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HAZARD IDENTIFICATION I: LUNG CANCER IN ACTIVE SMOKERS, LONGTERM ANIMAL BIOASSAYS, AND GENOTOXICITY STUDIES ă 4.1. INTRODUCTION Numerous epidemiologic studies have conclusively established that the tobacco smoke inhaled from active smoking is a human lung carcinogen (U.S. DHHS, 1982; IARC, 1986). A clear doseresponse relationship exists between lung cancer and amount of exposure, without any evidence of a threshold level. It is, therefore, reasonable to theorize that exposure to environmental tobacco smoke (ETS) might also increase the risk of lung cancer in both smokers and nonsmokers. As documented in the previous chapter, the chemical compositions of mainstream smoke (MS) and ETS are qualitatively similar, and both contain numerous known or suspected human carcinogens. In fact, ETS contains essentially all of the same carcinogens identified in MS, and many of these appear in greater amounts in sidestream smoke (SS), the primary component of ETS, than in MS, per unit tobacco burned (Table 31). In addition, both MS and SS have been shown to be carcinogenic in animal bioassays (Wynder and Hoffman, 1967; Grimmer et al., 1988), and MS, SS, and ETS have all been found to be genotoxic in in vitro systems (IARC, 1986). Furthermore, as the previous chapter also describes, exposure assessments of indoor air and measurements of nicotine and cotinine levels in nonsmokers confirm that passive smokers are exposed to and absorb appreciable amounts of ETS that might result in elevated lung cancer risk. This chapter reviews the major evidence for the lung carcinogenicity of tobacco smoke derived from human studies of active smoking and the key supporting evidence from animal bioassays and in vitro experiments. The evidence from the few animal and mutagenicity studies pertaining specifically to ETS is also presented. The majority of this information has already been well documented by the U.S. Department of Health and Human Services (U.S. DHHS) (1982) and the International Agency for Research on Cancer (IARC) (1986). The current discussion mainly extracts and summarizes some of the important issues and principal studies described in those comprehensive reports. In view of the abundant and consistent human evidence establishing the carcinogenic potential of active smoking to the lung, the bulk of this chapter focuses on the human data. Although EPA's carcinogen risk assessment guidelines (U.S. EPA, 1986a) suggest an extensive review of all evidence pertaining to carcinogenicity, we believe that the large quantity of human cancer studies on both MS and ETS provide the most appropriate database from which to evaluate the lung cancer potential of ETS. Thus, the animal evidence and genotoxicity results are given only limited attention here. Similarly, a discussion of the mutagenicity data for individual smoke components would be superfluous in the context of the overwhelming evidence from other, more pertinent sources and is not included. Extensive reviews of these data can be found in the U.S.DHHS (1982) and IARC (1986) publications. Claxton et al. (1989) provide an assessment of the genotoxicity of various ETS constituents. 4.2. LUNG CANCER IN ACTIVE SMOKERS ČStudies of active smoking in human populations from many countries provide direct and incontrovertible evidence for a doserelated, causal association between cigarette smoking and lung cancer. This evidence includes time trends in lung cancer mortality rates associated with increasing cigarette consumption, high relative risks for lung cancer mortality in smokers of both sexes observed consistently in numerous independent retrospective and prospective studies, and doseresponse relationships demonstrated with respect to smoking intensity and duration and for all four major histological types of lung cancer. 4.2.1. Time Trends While the overall cancer death rate in the United States has been fairly stable since 1950, the lung cancer death rate has increased drastically for both males and females (Figures 41 and 42). Ageadjusted lung cancer mortality rates in men have increased from 11 per 100,000 in 1940 to 73 per 100,000 in 1982, leveling slightly to 74 per 100,000 in 1987 (Garfinkel and Silverberg, 1991). In women, lung cancer mortality rates have risen from 6 per 100,000 in the early 1960's to 28 per 100,000 in 1987 (Garfinkel and Silverberg, 1991). The striking time trends and sex differences seen in lung cancer mortality rates correlate with historical smoking patterns. Increases in lung cancer death rates parallel increases in cigarette consumption with a roughly 20year lag time, accounting for the latency period for the development of smokinginduced lung cancer. Males started smoking cigarettes in large numbers during the years around World War I, whereas females did not begin smoking in appreciable numbers until World War II. Cigarette consumption per capita (based on the total population age 18 and older) in the United States rose from 1,085 in 1925 to a high of 4,148 in 1973. In the past two decades, cigarette consumption has decreased to 2,888 in 1989 (Garfinkel and Silverberg, 1991). This decline correlates with the leveling off of lung cancer mortality rates in recent years.  Figure 41 . Ageadjusted cancer death rates* for selected sites, males, United States, 19301986. *Adjusted to the age distribution of the 1970 U.S. census population. Source: U.S. DHHS, 1989. Figure 42 . Ageadjusted cancer death rates* for selected sites, females, United States, 19301986. *Adjusted to the age distribution of the 1970 U.S. census population. Source: U.S. DHHS, 1989.  4.2.2. DoseResponse Relationships More than 50 independent retrospective studies have consistently found a doserelated association between smoking and lung cancer (U.S. DHHS, 1982). Eight major prospective studies from five countries corroborate this association: XppppAmerican Cancer Society (ACS) NineState Study (white males) (Hammond and Horn, 1958a,b) pppCanadian War Veterans Study (Best et al., 1961; Lossing et al., 1966) pppBritish Doctors Study (Doll and Hill, 1964a,b; Doll and Peto, 1976; Doll et al., 1980) pppAmerican Cancer Society 25State Study (Hammond, 1966; Hammond and Seidman, 1980) pppU.S. Veterans Study (Kahn, 1966; Rogot and Murray, 1980) pppCalifornia Labor Union Study (Weir and Dunn, 1970) pppSwedish Study (sample of census population) (Cederl?f et al., 1975) pppJapanese Study (total population of 29 health districts) (Hirayama, 1967, 1975a,b, 1977, 1978, 1982, 1985). X` hp x (#%'0*,.8135@8:>& Canadian veterans study 19551956 207,397 subjects (aged 30+) [92,000] Selfadministered questionnaire (57% respondents) 6 years 9,491 deaths in men; 1,794 deaths in women NA&& British doctors study 1951 34,440 men (aged 20+) Selfadministered questionnaire (69% respondents) 20 years`(#? 10,072 deaths 99.7%&&   6,194 women (aged 20+) Selfadministered questionnaire (60% respondents) 22 years 1,094 deaths 99%&2 2 & ACS 25state study U.S. veterans study  19591960 1954  1,078,894 subjects, first followup: 440,558 men, 562,671 women (aged 3584); second followup: 358,422 men, 483,519 women 293,958 men (aged 3184) [248,046] Selfadministered questionnaire Selfadministered questionnaire (85% respondents) 4.5 + 5 years 26,448 deaths in men; 16,773 deaths in women 16 years 107,563 deaths 97.4% in women 97.9% in men in first followup Almost 100% ascertainment of vital status; 97.6% of death certificates retrieved&  & California study  19541957 68,153 men (aged 3564) Selfadministered questionnaire 58 years 4,706 deaths NA&((& `H(#8(continued on the following page) &&&&&& Swedish study 1963 27,342 men, 27,732 women (aged 1869) Selfadministered questionnaire (89% respondents) 10 years 5,655 deaths (2,968 autopsies) NA&nn&ܙJapanese study 1965 122,261 men, 142,857 women (aged 40+) Interview (95% of population in area)  16 years 51,422 deaths Total NA = not available. Source: IARC, 1986.  Table 42. Lung cancer mortality ratiosprospective studiesX` hp x (#%'0*,.8135@8:30 Nonsmokers1.8 (5) 7.4 (23) 1.0 (7)0.01 (0.008) 0.1   (0.06) 0 Xz 1The mortality ratio among nonsmokers was assumed to be 15.6 per 100,000 per year, as in the American Cancer Society 25state study. Figures in parentheses were computed by the IARC working group, applying the British doctors' mortality rate among nonsmokers (10.0/100,000 peryear). Source: IARC, 1986. X` |hp x (#%'0*,.8135@8:ratio ACS 25state study 'Nonsmoker )25+ g)2024 g)1519 (Under 15 w> 1.00 w> 4.08 a>10.08 a>19.69 a>16.77 ``Japanese study'Nonsmoker )25+ g)2024 (Under 20 w> 1.00 w> 2.87 w> 3.85 w> 4.44((U.S. veterans study'Nonsmoker )25+ g)2024 g)1519 (Under 15 w> 1.00 w> 5.20 w> 9.50 a>14.40 a>18.70Swedish study'Nonsmoker )19+ g)1718 (Under 16w> 1.00 w> 6.50 w> 9.80 w> 6.40  X` hp x (#%'0*,.8135@8:13.7 (351) @H0>19.1 (33) @H0>12.0 (33) @0?7.2 (32) @0?1.1 (5) @0?1.0 (32) Swedish study (Cederl?f et al., 1975)<10 >10 Nonsmokers@0?6.1 (12) @0?1.1 (3) @0?1.0 (7) British doctors study (Doll and Peto, 1976) Current smokers 14 59 1014 15+ Nonsmokers @H0>15.8 (123) @H0>16.0 (15) @0?5.9 (12) @0?5.3 (9) @0?2.0 (7) @0?1.0 (7) Rogot and Murray (1980) Current smokers <5 59 1014 1519 20+ Nonsmokers @H0>11.3 (2,609) @H0>18.8 (47) @80> 7.5 (86) @80> 5.0 (100) @80> 5.0 (115) @0?2.1 (123) @0?1.0 NA  NA = not available. X` hp x (#%'0*,.8135@8:1 pack/day FFAdenocarcinoma Squamouscell and undifferentiated carcinoma0.78 0.59 0.35 0.522.46 1.151.17 2.197.50 8.58 FF Hanbury (1964)܃    Women onlyFFNo. of cases (%) FF"Heavy" and "medium" smokersNonsmokers and "remainder" FFSmallcell carcinoma Undifferentiated carcinoma Squamouscell carcinoma Adenocarcinoma܃ 18 (47)  $ 9 (24)  $ 9 (24)  $ 2 (5)܃ 21 (34) 14 (23) 12 (19) 15 (24)      FF܃  `%.Q(continued on the following page)FF܃   FF܃   FF܃   F>>F Vincent et al. (1965) ܃ Number of cigarettes smoked/day    Women only FFTotal no. of cases  None  120  2140  41+  Unknown No. % No. %   No. % No. % No. %        FnnF Squamouscell carcinoma19 Smallcell carcinoma17 Adenocarcinoma...64 Undifferentiated...22 Others...   41 ...  163  10 53 3 16 2 10 2 10 2 10   2 12 7   41 6 35 2 12 0   0 51 80 6  $ 9 4   6 0  $ 0 3   5 12 54 4 18 6 27 0  $ 0 0   0 32  78  8 20  1   $ 2 0   $ 0 0    0   107  H 66   28 17   19 12 4  $ 2 5  $ 3      dd0L^- x  dd0L^- x 2882 Wynder et al. (1970)   Sex No. (%)   Cigarette Heavy smokers smokers Heavy = 41+ cigarettes/day((U22Kreyberg I M F  191 (91.0) 24 (80.0) 59 (29.9)    3 (12.0)22Kreyberg II M F 61 (82.4) 21 (58.3)    9 (14.1)    1   (4.8)22Controls M F  199 (47.4) 53 (40.2) 26    (9.8)    3   (5.4)  `).X `&.Q(continued on the following page)  H   dd01{IFit~  dd01{IFit~ 2sEEEEEEEEUsEEEEEEEEU2ReferenceHistological typeResultsComments222||2Deaner and Trummer (1970)   Undifferentiated carcinoma Adenocarcinoma Squamouscell carcinomaPack Number of years   tumors Smokers   40 40 40 (100%) 12 19 13 ( 68%) 52  $ 9  0 9 (100%) 22    dd0L^- x  dd0L^- x 2((2 Weiss et al. (1972)   Death rate per 1,000 manyears of   observation (adjusted for age and race)    No. of cigarettes/day    110 1019 20+22Squamouscell carcinoma Well differentiated Poorly differentiated Smallcell carcinoma Adenocarcinoma 0.7  0.8 0.4 0.3 0.6 2.1 1.0 0.7 1.0  dd ]  dd ] 2  2 Vincent et al. (1977)  Squamouscell carcinoma Adenocarcinoma Smallcell carcinoma Largecell carcinoma Bronchioloalveolar carcinoma Mixed Other No. of cigarettes smoked/day 0 120 2140 41+ Other      14 219   110   120   16   28 101 66 53  $ 7 4 103   62 56   6 2   40   32 33   0 6   20  0 9   6   0 0  < 9  $ 5  $ 5   0 6   30 19   17   4  `&.Q(continued on the following page)   dd8hj,  dd8hj, .@@@@@@@P@@@@@@@P.ReferenceHistological type ResultsComments.  . Chan et al. (1979) Smoking category (kg tobacco smoked during lifetime) ` +.\Women only  <100   100199   >200  Non Manufac Manufac   Manufac smokers tured All   tured All   tured All.\\.Squamouscell and smallcell carcinomas Adenocarcinoma 1.0 3.6 3.4 3.7 4.2 2.6 4.1 1.0 1.9 1.4 1.4 1.8 1.6 1.7 .. Joly et al. (1983) R-Relative risk by duration of smoking (years)   Men Women Nonsmokers, 1.0..     129 3039   4049 50+ 129 3039 4049 50+    .. Squamouscell carcinoma Adenocarcinoma Undifferentiated carcinoma Poorly differentiated carcinoma  15.0 15.9 39.5 42.2 4.4 9.4 31.4 51.9  $ 2.0   3.2  $ 5.3   5.7 2.1 2.7  $  4.7   4.0 26.0 26.4 40.7 50.0 3.9    15.6 20.6 28.3  $ 6.4   7.7 10.8 10.2 3.2 7.8  $  5.6 13.1 X` hp x (#%'0*,.8135@8: