866 x (.07) x (1/4) - 989 mesothelioma deaths among the less heavily exposed group. Therefore, there should have been at least-6,264 mesothelioma deaths in 1976 from the ww IX shi^ yard cohort. Analogous calculations can ba made. Table A-4 _______ 1976 Mesothelioma Deaths Among WW II Shipyard Workers If Total Exposed and Alive is* Percentage* Mesothelioma Deaths _________ Among All Deaths 7% 10% 7,000,000 10,000,000 6,264 5,077 8,949 7,253 1/4 for the less heavily exposed subcohort. - Using the figures in the Estimates Paper, thus far we have _ -- conservatively allocated the survivors to the cohort of WW II shipyard workers, - conservatively allocated the heavy exposures to the WW II shipyard cohort. A-6 i -- \ AP00008872 -- dealt only with the WW II shipyard cohort,' - considered vhlte age-sex adjusted death rates with no adjustment for increased risk, \ ' * and we-arrived at a lower bound of 5,000 to 6.000-1075`mesothelioma - - j_ -..deaths*. .If in fact the Mortality experience of the cohorts cited ' in the Estimates Paper is applicable to the surviving WGf II-ship yard, workers, the death rates should be Increased by at least 40%, increasing the lower bound to between 7*000 aad-6,400. The Available Data The following table contains mesothelioma incidence from the SEER program, obtained from NCI* Table -*-6 SEEX Areas Incidence of Mesothelioma for all Sexes and Races, all sites V Years Total 1973 1974 --1973 -- 1976 Connecticut New Orleans Atlanta Detroit Iowa Hawaii New Mexico San Francisco Seattle Utah 52 9 13 16 14 12 ** 1 7 4 2 ** a* ** 2 63 10 22 14 17 43 10 15 11 7 611 4 0 21 5 S 7 4 95 41 2**6 22 11 20 15 27 15 17 2 4 6 S Total 352 63 94 100 95 * Unspecified mesothelioma lesions were not classified with malignan cies in the Third National Cancer Survey and during the early part of the SEER program, beginning with the use of the 1976 SEER Code Manual (sometime in 1976 or 1977) unspecified lesions were eoded with malignancies. ** Not in the SEER program In that year. A-7 AP00008873 The SEER population represent about 10% of the U.S. population. Disregarding the faet that the SEER population should have an unusually large number of eases (if the projec tions of the Estimates Paper are true) since five of the areas bave a significant ship building industry# these data would in dicate a national incidence of about 950 cases of mesothelioma for 1975. Therefore# if there should be at least 7#Q00 to 8,400 deaths from the ww II cohort alone# the Estimates Paper lower bound for the estimate is at least an order of magnitude too 1/ high. Conclusions Thus far we have dealt* only with a conservative lower bound for mesothelioma using only the estimated survivors from the WW II shipyard cohort. If the large nuxabers of "heavily-ex-- posed" non-shipyard workers are considered# a substantial number should have been exposed during and immediately following WW II 1/ Any suggestion that incomplete diagnostic ascertainment " would account for at least an order of magnitude is un- supportable. The article referred to earlier in this document# co-authored by two of the contributors to the Estimates Paper# rejected this conclusion by noting that* "the failure to see greater numbers of this rara tumor among coastal residents raises the possibility of ship yard hazards in addition to asbestos." To the contrary# thera are data that suggest that asbestos awareness leads to an over-reporting of mesothelioma See McDonald and McDonald# Preventive Medicine# Vol. 5# at 426-446 (1977) (reporting on a mesothelioma survey of pathologists in Canada# the authors found that only 37% of the reported cases in Quebec were accepted by the Mesothelioma Panel of the Canadian Tumor Reference Centre# compared with 60% for the rest of Canada.) A-8 < AP00008874 if one accepts the logic set out in the Estimates Paper. Since the probable dead have already been taken Into account, all of the non-shipyard workers would have been at risk in 1976 yield ing a lower bound for incidence easily exceeding 10,000. These estimates are obviously unsupportable speculation. Standard lift table considerations reveal that far in exeess of 1,000,000 deaths would have occurred by 1978 in any civilian worker cohort of 4.5 million from WW II. If the WW II shipyard workers had axperianced the Increased risk of the heavily-exposed cohorts eited in the document, the WW u shipyard cohort would be almoat extinct by 1978. If that were the case, the projections of the next 30-35 years are obviously incorrect. Looking at the reasoning in the Estimates Paper from another point of view, if the WW II shipyard workers had been at the high risks attributed to them in the document, the marker tumor, mviothtlloni, should have shown up In the Third National Cancer Survey In epidemic proportions. Since it hasn't shown up, there is only one conclusion; the Estimates Paper has ignored the spectrum of exposures to asbestos, whieh, when considered with established dose-response, readily shows that the speculations are at least an order of magnitude too high. Additionally, there are several important recent studies not discussed in the Estimates Paper. While mortality data on shipyard workers are limited, two recent WIOSH technical reports on the mortality experience of the AFL-CIO United Brotherhood of Carpen ters and Joiners of America 1969-1970 (HEW, WIOSH publication 74- * A-9 AP00008875 152) both reported* "Ship carpenters locals have an SHR pattern for total mortality and cancer like the construetion worker locals. No remarkable in crease in any cancer type is seen." - (The reports did note a slight increase in malignant neoplasms of the pleura - ICD 163.0, an excess of 7.2 deaths over expected, out of 32,707 total deaths. It was attributed to past asbestos exposures' by the authors.) A-10 AP00008876 % APPENDIX B Comments on Estimates Paper with Respect to NOBS Data . Summary The NOBS survey was inappropriately used by the Esti mate* Paper authors as a measure of the aetual number of workers currently exposed to specific hazards. This survey in fact was only an estimate of the number of workers potentially exposed. Indeed, the authors of the NOBS report specifically "precluded determining relative risk to a given potential hazard." Introduction The National Occupational Bazard Survey was a two year study by the National Institute of Occupational Safety and Health intended "to describe the health and safety conditions in the American work environment and, more specifically, to dctarmin* tha extent of worker exposure ta chemical and physical agents." Purpose, Limitations and Uses In describing the study, the National Institute of Occupational Safety and Health states that the National Occupa tional Hazards Survey was "dasigned to obtain an instantaneous profile for use as a national health hazard information base (and) was to answer sueh questions est What occupational groups 1/ Preface, by Marcus M. Key, M.D., Director, National Institute of Occupational Safety and Health, NOBS, Volume 1, Survey Manual, May 1974. B-l AP00008877 are exposed to whet types of potential health hazards in the United States? in what types of industries can these hazards be found? what types of eontrols are used to prevent harmful 1/ exposure? and to what hazards are the most people exposed?" KIOSK indicated that "the National Occupational Hazard Survey {was] aimed at recording specific worker exposures to specific potential health hazards rather than at evaluating severity,...[that it] addressed merely whether a substance was bsing used,...[and that] this objective approach precluded determining relative risk to a given potential hazard." ^ A statistically selected sampling of the U.S. business establishment <outside of the agricultural .area) was developed by the Bureau of Labor Statistics. Fifty-two hundred differ ent business facilities, both large and small, were selected. Engineers who had taken a nina-week training course in funda mental industrial hygiene and in field data gatherine were / selected as a field staff. This is In contrast with the National Surveillance Network established by N10SH whieh used 1/ states*industrial hygienists as evaluators. The survey was begun in February, 1972 and scheduled to be completed by June y Ibid. y Ibid.i page 2-3 of introduction. V Ibid., page 2-3 of introduction. V Ibid, page 3 of introduction. V Ibid, page 1-2 of introduction. 8-2 y. AP00008878 of 1974. She authors of the report. In discussing the anti* cipated use of NOHS, indicate many of the limitations of the study and urge that reviewers "must not overlook its limitations. The survey's broad scope and narrow time span have precluded universal application of its results to the problem of occupa tional health. Though it comprises virtually all industry and employment in the O.S., the survey will not provide pre cise answers to every hazard query, nor will it stand as a definitive study. Xt will, however, reveal general occupa tional environment statistics which should be instrumental in developing research priorities in the supporting standards development. Moreover, it will serve as the foundation for 2/ new occupational studies of greater detail and precision. They continue, stating that, "within ten years, HORS as an Independent study, will be obsolete. Industry will bav* access to higher technology; its occupational health characteristics y will be correspondingly different." Exposure Characteristics * The surveyors for the NOHS were given instructions to include as exposure any exposure to a carcinogen or expos ure to a non-carcinogen whose concentration in a mixture is 1/ NOES, Volume XXX, December, 1977, page 1. 2/ HOBS, Volume X, Hay, 1974, page 5, introduction. 3/ Xbid, page 6, introduction. B-3 AP00008879 y greater than one percent. Exposures would inelude dusts, 2/ ` fumes, gases, vapors, solids, liquids or mists. Such expo sures may either he detectable to the human senses or nonV detectable. Duration of exposure was only considered as four or more hours of process use per day or not. Exposures were considered as existing if they were actual, potential or n- 5/ ferred. Exposures were to be considered those that would be 6/ existing in the absence of any personal protective equipment. The NOBS report well recognises that its determination is on an exposure-nonexposure model and pays no attention to dose level for exposure. Sampling Procedures A further recognized source of error bias in the es timation process is well recognized within the sampling struc ture es replication was not undertaken at either stage of sampling.V The first stage sampled Standard Metropolitan Areas (SMSAs) by size. The second stage also stratified by Standard 1/ Industrial Classification (SIC) and by size of worker population 1/ NOBS, Volume III, December 1977, page 8. 2/ NOBS, Volume I, May 1974, pages 18-19. 3/ Ibid. t/ ibid. page 191-20. 5/ NOBS, Volume Ill, December 1977, page 4. y NOES, Volume I, Hay 1974, page 19. y NOBS. volume Ill, December 1977, page 3. / Ibid. B-4 AP00008880 The second stage sampling was in terms of facilities with at least eight employees excluding those in agriculture# non- petroleum mining# railroad transportation# government agencies and private households.^ The authors indicate that unbiased variance estimates were not available as the sampling was not 2/ replicated at either stage of sampling. Further# because the seeond stage units were not selected independently within the first stage units# the authors suspect their estimator may 1/ understate the aetual sampling variance. After the data was collectsd# extrapolations to the total D.S. workforce were made through the sampling structure. Study Findings y In total, nearly 4.38 billion exposures to 198 speci fic ehemieal or physical hazards were identified for 36.2 million 5/ employes. This would indicate an average of 115 potential ex posures per worker# or that each worker, on the average, was potentially exposed to two-thirds of all the specific chemical and physical hazards evaluatad. Ho indication was given of the relative magnitude of risks to workers from these various hazards. However# because of the different rules for defining exposure to carcinogens and to non-carcinogens, the selection of hazards A/ NOBS# Volume III# December 1977# page 3. 2/ Ibid. y ibid. 4/ HOBS, Volume III# December 1977# Table 50# pages 444-448. y HOBS, Volume III# December 1977, Table 1# page 42. B-5 AP00008881 exposure oversampled relatively those exposures that were con^r*d a potential exposure at any concentration -- their' pre sence was indicated -- but for non-carcinogens their presence was indicated only if their concentration was greater than one percent. Conclusion The NOHS report is an initial attempt to seni-guantitatively describe the prevalence of various potential exposures in the workplace. From the beginning, its authors recognized its limitations and warned against its misuse. Problems in exposure definition and validation and in sampling bias hurt its utility. It'is a recognised imprecise attempt at describ ing the potential chemical and physical hazard exposures in the work environemnt in the USA in the early 1970's. That work environment has already markedly changed as a result of tech nological advancements and regulatory demands. The authors had originally predicted their study would be obsolete in ten years; their expectations are already realized only four years after publication. The Estimates Paper apparently elected to ignore the warnings of the MOHS Report authors against the potential for misuse of the data. 1/ NOHS. Volume III, December 1977, page 8. B-6 AP00008882 APPENDIX C Arsenic Calculations Contained in the Estimates Paper The Estimates Paper (Table 2) contains the following information on arsenic effects (respiratory tract eaneers)* Risk Ratio Age - Adjusted Incidence 100,000 Males 20 Years Est. No. of Workers Currently Exposed Expected Excess Cancers a-a 131 1,500,000 3,900-14,000 What these data purport to mean is that occupational ex posure to "inorganic arsenic" can eause cancer of the respiratory tract (trachea, bronchi and lungs) st a rate three to eight times that found in non-occupationally exposed persons; that the age- adjusted*Incidence of such cancers is 131 per 100,000 white males over the age of twenty; that one and one half million persons are currently exposed to inorganic arsenical* in the workplace, and that between 3,900 and 14,000 excess cancers from such arsenic exposures may be expected annually. These data and projections are flawed for a number of reasons; (1) The risk estimates are based on studies of past populations with extremely high exposures to inorganic arsenic, 3 some as high as 11,000 micrograms/m Not only do such axposures not now occur, but they are expressly prohibited by a recently promulgated OSBA standard which limits exposure to 10 micro3 grams/m. 43 Fed. Reg. 19583 (May 5, 1978). C-l AP00008883 (2) Available data suggest that eancar risks asso- elated with exposure to inorganic arsenic correspond with tbs duration and intensity of exposure. Zn the absence of high exposures such risks are minimal. (3) The lf500,000 population vhleh is assumed to be at risk is grossly exaggerated and based on old 1964 data eited in the 1975 NIOSH criteria document on inorganic arsenie. OSHA's 1976 Inflationary Impact Statement for the Znorganie Arsenie Stan dard (page A-42), estimated that there are no more than 7,000 employees currently exposed to inorganic arsenic at levels in 3 excess of 4 micrograms/m . indeed, the 1976 ersenic standard 3 calls for controls st 10 micrograms/m . The number of deaths expected annually by the Estimates Paper authors would be equi valent to the total number of workers exposed. Further, although more than 40 attempts have been made, arsenic when administered alone, has never been shown to produce cancer of any type in test animals. The only evi dence of an arsenic lung eancer theory comes from epidemiology studies: ". the relationship between lung cancer and arsenic alone can technically be considered only highly suggestive since other contaminants usually sulphur dioxide have also been pre sent (EPA, "An Assessment of the Health Effects of Arsenic", External Review Draft, 1976 (emphasis added).) Ani mal studies have shown that both arsenic trioxide and sulphur dioxide are primary irritants to the lung but not carcinogenic C-2 AP00008884 in animals. Isbinishi, et al. 1977, Laskin, at al. 197?. Therefore, any estimates of lung eanear based on arsenie xposura alona ara only speculative. Epidemiologic Studies Three reasonably good apidamiologic studies have bean conductad on inorganie arsenic. Each supports the conclusion that any cancer risk associated with exposure to inorganic arse* nie is a function of the duration and intensity of exposure. Only very high exposures have been associated with excess cancers. The three studies are discussed below. 1. Allied Chemical Corporation's Baltimore Pesticide Plant A study, "Cancer and (Occupational Exposure to Arsenic, a Mortality and Morbidity Study of Pesticide Workers," by Kabuchi, R. , Lillenfeld, A., and Snell, L.M., from the Department of Epi* demilogy at Johns Hopkins University, was completed in the first week of September, 1978 and is now "in press". The study analyzes the total and selected causes of death in 240 former employees who died between 1946 and 1977. The plant produced inorganic arsenic compounds from at least 1919 until 1976, except that eopper acetoarsenite 1/ Ishinishi, et al. "Preliminary Experimental Study of Arsenic Poisoning in Rat Lung," at 191*196 in Environmental Health Prospectus, Vol. 19 (1977). 2/ Laskin, et al. 1970 "Inhalation Carcinogenesis," AEC Symposium ~ Series No. T? (1970), edited by Hanna, M.G., Jr., P. Nettle* sheim, and J.R. Gilbert. C-3 AP00008885 4 (Paris Green) vas last packaged in 1946* Ths peak of produc tion of arscnieals occurred around 1950. Arsenic trioxide powder was the starting material for producing various arsenical compounds, most of which were ulti mately used as insecticides. The arsenic trioxide was shipped into the plant by rail# unloaded# and stored In various locations in the lot surrounding the Arsenic Acid Plant# where the trloxide vas reacted with nitric acid. The resulting liquid acid was stored in tanks for production of other arsenical*, or packaged for aales. Adjacent to the Arsenie Acid Plant, a main three-story structure, the `Insecticide Building", was located, and it was there thst various arsenical insecticides were manufactured. Lead arsenate was made by mixing lead-oxide suspended in water with the arsenic acid in a tank on the top floor. The precipitated lead arsenate ran down to drum dryers on the bottom floor. The dried product was screened end then conveyed back to the third floor for milling, packing and bagging. Production processes for other arsenicals were similar. Before 1952, hygienic control at the Arsenic Acid Plant was allegedly poor and workers in that location often developed skin lesions (keratoses) and other symptoms of arsenism, such as perforated nasal septa. Zn 1952, ths Arsenic Acid'Plant was re constructed and improved personal hygiene practices including daily showers and clothing changes were introduced. Also, in the 1950's a series of measures were taken to improve hygienic C-4 AP00008886 conditions in the Insecticide Building. Mabuchi and colleagues estimate that the atmospheric concentration of arsenic in the Insecticide Building was at least 3 1#000 micrograms/m during the 1950*8, and that in tha Araanie Acid Plant prior to 1952 the highest concentrations of arsenic 3 were at least 5,000 micrograms/m Allied Chemical had files available for all hourly workers hired in 1946 or later and for all salaried employees hired in 1955 or later. For some of those hired prior to 1946 and 1955* respectively, records were incomplete. Of the 3,141 persons employed between 1946 and 1974, 2,189 bad been employed for less than four months and, since it was not possible to trace many of them, 441 (a 20% random sample) were followed up. Bowever,' ofthe '952 who were employed four months or longerall were included in the follow-up study. Thus, the team of 441 who worked less than 4 months, and the 952 who worked more, made a total of 1,393 subjects who were eubjected to follow-up. 1,050 were males and 343 females. For each person, the degree of exposure to srsenicals was graded as "high", "medium" or "low". Those who worked in the arsenic acid araa and were near the "insecticide Building" were assumed to have had "high" exposure; maintenance and shipping workers were assumed to have had "medium" exposure and office workers were assumed to have had "low" exposure. Some "unspeci fied production workers* were placed in a "possibly high" ex posure category. (In summary, of the 1393 records studied, 718 C-5 AP00008887 were judged to have had "high" arsenical exposure, 289 "medium" exposure, 234 "low" exposure, and 151 "possibly high" exposure; tone person for whom records were missing was excluded]). As for the ex-enployees themselves, a surprisingly high number of those known still to be alive were able to be contacted. As noted, 240 of the 1393 were known to be deceased on the basis of death icertificates which were available to the authors. Of the 901 who were alive in 1977, 745 responded to a questionnaire or gave an interview; nearly 83%. Only 252 of the 1393 (18%) were lost to follow-up, and of these 35 were believed to be deceased but without obtainable death certificates. All of the 38 persons who had worked for more than 25 years and more than 98% of the >142 who had been employed for 5-24 years were traceable. Even among the 20% of those who had worked for less than four months, 76% were traceable. The statistically significant findings include an ex cess of deaths from lung, esophageal and lymphatic eaneers above the expected numbers in Baltimore City. However, the number of cases of esophageal eaneer in these categories were actually only 2 (0.1 expected) and of lymphatic cancer also but 2 (0.2 expected). For respiratory tract cancer the figures are clearly more striking. There were 13 cases of respiratory tract cancer (6.2 expected) among the 718 employees judged to have had "high" ex posure, another eight (5.1 expected) among 26ti with "medium" ex posure and 2 (0.3 expected) in a group with "possibly high" ex- C-6 I I I I I I I I I I I I I i 1 J I I I I AP00008888 t posure. The excess is statistically significant at the 51 level only for the "high" exposure group. The figure for expected num bers were taken from the experience of Baltimore City. Analysed as a function of date of initial employment, there were 10 respiratory traet cancers (2.S expected) in the group employed prior to 1946, and 13 (6.8 expected) in the group hired during the eight years between 194$ and 1954. Only in the ease of those hired before 1946 is the "excess above expected" significant at the 5% level. Analysed as a function of length of employment, there were 3 cancers (1.6 expected) In the 5-24 years group but 9 (1.3 expected) In the 25-plus years group. This last, an observed/ expected ratio of 6.78, is a statistically significant excess at the 5% level. It seems reasonable to draw the conclusion from these data that there is an association between exposure to trivalent inorganic arsenie dust and respiratory traet cancer, and that the association seems to have been dependent both upon duration of exposure and especially, given the history of the plant, upon the intensity of exposure. However, the study does not demonstrate any association between low level exposure to inorganic arsenic and respiratory tract cancer. 2. Asarco. Inc. Tacoma Washington Smelter A second major report associating exposure to airborne arsenie trioxide to lung cancer is that of Pinto, Enterline, P.E., Henderson, V., and Varner, K.O. (Environmental Health Perspectives, C-7 AP00008889 19*127-130, 1977), who reported on the ceases of death among S27 men retired from work at a copper smelter at age 65 after an aver age duration of employment of 29 years (range 7-54 years)* The 527 man cohort comprised those alive as pensioners on January 1, 1949, plus all who became pensioners in the 24 years until January 1, 1973. All deaths were tabulated through December 31, 1973. Death certificates were obtained on all who died. By using the complete job histories available for 525 of the men and by performing a urinary arsenic determination in 1973 for each of the 1,000 persons distributed among 33 departments in the smelter, the authors were able rather ingeniously to con struct retrospectively the exposure index that each man had ex perienced during his working years. This was done by taking the average urine-arsenic value for each of the 33 departments (as Observed in 1973) end by Risking the assumption that while the magnitudes of exposure in all departments had ehanged over time, the relative exposure between and among departments had been approximately constant through the years. Thus, multiplication of the average urine-arsenic value for any department by the number of years that a man had worked in that department resulted in an individual exposure index which had no units, but which served as a representative number for comparison purposes. Another unique contribution of the Pinto article is a graph of results of a study made in 1973 of 24 workers who wore personal monitors continuously for two full days prior to their regular work week, each day during the work week and for three C-B AP00008890 days foliowing it. (Cars was taken to avoid eating fish or other arsenic-rich foods.) Daily urine samples were also collected from each of the sen during the test period. The resulting data show a straight line correlation between airborne arsenic con- 3 eentration expressed as nicrograns/a and urine arsenic concen tration expressed as aicrograms/liter. By good fortune, there were available to the authors some scattered air analyses nade during the late 1930's and early 1940's showing that tha air borne arsenie level in that period was 5 to 10 times higher than in 1973. Thus, it is possible from the published date to approxi mate the concentration of airborne arsenic to which workers had been exposed during the years around 1940 which was about the tine when 50% of the cohort's work experience took placa (actual txposures 1910-1973} middle fifty percent of work experience 1928-1947). The results of the analysis by Pinto and his colleagues show a definite relationship between arsenie exposure index and daath from respiratory cancer. Tha total number of such cancers in the cohorts was 32 versus an expected 10.5, an SMK (Standard Mortality Ratios) of 304.8, significant at the five percent level. The following table from the article correlates exposure indices with SMR. If the Indices are plotted against SNR on arithmetic paper, the relationship is roughly linear. See attached graph infra, at C-24. C-9 AP00008891 TABLE I OBSERVED AND EXPECTED RESPIRATORY CANCER DEATHS AND _____________ SNR BY ARSENIC EXPOSURE INDEX_______________ Exposure Index (mean index) No. of Men Resoiratorv Cancer Deaths Observed Expected SMR 2000 (1514) 2000-2999 (2513) 3000-5999 (4317) 6000-8999 (7473) 9000-11999 (10,135) 12,000 (14,712) 36 109 205 109 38 29 1 0.9 111.1 4 2.1 190.5 11 3.9 282.0+ 7 2.3 304.3+ 4 0.7 571.4+ S 0.6 833.3+ -+ means p < 0 OS The authors presented thalr data in anothar fashion in the table below (see attached graph at C-25). TABLE II OBSERVED AND EXPECTED RESPIRATOR? CANCER DEATHS AND STANDARDIZED MORTALITY RATIOS BY INTENSITY AND DPRATION OF EXPOSURE Intensity of Exposure mg/litas urine _____________DURATION OF EXPOSURE < 25 year > 25 year Obs. Exp. SMR Obs. Exp. SKR 50 - 199 2 2.1 95.2 10 3.6 277.8+ 200 - 349 350 4 1.5 266.7 8 2.2 363.6+ 3 0.5 600.0+ 5 0.6 833.3+ + means p<0.05 The information in Table IX is especially useful in that it shows that vhila both Intensity of exposure and duration of ax- C-10 AP00008892 posure to inorganic arsenie are determinants of respiratory can cer, intensity holding constant for duration is a better predic tor than duration holding constant for intensity. This tends to eonfixm, with considerably more detail, what could be inferred from the Allied Chemical study cited above. Furthermore, the information in Table II is very impor tant in that it provides an excellent basis for calculating the sirborne intensity exposure to inorganic arsenic that is nacesssry to generate respiratory cancer. Each range of values for urine arsenie shown in the table corresponds to an airborne level range and the latter may be found from the plot of the urine arsenic against airborne arsenic which the authors constructed from their above-mentioned 1971 study of 23 volunteer workers. Urine arsenie concentrations less than 200 micrograns/ liter correspond to airborne levels of less than fifty micrograns/ m However, it is to be recalled that measurements of airborne arsenie made during the late 1930's and early 1940's were five to ten times higher than those in 1973. Therefore, around 1940, approximately the time when the middle fifty percent of the 527man cohort had its work experience, minimum eirborne arsenic ex- 3 posures ranged from 100 to 500 micrograms/m It is clear from Table II that persons with this past degree of exposure did not develop respiratory esneer if they worked for less than 25 years. One can, therefore, arrive at the conclusion that no individual in the cohort of retirees who developed eancer had worked in en 3 exposure range of less than 100 micrograms/m and very many may C-ll AP00008893 have worked at exposure* at 2000 micrograns/m or more* 3* Anaconda Copper** Smelter In Montana Zn justifying its recent rulemaking setting a permissible 3 exposure limit of 10 mierograns/m , OSHA relied heavily on a 1969 study by Zee and Fraumeni (J* Natl. Cancer Inst. 42:1045-52* 1969) reporting on the mortality experience of 8,047 white male arse nic trioxide-exposed smelter workers at tbe Anaconda, Montana Smelter who had been employed there for at least one year prior to 19S7. The study reported that from January 1* 1938 to December 31, 1963, 1,877 deaths were recorded* Of these, 147 were deaths from respiratory cancer, a rate 3*3 times the expected rate in Montana. This excess rate was said to be statistically signifi cant at the.one percent laval. " The cohort which Lee and Fraumeni studied was divided in to groups defined by length of service as veil as by intensity of exposure. Exposure intensities were designated "heavy", "medium" and "light*. The authors stated that "while measurements in work areas may hava varied over time, it seema reasonable to assume that these three broadly-defined categories denoting relative exposure remain fixed." Zn fact, the mean arsenic exposures from 1943-1959 were given by the authors as follows: Heavy (11,000 33 aicrograms/a }, Medium (580 nierograns/a ) and Light (290 alero- 3 grams/m ). Thus, tbe 1969 Lae and Frauaani study fully supports the analysis made by Pinto at el. <1977} and the conclusions which were derived from it as described above. C-12 AP00008894 4* Summary To summarize, discussion of three key epideraiologle studies of workers exposed to inorganic arsenie have shotmTthat any excess of respiratory cancer was associated with massive pre vious exposure, usually to trivalent arsenic trioxide dust, with 3 levels surely in excess of 250 micrograms/n , but ranging as high 3 as 11,000 micrograms/o Collected evidence has repeatedly fail ed to link low intensity exposure to inorganic arsenic dust with excess eancer of the respiratory tract. Present Day Occupational Exposure To Inorganic Arsenic While the Estimates Paper states that 1,500,000 employ ees are exposed to arsenic, OSHA has concluded in its inorganic arsenic rulemaking that the population at risk is only 460,000. OSHA recognized that the much larger figure (1,500,000), which it explicitly rejected, is out of date and includes many indus tries which have discontinued arsenic use or which involve ex posure to only organic arsenie compounds. OSHA exempted organic arsenic compounds from its rulemaking because of an absence of evidence suggesting such compounds have carcinogenic properties. OSHA concludeds 4. Employment and Exposure Figures Employment in all industries directly or indirectly involved in the commercial cycle of arsenic is about 660,000 employees. About 70 to 75 percent of these are production workers and, therefore, potentially exposed to inorganie arsenic. However, a large number of employees Included in these figures work in areas wheriPexposures to inorganic arsenicals are very low or C-13 AP00008895 non-existent. Relatively few employees are directly exposed to inorganic arserilcala."""* Estimates of the number of direetiy exposed employees working in the affected industries at any one tine currently ranges from 1500-1700, for exposure levels of 0.1 mg As/n3 and above, to almost 7000 for exposure levels of 0.004 mg As/ml and above. Host of the exposed workers are in the eopper smelters (especially ASARCOTacoma) and wood presarving Industries, where exposure levels are also the highest." Infla tionary impact Statement at IX-8 (emphasis added) 1* Pesticide Plants The major source of inorganic arsenical insecticides in the United States during the twentieth century was the Baltimore Race Street Plant operated by Allied Chemical Corporation from 1517 until mid-1976, when it was dosed. Zt has since been raxed. As was noted earlier in discussing the Kabuehi study, all of the excess respiratory tract cancer was found in persons hired prior to 1946 and in those who had been employed for more than 25 years. While it is conceivable that a few scattered cases might become evident in the course of the next fifteen years (assuming a "latent period" of approximately forty years), the population from which theae eases would have to eome is already wall past middle-age and numbers only st the very most 300. zt nay, therefore, be flatly stated that no large contribution is going to be made by Allied Chemical's former plant to any future pool of lung cancer in the United States. There appear to be only two operating arsenical plants in the United States. These plants, which employ even fewer than the ex-Allied plant, are owned by large and responsible AP00008896 corporations with sophisticated industrial hygiene departments. Ona has 17 employees engaged in making arsenic aeid from arsenie trioxide; the other has 6 employees who deal with this material which is used to produce organic arsenical* Zt may be reasonably assumed that worker exposures have been minimised ever the last decade* at least* Promulgation of the recent stringent Standard by OSBA which sets a permissible exposure limit of 10 3 micrograns/m will* of course, obtain* Bearing in mind that Allied's ax-plant in the last forty years appears to have gener ated an axcess of only 9.3 respiratory tract cancer eases compared with Baltimore expected rates (or 14.5 excess cases if comparison is made with United States rates)* it is clear that workers in arsenical pesticide plants currently operating are also unlikely to produce a large number of excess cancers in the decades ahead. 2. Smelters At this time* the major industrial exposures to inorgan ic arsenic dust is experienced by smelter workers. The reason for this is that practically all ores* especially copper containing ores* are contaminated with trace amounts of arsenic ranging from 0.001 to 5.0 percent* occasionally mere. In the process of heat ing crude ores to the melting point* arsenic trioxide.sublimes momentarily into vapor which nearly instantaneously returns to a solid particulate when it meets with air. There are at this time sixteen operating smelters in the United States (43 Fed. Reg. at 19601). The largest smelter and the one with the potential for the highest exposure is the C-15 AP00008897 1 on* operated by Asareo, Inc. in Tacoma, Washington* This is a custom* smelting facility which will smelt ores sent to it by others and it is not uncommon for it to deal with ores contain ing five percent or more arsenie as an impurity* The Taeoma smelter currently employs about 1,000 workers. Assuming, be cause the data are not readily available, that eaeh of the fif teen remaining smelters employs a similar number of people, it may be stated that there are approximately sixteen thousand per sons employed in all of the smelters in the United States. Lee and Fraumeni, who studied the Anaconda, Montana smelter in 1969, alleged that employees died of lung cancer about 3 times as often as could be expected on the basis of Montana state data. Tha ovarall rlskratio for the Asareo, Inc. smaltar in Tacoma (Pinto, Enterline et al., 1977) was alto about three, and we know that this is very likely the smelter operation with the highest exposure potential. Zf the experience of the Asareo Smelter is extrapolated to other smelters in the U.S., the maxi mum number of excess lung cancers they will generate within the next twenty-five years can be estimated. In doing this we will make the (unlikely) assumption that no industrial hygiene im provements have been made in any of these smelters in the past twenty-fiva to thirty years. The Pinto, Enterline 1977 study discovered an excess of 22 respiratory tract cancers in S27 retiraes of the Tacoma smelter over a 25-year period ending in 1973. If this experience was rep resentative of the other smelters, (undoubtedly an overstatement) C-16 AP00008898 a total of 352 excess respiratory cancers occurred in ell smelter retirees in the quarter century between 1949 and 1974. Assigning that the death rate for current workers continues unabated for another quarter century (i.e. assuming that the cancer-preventing effect of the recently imposed ten Bicrograms/m standard will not have an effact for 25 years# and# Ignoring evidenca provided by Pinto# Enterline et alt which strongly suggests that respir atory cancer risk falls off after cessation of exposure even after many years of chronic exposure)# we may at most expeet another 350 deaths from respiratory cancer in the next 25 years among smelter retirees. So, on the basis of exaggerated assump tions, one might expeet all U.S. smelter workers to generate up to 14 excess respiratory cancers' annually for the next 25 years. 3. Other Exposures Aside from plants that manufacture inorganic arsenicals and plants that smelt ores# there are only a few other major groups who have occupational exposure to inorganic arsenic. This includes 1/ certain glass workers and carpenters in Hawaii who work with copperchromearsenate (CCA) treated wood. CCA Is a pentavalent arsenic derivative which acts as a wood preservative. 1/ A recent telephone survey of highly placed technical experts in the glass Industry disclosed that of eight of the largest producers of glass In the United States only one still uses minimal quantities of arsenic trioxide at one of its small plants, where, at the most, six people are potentially ex posed to arsenic trloxlde itself. The survey also confirmed that the absence of arsenic from the glass process has been the ease for from 8-20 years. C-17 AP00008899 A study entitled "Cancer Mortality Among Carpenters in Hawaii" authored by Budy# A.N.# and Rashad# M.N. of the Depart* aent of Genetics and Cancer Center# University of Hawaii# published in the DEPCA proceedings April# 1976# and submitted into the OSHA Inorganic Arsenie hearing record showed that the relative risk tor cancer among Hawaiian carpenters exposed to CCA-treated wood is not elevated. The control series comprised carpenters who worked with non-CCA treated wood but whose experience was otherwise the same. 4. Summary Our estimates of the maximum number of arsenic*induced cancers that the nation may expect to discover during the next quarter century are set out below. Occupation Estimated No. of Exposed Employees Estimated Total NO. Excess Cancers Estimated Excess Cancers Per Year Smelter Workers* Arsenical Pesticide Workers Glass Manufacturing Hawaiian Carpenters 16,000 323 6 1,000 350 4 probably none 0 14 0.16 0 0 TOTALS 17,329 359 14.16 "This calculation assumes that all 16 present smelters continue to operate. As of this date# one smelter has been at least temporarily shut down. The calculation also assumes that all employees continue to smoke cigarettes at the same rate as in past deeades. C-13 AP00008900 Discussion Returning to the Estimates Paper, the following four state ments are made with respect to arsenie, none of which are borne out by the faetss 1. The "Risk Ratio (R)" is 3-8*. 2* The age-adjusted incidence [of Respiratory Cancer] per 100,000 males age 20 or older (I) is *131* 3. The Estimated No. of Workers Currently Exposed (N) is "1,500,000"* 4. The estimated number of annual eaneers attributable to arsenie [<R-1)N] is 3,500-14,000", Let us examine each of these in turn. 1. As given, a risk ratio of "3-6" is misleading* The source of the information is cited as Fraumeni, J.F. in the chapter on Occupation in the book Persons et High Risk of Cancer. Academic Press, New York, 1975, pp. 167-184. The figures are obviously based ultimately upon a study published nearly ten years ago by Lee and Fraumeni (J. Nat'l Cancer Inst. 42, 1045-1052, 1969) of mortality data from 8,047 workers who were exposed during 25 years from 1938-1963 to arsenic trioxide in the course of their work at an Anaconda Copper smelter in Montana. As was described earlier, industrial hygiene measurements taken at the smelter during the eritieal years 1943 to 1957 demonstrated that workers were exposed to concentrations of inorganic arsenic 3 ranging from 290-11,270 mierograas/m , massive doses. The eohert of workers exposed to the highest concentrations had lung cancer C-19 AP00008901 mortality up to 8 times the expected rate, while thoee exposed to the lower range of concentration had 2.1 to 2,5 times as many lung cancers as would have been expected on the basis of all Montana data* For all of the exposed employees the rate of lung cancer averaged three times the expected Montana rate. The por tions of the smelter where the highest exposures took place were torn down at least IS years ago* The study by Pinto# at ail. of retired employees of the Asarco smelter in Tacoma, Washington# where ores containing up to 5 percent contamination with arsenic were commonly worked with demonstrated a lung cancer rate three times the expected* OSSA commented on the data of Pinto when they were first made public at the Agency's April 1975 rulemaking bearing (43 Fed. Aeg* at 19589), stating that it " is an excellent study and deserves considerable credence. The study was based, upon careful follow-up of a group of long term exposed workers. Exposure indices, based on 1973 values# provided for a maxi mum utilization of the data. The consis tent dose-response relationship between 1973-based urinary arsenie levels and lung cancsr mortality strengthens the associa tion of the disease with worker exposures to arsenic. Thus# OSHA accepts the overall findings of excess lung caneer mortality observed in the study." From the above# it is clear that the best number to use for maximum "Risk Ratio" is 3; representing it as "3-8" is un warranted and misleading. ~ 2* .The figure 131/100,000 which is given as the ageadjusted incidence of lung cancer is attributed to Bridbord# K. C-20 AP00008902 1 (197.8), Hew Horizons In Occupational Medicine, national Insti tute of Occupational Safety and Health, Rockville, Maryland. This reference is available only in the form of a xeroxed paper dated Kay 1, 1978. A telephone call to -Or. Bridbord'a Office revealed that the paper is an Unfinished draft* and has not yet been published anywhere. Yet more astonishing is that Dr. Bridbord'a unfinished draft contains absolutely no mention of any Incidence data for any cancers. The only mention of arsenie in Bridbord'a 18-page "un finished draft" is in some tables appended to it. One of these tables is merely a verbatim copy of the table in Fraumeni's book referred to above in which the "3-8" risk factor was given. It is also notable that Bridbord'a (i.e. fraamenl) list of occu pations involving exposure to srsenie is also out of data. Of perhaps greater significance is Bridbord'a Table XI, attributed partly to the NOBS, Vol. ZXX, 1977, and again to the same table in Fraumeni from which he had copied his own Table X, as noted. Table 49 of the MOHS report entitled "Estimated Number of Persons Exposed Full or Part-Time to Occupational Carcinogens," specifically omits any mention of arsenie, though it does list asbestos, benzene, chromium, iron oxide, nickel, petroleum dis tillates and vinyl chloride. 3. Table XX of the document under consideration cites in the column "Estimated Ho. of Workers Currently Exposed (N)N the figure 1,500,000 as the number occupationally exposed to arsenic. NlOSH's 1975 Criteria Document is given as the reference. C--21 AP00008903 1 Perussl of the Criteria Document reveals, on the bottom of.page 14 and continuing on the top of page 15, the following paragraphs "Some occupations which have or in the the past have had potential exposures to arsenic are listed in Table X-2, (9) NIOSH estimates that 1,500,000 workers are poten tially exposed to Inorganic arsenic, includ ing arsine and lead arsenate** (Emphasis . added.) The bracketed (9) denotes reference to an 18-year old document edited by Gefafer, W.M.x Occupational Diseases ~ k Guide to Their Recognition, Publication No. 1097. U.S. Department of Health, education and Welfare, Public Health Service, 1964, pp. 83-84. k copy of Table X-2 follows. tuu x-: cccsjirtwirj -ski tvszzji Ausnc mssni Miirlaa <Tkui luacdtili aakara }aaalari allay aikm Uai bumara aalllaa alas Sahara laai ahae aakar* 4a4ilat rtin CC*iM Wtku, Sakb.es caul narkari ~l1aa4>ts.aMlsafrkam -lisa bursars 'klaMklei ywiu aikui 'steal eliiaafi baUar otmtsn 'steal reflates fctaac aakara alwnUttlin aakara kiwi MUM an aaaisar verkara bmates ugriui atyasit ahiadatl netiuilMn -pint aakara aaetls 119 nrkiil ytlatan uneU maaal ukut papas aakara tannin aakara car?as aaaltara paaralaiai riflatry aarkara lipact aakari OitUiu typiittua kiutU aarkara daltUast mkars plwbara 'liaachyl aaliata aakar, . sk aarkara 4n| aahass 4ja Sahara c*7va aakara MntleUi aakara alaeml7tle eappar aUut as&eaaksesor aakara ^iMmfUun akMf 41p aarkara aa Milan tint nflam aaia aakara fiaw 'funiUlm arks* aUinn (asbaaitaa aarkara familiar aakara talftfie wU aarkara HiMTk, aakin galtsslsan nWlinfm s imUi pnuui elaaa Sahara lls ascraators rinira era* rprayara SU csllasra 7V# aaeal aarkara kill iaaiaas aakara aaear aaW aaacraliars i kitklcUi aakara aprerat* 4 hlia piaatmn aa4 franmun aakara 'krONklnit ml strkirt woi pratarrara ^IUMmUbi |aa vatkars dM aklarlfa aakara (na Oafala* (91 "C-22 AP00008904 It should be noted that Gefafer's work was intended only to be a rough inventory of sorts and is out of date* _ 4. This column in the Estimates Paper is headed by "<lt-l)RX" which merely means that (Risk Factor) sinus one, multiplied by *N" (Estimate Number of Workers) and by *1* (Age- Adjusted Incidence per 100,000 males 20 years) yields a figure for the number of expected cancers each year* We find that the column lists 3,000 - 14,000 as the annual expected number of lung cancers due to arsenic. This figure is without any reasonable support for the reasons discussed above* Zn summary, we have shown that to project a factor even as high as 3 over the next 25 years is probably unwarranted. We have shown that the Estimates Paper failed to document the figure 131/100,000 es the age-standardized incidence rete for respiratory cancer, and we showed that the figure for estimated number of workers currently exposed is inaccurate. Finally, from an analysis of those occupations where dangerous exposure to inorganic arsenic has existed, we have demonstrated that the number of arsenic-induced cancers to be expected annually during the next quarter century will be no more than 15 because we have weighted every assumption in such a way as to maximize the expected number. C-23 AP00008905 90680000dV K-D LL6\ '0CWJT*6T 53AX103dS33d HXTY3H TYXK3KN03IAK3 *0'W 'MKHYA on* A 'H0SS30K3H "S'd '3NTXS3XN3'`S'S 'OlKId (XX32 338) X30KZ 33DS04X3 X3QNI 38lS0dX3 9IK3S3V Afi H2Y3G 333KV9 X30XV3IdS33 10 3SI3 3AIXVIZ3 RELATIVE R IS K (SMR) RELATIVE RISE OF RESPIRATORY CANCER DEATH BY INTENSITY OF ARSENIC'EXPOSURE AND BY DURATION OF ARSENIC EXPOSURE* Arsenic Exposure 8 Index 50-199 200-349 7 0 350+ RELATIVE RISK (SNR) LESS THAN 25 YEARS DURATION OF EXPOSURE 25 OR MORE YEARS DURATION OF EXPOSURE PINTO, S. 5., ENTERLINE, P.E., HENDERSON, V., AND VARNER, M.O. Environmental Health Perspectives 19:127-130, 1977 . C-25 AP00008907 APPENDIX 0 Consents on the Sstinstes Piper With Reoect to Chromium Review of the estimetes end the rationale for project ing in incidence of 7,900-16,000 new cites of respiratory tract cancer incurred annually Cron exposure to chrome and Its compounds reveals serious flaws, which are enumerated below* 1) The risk estimate ie bated on studies of workers heavily exposed in the 1930vs and pesaibly 40*s in the aanufaeture of chromates from chrome ore using the alkali roasting process. Such exposure conditions no longer exist anywhere in the western world. 2) The estimate of population includes workers not shown to be at risk) for example", those engaged in refractory manufacture, in the use of trivalent chromium pigments, and the use of trivalent compounds in the tanning industry. These two points are diseussed below. -T--h-e----R---is--k----E--s--t-i-m---a--t-e- 1/ The report eltes Enterline's analysis of s eobort of 1,200 workers in three chromate producing plants in the late 1930's. Zn this study Standard Mortality patios (SMR) for lung eancer steadily decreased ever the period of observations Tears 9WR 1941-1945 1946-1950 1951-1955 1956-1960 2909 1570 792 475 Enterline, Phillip E., "Respiratory Caneer Among Chromate Workers," Journal of Occupational Medicine 16s 521-526 (August 1974)." 0-1 AP00008908 Conditions in these plants improved considerably over the period through 1960 and have since improved. Enterline states in his discussion* The old chromate producing plants upon which the American epidemiologic data are based have now been either dismantled or completely rebuilt. For those plants that remain# it is probably too early to find out whether changes made have completely eliminated excess respira tory caneer.* Additional confirmation of a pattern of decreased risks over time was found in a stud conducted by Allied Chemical on active and retired employees# and reported in the NXOSH eri- 2/ teria document for Chromium VI. The study presents SMR's for lung cancer mortality for workers at the Baltimore Chrome Works beginning at different time periods. Years of first Employment SMR 1932-1941 1942-1951 1952-1961 1961-1974 680 480 160 <4100 (no cases observed) The authors concluded that a significant downward trend has occur red. This trsnd accompanies a reduction in dust exposure levels y over the years at the plant. Bill# W.J.f report submitted to NXOSH# 1974. Criteria for a Recommended Standard - Occupational Exposure to Chromium (VX)# O.S. Dept. HEW, NXOSH (1975)# p. 73. 1/ id S-2 ! |M AP00008909 ' Th most recent revision of this study* now in press* confirms that no esses have been observed after three additional years of follow up. A cohort study commissioned by Allied to the Johns Hopkins University School of Fublie Health* for employ ees who entered the work force on and after 1945* shows an SHR of about 200 for those employees in the 1945-1950 eohort* with progressive declines thereafter, the post-1960 cohort* with essentially complete follow up* confirms Hill's observation of no reported cases* even though et least one might have been ex pected from Baltimore vital statistics. The inappropriateness of applying a relative risk of 5* as does the Estimates Paper* to the population at risk of chromium y exposure is further shown by a recent report of chrome pigment workers. In this report by Davies* no excess risk was seen among persons with "low exposures" in two factories (exposure dates 1932-1954 and 1948-1967). Nor was excess risk found over all exposure strata in a cohort of workers employed during 19551967. Again* some excess respiratory cancer was found among men with early and heavy exposures* but even here the risks were about 2-3. 1/ Hayes* Richard B.* "A Study of Chromate Production Workers*" -- 1978 PhD (Epidemiology) thesis* The Johns Hopkins University* Baltimore* Maryland (1978). 2/ Davies* Joan M.* "lung Caneer Mortality of Workers Making " Chrome Pigments*" The Lancet. _1, p. 384 (February 18, 1978). D-3 AP00008910 The Population at Risk Table 2 of the Estimates Paper indicates that 1.5 mil lion workers ere currently exposed to chromium* Xt should be noted 1/ that the source document lists only 16% of these jobs as repre senting any exposure of four or more hours per day* Furthermore, among the 1.5 million exposed workers are a sizeable number of persons not exposed to those chromium com pounds considered to be carcinogenic. The table below, extracted from Table XI-4, page 191-193, of the NXOSH criteria document on Chromium (VZ) shows that not all Chromium (VX) compounds show evi dence of carcinogenicity. Solubility characteristics served as a major basis for classifying the inferred categories. TABLE I NIOSH CHROMIUM (VI) CRITERIA DOCUMENT - 1975 M<at CwMKlwtiM taftrrW MiwitelnetMi (*** tmc (r tatli Cm lafaraacta) _I*idat Cacclaoiaaa tcfarrH Cifilneawi Sodlua klehnaiti [33, u lurr, wriita aaaMnteaelaa, 1I73J SeC iu (btwti {U Lavy, vrltt*) mminte*clai 1I7JJ (33) UtMua kltktnit* Liehiua chrome* Foeaaaioa blchrmmet fKtatlw eWoMti RukUlui kldiraaae* XuhUlua ohremt* Cilia kUtitmtc emlua chrome* Asalia hichroaata A--nulga chrome* Calclua ehreuti 13,3, Alkali** aarth Chrome* 13,33,l,90,93,f, rnd klthrMti 94-102,107,119, 14 In,, write* ceaaamcselaa, 1973) C*~h9rume/1rl eiWhlmarildm* Debar tHroaiua(vi) ftitini ctlciwa aatarlal* rise llaeW ebroaata [101] ia thli tahi* A1U1U* Ha* TMittai piMHl ratlin* [13] Slat fiuilm chit* uei U Ury. orltta* caaialtitlt*. 1*73] UM hraa*ct [#!.] 1/ National Occupational Hazard Survey - Volume XXX, Survey ~ Analysis and Supplemental Tables, U.S. Dept. HEW, NIOSH, p. 280 (December 1977). D--4 AP00008911 This table pertains only to hexavalent chromium* Among the other forms of ehromium, not all compounds are thought to be carcino genic* Yet the population represented as at risk includes per sons with exposure to those materials not shown to have any in creased risk of respiratory cancer* In summary* the estimated number of deaths from chro mium is not accurate because the risk ratio used is not appli cable to present-day exposures and because the population consi dered at risk is inflated by the Inclusion of persons exposed to forms of chromium which are not carcinogenic* The only work groups ever shown to have been at excess risk are those involved in manufacture of chromates before 19$0f and certain heavily ex posed workers in the pigment industry. All told, these two in dustries account for no more than about 2000 workers in the United States today. D-5 AP00008912 1 APPENDIX E Comments on the Estimates Paper With Respect to Nickel The Estimates Paper has predicted an annual respiratory cancer frequency of 7,300 cases per year from nickel oxide expo* sure. This number is obtained by using the MOHS estimate of 1.4 million people potentially, inferred, or actually exposed to nic kel oxide in O.s. workplaces; a risk ratio of 5 for an excess risk ratio of 4; and an incidence rate of 131 per hundred thousand man years over the age of 20. These three numbers multiplied together give an estimate of 7,300. The basis for considering nickel oxide carcinogenic comes from a number of papers published in the past. The two major papers are those by Doll,*in England, who studied mortality experience of workers from the South Wales nickel refinery end y Pedersen who studied Norwegian nickel refinery workers, However, more recent studies by Bernacki et jl. (see supra, at E-5) have shown no increased association of nickel with lung cancer among workers exposed since WK II. The Doll Study Doll demonstrated that the workers, who worked in the South Wales nickel refinery and were exposed to the process of calcination of impure nickel copper sulfide to nickel copper 1/ Doll et al., "Cancers of the Lung and Nasal Sinuses in Nickel Workers .`""`Brit. J. Cancer 24*623-632. 2/ Pederson et al., "Cancer of the Respiratory Organs Among Workers at a Nick's! Refinery in Norway," Int. J, Cancer 12*32-41. E-l AP00008913 oxide, had a high incidence of lung cancer and nasal sinus can cer* Be demonstrated analytically that these high risks occurred only in men who were exposed prior to 1930 and did not occur in men who were initially exposed between 1930 and 1945. Mortality was followed up through 1971, Marked excess of nasal cancers were found in the work ers hired before 1930, where 56 to 58 caneers were identified but only *2 were expected* Mo workers whose initial exposure occurred after 1924 have died of nasal cancer* This is an important cut-off* For, in 1924 cotton masks were introduced to provide personal pro tection. These were particularly effective against the large particles which would otherwise be deposited in the nose. They were accepted by a high proportion of the men* Zt is reasonable to conclude that the introduction of this protective measure essentially eliminated the risk of nasal sinus cancer in thesa workars. Lung cancer had also been indicated as a high risk in these workers in their early years* These risks continued through 1930 when new processes were introduced in the plant, within the group of workers hired before 1930, 137 lung cancers were observed and 22 expected for an observed to expected ratio of 6*2. How ever, only 6 cases have been observed in the 205 men hired since 1929, while five and ope half cases would have been expected. The Pedersen Study The second study by Pedersen in Norway in 1973 studied the mortality experience of nineteen hundred and sixty men hired E-2 AP00008914 prior to 1961 who had at laast three years of employment in the nickel refinery between the years 1953 and 1971.* The mortality experience was followed through the end of 1971. In his entire study# he found an overall observed to expected ratio for all respiratory cancers of 5.6 and for lung cancers, of 4.B. The difference is primarily affected by the number of nasal sinus esneers in roasting, smelting and electrolytic processing in* dividual** Review of these records indicated two cohorts of workers: those hired prior to 1940 and those hired after 1945 through 1960. (The plant was closed down during the war years of 1940 to 1945.) The overall mortality rate from respiratory cancers for the first cohort showed a relative risk of 8.75 and for second eohort of 4.0. The second cohort should be separated out into those hired before 1950 and those hired after 1950, for major process changes were introduced then which greatly reduced the fume and dust exposure. Unfortunately, the cohort was split at 1955 in stead of 1950. Despite this, they have demonstrated that even within that eohort those hired subsequent to 1955 had e lower risk than those hired before 1955. The date is not separated appropriately nor probably of sufficient extent to determine if the excess risk continued significantly past the time of the new process changes. Present Pats Measured Against Estimates The Estimates Paper does not consider the number of nasal cancers that might now be attributable to nickel exposure. E-3 AP000089I5 However, extending its logic should produce an estimate consis tent with available data. It does not. Doll's report indicates 40% as nany nasal sinus caneer cases as non-nasal respiratory cancer cases in the nickel workers, Pedersen's report indicates 26% as nany nasal cavity cases as non-nasal respiratory cancer cases in nicksl workers. Thus, it Can be estimated that if 7,300 non-nasal respiratory cancer deaths annually can be attributed to niekel exposure, then [(26-40%) of (7,300)] or 1900-2900 eases of nasal cavity cancer dtath (page 37) can annually be attributed to nickel exposure. This estimate, however, well exceeds the total U.S. annual nasal cavity cancer incidence o about 800 eases as listed in the Third National Cancer Survey and would indicate all nasal cavity cancers are attributable to nickel exposure, ignoring the other considered eauses such as chronium, wood working, furniture industries, and non-industrial agents. The Estimates Paper did not Include nasal cancsre in its projections. Zn neither of the cited references is a nasal cancer found in a worker whoae exposure began recently. Zn Doll's study, no case was found in a worker beginning after 1924, and In Pedersen's study, no case was found in a worker beginning after 1940, The authors of the Estimates Paper thus probably concludtd that at current exposures the risk might be negligible, similar logie, however, was not carrisd ever to observe the concurrent marked reduction in lung cancer risk. Recent work on U.S. workers exposed to nickel since ww II E-4 AP00008916 y. h*a found no increased association with lung cancer 1/ BernacXi et al. *Znveatigation of Exposure to Niefcel and Itung Cancer Mortality; Case Control Study at Aircraft Sngine Paetory," Ann. Clin. Lab. Set. 6(3)*190-194, 1978. E-5 AP000089I7 APPENDIX F Comment* on Estimates Paper with Respect to Petroleum Distillates To estimate the lung cancers attributable to Polynuclear Aromatic Hydrocarbons (PNA) exposure# the Estimates Paper inap propriately applies the relative risk of various cohorts of coke oven and gas workers to a wide variety of workers presently exposed to PNA's. The 3,900,000 workers estimated by the NZOSB survey to be exposed to PNA's are employed in approx imately 30 industries, including transportation equipment, rubber, petroleum workers, and the printing end publishing industry. The exposures in these industries are very different from the exposures of. coke oven and gas workers. In addition to FNA's, coke emissions are composed of such chemicals as arsenic, aromatic amines and ammonia, some of which themselves have been implicated as carcinogens. To use such risk estiaisess for ell workers exposed to SNA'* is to misuse data. The difficulty in applying relative risks from one industry to another may be highlighted by the differences in the relative risks of different subgroups in the same cohort in the same study. See Table 1 below for a list of relative risks of respiratory cancer in different aubaeta of Redmond's coke plant cohort.Mote that only in workers working at coke oven sites is the risk higher than 3.0. 1/ See Table 1 for reference. F-l AP00008918 Table 1 Relative Risk of Respiratory Cancer* work Site Ever Employed Employed 5 years or More Coke Plant Coke Oven Non-Oven 2.01 3.31 1.01 2.09 3.67 0.51 Redmond, C.K. Epidemiological Study of.Cancer Mortality in Coke Plant Workers (1976). 7th Conference on Environmental Toxicology, Dayton, Ohio. should be viewed with caution. The county studied (Los Angeles) is known for having had unusually high pollution levels. Even though there may have been an occupational component to the deaths, these rates should not be selected for extrapolation across the entire United States. Xn addition, the study is a cross sectional study and not a cohort study. The strongest conclusions that can be derived from studies with such a design is that certain faetors are associated. Data from other studies in the literature are more applicable to industries composing the exposed group. Tabersbaw-Cooper Associates did a cohort mortality study of 10,163 mortality from respiratory cancer increased with increased 1/ Menek, B. and Henderson, B.C. 1976 - "Occupational Difference in Rates of Lung Cancer," Journal of Occupational Medicine, 18, 797-801. 2/ G&ffey, W. "An Epidemiologic Study of Petroleum Refinery " Workers," a study performed by Tabershaw-Cooper/Associates. for the American Petroleum Institute. P-2 AP00008919 exposure, the observed mortality was nevertheless below the expected value in the high exposure group. Further# LXoydx Decoufle, and Calvin's^/ proportionate mortality analysis of 2,604 deaths in the printing industry found a non-significant ineraase for eaneer of the lung and bronchus. In short# it is incorrect to apply risk factors associated with high-risk PKA-exposed workers to all workers with PNA exposure. 1/ Lloyd# J. W.# Oecoufle, P. end Calvin# I#.G.,"1977 Unusual Mortality Experience of Printing Pressmen." Journal of Occupational Medicine. 19, 543-550. F-3 AP00008920 * APPENDIX G Comments on the Estimates Paper With Respect to Benzene The estimate of the number oE eases of cancer due to bensene exposure has been based on the study by Infante at si., of the leukemia experience of some of the workers in parts of the 1/ two Pliofilm plants in Ohio in 1940-49. Infante reported seven cases of leukemia of two different forms among 746 workers. As suming this had been an appropriately designed study* it would have indicated an approximate four-fold excess relative risk of leukemia among the workers (confidence range of 0.2 to 7). This study* however* suffered from s number of major design problems that diminish its value as an estimate of `leukemia risk from benzene exposure. Firstly* the identifica tion Of the seven esses was already known prior to the final 2/ formulation of the study and, in fact* had been published in the local newspaper before any analysis had been performed. Further* only part of the group exposed to benzene at this in dustrial site were included in the study. The study reported seven cases among 746 workers, but did not report the fact that 1/ Infante et al. "Leukemia in Benzene Workers." The Lancet " 76-78, 3uly"l977. " 2/ "In evaluating reports in the medical literature of the excessive incidence of any given disease* particularly when the authors possess beforehand reasons to anticipate or suspect an excess frequency of that disease* everstimatlon due to the incentive feature may ereap in." Jandl* J.H., "A Critique of EPA'a Assessment of Health Risk Associated with Atmospheric Exposure to Benzene*" December 2* 1977* p. 9 (submitted to 6PA and Env. Health Comm, of the Science Advisory Board* Decembar 9, 1977). C-l AP00008921 there were no easts among the 404 ether workers in the plant. Had the total working population at that time (1,152 workers) been included in the study, the statistical significance and the measurement of the excess would have been markedly dimin ished. Another major problem is that the study presents mis leading information on the amount of benzene present in the occupational exposure. The study states that the levels were generally between zero and 10 to IS parts per million. However, reports from the Ohio State laboratories at the that time in dicated levels of 500 parts per million st pieces where workers were known to spend a considerable amount of time. In addition, reports at that time, and subsequently at hearings, have indi cated thet the amount of benzene eontaet et the plant was suf ficient for a worker's elothing to still be drenched with ben zene when he returned home, direct body contact with benzene liquid was quits frequent, and that containers of benzsne very frequently were open and fully exposed to the stnosphers. This amount of exposure is considerably different from zero to 10-15 ppm benzene which was detectable at that time only with very technically sophisticated equipment. Therefore, not only is the relative risk of leukemia artificially exaggerated within this population, but the level of benzene exposure is markedly underestimated, thus vastly increasing the apparent risk of leukemia from a specific dosage. Further, analysis of the leukemia cases in these two G-2 AP00008922 duster* indicate that the cell-type distribution is quite simi lar to that which would be expected in s population who died at the ages these cases did. Were there to be a specific cause of a specific type of leuleeaia among the population, one might assume there would be an excess of one specific type of leukemia which the authors do not claim. Thus, the very study upon which the national estimate of bensene-induced leukemia has been based is seriously flawed in terms of all of its specific and essential components. Additionally, the last of the six pertinent deaths reported by Znfante, et al, occurred in 1961 in an individual exposed in the 1940's. Unmentioned is the fact that no leukemia deaths sines 1961 within the United States attributable to occu pational exposure to benzene have been reported in the medical literature. Surely, if there is any validity to the Znfante study implication that workplace exposures to 10 ppm of benzene or less can produce leukemia, we should have had reports of sev eral such eases in the last 17 years. G-3 AP00008923 APPENDIX H Comments On Estimates Paper With Respect To Vinyl .Chloride Table 1 of the Estimates Paper lists vinyl ehloride as chemical associated with cancer induction in man and shows the target organ to be the liver with Indicative evidence of the in duction of brain and lung cancer as well. Further, the table estimates the number of employees at risk from vinyl chloride ex posure at 2,200,000. The available data suggest s reexamination of these statements. While vinyl chloride (VCM) has been shown to eause cancer of the liver, the evidence for the involvement of other organ systems is so weak that only cancer of the liver can be used in attempting to assess the carcinogenic hazard of VCM ex posure. There are Indications of an excess of brain eaneers in employees exposed to VCM, but the most complete epidemiological study of vinyl chloride workers, Epidemiolodcal Study of Vlnvl Chloride workers, Final Report, prepared for the Manufacturing Chemists Association bv Equitable Environmental Health, Ine., January 1978, casts serious doubt on any causal relationship between VCM exposures end brain cancer. It reports a total of 12 brain tumors, but shows no apparent relationship with maximum exposure or total integrated exposure. Additionally, only four of the 12 brein tumors were confirmed by autopsy or craniotomy, leaving the distinct possibility that some of them may have been metastatic tumors from unknown sites or other non-malignsnt apace occupying lesions. H-l AP00008924 The evidence Cor lung eancer is similarly unsettled* In a recent epidemiological study, an Epidemiologic Investiga tion of Lung Cancer in m Multixenobiotlc Occupational Environ ment by Richard J. Waxweller* doctoral dissertation (Epidemiology) University of North Carolina. Chapel Hill, M.C. 1978, Waxweller finds an association between polyvinylchloride (PVC) manufacture and excess lung cancer, but makes the association with PVC dust rather than VCM, thus casting doubt whether this excess, if real, is caused by exposure to the monomer, to mechanical effects from the polymer, the polymer itself, or the soap-like materials which commonly coat PVC particles. The association between angiosarcoma of the liver and VCM exposure seems unequivocal* It is, however, noteworthy that in the 25 cases which have occurred in the 0*S* and the additional 45 which are reported elsewhere in the world where information is available, there has been in each case the opportunity for repeated exposures to high levels of VCM* That is, in each case, the employee had been associated with the cleaning of reactor vessels or other operations which would occasion exposuras to hundrads and sometimes thousands of parts per million (ppra) of VCM* Mo cases are reported in employees who worked only in those parts of the PVC manufacturing and distribution process where ex posures are commonly much lower, that is, regularly below to 50 ppra. Xt would seem then, that the population at risk of liver cancer from exposure to VCM is no greater than the population en- E-2 AP00008925 gaged In the manufacture of VCM and its polymerisation to FVC. This population is a relatively small one. It is estimated at approximately 2,300 employees for VCM and 5,000 employees for PVC in the recent Foster Snell survey (contained in AXBC testimony at the OS HA hearings). The NIOSH estimate of the number of em ployees involved in FVC manufacture in 1974 is 4,040, Engineering Control Technology Assessment for the Plastics and Resin Industry. March 1978, kiosh Publicstion 78-159. These two estimates are in close agreement and surely the total number of employees occupa tionally exposed to VCM, either in the manufacture of VCM or its polymerisation to FVC, does not exeeed 10,000 in the U.S. This number of 10,000 stands, of course, in sharp con trast to NXOSK's estimate of 2.2. million persons exposed. The difference is made up of those persons who are employed in the molding and/or fabrication of the pvc resin into the ultimate end produet. This group is so wide and diverse that there has been no thorough epidemiologic study, but a substantial effort in studying this group was made by Chiazzi and Nichols and reported in the Journal of Occupational Medicine, Vol. 19 No. 9, September 1977. pg. 523. This study examined the death certificates on 4,341 deaths which occurred among former employees of 17 PVC fabricators during the period 1964-1973. No cases of angiosarcoma were discovered. Thus it appears that the one clearly identified human risk from VCM exposure is angiosarcoma of the liver and that it has been observed only in exposures arising from the manufacture H-3 AP00008926 and polymerisation of VCM and not from the subsequent fabrica tion of the polymer into the end use products. It would appear, then, that there should be serious doubt about the usefulness of HXOSfl* s estimate of 2.2 million as the number of employees at risk and that unless future data indicate otherwise, the correct number of persons at risk from VCM exposure is not more than 10,000. H-4 a AP00008927 APPENDIX Z Comments on Appendix A of the Estimates Paper A fundamental assumption of the Estimates Paper Is that for a given exposure cohort, the increased relative risk due to that exposure is constant for the rest of the lifetime. Appendix A was attached to the Estimates Paper in an attempt to provide the theoretical justification for that assumption. However, Appendix A misinterprets data and develops an analytic explanation irrelevant to the assumption. The Appendix provides an explanation for why the in cidence rate for exposed cohorts reduces toward that of un exposed cohorts upon withdrawal of some exposures but not of ethers. The relative risk of lung cancer in ex-smokers (rate for ex-snoker relative to that for non-smoker of the same age) returns toward "1" about five years after cessation of smoking, but the relative risk of mesothelione (rate for formerly asbes- tos-exposed worker relative to never-exposed worker of sane age) does not approach *1", although both cancers have latency periods that exceed twenty years. The Appendix, using a multi-stage model of cancer development with some exposure (dose)-dependent stages, develops an explanation. The twenty-year latency periods indicate that some exposure-dependent stages occur aarly in the development of cancer (some twenty years prior to the appearance of cancer). The lack of a reduction in incidence rates with subsequent re duction of exposure in that cohort indicates that the rate- 1-1 AP00008928 limiting steps in the later stages of the cancer development are not exposure-dependent. Asbestos exposure may only be necessary for induction of early stages in the development of mesotheliomas. On the other hand, cigarette smoke may participate not only in the early stages of cancer develop* mentr but also in some of the penultimate stages. Thus# cessation of smoking may lead to a return of incidence rate to that expected of non-smokers beeause the cigarette smoke is not present to participate in those final stages. This is conceptually what the Appendix deals with. Further explanation of the theoretical support for the assumption is unnecessary, for review of some of the data referred to demonstrates-the lack of generalizability of the assumption throughout the area of occupational carcinogenesis. The assumption holds that for a given exposure level and a given target cancer, the incidence rate in the exposed group will be a constant multiplier of the incidence rate in the unexposed group of the same age or observation period. This model is demonstrated in figure 1 and figure 2. Sqsosure Dose Incidence Fate Figure 1 1-2 AP00008929 Relative Incidence Rats (Relative to Unesfosed) 43* Figure 2 1 PfpOSUTB Cose 4 units 3 units 2 units 1 unit taro 5 10 15 20 25 30 35 40 Age or Period frcni Qqxeure A review of some of the data cited will demonstrate the inapplicability of the model* Figure 3 [infra, at 1-5) shows Selikoff's data on the observed and expected risks of lung cancers (3A) and of the relative risk in asbestos workers (3B) and the risk of mesothe liomas in asbestos workers (30* Selikoff's work supports that of Mewhouse and Sorry in predicting a current markedly increas ing risk of mesothelioma in WW II workers exposed to asbestos (30* However, analysis of his data on lung eancer shows that the lung eancer rates of these workers has leveled and that the relative risk, some 35 years after exposure is rapidly dropping. For neither mesotheliomas nor lung cancers in asbestos workers is there evidence of a constant multiplicative relative risk. Zn fact, the evidence is* to the contrary. Assuming a constant relative risk of lung cancer over the next twenty years for this cohort based on its current or recent lung eancer experi ence will greatly magnify the risk and is definitely not 1-3 AP00008930 conservative For nickel, the evidence from Doll's papers is that the relative risk for lung cancer and for nasal sinus cancer esneer have significantly fallen for successive cohorts over the decades following the reduction in hazard contrary to the Estimates Paper statement on page 3 of Appendix A. Doll does not give sufficient data to examine the behavior over time of the relative risk within each cohort. However# Pedersen does for the Norwegian study. Pedersen's data analyzed by cohort shows that for all four exposure cohorts# neither singly nor collectively does the "relative risk for lung cancer remain constant for the rest of the lifetime" (under observation). The relative risk for nasal cancer does sppesr to be constant for the 1930-40 cohort but not for either the 1910-29 cohort nor the entire group. With the ex ception of the nasal cancers in the 1910-40 cohort# none of the cohorts demonstrate a constant relative risk thoughout the period of observation. Contrary to the statement of the Appendix# the Norwegian study demonstrates a marked drop in the relative risk of nasal cancsr from 67 in the cohort proceeding the 1950 reducion in exposure to zero in the cohort succeeding the reduction and for lung cancer similarly from 4.5 to 2.5. See Figure 4B infra, at 1-6. Thus# the two examples of occupational carcinogens given in Appendix A do not support the Estimates Paper assump tion of a constant relative risk. 1-4 AP00008931 R isk/ h ra o n -y ttn * RISE AND RELATIVE RISK OF MESOTHELIOMA AMP LONG CANCER XN ASBESTOS WORKERS BY INTERVAL SINCE INITIAL EXPOSURE* 14 3B Lung Cancer Tatra line* Iantill axpesur* 3C Mesothelioma Tatra tinea initial oxpeaura M s k /lt1 ta rm -ya a n Tatra alaca initial exposer* * Sallkofff. 1. tad Emend. K.Q.. Aabaatos-Aaaocistad Biaataa in Cnitaf Stataa Shipyards. . CM.. 2I(2),I7 (1*711. Kawheusa, K. tad Barry, C.. Predictions of Mortality from M*toth*litl Tuner* in Asbestos raetery Workers, .. Xad. M*d. 22, 147*1X1 (1*7). AP00008932 680000dV 9-1 cum 'vaaro *f ** 'iwoa ki MSlZlin ZZBZK Y iY nmOM 9K0W RNY9Y0 XY01YX4Sn YO V38HY3 "?Y * 4 *3 'K1W3GM tl rs or ii -S*-ir-OI-OTT r-ex*T I MXATIVR RISK RMAT1VB RISK 820HYO TYSYH Q | Ofx S30NY0 TYSYK Of or rs or it -ss-sr-oc -otn TflOI OS-SfiCT LH0ZO3 rc-srn or-otst SX-OTST s u-mk ta IMIIT s-cfftim M0X1YAX3S1O iO sooxyk S20HY0 OKflT 89 830NYO 9KM Y9 * S83S80M 3330111 KYI93M80K KI 330KY0 ONTH OKY 830KY0 TYSYN 80J 3SI8 3AIIYI28 2 7.H-3 ESTIMATES OF THE FRACTION OF CANCER XN THE UNITED STATES RELATED TO OCCUPATIONAL FACTORS Prepared by: National Caneer Institute National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health Contributors (alphabetical order): Xenneth Bridberd, M.D., NIOSH Pierre Decoufle, *Se.D., NCI Joseph F Frauaeni, Jr., M.D., NCI JDavid 6. Soel, Ph.D., HXSSS Robert N. Hoover, N.D., Sc.D., NCI rDavid P. Rail, M.D., Ph.D., NXEBS, Director Uaberto Saffiotti, M.D., NCI Marvin A. Schneideraan* Ph.D., Nd Arthur C.,Upton, M.D., MCI, Director * Contributor to the Appendix: Nicholas Day, Ph.D., NCI, XARC September 15, 1978 AP00008934 INCIDENCE OF MAJOR CANCERS POSSIBLY INDUSTRIALLY RELATED WHITE MALES AGE ADJUSTED (1970 U.S. POP.) PER 100,000 Site MOST LIKELY Lung Bladder Liver, gall bladder & biliary passages Lymphoma & Multiple Myeloma Melanoma 19691971 70.7 23.5 1975 75.6 27.4 1 Chance +7 +17 Proportion attributed to other possible causes .85 Smoking .45 Smoking . 5.6 - 6.0 -11 16.1 4.6 18.9 6.3 +17 +37 1 .75 Sunllqht Total minus "attributable* 1969- 5 1971 1975 Chenqe 10.6 11.3 + 7 12.9 15.1 +17 6.6 5.0 -11 16.1 18.9 +17 1.15 1.58 +37 SubtotaT 120.5 133.2 +11 46.4 51.9 +12 LESS LIKELY Intestines & Rectum 51.2 53.1 + 4 Pancreas 12.2 12.5 + 2 .55 Smokina 51.2 53.1 + 4 5.5 5.6 + 2 Subtotal 63.4 65.6 + 3 56.7 58.7 + 4 GRAND TOTAL 183.9 198.8 + 8 103.1 110.6 7 AP00008955 I This statement addresses the questions "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 forsi e future?* Previously published estimates of this fraction have been as low as 1% to 5% for past data (reviews by Higginaon (1-3)# Wynder and Gori (4)# and Soil (3)] and as high as lot to 15t (see the discussion by Cole (6)}* All these estimates are somewhat speculative and several were seriously incomplete or deficient. Host are now out of date, if recent evi dence is considered and if tha full eonsequenoes of occupational exposures in the present and recant past are taken into account# estimates of at least 20% appear aueh mere reasonable# and say 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. .Tew industries have been investigated P 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 data. The International Agency for Research on Cancer (XAAC) has an ongoing program to review data on chemicals for potential carcinogenic affects* To date# seme 348 chemicals and industrial processes* have been reviewed. According to a recent 1 AP00008936 whereas cancer appears to be a disease of interaction*. The initia tion and development of cancer is a multi-phased, multi-causal process in which both external and internal factors act# probably at each of several stages# before frank# clinical cancer appears. Zt is likely that many# if not most# cancers are influenced by two or nore different external factors acting simultaneously or sequentially. Thus# alcohol by itself appears to be e minor cause of cancer--but alcohol combined with cigarette smoking leads to risks 15 times higher than those experienced by non-smoking non-drinkers. X a drinker smoker develops cancer of the oral cavity# to which "cause" should ita be attributed? Prinking or smoking? If we eeuld correctly identify the proportions of cancer incidence "attributable to" each of the classes of environmental factors considered by Wynder and Gori# the sum of these percentages would be considerably higher than 100. One of the best-studied examples of interaction between exogenous agents is that between asbestos and cigarette smoke in inducing lung c&neer (9). Most lung cancers "attributable to" asbestos are probably simultaneously "attributable to" smoking. Zf current theories of a skulti-ci^al process are eorreet, *tt seems likely that a large fraction of caneers which at first appear to be "attributable to" smoking should also be "attributable to" asbestos, radiation# and/or other occupational factors. (e) period, toe, and duration of exposure. Most occupa tional carcinogens are characterised by "latent periods" of 10 to 50 years between the onset of exposure and the clinical appearanee of tumors (7). Shis is consistsnt*with a multi-stage process. When occupationally related cancers are detected# they usually reflect 3 AP00008937 I I I exposures which started one or sort decades in the pest. Accurate numerical assessment is further complicated by the strong dependence ! of cancer incidence upon age and upon duration of exposure. Even in cases where an/^Lxcess risk is detected within one or two ! decades* this dependence on age implies that most of the attribut able cancers will not eeeur until later in the life span of tha I exposed .workers, perhaps as much as 40 or 50 years after the. first exposure. Zt is difficult to trace anyone for so loop a time, end ! those epidemiological studies vhieh do not follow people for a full lifetime are likely to underestimate lifetime risks. Host in i dustrial-epidemiologic studies have not (and probably could net) fol low a'working population to its extinction. This problem is dis l cussed in more detail in the Appendix# but e numerical example f illustrates its importance. Per many types of cancer, incidence i increases approximately as tha fourth er the fifth power of age (10); hence the cumulative number of eaneers occurring in a popula tion ever a lifetime increases as tha fifth or sixth power of age. Zf exposure to a carcinogen results in a constant multiplicative increase in risk at all ages, .then the number of eaneers occurring in an exposed group will similarly increase as ths fifth er 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 axpeeted by age 70* For this reason epidemiological studies often enumerate only a small fraction of the total excess eaneers attributabls to an agent. Any overall assessment of the importance of occupational carcinogenesis should take this into account. 4 AP00008938 t (d) Change in exposure p&tttrni. Th dependence of eaneer risk upon age end duration of exposure is further complicated by changes in patterns of exposure to potential earcinogens. Tew, if any, workers are exposed throughout their entire working lives to the sane chemical at similar concentrations. American workers change jobs fairly frequently! even within the sane job# the chemi cals to Which a worker is exposed msy be changed from tine to tine. By the time an occupationally related cancer develops*. the workers will frequently have been exposed to different chemieals and may well have changed occupations* Zt is particularly difficult to make estimates of the consequences of prssent-day exposux/, because the ' chemicals er which we have the best dose-response information are those which are generally recognised as^eareinogenie. Several of them have been regulated* so that exposure to these ehemic^jf has been re duced; this leaves other carcinogens that arc not well controlled* Previous Attempts to estimate the Importance of Occupational Carcinogenesis . In 1969# Bigginson (1) tabulated estimates of *the extent to which occupational and cultural eaneers have bsen recognized." Se attributed to known dceupaticnal factors 1% of mouth eaneers* 1^2% . of lung eaneers* 10% of bladder cancers and 2% of skin cancers. (Ho detailed development of these estimates was given* however.) Bigginson limited his attributions to factors that "have been recog nised*" the majority of eanears were assigned to "unknown" factors. 5 I AP00008939 In 1976, Higginson and Muir (2) again estimated the impact of environmental factors in human eancar. 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 environment*3 * factors*" It would appear Sren figure 1 in their paper that their median estimates for the fraction of cancers at* tributable to occupational factors were 4% for men and 2% for women. Their explanation for these estimates was: "The data presently available are# at best, educated estimates.of the.relationship between specific cancers and specific occupational groups. Cole ct al. (56) suggested that 201 of bladder eancers occurring in males in th Boston area are related to occupational exposure* In certain counties of New Jersey, the increased risk for this cancer appeared to be high among worker* in certain Chemical industries. Bailar (personal communication) estimated that the occupa tional contribution to total eaneer incidence in males lies between 1 and 5%, tend a similar estimate was made by Nelson (personal communication) General estimates of the percentage of all human caneers related to occupational exposure range between 1 and 10% How ever,' identification of speeifie high-risk groups, hazardous exposure levels, and related eaneer inci dence rates is yet to be determined*" Za addition to the error of "ene-effeet, one-cause" thinking pointed out above, their reliance on "educated estimates," "personal cowman1- eations," and "general estimates* makes the resulting conclusions tenuous. And again, of course, no attempt was made to estimate future consequence* of past exposures. 6 AP00008940 In 1977, Doll (5) published a survey of tha importance of environmental, factors in human cancer in the 0-1C. Be 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 oaneer that is occupationally-induced to be less than 15% for men and less than 5% for* women. Ba explained the basis for these estimates as follows i _ "I estimated that the occupationally-induced burden was less than 151 for men and less than 5% for women. The major causes of cancer deaths axe cancers of the lung, the brsest and the colon* end these are largely or totally noa-occupationally induced. Lon? cancer .is 901 cigarette-smoking-induced; breast eaacer is probably not at all occupationally induced* there may be some* probably small, occupational component in caneer of the rectum. Other sites sueh as cervix or ovary have a negligible occupational component, if any*. The above listed sites account for about half of the caneer deaths, for other sites, it -is diffi cult to assess tha occupational component. However, even en 'occupationally-related* caneer like bladder caneer can be attributed directly to occupational exposures only about 25% of tha tima. with.half the eaaeer essentially aon-oecupationally induced, and half the cancers occupationally-indueed less than 25% of the time, a seasonable estimate seemed to be 15% for males." # This argument also assumes `that a eaaeer whieh is related to a non- eecupatieaal factor cannot also be occupationally related, cole's statement of the basis for his estimatas 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 ere 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 AP00008941 future risks. It is not even a correct reflection of the published estimates, which range up to 10% (4) or 15% () Re-formula-tino the Question Another defect of th* studies s^amarised 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 ia 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 reeert past will not be manifested until some time in the future. The question that needs to be addressed is "fthat is the likely contribution of presentday occupational exposures to future cancer incidence?* An answer to this question oust be somewhat speculative, because we do not know which of the ehemieals in the present-day workplace will be identified sometime in the future as causing cancer. Accordingly, to provide a basis for making appropriate estimates, we will first attempt to estimate the-contribution, of occupational exposures to known carcino gens in the reeent peat 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 ss a Well-Studied Example The consequences of occupational exposura to asbestos in the United States have only begun to be recognized in the reeent past (12-14) It has been estimated* (11) that between 8 and 11 million *' Several authors oi ems report wars responsible for preparing these estimates. AP00008942 worker* have been exposed to asbestos In the U.S. sinee the beginning of World War II. Of that total, approximately`1.5 to 2.S million are presently employed. Probably a million have already died, while the remainder--between 5*5 and 7.5 million workers--were formerly employed in 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 eaacer -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 perr cent) would have beei expected to die of cancers at thesa sites.) Assuming that the excess risk to the remaining less heavily exposed workers is ene-quartsr of that to the heavily exposed workers (an . assumption suggested by the data is 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 eaneers will be aunifested ever a period of 30-35 years, the expected average number 9 v AP00008943 of eaneer deaths associated with wbestsi par year in that period will be between 58*000 to 75,000.* Such nuabers would comprise 13-18% of ell cancer deaths expected in the United States in the forseeable future (assuming that total eaneer 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 predieted offsets 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 axe also related to smoking (lung and esophagus) or are in tb? gastre-iatsstina? tract (esophagus, stomach, and colon), where cancers are usually assumed to be not occupationally related (1,4,5,6). Hence, if the old one-effeet, one-cause approach ware used, the occupational origin of moat 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'1'general population. Thera are several reasons for this: " (a) two of the major types of asbestos-related eancer, pleural peritoneal mesothelioma, are not classified as such in the national health statistics, but are usually listsd as Xtiag cancers Or'as . various abdominal cancers, respectively; (b) most asbestos-related lung esneers are also smoking-related, * Selikoff (l) made an estimate of 50,000. per year, exclusive of the added eases that would come among the less heavily' exposed group. 10 AP00008944 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; (e) any increase in asbestos-related cancers of the stomach and colon vould be masked by the ether 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 Issson to be learned from the asbestos story is that a major publie health disaster can develop while its early manifestations art 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 AP00008945 Comnsrison of Risks due to Asbestos with those flue to five other High-Zxoosurs Substances ~ Xa Table a we bare 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* She tabulation is similar to that pre sented in ref; 17, but incorporates more recant data vhare avail able, and is limited to the substances and cancer sites for which ths best data .are available on both exposure and relative risks. The first three column* in Table 2 list the agent, the affected organs, and the observed risk ratios (JO (from Table 1 in ref. 7) The fourth column lists the age-adjusted incidence (Z) 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, # p 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 is the Table. The last column in Table 2 lists values of the quantity (R-l)KX. This is the average number of excess .cancers that would 12 AP00008946 be expected to occur In a population of size w, subject to a site-specific risk R times 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* jeetions of the numbers of excess cancers in only one'cohort of H workers, because of turnovers in the workforce, the number of exposed workers and ex-workers subject to excess cancers at any one time will be several times larger than N, Xf, 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. Xt 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 eancars attributable to these substances. The other major assumption that is neeessary before the figures in Table 2 can be used as predictions of future cancer 13 AP00008947 mortality is that the relative risks R would remain the same as those reported in the published studies throughout the workers' lives, even if exposures ceased. The basis for this assumption is discussed in Appendix A, where both observational end theoretical reasons for assuming constancCy^of R are put forward. In any easa several of the studies from which the i figures la Table 2 ere derived reported average risks over e substantial fraction of the workers* lives* Several other factors complicate the interpretation of the figures is Table 2, including the potential ednseguenees of simultaneous or sequential aa^osure to other carcinogens or modifying factors. One reason why Table 2 may overestimate numbers e 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 can*cers, but it is reas* onable to compare them with the data derived by the same method for asbesto^related cancers. * At the least, the data summarised `in Table 2 show that the five ether 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 9 cancers per year, versus 13,900 for asbestos. In presenting this comparison, it should be emphasised that the former figure includes only the primary sites of action. Inclusion of ex pected excess cancers at other sites would increase the 14 AP00008948 estimates substantially. It should be re-emphasized that many of the cancers con sidered hare 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 earcinogenie risks to exposed workers. He omitted from Table 2 several agents listed as occupational carcinogens in refs. 7* 8 and 17* because we had difficulty matching data on relative risks to data on the number of workers exposed. -These agents include cadmium* eeal tar pitch volatiles* hematite* and* vinyl ehloride. The data we used on the number of "workers exposed to carcinogenic petroleum fractions are probably \ conservative. .The' XAR& (8) has already reviewed 221 agents ^ identified as qapable of inducing cancer in experimental animals. Although some occupational exposure is known to occur for most of these chemicals* epidemiological and case studies or their possible association with cancer in humans were lacking or were judged te be inconclusive." Other carcinogens have been reposted in the literature. To date only a very small proportion 15 AP00008949 * of all the chemicals la us* have been tested for carcinogenicity. Table 3 lists a number of occupational groups ^hat have been shown to be at increased risk of cancer at speeifie sites, without speeifie causative agents having been identified. Al though risks^ratios are available in most of these eases,'the * imprecision of iaforaatien on the nuabers of workers in the jobs concerned prevented us from making estimates about the number of cancers to be anticipated; In addition to cheaieal carcinogens, occupational exposure to radiation is known to be a significant cause*of cancer in U.S. workers. Croups st 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 arid fishermen are subject to in creased risks of skin eancer associated with solar radiation. Ke 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 PresenVDay Exposures She estimates of potential excess cancer mortality that are listed in Table 2 are projections of the future consequences of pest exposures. The estimates of risk ratios listed in Table 2 are derived from studies published between 1947 end 1978, mostly since 1966 (7) The estimated numbers of workers exposed ere derived from a survey in 1972*74 (20). The entieipated exeess 16 AP00008950 t cancer incidence* are those expected to be observed in the next 'three decades, end 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 vert published. Exposure to asbestos, benzene, coke oven emissions and vinyl chloride has been limited (although not eliminated) by reeent OSEA regulations. Thera Is also evidence, however, that not all tha major occupational carcinegans have been eliminated. Of the agents in Table 2, there is today widespread exposure to arsenic, chromium, nickel, and many petroleum products. Host 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 tsuch as agricultural field workers) have not been adequately surveyed for excess cancer risks. Only a handful of the 221 chemicals foundjositive -in experimental animals and revlawed by the SAJtC (8) have been regulated as carcinogens In the 'US: workplace. Among those net 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 apideao- logical studies. , Tor public polley purposes, It would be very desirable to make numerical estisetes.of the potential consequences of present- day exposure to carcinogens in the workplace. Such estimates 17 AP0000895I would, however, require numerical date 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 nan. In our view, existing methods for such extrapolation leave enough questions open eon- e earning their precision so as to make us unwilling to attempt large scale estimates -- particularly in the absence of exposure data. Banes, we can say nothing firm about the magnitude of future risks attributable to the unquantified preseat-day ex posures . There is no evidence, however, that these risks are sub stantially less than the risks resulting from exposures in the reeent 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 U.S. workplaces; the total volume of synthetic organic chemicals produced in the U.S. continues to.increase rapidly. If only one of the thousands o, f chem> \icals introduced into commerce in the past 30 years .proves to be as hazardous'as asbestos, this eould suffice to maintain comparable rates of occupatiSnalXy-feTated -cancer for decades into the future. In our view, any complacency about the future consequences of present-day exposure to uncharecterized chemicals would be unjustified. 18 AP00008952 Two Alternative Approaches Other ways can be used to estimate the possible contribution of occupational exposures to human cancer incidence. Although none, to oux 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 analyse trends in total eancer incidence (or mortality) in the U.S. population. The argument is made that if occupational faetcrs were important causes of eancer, then total eancer incidence vhould be increasing rapidly, reflecting the rapid increase in the number and amount of synthetic organic chemicals produced in recent decades, Za feet (the argument runs), the continued increese in cancer incidence and mortality is almost solely due to increases in lung canoes and ether smoking-related cancers. Zf 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 arguments 1. Host of the increase in production of synthetic orgaaie chemicals is .too recent to be reflected in eurrent cancer statistics.'' 2. The increase in production of synthetics (some of which ere potential eareinogens) in the period 1940-1960 may well have bees offset by reductions in the intensity of exposure to other chemicals, resulting from improvements in industrial controls stimulated, is part, by government regulation. Exposure to several major careinogans has been redueed substantially in recent years. Exposure to other potential carcinogens (such as carbon tetra-- chloride) was redueed earlier, to reduce other types of toxic * 19 AP00008953 hazard. The predieted 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 some 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 "oecupationally-related* cancers are best recognized. Many of the smoking-related eaneers should be simultaneously attributable to occupational factors. On a per-eapita basis sinking 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" eaneers srs removed from the total. If the smoking-related cancers are not subtracted/ total age-adjusted cancer incidence in the U.S. t is increasing at more than 1% per annua (37) 4. Not all of the smoking-related eaneers, i.e. those in the lung, pancreas, and bladder, are attributable to~smoking. Sven if e liberal figures-, is used for attributable risk, the frac tion of lung caheer incidence not attributable to smoking is increasing and total eancars possibly industrially related.hava been increasing mors 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 ispaet of asbestos-related cancer is just beginning to be re fleeted in overall cancer statistics, despite 37 years of heavy exposure. One should hardly expect more recent additions to have shown m great effect already. 20 AP00008954 A second approach is to coapara cancer incidence in men and woman. To the extent that exposure to chaaical carcinogens occurred in occupations in which most workers are (or were) male# this should bs reflected in differences in overall .cancer incidence (and trends in incidsncs) in ths 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). Xn par ticular, incidence is much higher in males than in females in the key occupationally related sites: lung, liver, bladder, kidney, * and lymphatic system and perhaps stomach and pan- w creas (19) Nonetheless, there are some flaws in this argument, too. Not only male workers have substantial expesura to carcinogens. Although male workers doubtless predominate in chemical manu facturing and heavy industry, women have long been employed in large numb/ ers In light industry where there is substantial exposure-to certain carcinogens*, e.g. the radium dial painters. The fraction of occupationally related cancers in woman may increase in future years due to increased employment of woman in jobs where they are exposed to carcinogens. Sven housewives have greater occupational exposure to some potential carcinogens than typical working men.* We regard the home as a workplace, even if it dees not fall within the jurisdiction of OSSA. 21 AP00008955 i i Zt would clearly be valuable to make a rigorous comparison between employed end never employed women* but such a study would 1 be difficult to eonduet and interpret because of the many con 1 founding variables. In our view* there is nothing in the -gross cancer statistics for tha u.S. population which is inconsistent l with the hypothesis that op to 20-40% ef all eancers era (or will be in the next several decades) attributable to occupational 1 factors ! Relation between Occupation*! end Other Contributing factors These estimates do not diminish the importance e other J contributing factors to cancar risk such as smoking* diet* and perhaps urban-rural differences. While much of the data on 1 occupational cancer risk considered in this paper does net I speeifieelly consider factors such as smoking (except for asbestos) J end diet* it is else fair to state that the prevailing body of data linking smoking and diet with eancer risk dSf not adequately consider the contribution of exposure to occupational carcinogens. i This is largely because the available scientific methodologies I do not facilitate, adequate consideration of all contributing factors "'in any single study or approach. Until recently cost 1 scientists did not take into account the multiple etiologies and tha multi-stage nature of cancer. In retrospect* it is likely that cancer risk is e 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 agents.in the workplace. 22 AP00008956 Opportunities for Prevention The estimates of cancer attributable to occupational ex posure given here should be viewed at pointing up the oppor tunities that exist to prevent disease in Suture generations. She causes of caneer are multiple, with more than one factor eon* tributing to caneer risk. In such a situation, any percentage accounting of contributing causes to caneer well exceeds 100%. To prevent cancer, one must concentrate on eausative factors that can be reduced so thet we can dacreasa 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 rsdues risks and subsequent disease in other occupations are at hand. Sumarv and Conclusions 1, The estimates that only 1% to 5% of total eancers in. the United States ers attributable to occupational factors have not bsen scientifically documented and have little meaning for estimating even short-teym .future risks. 2. Most cancers have multiple causes: it is a reduction ist error end not in keeping with current theories of cancer eausation to attempt to assign saeh caneer to an exclusive single cause. 2* Because cancer incidence is strongly dependent on age end upon duration of exposure, end because most eancef^ occur late in life, many industrial epidemiological studies detest only a small fraction of caneers (i.e. those developing early) 23 I 1 I i i I l ( t \ i I ! i I I I I f AP00008957 4. Past exposure to asbestos is expected to result id up to 2 Billion excess cancer deaths in the next three decades: this would correspond to roughly 13*16% of the total caneer 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 say be cotsparahle in their total effects to asbestos. 6. These projections suggest .that occupationally related cancers say comprise as such es 20% or sore of total eancer mortality in forthcoming decades. Asbestos alone will probably contribute up to 13-18%, end the data in Table 2 suggest at least . 10%-20% more. These data do not include effects of radiation# nor effects^ 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 ere still many unregulated carcinogens in the U.S. workplaces; a number of occupations are characterized by excess eancer risks' which have not yet been attributed to specific agents. 8. There is no sound 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 eancer incidence (and mortality) in tba U.S. are consistent with the hypothesis that occupationally-related cancers comprise a substantial and in creasing fraction of total eancer incidence. 24 AP00008958  REFERENCES I I 1. EXGGXNSOK# J.1969. Present trends in cancer epidemiology. Proe. Caned. Cancer Cengr. 8:40-75. e | 2. BIGGINSON, J. # and MDIR, C.5. 1976. The role of epidemiology la elucidating the importance of environmental factors in human cancer. Cancer Detection and Prevention 1:79*105. I " 3. BIGGINSON# <7. 1976. X hazardous society? Individual versus community responsibility in eaneer prevention. Amer. J. Publ. Health 66:359-366. 4. WINDER, E.Ii. f and GORX# G.B. 1977. Guest Editorial: Contribu tion of the environment to cancer incidence: an epidemio logical exercise. 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Sei. 271* 40-48. BRJDBORD, E, 1978. New Horizons in occupational, medicine. National Institute of Occupational Safaty and Health, Rockville, Maryland. NATIONAL CANCER INSTITUTE. 1975. Third National Cancer Survey: Incidence data. Nat. Cancer Inst. Konogr. 41*1-454. (S.J. Cutler and J.L. Young, Jr., eds.). NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH. 1977. National Occupational Xasard Survey. Vol. 111. Survey Analysis and Supplenental Tables. DHSW (NZOSH) Publica tion No. 78-114. Cincinnati, Ohio. LEE, A.M. and FRAUMSNZ, J.F., JR. 1969. Arsenic and respira tory eaneer in men* An occupational study. J. Nat. Cancer Inst. 42*1046-1052. INFANTE, P.F., RXNSXY, R.A., WAGONER, J.V., and YOUNG, R.J. 1977. Leukemia in beaseae workers. Lane*ti?6-78, July 9, 1977. '* ' R0O3TTE, H.`E.'1977. Cause Specific Mortality of Coal Miners. J. Occup. Med. 19:795-801. LI, F.F. i FRAUMENI, J.F., JR., MANTEL, N. and MILLER, R.W. 1969. Caneer mortality among chemists. J. Nat. Cancer Inst. 43*1159-1164. KCSEELA, RIITA-SXSEO, HERNRERG, S., XARAVA, R., JARVXNSN, S. and NURZNSN, M. 1976. A mortality study of foundry workers. Sean. J. Work Environ. Health 2xsu?pl. 1, 73-89. GIBSON, E.S., MARTIN, R.H., and LOCEXNGTON, J.N. 1977. Lung cancer mortality in a steel foundry. J. Occup. Med. 19: 807-812. 27 AP00008960 27 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. I I MOSS, E. and LEE, W.R. 1974. Occurrence of oral and pharyngeal cancers la textile workers. Brit. J. ind. Mad. 31*224-232. I ZXOXD, J.W., DECOUTL2, P., and SALVIN, L.G. 1977. Unusual oxtality experience of printing pressman. J. Occup. Mad. 19*543-550. WAGONER, J.K. , MILLER, R.W., LUNDIN, F.S., JR., FRAUHENX, J.F., JR., and XAIJ, M.E. 1963. Unusual eaacar mortality among a group of underground natal miners. Raw Engl. j. Mad. 269*284-289. REDMOND, C.E., STROBXNO, B.R. and CYFESS, R.B. 1976. Cancer ' experience among coka by-product workers. Xa Occupational Carcinogenesis. (Eds. U. Saffiotti and J. Wagonar) Ann. N.Z. Acad. sci. 271*102-115. I I 1 ! LEMON, R.A., LEE, J.S., WAGONER, J.E. and BLEJER, B.P. 1976. Cancer mortality among cadmium production workers. In Occupational Carcinogenesis. (Eds. U. Saffiotti and J. Wagoner.) Ana. 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". 271*250-259. MONSON, r.r. , and NAXANO, x.K. 1976. Mortality among rubber workers; X. White mala union employee* in Akron, Ohio. Amar. J*. Epidemiol. 103:284-296* PEDERSEN, ., BOGETVSIT, A.C., and ANDERSEN, A. 1973. Cancar Of respiratory organs saong workers at a nickel refinery in Norway. Sat. J. Cancer 12:32-41. I I i ! I DOLL, R., MORGAN, L.G., and SREZSSR, F.S. 1970. Cancers of the lung and nasal sihusas in nickel workers. Brit. J. Cancar 24:623^632'. \ ENTERLIME, P.E. 1974. Respiratory cancer among chromate workers . J.Occup. Mad. 16*523-526. SCENEXDERMAN, M. 197S. Statement prepared for OSEA hearings. SCSNSZDERMAN, H. .1978. Supplementary statement prepared for OSSA hearings. ACSESON, E.D. 1976. Nasal cancar in the furniture and beet and j shoe manufacturing industries. Prav. Med. 5:295*315. 1 3RZHT0N, L.A. 1977. A death certificate analysis of nasal can- J eer among furniture workers in North Carolina. Cancer Res. I 37*3473-3474. AP00008961 41. axsoy, M. at al. 1974. Leukeaia in shoe workers chronically exposed to ben2ene. Blood 44:837-841. 42. RATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH. 1975. . Criteria for a recommended standard: occupational exposure to inorganic arsenic. National Institute for Occupational Safety and Health. BEN Publication No. (NIOSH) 75-149. Rockville, Maryland. 29 AP00008962 TABES 1 CSB4ICA1S OR INBCSTKAI, FB0CESS2S ASSOCIATES WITH CMK3* ZH&OCSIQM ZS KAN (Sarivad from rmf. 9, with *** also foetaotas to Tahls J.) 1 of data on warkar axposura from rf. 19; ffigffri nt or Industrial FSBOMI Aflatoxi&s' 4-Aaiaobiphaayl Azsanie eaopou&ds Xabutoi Xtia Typo of xponna tevirteaantal, occupational6 Occupational Occupational, MdieiAAl, ftTittniBiBtil Occupational JLusasin* (auufaetsra) Scasa&a Occupational Occupational ' Banridina BisCchlorcaathyl) athar CtlteltS iadaaarias (? cadalua cxids) Occupational Occupational Occupational target Organs la Maa - Mala ' Boots of fcyosurf li-rar Bladder Skin* luag, liver Oral, inha lation Inhalation, skin, oral Inhalation, skin, oral lung, pltural cavity, g.i. tract Bladder Hoaato* poiotie systaa Bladdar log Inhalation, oral Inhalation, akin, oral Inhalation, akin Inhalation, akin, oral strata, log Inhalation, oral Zctiaated Ho. of Voskers Exposed in 9,1, d 100 1,500,0009 1,COO,000 d 1,900,000 2,300 d 1,400,000 30 * AP00008963 Chemical or Industrial ftpe>n Mala Type of fiepecure*' ttloreaphenieel Medicinal Chlsromthyl methyl ether Giro*^urn (chroi_>t* producing industries) Cyc1pbosphaaids Disthylstilbestrol Haematite mining Isopropyl oil Helphalan Occupation*! Occupational Medicinal Medicinal Occupational Occupational Medicinal MusUrd gu Occupational 2-Kaphthylaavlno Nickel (oxides) Chlesnaphasine Cxymetholoae Pheaaeatin " Occupational Occupational Medicinal Medicinal Medicinal Target Organs is Mas Main BSUtS Of Sa^esnrefe*' Sstlsated No* of Workers Sxpoeod in C.S, Banatopeietie system Oral* injec tion Lung e .Inhalation Lung* nasal cavities6 - Inhalation Bladder Oterus* vagina Lung Oral* injec tion Oral Inhalation a A 1*500,000 (chromium oxides) ______ d __ d 19*000 Nasal cavi ty, larynx Senatepeietie systea . . , .lung,* larynx Bladder Basal cavi ty* lung Bladder ' Inhalation Oral, injec tion `-- Inhalation Inhalation* skin* oral Inhalation Oral 4 d ^d 1*000 1*4 00,00^ liver Sidney Orel Oral 31 AP00008964 Chemical or Industrial Process Main type of feature* Target Organs ia Man Main Scute ef Exposure* estimated So. of Workers deposed la O.S* Sheaytoia Soot, tars sad oils vinyl chlo ride Medicinal Occupational, environmental Occupational ly^taereticolar tiaaces Z8&9i skin, aerettss Liver. brain, lung* Oral, iajeeties .Inhalation, akin Inhalation, akin ______ a _____ s 2,200,000 *The main types of txposuz* asationod irt tbese by which the association hu bean . demonstrated. Ths asla routs*- of exposure given say aot be tb only ones by which aueh could occur. Jfioaotss indicative evidence *ot; recorded in the survey* exposure very trail la all easts except aflatoxias. *Bo of workers exposed to fticJci oxide, only above 230 worker* exposed to "jok*! -casboayl ^Exposure very large but sot characterized aasorieally f f I I I l AP00008965 - TABLE 2 EXPORTED RISES ASSOCIATED WITS OCCUPATIONAL OffOSUBE* COMPARISON BETWEEN ASBESTOS AND rcvx OTHER HXGB-EEPOSOBE SUBSTANCES Chemical Substance Affsetad Organs Bisk Ratio cw* Aga-adjostsd Zneidsaes par 100,000 Hales >20 vrs (S)b Estinatad No. of workers Currently Exposed (N)c (R-l)KI A&bestos Loaf, pleutal and peritoneal mesothelia Asbestos LuAg, plsural and peritoneal casethclia Asbestos Esophagus Asbestos Asbastos Stomaeb Coloa/ractua Arson* e Respiratory tract Beaten* Leukemia CtlTO&i Vft Baspiratory tract Hiekel (oaddss) Respiratory " tract Patrolsam fractions (including arenaties) Lung K5-12 6.6d .2.1* 1.7* 1.6* 3-B 2-5* 5-9 ;} U S-10 (2-33)f 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 1,$00,0009 250 400 800 3 ,900-14,000 2,000,000 1 ,.500,000 350-1400 7 ,900-16,000 1,400,000 7 ,300-16,500 3,900,000f 9,100 * rrete nf. 7 anises otherwise stated* h Free rsf. IB * Prea rsf. 17, derived free rsf. 19 4 Pr Table 3 in rsf. IS * Pros rsf. 21 * Pm rsf. 16* scs notes bslow 9 Pros rsf. 42 see also detailed setaa bslov. 33 AP00008966 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 prdvide further data drawn from the principal published references for each substance* ASBESTOS number of workers potentially exposed: About 1,600*000 Risk Ratios: l.S - 12 for lung, pleural and peritoneal sesothelia Projected number of excess cancers per year: 13,900 From the studies of Selikoff (ref. IS) the relative risk for lung esneer among asbestos-insulation workers in the c.S. is about 8.6, which accounts for about 20% of their deaths. A further 7% of eases are due to mesotheliomas which otherwise occur rarely. Applying the 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 pir year. Provisional projections for excess cancers in the respiratory tract, based upon the observed relative risks in Selikoff's 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-Bee and Prauaeni (ref 21) evaluated the mortality experience of 8,047 white male smelter workers exposed to arsenic -1 AP00008967 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 arsenie 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 bean associated with excess cancers of the skin and liver (7): these sites are not considered here. AEKZZNS Number of worker# potentially exposedtafcgut 2,000,000 Risk Ratios* About 5 for leukemia^^**^s \ Projected number of excess cancer^ per years : 1,400 a'study by Infante, Rinsky, Wegonarfc'*xnTToung (ref. 22) examined the mortality experience of workers exposed to benzene from 1940 to 1949. A significant 5-fold excess risk of death from leukemias was observed compared to controls (7 observed vs. about 1.4 expeet&d) This study represaats an understatement of risk sisee the 25% lost to followup in the study population were regarded as alive in the statistical analysis. These data are consistent with numerous ease reports of leukemia deaths 35 AP00008968 among workers exposed to benzene. Based on these figures end 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 bexavalent 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 eancers per year: 7,900 Eaterline (36) noted that the overall SKR 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 wera born after 1889, was 942.6. SMRs decreased steadily over the observational period from e high of 2909.1 In the interval from 1941-45 to e low of 474.7 in 1956-60. From the above, it would seem that a reasonable estimate of the risk ratio for all respiratory eancars among workers exposed to chromium would be at least 5 and perhaps as high it 9. Assuming that an overall risk of 5 can, be-applied to the approximately 1.5 million exposed workers, it is estimated that about 7,900 exeess cancer eases 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 exeess cancers per year: 7,300 A Norwegian study by Pedersen et al. in 1973 (34) observed an overall excase respiratory cancer increase of 5.6 fold among 3$ AP00008969 nearly 2,000 men exposed to nickel. The highest risk (risk retio of 14.0) was observed in men first employed before 1930 end followed for at least 40 years. Assuming that an overall risk ratio of about 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 exeess respiratory eaneers, excluding nasal e*7*ear, will occur each year. Studies by boll (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 exeess eaneers of the nasal sinuses (7)s these eaneers 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 hyffife&arbons (PNHs) have been'well stud- ' 1 led, lung eeneer risk ratios in the rsnge of 2 to 33 have been observed for eoke even and gas workers in the U.S.v England, and * Japan exposed to PBNs which ere contained in petroleum products (Doll, Lloyd, Kavai, Xaliuadar, Redmond). Excess lung cancer risk rates have elso been observed for roofers in the U.S. (Esmond). Less well appreciated is the feet that many ether occupational groups are exposed to arom&tie hydrocarbons, including poly nuclear aromaties; these groups includs meehanies, electricians, and workers in the printing industry. (Hensk and Senderson^ref. 37 AP00008970 16) . The risk ratios for lung eanear 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 caneer risk ratio of 3 can be applied to these workers, it is estimated that about 9,100 exeess lung cancer deaths each year might occur in this group. 38 AP00008971 TABLX 3. OCCUPATIONAL GROUPS IN WHICH EXCESS CANCER INCIDENCE HAS BEEN REPORTED WITHOUT IDENTIFICATION OP A SPECIFIC ETZOLOGIC AGENT Occupational Groups Coal Miners Chemists Foundry workers Textile workers Printing Prersaes (newspaper) Metal Miners Coke by-product Workers Cadmium Production workers Rubber Industry Processing Tire Building Tire Curing Furniture Workers Shoe Workers Leather Workers Cancer Site(s) Stomach s Pancreas# lymphomas Lung Mouth and pharynx Mouth end pharynx Lung Large intestine# pancreas Lung, prostate Percent Exetss Reported 40 64 79 50-150 77 125 200 181 . 312 135 248 Stomach# leukemia Bladder* ..Brain Lung Nasal cavity end sinuses Nasal cavity and sinuses# leukemia Bladder 80 140 8 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 Notes Kith the possible exception of the lung eaneers end leukemias, there is no overlap between the excess eaccers listed in this table and Table 2. 39 AP00008972 APPENDIX A ESTIMATION OF LIFETIME RISES* FOLLOWING OCCUPATIONAL EXPOSURE A major part of tha preceding paper concarr? tha prediction of -- lifetime risk following occupational exposure to carcinogens during all or part of a working life* Tha estimates ware derived assuming that relative risks remain constant for the rest of the life-time, the estimated values for the relative risks being derived from cohorts with their own particular distributions of age, and both age at* sad 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 spidemiolegieal data and the predictions of mathematical models of carcinogenesis will be considered. Epidemiological'data from four types of exposure ere discussed: asbestos, nickel, radiation, and cigarette smoking. The latter two are not primarily occupational exposures, but they .provide the two examples best studied with regard to evolution of risk after exposure. For cigarette smoking,-, the incidence of lung cancer increases with the daily .amgunt' smoked (either linearly or perhaps quedsatically) and with the fourth power of duration of smoking, for eurrent smokers. On stopping smoking the incidence does not further increase, but re mains approximately constant with ege until it approaches that of non-smokers after seme 20 years (boll and Fats 1976) The relative risk therefore falls within five years of stopping smoking, as shown in Figure la. For radiation, leukemia behaves differently from tumors of epi thelial origin. Following e single course of radiation treatment for' A-l AP00008973 ankylosing spondylitis (Smith and Doll 1976), the ralativs risk for leukosis 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 le) Other epidemiologies] data on risks from irradiation shew simi lar behavior for leukemia (Abot survivors) and for breast cancer (A-bomb survivors* women given radiation tree tenant 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 niekel provide two examples of occupational expo sures where cohorts have been followed, over an extended period of time. Asbestos eauses lung cancer* eancer of the gastrointestinal tract, end mesotheliomas (Selikoff tad Hammond 1978). Among a eohort *. . ,T V mors than two thirds of whoa had been exposed for less than two years (Kevhous* and*Harry)* the incidence of mesotheliomas inersassd 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-oesupetienally related disease. However* the absolute risk**as given by tbs incfdance'figure* aKows no sign of leveling off even thirty years after cessation of external exposure. Extrapolation of the incidence eurve to higher age groups A-2 AP00008974 would seem justified, to give an estimate of 8-10% of deaths due to mesothelioma predicted in the group under study (Nevhousa end Barry 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 store than twenty years after start of exposure cospared to 10-19 years after start of exposure. Assumption of a con stant relative risk would appear to be conservative .(Selikoff and Baoaond 1978; Pete at al. 1977; Nevhousa and Berry 1976; Knox at al. 1968). For nickel, the main carcinogenic hazard for the cohort front Wales appears to have been renoved from the environment around 1930 (Doll, Matthews end Morgen 1977). Nevertheless, there hes been no indication that the relative risk for either lung cancer or for canear of the nasal' sinuses has fallen over the decades following the reduction in hazard (Poll et el. 1970,1977) up to the most recently reported follow-up ending in 1971. Similarly in the Norwegian study .-{Sedersan 1973), the greet reduction la exps^iretta dust end fumes ^ sines 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 eases) for the Welsh cohorts expostd before 1930 end the Norwegian cohort exposed before 1950 were similar, approxi mately io-foid. 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 eigarette smok ing. Exposure to the aromatic amines would seem similar with risk AP00008975 aong the exposed not felling two n 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 Collies 1976). The different types of behavior described above can be desists from the widely accepted multi-stage theory of carcinogenesis, whereirw a cancer is assumed to arise from a single cell which then passes through e series of stages, the last of which leads irreversibly to a clinically apparent tumor. Kith k stages, and with probabilities of transition constant over age, one .would predict the age-specific incidence to increase with age to be <k-l) power, as is observed for most epithelial tisaors with k 5 or 6 (Whittemore 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 multi-stage process, then the effect on the inci dence cf the target organ cancer, and on the relative risk, will de- ew pend on which stage in the process is primarily affected. If the initial stage is .effected then we expect the relative risk at time t (t>t2) to be of the forms RCtl 1 e 1(1 - t (1 - t2/t)k<] vfaexe e Is proportional to the dose. R(t) is shown graphically for various values of t2 and t2 in Figure 2a. The approximate con stancy of the relative risk over time for a range of values of and t2 Is apparent, similar to the behavior for epithelial tumors after irradiation, and probably similar to the effects of asbestos and nickel. A-4 AP00008976 If tha* penultimate stags is affected# the behavior is different# the relative risk at tine t (t>t) being given by wi 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* Ter mesotheliomas, where beeauae of the low"spontaneous inci dence relative risk calculations are of little value# a multi-stage (,.C model (with 3) has been successfully fitted to both animal data and data from 35 years of follow-up of a eohort (Hevhouse and Berry 1976). The multi-stage model appears to give a coherent pieture of the volution of risk after exposure during a limited interval which is consistent with available epidemiological data# at laast for epi- thalial tumors which comprise the great majority of occupationally I A-5 AP00008977 references COOK, P.J., DOLL, R, and FELLXNGEAM, S.A. 1969. A mathematical model for the age distribution of caneer in sen. 1st. J. Can. 4s93-112 r DOLL, R. , MORGAN/ L.G., and SPEXdER, F. 1970. Caneers of the lung and nasal sinuses in nickel workers. Brit. J. Can. 24:623632 / COLL, It., and PETO, R. 1976., Mortality in relation to smoking: 20 years' observation on male British doctors. Brit. Med. J. 2:1525-1536 0011/ R., MATKFWS, J.D., end MORGAN/ L.G. 1977. Cancers of the* .lung and nasal sinuses in nickel workers s A reassessment of the period of risk. Brit. J. Zadust. Med. 34:102-105 FOX, A.J., and COLLIER, F.r. 1976. A survey of occupational can cer in the rubber and eableaaking industries: Analysis of deaths occurring in 1972-74. Brit. j. Indust. Med. 33:249- 264 KNOX, J.F.r HOLMES, 5., DOLL, R., and HILL, X.D. 1968. Mortality from lung cancer and othar causes among workers in an asbestos textile factory. Brit. J. Zadust. Med. 25:293-303 NEWHOOSE, M.L., end BERRY, G. 1976. Predictions of mortality from mesothelial tumors in asbestos factory workers. Brit/ J. Indust. * Med. 33:147-151 PEDERSEN, E., B0GE7VSIT, A.C., and ANDERSEN, A. 1973. Cancar of respiratory organs among workers at a Nickel refinery in Norway. Int. J. Can. 12:32-41 v PE70, J., DOLL', R.r HOWARD, W.V., EXNZ2N, L.J., and 1EWXNSHOH, B.C. 1977. A mortality study among workers in an English asbestos factory. Brit. J. Indust. Med. 34:169-173 SSLXX0F7, I.J., and HAMMOND, Z.C. *1978. Asbestos-associated disease in United States Shipyeaxd* taa*. 28(2):|7-99 ~ SMITH, P.G. and DOLL, R. 1978. Age and time dependent changes in the rates of radiation induead eaneers in patients with ankylos ing spondylitis following a single course of V-ray treatment. Presented at the International Atomic Energy Agency Symposium on Late Biological Effects of Ionizing Radiation, Vienna, March 13-17 WHITTEMORS, A,?. 1977. The age distribution of human cancer for carcinogenic exposures of varying Intensity. Am. J. Epid. 106 (5):418-432 A-6 AP00008978 * LSSENOS FOR FIGURES 1. a. Incidence rate of lung cancer as a percent of rata 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 tht heavily irradiated sites, following irradiation 1 for ankylosing spondylitis. Vertical axes as in lb. d. Incidence of oesotheliomata, expressed as cumulative number observed. In years since first exposure to asbestos. Expected Incidence obtained from a Welbull model with Risk c (t-w)* where c, w and k are constant (as given in the figure) and t tht time sinea first exposure. 2. Evaluation of risk after exposure of limited duration as predicted by a multi-stage model of carcinogenesis. a. first stage effected by the exposure. b. Penultimate stage fffacted by tht exposure. cu * i ' * ;* X-7 AP00008979 FIGURE u PERCENT OF RATE AT TIME OF STOPPING 10004* Continuing clgarettj smokers. Ex-elgerett* smokers 0 S 10 15 20 Years since stopping FIGURE 18 A-e AP00008980 FIGURE 1C FIGURE ID i AP00008981 FIGURE 2A 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 AP00008982 FIGURE 2S PENULTIMATE STAGE irFECTED, EXPOSURE BEGINS AT AGE 20 \00 - JZfiesjzr t* &* 7* .B0-- ,60*. v OS , 40 . .20- irt----- sc 40 50 SO AGE IN YEARS At* A&f +4 4&S Sc TO Evolution of Risk After Limited Duration Exposure, Expressed as Percent of Risk Associated with Exposure Through Age 70 / A-2I AP00008983 This statement will address the question: "Whet fraction of the cancer incidence in the United States is attributable in whole or part to occupational exposure to carcinogens in the workplace?'* The conventional, estimates have been that this fraction is quite small, and figures* of between one percent and five percent are often quoted. However, as we will show below, these estimates were admittedly speculative and were incomplete or deficient in several respects. If the full consequences of occupational exposures in the presene and the recant past are taken into account, estimates of at least 20 percent appear much more reasonable and may even be conservative. Basis of the Estimation that 20 Percent of Cancer Deaths wllj--be Associated with Occupational Exposure to Chemicals I, Asbestos as a Well-Studied Example The consequences of occupational exposure to asbestos in the United States have only been fully recognized in the past year. According to estimates made by the U.S. Department of Health, Education, and Welfare, between eight and eleven million workers have been exposed to asbestos in the U.S. since the beginning of World War II. Of ch&c total, approximately 1.5 to 2.5 million are presently employed, while the remainder -- between 6.5 and 8.5 million workers -- were formerly employed In environments with significant asbestos exposure, including 4.5 million who worked in shipyards during World War II. Of these workers, approximately four million are believed to have had heavy exposure to asbestos. Based on epidemiological studies of workers, it is estimated that 20-25 percent of heavily exposed workers die of lung cancer, 7-10 percent of pleural or peritoneal mesothelioma, and 8-9 percent of gastrointestinal cancers. These figures are probably underestimates, of lifetime risks, because relatively few workers have yet been followed to the end of their normal lifespan. The total fraction of heavily exposed workers likely to die of these cancers is probably between 35-44 percent. AP00008984 i -2- Of the four million heavily exposed workers, approxi mately 1.6 million are thus expected to die of asbestosrelated cancers. Assuming that the excess risk to the 4-7 million less heavily exposed workers is one-quarter of that to the heavily exposed workers, the total number of eaneers associated with asbestos .In the less-heavily exposed group would be expected to be about 0.55 million, raising the total to about 2.15 million. Since most of these eaneers will be manifested in the next 30-35 years', the expeeted average number of eaneers attributable to asbestos per year in that period will average about 67,000. Such numbers would represent about 17 per cent of all eaneers detected annually in the United States. IZ. Other Less Well Studied grannies Arsenic Number of workers potentially exposed: about ' 1,500,000. Risk ratios*: 3-8 for lung cancer. Estimated number of excess cancers per year: 2,100 - 7,300. Ber.gene Number of workers potentially exposed: about 2,000,000. Risk ratios: 2-3 to 7 for leukemia, stisated number-of excess cancers per year: 240 - l,400v Tar Pitch Volatiles and Coke Oven Emissions Number of workers potentially exposed: about 60,000. Risk ratios: 2-6 for cancer of the lung, larynx, __ skin, and-scrotum. Estimated number of excess eaneers per year: 160-800. * Risk Ratio: The ratio of .cancers to the number expected in a normal population. ` A risk ratio of two means a doubling of the risk. AP00008985 -3 Vinyl Chloride Number of workers potentially exposed: about 2,260,000. Sisk ratios; 200,4 and 1,9 respectively for hemangiosarcoma, brain and lung cancer. Estimated number of excess cancers: 1,940. A total of 1-3 percent of the cancers occurring in a year will be associated with these four substances. III. Substances for which excess cancer incidence has been recorded but for which estimates of the number of workers exposed may be less accurate. ChTTWWf.llTW Number of workers potentially exposed: about 1,500,000. Risk ratios: 3-40 for nasal cavity and .sinus, lung and larynx. Estimated number of excess cancers per year: 46;000. \ Iron Oxide \ 2,400- Number of workers potentially exposed: about 1,600,000. Risk ratios: 2-5 for lung and larynx. ' . Estimated number of excess cancers per year: 1,300- 5,000. Nickel Number of workers potentially exposed: about 1,370,000. Risk ratio: 5-10 for lung. Estimated number of excess cancers per year: 3,800- 5,000. Petroleum Distillates Nimober of workers potentially exposed about 3,000,000. Risk ratios; 2-6 for lung and larynx. , .Estimated number of excess cancers per year: 2.40012 000 A total of 3-18 percent of the cancers occurring in a year will be associated with these four substances. AP00008986 -4- 'IV. Totals. Thus the total excess Incidence vould be from 21 to 33 percent. Ve choose to use the figure 20 percent in order to be conservative. Summary end Conclusions 1. The oft-quoted estimatess that only 1 percent to 5 percent of total cancers in the United Stetes are attributable to occupational factors have not been scientifically documented. 2. Host cancers have multiple causes: it Is an error 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, most cancers resulting froa exposure to carcinogens will occur late in life: many epidemiological studies detect only a small fraction of early-developing cancers. 4. Fast exposure to asbestos is expected to result in over 2 million premature cancer deaths in the next three decades: this corresponds to roughly 17 percent of the total cancer incidence expected in that period. 5. Reasonable projections of the future consequences of fast exposure to established carcinogens suggests that at east 3 other substances may contribute substantially to cancer incidence comparable in their total effect to asbestos. 6. The projections suggest that occupationally-related cancers say comprise 20 percent or sore of total cancer incidence in forth-coming decades. (This does not Include cancers attributable to ionizing radiation.) 7. Although exposure to some of the sore important occupational 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 cannot yet be attributed to specific egents. 8. There Is no sound reason to assume that the future consequences of present-day exposure to carcinogens in the workplace will be less than those of exposure in the recent past. 9. Patterns and treads in total cancer incidence (end mortality) in the U.S. are consistent with the hypothesis that occupationally-related cancers comprise a substantial and increasing fraction of total cancer incidence. AP00008987 APPENDIX In addition, the following table lists occupational-groups in which an excess cancer Incidence has been reported without identification of an etiologic agent. When these are fully studied, the overall excess incidence may be assessed. OCCUPATIONAL GROUPS IN WHICH EXCESS CANCER INCIDENCE HAS BEEN REPORTED WITHOUT * IDENTIFICATION OF A SPECIFIC ETIOLOGIC AGENT Occupational Groups Coal Miners Chemists Foundry Workers Textile Workers Printing Pressmen (newspaper) Metal Miners Coke by-product Workers Cadmium Production Workers Lead Workers Rubber Industry Processing Tire Building Tire Curing Woodworkers Leather and Shoe Workers Cancer Site(s) Stomach Pancreas, lymphomas Lung Mouth and pharynx Mouth and pharynx Lung Large intestine, pancreas Lung, prostate Lung Percent Excess Reported 40 64 *79 50-150 77 125 200 181 312 135 248 30 Stomach, leukemia Bladder, Brain Lung Kasai cavity and sinuses Kasai cavity and sinuses, bladder 80 140 88 90 61 - 5,000 150 -- AP00008988