Document x5MELJRq55m91DJD3dOQYM2vQ

VOLUME 338 The New England Journal of Medicine 0 Cnpyrighr, bv (tic MasiachuitftU Medical Sociccv M.\i- 28. 1998 NUMBER 12 NONOCCUPATIONAI. EXPOSURE TO CHRYSOTILE ASBESTOS AND THE RISK OF LUNG CANCER Michel Camus, Ph.O., Jack Siemiatycki, Ph.O., ano Bette Meek, M.Sc. Abstract Background Heavy industrial exposure to asbes tos causes lung cancer and mesothelioma, but it re mains unknown whether much lower environmental exposure to asbestos also causes these cancers. Nev ertheless,- regulatory agencies, including the Envi ronmental Protection Agency (EPA), have assessed the risk of lung cancer by extrapolating known risks from past industrial exposure to asbestos to today's much lower environmental asbestos levels (roughly 100,000 times lower). We also tested the ERA'S model for predicting the risk of asbestos-induced lung can cer in a population of women with relatively high levels of nonoccupationai exposure to asbestos. Methods Mortality among women in 2 chrysotileasbestos-mining areas of the province of Quebec was compared with mortality among women in 60 control areas, and age-standardized mortality ratios were derived. With the help of an expert panel, we estimated past exposure to asbestos among women in the mining areas and used these data with the EPA's. model to predict the relative risk of lung can cer. Wa then compared this prediction with the ob served mortality ratios. Results On the basis of the estimated exposure in the asbestos-mining areas, a relative risk of death due to lung cancer of 2.1 was predicted by the EPA's model, amounting to about 75 excess deaths from lung cancer in this population. By contrast, we cal culated a standardized mortality ratio of 1.0 and a standardized proportionate mortality ratio of 1.1 (P>0.05), suggesting that there were between 0 and 6.5 excess deaths from iung cancer among the wom en with nonoccupationai exposure to asbestos. Sev en deaths from pleural cancer were observed (rela tive risk, 7.63; PC0.051. Conclusions We found no measurable excess risk of death due to lung cancer among women in two chrysotile-asbestos-mining regions. The EPA's mod el overestimated the risk of asbestos-induced lung cancer by at least a factor of 10. (N Engl J Med 1998; 338:1565-71.) 1998, Massachusetts Medical Society. SBESTOS is a commercial group ofstrong, Aductile, and fire-resistant mineral fibers. These properties, which differ among different mineralogic types of asbestos, strongly affect its in vivo persistence and toxicity.1J Chrysotile asbestos, which constitutes about 99 per cent of airborne asbestos fibers in the general envi ronment, is cleared much more rapidly from the lung than amphibole asbestos.-*-4 It has been recognized for several decades chat ex posure to asbestos at high levels, as was common among asbestos workers in the first half of this centu ry, can cause lung cancer and mesothelioma of the pleura and peritoneum.5 Among asbestos workers, nearly all mesotheliomas are induced by exposure to asbestos, whereas most lung cancers are attributable to smoking. Yet because mesothelioma is so rare, asbes tos-induced cases of lung cancer greatly outnumber cases of mesothelioma among asbestos workers.511 In the 1980s, after labor-union campaigns and gov ernmental regulations had gready reduced occupa tional exposure to asbestos, public attention turned to environmental exposure.11 Pressed to recommend preventive regulations and remedial measures, public health authorities assessed the risks of asbestosinduced cancers in the general population on the basis ofoccupational data.511 The validity of such es timates of risk has been questioned for several rea sons.14-11 Extrapolations were made to environmental,.exposure to asbestos at levels that were 1/100,000 of those to which workers had been exposed in the past. The amphibole content of airborne dust con taining asbestos (aerosols) is much lower in the gen eral environment now than in historical occupation al settings. In addition, past studies of occupational from the Unit of Epidemiology and Biosurutici, Itucirut Armand- Preppier. University of* Quebec. Laval, Que. (M.C., J.Sj; the Department ul Epidemiology and Btoscacucio. McGill University, Montreal (M.C.. I-S and the RnviftHimcitr.it Hejtrh (`enter. Health Canada. Ottawa, Oat. (M.C.. R.M.l. Addrets reprint requests to Dr. Camus at the institut Af* mand-Frappicr. S31 Roul. Jet Pniries. Laval. QC HA' +Z3. Canada. Sea England Journal of Medicine exposure to asbestos were methodologically limited, dose-response estimates varied by a factor of 1000 among studies, and estimates of the risk of asbestosinduced cancer have not been validated in nonoccupationallv exposed populations. U'e tested the Environmental Protection Agency's I EPA's) dose - response model for asbestos-related lung cancer in a population exposed to asbestos at levels intermediate between those encountered bv asbestos workers and those encountered by today's urban populations. A small region of the province of Quebec, Canada, produced most of the world's as-' bestos until 1954 and remains the world's largest ex porter of asbestos. Between 1891 and 1980, asbes tos-dust emissions and fallout were usually visible. Asbestos aerosols were similar mineralogically to those found in cities today; more than 98 percent were chrysotilc.-'J Our study was restricted to wom en in order to exclude most asbestos workers.14 In contrast to previous studies of general popula tions,15-11 we estimated levels ofexposure to asbestos in order to quantify- the relation between asbestos and lung cancer. We used data obtained from death certificates, which are adequate to study the risk of lung cancer but not that of mesothelioma.3154 Mes otheliomas are currently being investigated in a sep arate study. METHODS The study comprised three distinct components: a mortality study to measure the actual relative risk ofdeath due to lung can cer and other causes, a historical exposure assessment, and a risk assessment to predict the relative risk of lung cancer on the basis nf the exposure assessment and the EPA's risk model. We as sumed. as in the EP.Vs risk-assessment model, that the risk of death due to lung cancer seas nearly identical to the risk of lung cancer -- a commonly accepted approximation tor diseases in hich survival is short. Mortality Study We determined the number of deaths that occurred between [970 and 1989 among women at least 30 years of age who lived in 1 ehrysotilc-asbestos-mining areas or 60 reference areas in the province of Quebec. An area was defined as a group of contigu- . out municipalities with a total population of at least 4500, The areas where the population was exposed to asbestos were Thet- Ibrd Mines (population, 29,095 in 1981) and Asbestos (popula tion, 14,225 ); these two areas comprised eight towni, of which three (Thctlord Mines, Black Lake, and Asbestos) contained nearly all the asbestos mines and mills. The residents of these ar eas lived within 10 km of a mine or mill, and 80 percent lived within 4 km. Among the other 65 areas in Quebec, 4 large urban centers and 1 shipbuilding area were excluded. The remaining 60 reference areas were spread across the province and had popula tions tanning from 8000 to 41,000 (total population. 1,373,370 in 1981).' ' .. To compute the relative risk of death due to specific causes in the asbestos-mining areas, we compared the observed numbers of deaths with the numbers expected cm the basis of the rates in the unci posed areas. Since there was migration in and out of the as bestos-mining areas during the period of observation, the study population actually consisted of different people each year. The annual population numbers, which we used as denominators for niorralitv rates, were based mi Canadian census data. Over the entire observation period, among women 30 years of age or oj-` cr, there were 221.375 person-years in the asbestos-mining all ami 8,629.630 person-years in the reference areas. : The numerators for our calculations came from Quebec's mor tality registry; we obtained the death certificates of women 30 years old or older who died from 1970 to 1989 in Quebec Prov ince. The municipality where each woman resided at the time of her death was used to assign the death to an asbestos-mining area, to an unexposed reference area, or to a municipality excluded from the analysis. The conventional standardized mortality ratio and standard ized proportionate mortality ratio were estimated for the two as bestos-mining areas separately and together, as compared with the reference areas. 8orh measures are ratios of the numbers of observed deaths in the population under study to the expected numbers, svith adjustment for age and calendar year. For the standardized mortality ratio, the expected number is based on the absolute mortality according to cause in the reference population. For the standardized proportionate mortality ratio, the expected number is based on the proportion of all deaths in the reference population that are due to each cause. The confidence intervals for the standardized mortality ratios were computed with use of Bvar's approximation; the confidence interval for each standard ized proportionate mortality ratio was computed with use of an approximation of the standard error of its natural logarithm.w J Estimates of Exposure to Asbestos To predict the risk of lung cancer according to the risk model, we estimated the population's average cumulative exposure to as bestos, which is the product of the intensity and the duration of exposure. These two components were estimated separately for each of three possible types of exposure: neighborhood exposure, resulting from emissions tram asbestos mining or milting in the towns' outdoor air, household exposure, resulting from dust brought home by asbestos workers; and occupational exposure. We present here a brief summary of the rather complex process,-- of assessing exposure, described in detail elsewhere." (f i Neighborhood Exposure Our objective was to estimate historical levels of asbestos in the mining towns and to derive time-weighted average exposure levels for the "average" female resident. Information on airborne asbes tos levels in the^asbestos-mining towns was obtained from con tinuous measurements ofdust made by a government agency be ginning in 1972; annual measurements of asbestos fibers in the air, made by the asbestos industry since 1974; and two recent surveys.9Jr To derive estimates of exposure for earlier periods,' we took the following steps to obtain evidence; Annual production volumes were computed for each asbestosmining town from 1900 to 1984. Detailed information about determinants of asbestos pollution going back to 1900 was obtained -- specifically, the classes of fi bers produced, controls on emissions, location of mining or mill ing sites and tailing piles in relation to inhabited areas, urbaniza tion, topographic maps, and the directional distribution of winds. t The relation among levels of airborne dust, annual asbestos pro duction. and dust controls was estimated for each mining town for the period from 1972 through 1984, and extrapolations were made back to 1900. .- The frequency and intensity of past visible asbestos deposition and the distance ofresidences from mines and mills were estimat ed on the basis of the responses of a representacivc'sample of 817 elderly female residents to a survey. The volume and characteristics of asbestos dust currently retained by the plants' dust-emission filtration systems were entered into 1566 Mis 'S. 1908 HWBUI0009045 NON OCCUPATIONAL EXPOSURE TO CHRYSOniE ASBESTOS AND THE RISK OF LUNG CANCER a standard aerosol-dispersion model to estimate airborne asbe.su levels in the town of Asbestos, Quebec, before the unset of dust controls in the 1950s. mg> polluted uith adv^ftin. * in himic- in naruralh v>4<nt.uiui.it- cd areas t the worUl.u` * and u a experiment e\ itl\ clutho o>Minnuted vwih ashocn* Just ) We analyzed the relation between the lung burden or' asbestos Occupa tionei Exposure and the histories of' occupational exposure among 89 Quebec miners and millers studied at autopsy by Scbascicn a si.* \\V From cur Minev m the area. c c'rimjfcd that aNut 5 pertenr then applied that relation to the lung burdens of 22 deceased res nt Ureal w uroco hail uinkcd in the ad'oro^ tuditNcrv r h,>J idents of the mining area who had no occupational exposures to mended bag> u>cd liir dupping a>bewi*i. A large uccupacwmal asbestos, as reported by Case and Scbasticn,w to estimate past ex *>tud\ in the local a>hc>rm mduxry e>rimjted due the few Knuic posure levels. workers had worked in less Ju*cy jobs dun male workers .uid had accumulated less than 50 riber vears per milliliter e itbcrwars are VVe then asked an international panel of five experts on the i calculated by multiplying average annual expowrv bv wars ofcvmeasurement of exposure to asbestos to consider the evidence. ; posurcl/*1 We used this value to esmture cumulative cxpimtrc for Alter evaluating the data critically, the panel cstimared average I the proportion ufperson-years spent by the population in work neighborhood exposure levels in the three main mining towns lor ; in the asbestos industry. four key yean (1945, I960,1974, and 1984), which cover the im j portant phases in the implementation of dust-emission control. Duration of Exposure The panel also provided guidelines for estimating yearly average In 1989, sve interviewed 817 elderly female residents of the as levels from 1900 to 1989, based on (he values lor the key years bestos-mining areas about (heir lifetime residential and employ and on town-specific asbestos-production levels (Fig. i). Average ment histories and those of the persons they had lived with. Tim annual ambient levels were estimated to have peaked at 1 fiber per inquiry gave us information about the numbers of person years milliliter or more (this value reflects the number of fibers longer j of residence in the area, residence with an asbestos worker, and than $ ftm and visible on optical microscopy per milliliter of air) asbestos-rciared work for women of different birth cohorts in between 1940 and 19S4 and to have been above 0.2 fiber per ` each of the asbestos-mining areas. milliliter from about 1905 to about 196$. The panel thought that the true values were unlikely to lie below 33 percent or above 300 Cumulative Lifetime Exposure percent of their best estimates, thereby providing subjective plau sibility ranges. Furthermore, it was estimated that the three main towns were 7 to 20 times more polluted than the five ocher mu nicipalities in the two asbesros-mining areas. For each woman in the 1989 survey, the lifetime cumulative neighborhood exposure was estimated bv multiplying years of ex posure by the estimated asbestos levels for each year and town in which she had lived. Cumulative household and occupational Hav3hM Exposure exposure was computed in the wine way but adjusted tar discon tinuous exposure. We extrapolated values for the cumulative ex Seventy percent of the women in the asbestos-mining areas had posure of the women we surveyed to the entire exposed popula each lived in the same household as an asbestos worker,14 but tion and the study period {1970 through 1989) by assuming that there were very few data regarding indoor exposure. We estimated the women interviewed in 1089 were representative of the entire indoor exposure on the basis of the results of autopsies of 10 res population with regard to their history of exposure. idents who had lived with asbestos workers. Using data on the Table I shows the estimated cumulative exposure for the pop ^ relation between the lung burden of asbestos and lifetime expo- ulation in the asbestos-mining areas according to the type of ' sure to asbestos among workers, we calculated that the asbestos, exposure. Neighborhood exposure represented about 65 percent lung burden of those 10 residents had resulted from indoor as of the study population's average cumulative exposure, household bestos levels that were roughly 0.3 fiber per milliliter higher than exposure -about 30 percent, and occupational exposure about the outdoor levels. This estimate was consistent with die meager 5 percent. The estimated average cumulative level of exposure documentation on indoor asbestos levels (0.1 to 6.0 fibers per was 25 fiber-years per milliliter. Considering the range of plausr- milliliter) in the homes of asbestos miners in Quebec/* in the ! bie values around the expert panel's neighborhood-exposure es- homes of chrysocilc-asbestos miners elsewhere,4 in urban build- i timates, the greater uncertainty of the household-exposure esci- Figurs 1. Mean Ambient Asbestos Uvels in Three Asbestos-Mining Towns in the Province of Quebec. 1900 through 1989. Based on Estimates by an Expert Panel. Asbestos levels are expressed as the numbers of fibers longer than 5 pxn and visible on optical mi croscopy per milliliter of air. The vertical lines indicate the years for which the panel estimated asbes tos levels 11945, 1960. 1974, and 1984); other values were Interpolated on the basis of local asbestos production volumes. Volume 55S Number 22 1567 j HWBUI0009046 The N England lournjl at' Medicine Table 1. Average CcMCLtnvf. Lifetime Excuse at of the rorcuriON in the Asrhstos-,Mining Areas, Accoroing ro TtreoF Exroscar. 1970 through 1989.- TtPt o* Ex"osu*t SsttMATfO CUMUCAnV fiXfOSUfflg Neighborhood exposure Household exposure Occupational exposure Tout cumulative exposure Subjective plausible range of*exposurcf fiber-yitfml 160 78 1.2 2S.0 5-12S Values shown are averages lor women 30 year? of age or older who were living in the two iibescos-mining areas during the follow-up period* with adjustment for Che duration ol*exposure. Values are expressed in fiber-years per milliliter of air, calculated by multiplying years of exposure by the av erage exposure level, and reflect cumulative round-the-clock exposure {l fi ber-year per milliliter is equivalent ro 4.2 fiber-years per milliliter of cumu lative exposure calculated for worker? exposed 40 hours per week). fThe subjective plausible range provides for errors in estimating past en vironmental and household exposure levels and for errors in sampling and measuring in our exposure-history survey. The lower limit of 5 fiber-years per milliliter corresponds, for example, to SO years of exposure to asbestos a level nr 0.1 fiber per milliliter (the actual mean ambient airborne-asbes tos level in the irn in 1974); the upper limit of 12S corresponds, for ex ample. to 50 yean of exposure to 2.5 fiber* per milliliter -- a relatively low exposure level in local asbestos-mining and asbestos-milling industries be fore I960. mates, and the uncertainty in our extrapolation from the sample of women surveyed in 1989 to the entire population in the asbes tos-mining areas, we determined a subjective plausible range ex tending from 20 percent to 500 percent of this estimate. Estimates of Risk The dose-response model used by the EPA expresses the rela tive risk of lung cancer in a population as a linear junction of its average cumulative exposure to asbestos,1 as follows: R=*t-HCL-X, where Kt is the toxicity gradient, or the increase in the relative risk of lung cancer for each additional fiber-year per milliliter of cumu lative exposure, X is the estimate of mean cumulative occupational exposure based on a workweek of 40 hours, and R is the risk of lung cancer in an exposed population as compared with that in a comparable unexposed population with similar smoking habits (we used the standardized mortality ratio and the standardized propor* tionate mortality redo as estimates of this relative risk). The EPA's estimate of Kt (0.01) is the geometric mean of rel ative-risk gradients estimated on the basis of data from U occu pational studies.7 The model requires that the exposed and refer ence populations have similar smoking habits, regardless of the smoking habits of workers in the original cohort studies. Accord ing to the model, a continuous exposure of 168 hours a week is equivalent to 4.2 40-hour workweeks of exposure to the same level of airborne asbestos. We applied this model to the exposure level estimated for the populations in the asbestos-mining areas to predict its relative risk of lung cancer. ! j | j RESULTS - j Given the estimated average cumulative exposure j of the population in the asbestosrmining areas (Ta- j ble l), the EPA model predicted a relative risk of j lung cancer of 2.05 (plausible range, 1.21 to 6.25). Table 2 shows the standardized mortality ratios and standardized proportionate mortality ratio death from selected causes in the exposed pop. . ? cion. The standardized mortality ratio in the two as . ^ bestos-mining areas combined was 0.9L for death from all causes (2242 deaths observed) and 0.92 for death due to all cancers (595 deaths observed). There were 71 deaths due to lung (or bronchial) can cer among the exposed women. The standardized mortality ratio for lung cancer was 0.99 (95 percent confidence interval, 0.78 to 1.25), whereas the stand ardized proportionate mortality ratio was 1.10 (95 percent confidence interval, 0.88 to 1.38). The con fidence intervals barely overlapped with the plausible range of the relative risk predicted from the EPA's model. The difference between the expected number of deaths, based on rates in the reference population, and the observed number of deaths yields an esti mate of the excess number of deaths in the exposed population. Applying the relative risk predicted by the EPA's risk-assessment model to the same expect ed numbers, it is possible to derive the number of ex cess deaths that would be predicted by the model. Table 3 shows these computations. Depending on whether one bases the computation ofexpected num bers on die standardized mortality ratio or the stand ardized proportionate mortality ratio, the risk-assess ment model predicts between 68 and 75 excess deaths from lung-cancer, whereas we observed 0 to 6.5. Thus, the EPA's risk-assessment model overcs' .. . maced the mortality attributable to asbestos by a fa ' tor of at least 10 (68-5-6.5). . . ,) There were, however, two significant elevations in risks associated with residence in the asbestos-min ing areas. The standardized mortality ratio for pleu ral cancer was 7.63 (95 percent confidence interval, 3.06 to 15.73), and the standardized mortality ratio for asbestosis was 23.49 (95 percent confidence in terval, 2.64 co 84.83). DISCUSSION Regulatory polities regarding asbestos are influ enced by estimates of the risk of lung cancer and mesothelioma attributable to environmental exposure to asbestos. Such estimates are controversial because they rely on unverified assumptions and imprecise da ta. In this study, the EPA's model overestimated the risk of asbestos-induced lung cancer among women who lived in chrysocilc-asbestos-mining areas be tween 1970 and 1989 by at least a factor oflO. Such risk assessments may also overestimate the risk of as bestos-induced lung cancer in other populations with nonoccupational exposure. Our units of observation were clusters of ti >w ns, not individual residents, since it was not feasible to identify a large cohort of individual residents and as certain their exposure levels and vital status. The ,tp- 1568 May 28. 1998 HWBUI0009047 f NONOCCU RATIONAL EXPOSURE TO CHRYSOTILE ASBESTOS AND THE RISK OF LUNG CANCER Table 2. Standardized Mortality Ratio (SMRi .lnd Standardized Proportionate Mortality Ratio (SPMR.) tor Death from Selected Causes among Women in the Asbestos-Mining arlu. as Compared wtth Mortality among Women in the Reference Population, FROM 1970 THROUGH 1989." Caus* of D<um All cause* Circulatory dixuo Respiratory disease* Asbestos!* .All cancen Digestive cancer Oral cancer Breast cancer Genial cancer Urinary cancer Lymphatic or hematopoietic cancer Respiratory cancer Larynx Lung or-bronchu* Pleura No. t OeAms 2242 1087 104 2 395 205 4 no *4 19 42 82 2 71 ? SMR (9$ft CM 0.91 i0.87-0.95l 0.89(0.83-0.941 0.81 r0.66~0.98l 23.49(1.44-84.83) 0.92 ,0 85-1.00} 0.96(0.83-1.10) 0.68 {0.18-1.74) 0.88 (0.73-1.06) 0.85 (0.65-1.08) 0.84 (0.51-1.32) 0.78 (0.56-1.05) 1.06 (0.84-1.32) 0.64 (0.07 - 2.32) 0.99(0.78-1.25) 7.63 (3.06-15.73) SPMR 195*. Cl) (.00 1--1 0.98 rO.94-1 02) 0.39 10.73-1 08) 24.10 16.06-95.8 tl 1.02 10.96-1.10) 1.06 10.93-1.2)1 0.75 (0.38-2.00) 0.97 10.82-1.15) 0.93 10.73-1.18) 0.94 (0.60-1.46) 0.35 (0.63-1.15) 1.17,0.95-1.45) 0.72 (0.18-2.83) 1.10 ( 0.88-).38) 8.2) (3.92-17.18) "There were no noticeable differences in momltry between she two asbestos-mining areas tor death from any cause, except for the fret that all tcven deaths from pleural cancer occurred in the Theefbrd Mines area. C! denotes confidence interval. proach we used was nevertheless adequate, because exposures- to asbestos differed much more between the exposed and reference populations than within either one. Furthermore, risk estimates such as these , ' )arc applicable to group averages. ; . The study populations were dynamic; during the study period, people migrated between asbestosmining areas and reference or excluded areas. For cultural and linguistic reasons, the population of Quebec was very stable until quite recendy. The pros perity of the asbestos-mining areas attracted mi grants until 1980. Those who left this area most of ten moved to large cities that were excluded from this study. Migration patterns would have been sim ilar in the reference areas, albeit with somewhat less in-migration. Migration from exposed to reference areas would not significantly have 'affected mortality in the reference population, since it greatly outnum bered the exposed population (by 40 to 1). Migra tion from reference areas to asbestos-mining areas was not substantial, according to our survey of eld erly female residents of the asbestos-mining areas. Finally, exposed and reference areas had similar health services, making it unlikely that out-migration from an asbestos-mining area would have been more strongly related to lung cancer than out-migration from reference areas. For these reasons arid because of the results of simulations with various plausible assumptions, we concluded that in- and out-migra tion could not have distorted the relative risk sub stantially. Substantial bias due to confounding is unlikely in this study. Both the exposed and the reference popillations were small-town homemakers of FrcnchCanadian ancestry (93 percent) who were born in the early part of this century in a society that was culturally and socioeconomically homogeneous un til the 1960s. According to the 1987 Quebec Health Survey54 and our local survey in 1989, die women in the exposed and reference populations were similar in ethnic background, lifestyle, and socioeconomic characteristics. However, the population in the asbescos-mining areas may have smoked slightly less (25 percent were current smokers and 54 percent had smoked at some time) than the women in the reference areas (31 percent and 55 percent, respecrivciy). According to Axelson's method ofcorrecting risk ratios,35 differences in smoking status should not have distorted the relative risk of lung cancer by more than 7 percent. In view of possible confounding and bias due to migration, and given the low mortality from all causes and from cancer in the as bestos-mining areas, we believe that the best esti mate of the relative risk of lung cancer fails between the standardized mortality ratio of 1.0 and the standardized proportionate mortality ratio of 1.1. The results of the eclectic and varied methods used as the basis for the retrospective estimate of ex posure were sufficiently coherent that five experts agreed easily on past levels of neighborhood expo sure. Our assessment of exposure was similar to the assessment in historical cohort studies of asbestos Volume 333 Number 22 1569 \ : ! ! : ; ! i I i HWBUI0009048 The New England Journal o!' Medicine Table 3. Excess Deaths from Lise Cancer among women IN THE A$8E5TO$-Mt>-*lNG AREAS, AS COMPARED WITH the Excess PrD(ctd on the Basis of the EP.Vs Risk-.Assessment Model.* to asbestos may be lower among nonsmokers chan among smokers, contrary to the model's assump" : ^ ot constant relative risks.17-34 And finally, the statistical analysis may have overestimated the dose- .... response gradient (a recent meta-analysis found the Vaaiaslc Svuwxow Fqamuu Basis fo* Estmahno Ew*scTfQ Ocatks mote R*r*s m Rikmmcs Aaisf SMR SPMR j EPA's estimate to be between 4 and 24 times coo high).57 The results of this study are reassuring with respect co lung cancer, but there were significant ex- Expected deaths E 71.4 64.5 i cess numbers of deaths due to pleural cancer (seven ? Observed deaths O 71 71 1 deaths) and asbestosis (two deaths). The instances of Observed relative riskf O/E 1-0 l.l | pleural cancer suggest an excess risk of mesothelio- Observed excess deathi Predicted relative riskf Predicted deaths Predicted excess deaths Ratio of predicted ro observed excess deaths. O-E R. P-R-E P-E (P-E)/(0-E> -0.4{ 2.1 146.4 73.0 Undefined^ 6.5 I ma. However, since historical death certificates re- 2.1 I fleet the incidence of mesothelioma poorly,13-5* wc 132.2 1 have launched a separate study based on a province67.7 j wide survey of hospital records. 10.4 * denotes rhe expected number of death* in this population, based on the death-races or proportion of deaths in the reference population, O the observed number, and Rthe relative risk that is predicted in the population b; applying the EPA*s model to the estimated exposure level in this popu lation. Supported by contracts with Health Canada and by a grant from the Na tional Health Research and Development Programme (NHRDP) of Oft* ada. Dr. 5iemiatycki was the recipient of a Scholar Award from she NHRDP and a Visiting; Scientist Award from the International Agency for Research on Cancer. \ {The estimate of the number ofexcess deaths in the population depends We are indebted to the members of the expert panel on exposure \ on rhe number that was expected on the basis of the rates of cancer in the reference population. Since we derived two versions of the expected num assessment: Dry, Bruce Case ofCanada, Merton Cent ofthe United ber -- one based on rhe standardized mortality ratio (SMR) and one based States, Graham Gibbs ofCanada, William Nicholson ofthe United on the standardized proportionate mortality ratio (SPMR) -- the excess States, and Patrick Sibastien of France; to our eoUaberssort, without 1 numbers corresponding ro each of these calculations arc shown. Observed whose professional work the research reported here would nets have deaths and predicted relative risk are the only variables in this table that do not depend on the expected number of deaths; they are therefore neces sarily equal in the two columns. keen possible: Ron Dewar, Lesley Richardson, Marie Desy, Louise Nadon, Denise Bourbonnais, and AUda-Henry as she Instirus Armand-Frapp&r and Esther Utoumesm as the Quebec Statistics Bu {The negative value for O --E was interpreted ss an absence of effect: (O-E^O). leading ro art undefined value for the ratio (P-E)/{0-E). reau; to Professors Ma^aretBeehlok^John Bailor, Andri Du/resm, Ben Armstrong, and Jim Hanley as McGsU Univcrsisfr Depart ment of Epidemiology, Biostatistia, and Occupational Health,\ f their advice; and to Richard Ltdue efQu*bet*s Environment Mi istry, for performing dte computerized aerosol-dispersion simula ! workers, which also relied on incomplete data and tions. on subjective and imprecise retrospective estimates. > REFERENCES These uncertainties and those resulting from the es timation of cumulative exposure on the basis of a survey conducted in 1989 were accommodated by assigning a large plausible range to our best estimate of exposure levels. There arc several possible reasons for the ovcrcs- 1. McClellan RO, Miller Ff, Hesterberg TW, et iL Approaches ro evaluat ing the toxicity and carcinogenicity of man-made fiber*: summary of a workshop hdd November 11-13, 1991, Durham. North Carolina. Regul Toxicol Pharmacol 1992;16:321-64. : 2. McClellan RO, Heaczbcrg TW. Role of biopenistencc in the pathoge nicity of man-made libers and methods for evaluating biopenbcence: a summary of two round-cable discussions. Enroots Health Perspcct 1994; l02:Suppi 3:277*83. timation of the risk of lung cancer by the EPA mod el. First, the risk in the low-dose range may be less 3. Wagner JC, Berry G, Skidmore JW, Timbrell V. The effects of the inhalation of asbestos at rats. Br I Cancer I974;29:2S2-69. 4. Scbaiden P. Pulmonary deposition and clearance ofaiibome mineral fi than would be predicted by a linear model. Second, bers. m Liddell D Miller K. eds. Mineral fibers and health, Boca Raton, cumulative exposure may be a poor measure of the biologically effective dose of asbestos (the actual Fla.: CRC Press, 1991:229-48. 5. Upton AC, Barrett fC.BccUake MR, etsi. Asbestos in public and com mercial buildings: a literature review and symbols of current knowledge. dose that contributes to the risk of disease). Third, exposure-risk gradients in occupational studies may Cambridge, Mass.; Health Effects Institute-Asbestos Research, 199 L. 8. Achcson AD, Gardner MJ. Asbestos: the control Emit for asbestos: an update of the relevant sections of the ill effects of asbestos upon health. have been overestimated .because exposure was un London: Health and Safety Commission, Her Majesty"b Stationery Office, derestimated, because of confounding by smoking, or because inappropriate reference populations were 1983. 7. Nicholson WJ. Airborne asbestos health ascumcnj update. Washing ton, D.C.: Office of Health and Environmental Assessment. Environmental used. Fourth, chrysotile fibers may be less carcino- j Protection Agency, 1986. (Report no. EPA-600/8-84/003E) genic than amphibole asbestos, which was propor- i 8. Doll R, Pcto J. Asbestos: effects on health ofexposure to asbestos. Lon don: Health and Safety Commission, Her Majesty's Stationery Office, tionately more prevalent in the environment of the | 1985:1-38. occupational cohorts used to estimate the dose- $. Committee on Nonoccupational Health Risks of Asbestiform Fibers. Asbestiform fibers: nonoccupariunal health risks. Washington, D.C.: Ns- response gradient than in the general environment - rional Academy Press, 1984. today. Fifth, the relative risk of lung cancer due 10. Report of the Royal Commission cm Matters of Health and Salccy 1570 - May 2d. 1998 ) W HWBUI0009049 NON OCCUPATION A L EXPOSURE TO CHflYSOTILE ASBESTOS ANO THE RISK OP LUNG CANCER Arising from the Use of Asbestos in Ontario. VbJ. i. Toronto: Onrario Ministry of the Attorney General, 1984, 11. Report to the U.$. Consumer Product Safety Commission bv the Chronic Hazard Advisory Panel on Asbestos. Washington, D.C.: Director ate for Health Sciences, Consumer Product Safety Commission. 1983. 12. Tonne! AB, Goldberg M, Hemon D, ec ai. ERfea fur la unt4 des principaux types derposioon 1 I'amixme. Paris; Les Scions INSERM 1997. 13. Puncturing a panic. Wail Street Journal. September (8. 1989-.U6. * rile asbcstoi-mjnmg *reu compared to that predicted by the L` 5. E.PA. exposure-efftet model. |Ph.D. rhem. Montreal; McGill Umverutv. 19971 i 37. Gibbs G>V, Rowlands S'. Brulotrc R. A pilot cuJv cm the measure mcnc of airborne asbestos fibre concentrations m ambient air. Presented jt foe 73rd Annual Meeting of the Ait Pollution Control .Association. Mon Itreal, June 22-27.1980. I 38. Scbuncn F, McDonald JC. McDonald AD, Cue 8, Harley R. Respi- mtory cancer in chrysonic textile and aiming industries: exposure mfcrtnc* | cs from lung analysis. Bf J ind Med 1989;46:180-7. 14. Abebon PH. The asbestos removal Sisco. Science I990;247:t0l7. | 39. Case BW, Sebutien P. Fibre levels in lung ami correlation uh air urn- 15. Berry h EM and asbestos removal, Science i990*,248:lS9$, IS. Linger AM, Nolan RP. Ross M. Asbestos poltcv. Science 1990;249; U8S. 17. Moasman BT, Btgnon ). Com M, Seaton A, Gee J8U Asbestos: sci pies. In; Bignon J, Peso $, Saracci R, cdi. Son-occupational exposure to mineral fibres. Lyon, France: international Agency for Rcseireh on Cancer. t989;207-18. (LARC scientific publications no. 90.) 40. Nicholson WJ. Rohl .AN, Weirmin f, Selikorf IJ. Frmronmcntai atbev entific developments and implications for public policy. Science 1990*24-7* 294001. 18. Stone R. No meeting of die minds on asbestos. Science 199l;2a4: 928*31. tos concentrations in the United States. In: Wagner 1C. cd. Biological ct* fcco of mineral fibres. Vol. 2. Lyon. France: International Agency for Re search on Cancer, 1980:823-7. {LARC scientific publications no. 30.) 41. Gibbs GW, Lachance M. Dust exposure in the chrytotilc asbestos 13, Nicholson Wf, Johnson EM, Harington J$, Meiiu J, Landrigan PJ. mines and mills of Quebec. Arch Environ Health 1972;24:189-97. Asbestos, carcinogenicity and public policy. Science 1990;248:796-9. 42. Carter RE The measurement of asbestos dust levels in a workshop en 20. Brody AR. Asbestos, caronogensdcy, and public policy. Science 1990; 248:795. vironment. Harwell, United Kingdom: Atomic Energy Weapons Research Establishment. 1970. (Report no. AEWRE-028/70.) 21. Samuels $W. Asbestos, camnogenkicy, and public policy. Science J990;248:79$*d. 43. Lumlcy KPS, Harries PG, O'Kelly Ff. Buildings insulated with sprayed asbestos: a potential hazard. Arm Ckcup Hyg I97l;l4:255'7. 22. Mossman BT, Gee JBL. Asbestos-related diseases, N Engl) Med 1989; 44. Sawyer RN- Asbestos exposure in a Yale building: analysis and resolu 320:1721-30. tion. Environ Res 1977;13:146-69. 21 Sibiltaen R Ffousde M; Robb R, Rosa M, Nados B, Wypnak T. Am 4S. CON5AD Research Corporation. Economic analysis of the proposed bient air asbestos survey in Quebec mining towns. 2. Main study: report revisions to the OSHA asbestos standards for construction and general in co Environmental Protection Service, Environment Canada. Ottawa, One.: dustry. Washington, D.C.: Oeparonent of Labor. 1990. (Report no. OSHA Environment Canada, 1986. (Report no. EPS 5/AP/RQ-2.) J-9-M-0033.) 24, StemuryeJci J, Mortality in the general population uyasbestos mining 46. Rohl AN, Longer AM, Moncure G, SelikoffU, fischbein A- Endemic areas, tn: Proceedings of the World Symposium on Asbestos, Montreal, pleural discaac associated tvifo exposure to mixed fibrous dust in Turkey. May 25-27,1982. Montreal: Canadian Asbestos Informxoon Centre, Science 1982;216:518-20. 1982:337*48. 47. Baris (. Simonato L, Artrinli M. ct a). Epidemiological and environ 25, Anderson HA, Family contact exposure. In: Proceedings ofthe World mental evidence of the health effects of exposure to erionite fibres: a tour- Symposium on Asbestos, Montreal, May 25-27,1982. Montreal: Canadian year study in the Cappadocian region of Turkey, (at J Cancer 1987;39:10-7. Asbestos Information Centre, 1982:349*63. 48. Constantopoulos 5H, Goudcvcnos JA, Saratzb N. Langer AM. Se* 28. Botha JL, Irwig LM, Strebel PM. Excess mortality fiem stomach can likoff (J, Moutsopouloa HM. Mctsovo lung: pleural caldficarion and re cer, lung cancer; and asbestos!* aod/ot mesothelioma in ooddoUtc mining strictive lung function in northwestern Greece: environmental exposure to districts in South ASk Am J Epidemiol 1986*423:38-40. mineral fiber u etiology. Environ Res 1985;38:319-3 L 27. Hamnsofid EC, Settkoff IJ, Seidmaa H. Asboses cxposatrCfrigpuecre 49. Linger AM, Nolan RF, Constantopoulos SH, Moutsopoulos HM. As- smoking and death rates. Aim N T Acad Sd 1979;330:473-90. tociadon of Mewovo lung and pleural mesothelioma with exposure to 28. Magsarti C, Terracim S, Ivaldr C, ce aL A cohort study on moroiicy trcTOOtite-contasning whitewash. Lancer 1987;1:965-7. I among wives of workers is foe isbestos cement industry in Casals Monfemco, Italy. Br find Med 1993;50:779-84. SO. Luce D, Brocturd P, Qucnel P, et al. Malignant pleuni mesothelioma associated with exposure to tremoliw. Lancet 1994;344:1777. 29. LosUer L. Eovironoemeot surtnorolice 4 Asbestos Tfredord 51. Goldberg P, Luce 0, BiBon-Goltand MA, ct al. Rite potcnciel dc Pcx- Mines. Med Quebec 1983;18:97-9. posttion cnvironncmencale ee domesrique 1 la ercmolite dans Ic caoccr de 30. Pajnpafdn R, Skmracyctii J, Slanchet M. Pollution crrfirofuicmcncde la pfivre cn Nouvclie Caledonic Rev Epidemiol Sari re Publique 1995-.43: par I'amiante ct sami publiquc au Quebec. Union Med Can 1982:111:475* 444-50. 89. 52. Hunt R. Difforettecs between the re-aerosolabilicy of settled airborne 31. Wlgle DT. Cancer moroiicy in rcladon to asbestos in murudpal water chrysorile and amphibole duscs. Clcekheaeon, United Kingdom: .Asbestos supptfcj. Arch Environ Health 1977;32:185-90. Research Coundl, 1982. 32. RibaJc J, Scidmaxt H, Sctikoff IJ. Amoritc mesothelioma in a cohort of S3. McDonald /C. Lidddl FDK, Gibbs CAY, Eyuen GE. McDonald AD. asbestos workers. Stand J Work Environ Health 1939;15:106-10. Dust exposure and moroiicy in chrysodle mining, 1910-75. Br \ Ind 33. Ribak J. LilU R, Suzuki T, Fenner L, SelifcofTIJ. Death ccmficacs cat Med 1993;SO:10S8-72. egorization of maijgisist pleural and peritoneal mesothelioma in a cohort Si. &mond A, Guyon L, Camirand R Cbcnard L, Pineaulc R% Robicaillc of asbestos iruuladofi workers. 1 Soc Occup Med 1991;41:137-9. Y. Er la santc, pa va Rapport de Tenquete Since Quebec. 1987. Quebec. 34. SelskofF IJ, Scidrmn H. Use of death certificate* io epidemiological Canada: Mmiat&re de U Sanw ec des Serricea Sociata, 1988. studies, including occupational hazards: variation*-in discordance ofdiffer* 55. Axetson O. Aspects on confounding in occupariona) health epidemiol ent asbestos-assodared diseases on best evidence ascertainment. Am J Ind ogy. Scjnd 1 Work Environ Health 1978;4:98-102. Med 1992;22:481-92. 35. Breslow NE, Day NE, Statistical methods in cancer research. Vol. 1 58. Saracci R. Asbestos and lung cancer: an analysis of the epidemiological evidence on the asbestos-smoking intenetion. Inc J Cancer 1977;20:323- The design and analysis of cohort studies. Lyon, France: International 31. Agency for Research on Cancer, 1987. (IARC scientific publications no. 57. Lash TL, Crouch EAC, Green LC. A mcca-analvsis of the relation be* 82.) tween cumulative exposure to asbestos and relative risk of lung cancer. 36. Camus M. Lung cancer mortality among females in Quebec's chryso- [ Occup Environ Med 1997;54:254-63. i Volume 3 38 Number 22 1571 HWBUI0009050 E04S84 New England Journal of Medicine Established in 13 12 as The New England |oljnal of Medicine .iso Scrcext VOLUME 338 MAY 28, 1998 NUMBER 22 ORIGINAL ARTICLES Nonoccupacionai Exposure to Chrysotile Asbestos and the Risk of Lung Cancer ......... 1565 M. Camus, J, Siemiatycki, and B. Meek Lack of Efficacy of Light Reduction in Preventing Retinopathy of Prematurity....1572 J.D. Reynolds and Others Association of Mutations in the Apoh'poproteim B Gene with Hypercholesterolemia and the Risk of Ischemic Heart Disease ....... 1577 A. TrBi.en.G-Hansen, r. Steffensen, H. Meixertz, P. Schnohr, and B.C. Nordestgaard Brief Report: Transient Angiolymphoid Hyperplasia and Kaposi's Sarcoma after Primary Infection with Human Herpesvirus 8 in a Patient with ' Human Immunodeficiency Virus Infection ..............................................................1585 E. Oksenhendler and Others IMAGES IN CLINICAL MEDICINE Achilles'-Tendon Xanthoma in Familial Hypercholesterolemia ..................................... 1591 H.C.M. van den Bosch and L.D. Vos REVIEW ARTICLES Mechanisms of Disease: Eosinophilii.................. 159a M.E. Rothenberg Current Concepts: Neuropathies Associated with Paraproteinemia....................................... 1601 A.H. Robper ano K.C. Gorson - CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL A 53-Year-Old Man with Left Ventricular Dysfunction Four Years after a Heart Transplantation................................................ 1608 F.A. [archo and E.J. Marx EDITORIALS Asbestos -- Still a Carcinogen .......................... i6t8 P.I- Landrigan Preventing Blindness in Premature Infants..... 1620 A.v. Drack CORRESPONDENCE Walking and Mortality in Older Men ................... 1612 More on Low-Fat Diets.................................. _...... 1623 Polymorphism of the Cholestcryl Ester Transfer Protein Gene................................................................... 1624 Genetic Polymorphisms and Disease............................ 1626 Acid-Base Disorders .........................................'.... 1616 Underreporting of Lyme Disease ........................... 1629 Corneal Ulcers from Contact Lenses during Travel to Remote Areas ........................................................... 1629 Book Reviews ..................................................1631 Books Received ............................................. [633 Notices ...................................................................1634 HEALTH POLICY REPORT Must Good HMOs Go Bad? Second of Two Parts: The Search for Checks and Balances .................................................... 1635 R. Kottner Information for Authors........................164 0nJ. fuWlluJ. oni O "fyrtfhtri. IQ1K. tt THt MAtlACKVMm MEDICAL SpCIITT P E #BXNB,f3&***********'* 5-B5SW-.23501 mR ft849397/&# 011101 052898 0030 23. l 0 D 1 C E VIRGINIA MED SCH LIB P0 BOX 1980 NORFOLK Vft 23502-1980 A L liili}iilliiMillmmllnil)l)iilii))hiiiiiMi S N E W s p A P E R. THt Nile EncLano ImiRNAL ue Mroicihr (ISSN 0Q28-479JI u pubAUccd -.vtUy Item eJitwiil wRta it 10 Shimidi Street Botton. MA 03115-4094. SobienpnoH ^ SI2J.O0 pee rev. IVriDjkilt poetise pod it Boiton uid it iddiaoml (nulinjf irfRei POSTMASTER: Sttul iAireu<ht*|e to T.O- Box 803, Wilihun. MA 02254*0403. 1534-6 Eastern Virginia Medical School Moorman Memorial Library 29?.o. box i?so -M im Norfolk. 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