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CHAPTER 6 ASBESTOS-EXPOSED WORKERS

CONTENTS Introduction Asbestos-Exposed Populations. Lung,Cancer Lung Cancer in Nonsmoking Asbestos Workers Lung Cancer in Cigarette-Smoking Asbestos Workers Threshold Cessation of Exposure Mechanisms of Carcinogenesis in Cigarette-Smoking Asbestos Workers Animal Studies of the Carcinogenic Interactions Be- tween Cigarette Smoke and Asbestos Concepts of Carcinogenesis Conclusions Chronic Lung Disease. Chronic Lung Disease Death Rates Pulmonary Function TestingSmall Airways Function Chest Roentgenographic Changes Roentgenographic.Changes in Nbn-Asbestos-Exposed Populations Roentgenographic Changes in Asbestos-Exposed Popu- lations Interstitial Fibrosis in Asbestos-Exposed Populations Immunologic Response to Cigarette Smoke and Asbes- tos Dust Humoral Immunity Cellular Immunity Sister Chromatid Exchange Frequency Public Health Implications Summary and Conclusions References 197

A9tlestos 0 $e pBntlne chrysctlle Wnde as6estos Mg. (SiaOe) i(OH). TremdOe Ce.Mge (SLO..) (OH), Actinulle Cai (Mg..Fe)e (SIiOv) (OH)x Amphlboles GociOplita elub asEegosNeiFell.Felly (61.0.) (OH), . Artwsile (Fe. Mg), (SIe0u) (OH), FIGURE 1.-Principal varieties of asbestos soOHCP.: cMamemU991)~ increased risk of lung cancer (1ARC, im press). The exposure of the wives and children of asbestos workers to asbestos on work clothing and in the home environment is thought to be associated with an increased risk for mesothelioma and possibly other diseases (5elikoff and Lee 1978). The risk from these low dose exposures is smaller than the risk for individuals directly exposed to these agents (active cigarette smokers.and workers occupationally exposed to asbestos dust): "Asbestos" refers to a specific group of fibrous silicates; the principle varieties of which are listed in Figure 1. Commercial use of asbestos stems from its qualities of resistance to heat and acid and its ability to be woven into fabric (Zoltai and Wylie 1979). Commercial products known as asbestos differ in the configurations and dlmen. sions of their fibers as well as in their chemical makeup and crystalline structure. These properties determine, in part, the deposition patterns of fibers in the respiratory tract and the. mechanisms. whereby the fibers interact with the cells of the lung. 200 AnthophylNe (Mg, Fe), (sy0.) (OH)j

Introduction Cigarette smoke and asbestos are agents with well-documented risks associated with exposure. Large numbers ofl individuals have had exposure to either or both of these agents sufficient to generate significant excess death and disability. The focus of this review is the, effects of combined' exposure to asbestos and cigarette smoke: The literature that establishes the causal nature of the risks associated with each of these exposures and the.nature and extent of the disease that can occur is extensive, and has been reviewed in detail elsewhere (US PHS 1964; US DHEW 1979; US DHI-IS 1980, 1981, 1982, 1983, 1984; Selikoff and Lee 1978; Ontario, Royal Commission 1984; NRC 1984). However, populations with asbestos exposure commonly have coincident cigarette smoke exposure, and the magnitude of the risk of lung cancer and chronic lung injury produced by smoking necessitates a careful examination of the smoking habits of asbestos-exposed workers in order to define the risks of isolated and combined exposures. A number of conditions or diseases known to be associated with smoking, asbestos, or both, including mesothelioma, heart disease, pleural plaques, adverse reproductive outcomes; and cancers other than lung, are not discussed here; the focus of this chapter is lung cancer and chronic lung disease;the disease processes for which the largest amount of data on the effects of combined exposure is available. Asbestos-Exposed Populations Some exposure to both cigarette smoke and asbestos appears to be an inescapable consequence.of living.in the urban U,S. environment. The relatively omnipresent nature of cigarette smoking as a social phenomenon makes at least.incidental exposure to cigarette smoke a universal experience, and the digestion of lung tissue from individu- als with no, known asbestos exposure commonly reveals low concen- trations of asbestoss bodies and asbestos fibers (Churg and Warnock 1977, 1980); It is technically extremely difficult to establish the presence or absence of an effect in populations who have had no exposure to asbestos other than the levels in ambient air or who have not had repetitive exposure to smoke through active or involuntary smoking. However,, it is generally accepted that these extremely low dose exposures do not substantially alter the occur- rence of lung cancer or chronic lung disease in the generalpopulation (Ontario, Royal Commission 1984). The same statement cannot. be made for individuals with repeti- tive low dose or indirect exposures to either of these agents, however. Evidence continues to accumulate that shows that nonsmoker exposure to environmental tobacco smoke may carry with it an 199 0

and colleagues (1983) showed lower rates of smoking,among shipyard workers in South Carolina. Only 42.9 percent reported that.they, were current,smokers; and 24.8 percent had ceased smoking. This decline in smoking found: in the United States is not evident in studies of asbestos workers in Great Britain. Lung Cancer Cigarette smoking is the major cause of lung cancer in the U.S: population considered as a whole (US DHHS 1982); Among U.S. men aged 50 to 70 (the group most commonly examined in occupational mortality studies), over 110 percent of the deaths were due. to lung cancer in 1977 (McKay et al. 1982)j The prevalence of smoking and the percentage of deaths due to lung cancer vary substantially in the studies of asbestos-exposed populations reported in the literature, but in the largest study (Hammond et al. 1979) of heavily exposed workers with a high smoking prevalence (82.3 percent), 21.4 percent of the deaths were due to lung cancer. The high incidence of lung cancer in both asbestos-exposed workers and: the U.S. population, together with the potency of cigarette. smoking in determining lung cancer risk, makes the determination of the smoking habits of asbestos-exposed populations essential to any evaluation of lung cancer. The prevalence of smoking varies markedly among men born in different years of this century, between blue-collar and white-collar workers (see the chapter on smoking patterns), and among the populations of asbestos workers studied in the literature. In particular, men born between 1910 and 1930 have a higher prevalence of smoking than men born earlier; men born after 1930 have.had lower prevalences of smoking at any given age than the men born between 1910 and 1930. Levels of asbestos exposure have also not beem constant with time. Since the recognition of the hazards of asbestos exposure, improved control of asbestos dust hae reduce the levels of asbestos in mines and manufacturing plants. and, more recently, in other areas where. asbestos exposure may a16o occur. These temporaL trends of smoking prevalence and asbestos dust levels result in complex reltttionships between cumulative asbestos dust exposure and cumulative smoking. exposure. The oldest workers (those born before 1910) may have higher cumulative asbestos dust exposure at any given age than younger workers,, but will have aa lower smoking prevalence... Workers born between 1910 and 1930 are likely to have both a higher smoking prevalence and a higher cumulative asbestos exposure at any given age than workers born after 1930. Therefore, in many studies ofburrently employed asbestos workers, cumulative asbestos exposure will be somewhat correlated with smoking preva- lence, and biased estimates of dose-response relationships with 205

Study Number and type of populetion Smoking charscterietim (perrent) Cammenta Mclkrmott at A. 7bro gruupe of eebesrne SM EX NS (1982) wo[kere, Swgr,ilpnd Group 38 10 Gmup 33 4 2 Acheeon et el. Amosite sebretae wnrkere, 77 5 19 (1984) Great Britain Berry at el. 1,7b3 msle end 423 femsle Men 74.5 19.6 5.9 (1965) aebaetae factory workers Women 49.4 22.7 27.9 NOTE: SM=Smoker, E%=Exsmoker; NS=Nuuemuker. sLesovoe

The asbestos. minerals are. classified according to structural features into two groups, serpentine and amphibole. Chrysotile, a serpentine (white asbestos), comprises pliable, curly fibers that are formed individually from fibrillar subunits. Layers of linked silica tetrahedra alternate with layers of magnesium hydroxide octahedra to form long, hollow, scroll-like structures. Chrysotile accounts for approximately 95 percent of the world: usage of asbestostod'ay. The major producers are the Soviet Union and Canada. The amphibole types of asbestos (crocidolite, amosite, tremolite, actinolite, and: anthophyllite). are generally made up of straight, needle-like fibers consisting of strips of silica tetrahedra linked by one or more cations (calcium~ sodium, magnesium, and iron). The mineral names are often distinguished by adding the modifier asbestos after the.name.for those minerals that may occur both as a fiber and not as a fiber. In t'his.text, crocidolite refers to asbestiform richterite and amosite refers to asbestiform grunerite. In the United States, amosite and, to a lesser extent, crocidolite were widely used in the past, but their commercial importance has decreased dramati- cally in the last two decades (Craighead and Mossman 1982). Thee amphiboles tremmlite,, actinolite, and anthophyllite. are minor con- taminants of some chrysotile and industrial talc products, are present in both asbestiform and nonabestiform types, and are not produced for commercial use. The occupations and industries in which the major mortality studies of asbestos-exposed workers have been conducted are pre- sented in Table 1. Groups.not described in this table, but for whom there is considerable concern about substantial asbestos exposure, include workers in the building and demolition trades and mainte- nance workers. The number of workers exposed to asbestos.in the United States has been variously calculated, but a detailed review by Nicholson and colleagues (1982) estimated that 18.8 million workers have had more than.2 months.of exposure in occupations where significant asbestos exposure may have occurred. An earlier chapter of this Report documents that age and occupation are associated with substantial differences in smoking behavior. These differences would be expected to substantially alter lYrng cancer and chronic lung disease mortality; therefore, a careful examination of the smoking habitsof asbestos-exposed populations iss needed in order to interpret the data on mortality and disease incidence and prevalence reported in the literature. Table 2 presents the smoking habits of asbestos workers from a number of studies of asbestos-exposed populations. In most of the studies of asbestos- exposed populations, approximately 70 to 80 percent of male asbestosworkers smoked. In some.subset's of workers, well over 90 percent of the individuals were current smokers or had smoked in the past. Li 157-964 0 - 86 - 8 201

TABLE 1.-Mortality from asbestos-related diseases in various cohort studies Asheetosia Lung cancer Type of activity Study Plece Fiber type Percent smoking Numher in cohert Tolol deaths Meao- thelioma (pneumo- coniosie) Oheerved -- @hpeNed SMR Mining McDonald et al. Quebec Chtyeotile 10839 3,291 10 42 290 184 125 (1980) Nicholson et al. Quehec Chryeotile 544 178 1 26 29 11.1 252 0979) Ruhino et al. Italy Chrysotile 952 332 0 9 ll' 10.4 106 (1979) Hahhe et al. Western G1vcidolite 6,2U0 526 17' 14 60 38.2 157 (1980) Australia Meurmso et al. Finland Anthophyllite 68.7 1,092 248 0 13 21 12.6 167 (1974) Friction Berry and England Chrysotile M 9,113 1,840 8 NS 143' 139.5 103 meteriale Newhou9e CYaeidolite• W 4,347 346 2 NS 6' 11.3 53 (1983) McDoneld et al. Connecticut Chryeatile 3,641 1,267 0 12' 73 49.1 148.7 (19841 6'ocidolite• Anthophyllite' General Hendemon and United States ChryeotBe 81 1,075 781 - 5 31 63' 23.3 270.4 menufecturing Enterlinc E.Yacidolite (1979) Amaeite Newhauee snd Englend Chryeotile M 2,687 545 46 NS 103' 43.2 238 Berry (1979) Ltocidolite W 693 200 21 NS 27' 3.2 844 Amaeite 11 nv. . ••1."M . 14, 2~ _ .I'j:- 11 v"RGOYOS

examined the mortality experience of the 17,800 members of the International Association of Heat and Frost Insulators and: Asbestos Workerswho were alive on January 1, 1967. This group was followed to December 1976, and the mortality of the 12,051 workers. more than 20 years after onset of exposure was analyzed. Of this group, smoking histories were availablp for 8,220, of whom 6,841 (83.2 percent) had been regular smokers. at some point and 891 (10.8 percent) had never smoked regularly. Of the 891 workers who had never smoked regularly, death certificates. indicated that. 4 died of lung cancer. The expected number of deaths was calculated: from the mortality experience of a population of blue-collar workers who had never smoked regularly, drawn from the American Cancer Society (ACS) prospective mortality study of 1', million men and women. The resulting expected number of lung cancer deaths of 0.7 and the observed: number of 4 yielded a relative risk for asbestos exposure of 5.33: When the deaths were classified according to the best estimate of the cause of death from all available data, rather than from the death certificate alone, one additional case. of lung cancer was identified, ina worker who had never smoked regularly. Selikoff, Seidman, and Hammond (198%reported the mortality of 933 men who began working in an amosite asbestos factory between June 1941 and December 1945. Of these men, 78 (8.4 percent) weree known to have never smoked regularly; the death certificates of 5 of this group listed lung cancer as the cause of death. When the best estimate of cause of death was used, only three men were believed to have died of lung cancer. The expected number of deaths was 0.2, based om the ACS mortality study. This led to a relative risk of 25 (5/0.2).for workers who had never smoked regularly. McDonald and colleagues (1980) examined the mortality experi- ence of Quebec asbestos miners, and millers and reported a dose- response relationship between cumulative asbestos exposure and lung cancer in nonsmokers. They compared the standardized mortal- ity ratio (SMR) for lung cancer in miners who had never smoked, using the mortality rates for the Province of Quebec,.which are based on both smokers and: nonsmokers. The SMR increased from: 0.18 among nonsmoking miners with less than 30 million particles per cubic foot times years (mppcf.y) of exposure to 0.36 in miners with 30 to 299mppcfl.y of exposure. and 1.24 in nonsmoking miners with more.than 300 mppcf.y of exposure. There were 19 lung cancer deaths among nonsmoking asbestos miners. These authors (McDon- ald et al. 1980)) also performed a case-control study of the 245 miners who had died of lung cancer. The distribution of cumulative asbestos exposure.among the 20 nonsmoking miners with lung cancer and 20 nonsmoking control miners matched for year of birth and smoking status was examined~ and the relative risk for lung cancer was found: 211

90 ^Vi $3.24 0 e. t ii I Nonmoksrs Nonsmoking Smoken Smoldng 87:36 I notezpusm esbsstos ncteDPosed asbestos (>tpeck/dey)l to asbestos workers to as0estos workers esEestos workers 0 FIGURE 2.-Relative risk of dying of lung cancer for smoking and ndlsmoking asbestos workers and smoking and nonsmoking control group members 6OUIIQM:: enmmnnd et al-ll9'19). risk of developing lung cancer. Finally, cumulative asbestos expo- sure, age, and cumulative cigarette smoking exposure are generally 218