8
Laryngeal Cancer and Asbestos

NATURE OF THIS CANCER TYPE

The larynx, commonly known as the voice box or Adam’s apple, is above the trachea and below the pharynx (Figures 7.1 and 8.1). It includes three anatomic subsites: the glottis, including the vocal fold or vocal cords, depicted near the middle of Figure 8.1; the supraglottis, which encompasses all tissues above the vocal folds and below the pharynx and includes the epiglottis, a fold that closes the larynx during swallowing to prevent food inhalation; and the subglottis, or area below the vocal fold.

The American Cancer Society (Jemal et al. 2006) has estimated that about 9,510 new cases of and 3,740 deaths from cancer of the larynx (ICD-9 161; ICD-O C32.0-C32.9) will occur in 2006. Laryngeal cancer ranks 16th in incidence and mortality among men in the United States, and 28th and 25th in incidence and mortality, respectively, among women. Both incidence and mortality are more than 4 times higher in men than women and are higher among blacks than whites, especially in men. The risk of developing laryngeal cancer increases with age. However, the incidence of laryngeal cancer, adjusted for age, has decreased by an average of 2.6% per year since 1988.

Most cancers of the larynx are squamous-cell carcinomas that arise from the thin, flat cells (squamous cells) that line the upper airway. Those tumors, like squamous-cell carcinomas of the oral cavity and pharynx, develop gradually as normal cells develop into clones of progressively abnormal cells. As the clones accumulate genetic damage, some may undergo malignant transformation, first into carcinoma in situ, and later into inva-



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8 Laryngeal Cancer and Asbestos NATURE OF THIS CANCER TYPE The larynx, commonly known as the voice box or Adam’s apple, is above the trachea and below the pharynx (Figures 7.1 and 8.1). It includes three anatomic subsites: the glottis, including the vocal fold or vocal cords, depicted near the middle of Figure 8.1; the supraglottis, which encompasses all tissues above the vocal folds and below the pharynx and includes the epiglottis, a fold that closes the larynx during swallowing to prevent food inhalation; and the subglottis, or area below the vocal fold. The American Cancer Society (Jemal et al. 2006) has estimated that about 9,510 new cases of and 3,740 deaths from cancer of the larynx (ICD-9 161; ICD-O C32.0-C32.9) will occur in 2006. Laryngeal cancer ranks 16th in incidence and mortality among men in the United States, and 28th and 25th in incidence and mortality, respectively, among women. Both incidence and mortality are more than 4 times higher in men than women and are higher among blacks than whites, especially in men. The risk of developing laryngeal cancer increases with age. However, the inci- dence of laryngeal cancer, adjusted for age, has decreased by an average of 2.6% per year since 1988. Most cancers of the larynx are squamous-cell carcinomas that arise from the thin, flat cells (squamous cells) that line the upper airway. Those tumors, like squamous-cell carcinomas of the oral cavity and pharynx, de- velop gradually as normal cells develop into clones of progressively abnor- mal cells. As the clones accumulate genetic damage, some may undergo malignant transformation, first into carcinoma in situ, and later into inva- 173

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174 ASBESTOS Median glosso- epiglottic fold Lateral glosso- epiglottic fold Epiglottis Tubercle Glottis Wall of Pharynx Arytenoid Vocal fold cartilages Pyriform sinus Cricoid cartilage FIGURE 8.1 Larynx viewed from behind. SOURCE: Modified from Grey’s Anatomy of the Human Body. Available at http:// www.bartleby.com/107/236.html. sive cancer. Premalignant lesions often regress after the discontinuation of tobacco use and alcohol consumption. The most important risk factors for laryngeal cancer are tobacco- smoking (all forms) (IARC 2004) and heavy consumption of alcohol, espe- cially when drinking and smoking occur in combination (IARC 1988). Can- cer of the larynx is rare in lifelong nonsmokers, even though nonsmoking drinkers have been reported to have increased risk (Burch et al. 1981, Elwood et al. 1984). Risk increases with the number of cigarettes smoked per day and duration of smoking. The independent effect of tobacco on laryngeal cancer is greater than that of alcohol consumption. The effects of occupation on the risk of laryngeal cancer have been difficult to study, because of the powerful relationship of this cancer with tobacco use and alcohol consumption, and the little information on alcohol consumption and tobacco use in many occupational studies. Exposure to strong sulfuric acid mist is an established cause of laryngeal cancer (IARC 1987). Other factors that may increase risk, but on which current data are limited, in- clude exposure to mustard gas (HHS 2004), steam and fumes from isopro- pyl alcohol (IARC 1987), metalworking fluids (Eisen et al. 1994, Zeka et al. 2004), and chronic infection with human papilloma virus (Rees et al. 2004).

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175 LARYNGEAL CANCER AND ASBESTOS The combination of tobacco-smoking and heavy drinking causes a much larger increase in laryngeal cancer risk than would be expected from the sum of the relative risk (RR) estimates associated with the separate expo- sures. For example, a study of laryngeal cancer published in 1976 (Wynder and Hoffmann 1976) found that, compared with men who neither smoked nor drank, those who reported both smoking (35 or more cigarettes per day) and drinking (seven or more alcoholic drinks per day) had an RR of 22.1 (95% confidence interval [CI] 7.8-62.1). Smoking alone was associ- ated with an RR of 7.0 (95% CI 2.5-19.4), whereas the RR of this level of alcohol consumption alone could not be calculated because of the absence of cases. That study, conducted during the period when many studied occu- pational populations were experiencing exposure to asbestos, illustrates the strength of the association of laryngeal cancer with smoking and drinking. EPIDEMIOLOGIC EVIDENCE CONSIDERED The association between asbestos exposure and cancer of the larynx has been examined in many cohort and case-control studies. As discussed previously, the major strengths of the occupational cohort studies are that the magnitudes and durations of asbestos exposure tend to be substantially higher and the exposure information better documented than in case- control studies of the general population. Most of the cohort studies ad- dress death from laryngeal cancer—an imperfect surrogate of incidence be- cause survival of laryngeal cancer is high. The case-control studies are also important with respect to laryngeal cancer because their analyses are based on incident cases rather than deaths; the number of cases is larger, thus providing greater statistical power; and some of the case-control studies collect information that can be used to adjust for or stratify on tobacco or alcohol use. Cohort Studies The cohorts that presented usable information about the risk of laryn- geal cancer and their design properties are described in Table B.1, and the details of their results concerning cancer at this site are abstracted in Table D.2. The results of the cohort and case-control studies are summa- rized in Table 8.1, and Figures 8.2 and 8.3 are plots of RRs for overall exposure and for exposure-response gradients from the cohort studies reviewed. The committee identified and included in its analyses 35 cohort popula- tions from 29 published papers that examined the RR of a diagnosis of or death from laryngeal cancer among among people with any occupational exposure to asbestos compared with people in the general population with-

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176 ASBESTOS TABLE 8.1 Summary of Epidemiologic Findings Regarding Cancer of the Larynx Study Summary Study Populations No. Study RR Between- Type Figure Comparison Included Populations (95% CI) Study SD Cohort 8.2 Any vs none All 35 1.40 — (1.19-1.64) 8.3 High vs Lower 11 2.02 — nonea boundb (1.64-2.47) Upper boundb 11 2.57 — (1.47-4.49) Case- control 8.4 Any vs none All 15 1.43 0.27 (1.15-1.78) 8.5 Any vs none EAM = 1 10 1.21 0.02 (1.04-1.40) EAM = 2 5 2.56 0.65 (1.20-5.43) 8.6 Any vs none EAM = 1 7 1.18 0.00 Adjustedc (1.01-1.37) EAM = 1 3 1.58 0.27 Unadjustedc (0.86-2.91) 8.7 High vs EAM = 1 7 1.38 0.27 nonea Lower (1.02-1.86) boundb EAM = 1 7 1.53 0.07 Upper (1.21-1.93) boundb NOTE: CI = Confidence interval; EAM = exposure-assessment method; high quality, EAM = 1; lower quality, EAM = 2; RR = relative risk; SD = standard deviation. aUsed studies that reported dose-response relationship (RR on an exposure gradient). bSome studies reported dose-response relationship on multiple gradient metrics. In comput- ing the summary RR, “lower bound” calculation used the smallest “high vs none” RR, and “upper bound” calculation used largest “high vs none” RR. cAdjusted: RR was adjusted for both smoking and alcohol use. out such exposure (Table D.2 and Figure 8.2). Other reports were not in- cluded in the analysis, because they were superseded by later reports based on longer follow-up of the same cohort (e.g., Clemmensen and Hjalgrim- Jensen 1981; McDonald et al. 1986, 1993; Rubino et al. 1979), were not primarily asbestos cohorts (e.g., Magnani et al. 1986, Imbernon et al. 1995),

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177 LARYNGEAL CANCER AND ASBESTOS Armstrong88 (men) Battista99 (men) Berry00 (male insulators, RR=0) Berry00 (male factory workers) Berry00 (female factory workers, RR=0) Berry94 (men) Botta91 (men) Botta91 (women, RR=0) Dement94 (men + women) Enterline87 (men) Finkelstein04 (men) Finkelstein89 (men) Gardner86 (men + women) Germani99 (women with asbestosis) Giaroli94 (men) Hughes87 (men) Study Reference Karjalainen99 (men with asbestosis, incidence) Karjalainen99 (men with benign pleural disease, incidence) Karjalainen99 (women with asbestosis, incidence, RR=0) Levin98 (white men) Liddell97 (men) Meurman94 (men, incidence) Parnes90 (men) Peto85 (men) Peto85 (women, RR=0) Piolatto90 (men) Pira05 (men + women) Puntoni01 (men) Raffn89 (men, incidence) Reid04 (men, incidence) Selikoff91 (male members insulation unions 1967) Sluis_Cremer92 (men) Smailyte04 (men, incidence) SzesDab02 (men with asbestosis) Tola88 (men, incidence) Summary 95% Interval 0.01 0.1 0.25 0.5 1 2 3 5 7 10 Relative Risk FIGURE 8.2 Cohort studies: RR of laryngeal cancer in people with “any” exposure to asbestos compared with people who report none. did not specify the standardized mortality ratio or expected number of cases of laryngeal cancer (e.g., Djerassi et al. 1979; McDonald et al. 1983, 1984; Zhu and Wang 1993), or did not report the larynx as a separate cancer site (e.g., Seidman et al. 1986, Selikoff et al. 1979). Figure 8.2 shows the RR estimates and 95% CI estimates in 34 cohort

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178 ASBESTOS Berry00 (male factory workers) Finkelstein89 (men) Liddell97 (men) Meurman94 (men, incidence, largest RR) Meurman94 (men, incidence, smallest RR) Parnes90 (men) Peto85 (men, RR=0) Study Reference Study Reference Piolatto90 (men, largest RR) Piolatto90 (men, smallest RR) Pira05 (men + women) Puntoni01 (men, largest RR) Puntoni01 (men, smallest RR) Raffn89 (men, incidence, largest RR) Raffn89 (men, incidence, smallest RR) Smailyte04 (men, incidence, largest RR) Smailyte04 (men, incidence, smallest RR) Summary 95% Interval (using largest RR) Summary 95% Interval (using smallest RR) 0.01 0.1 0.25 0.5 1 2 3 5 7 10 Relative Risk FIGURE 8.3 Cohort studies: RRs of laryngeal cancer among people in most extreme exposure category compared with those with no exposure (♦ = more than one exposure gradient reported in citation, so the plot contains both highest and lowest estimates of risk at most extreme category over all gradients).

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179 LARYNGEAL CANCER AND ASBESTOS study populations that reported “any” occupational exposure to asbestos, compared with unexposed subjects. The cohorts were drawn from a wide array of industries, including mining, textiles, and insulation. Five of the studies (Karjalainen et al. 1999, Meurman et al. 1994, Raffn et al. 1989, Reid et al. 2004, Smailyte et al. 2004) compared the incidence of laryngeal cancer in exposed and unexposed subjects; the remainder assessed mortal- ity. The number of cases or deaths in the reports ranged from 1 (Gardner and Powell 1986, Germani et al. 1999, Szeszenia-Dabrowska et al. 2002) to 36 (Liddell et al. 1997). The RR estimates exceeded 1.0 in all cohorts with 10 or more cases of or deaths from laryngeal cancer (Finkelstein and Verma 2004, Liddell et al. 1997, Puntoni et al. 2001, Raffn et al. 1989, Reid et al. 2004, Selikoff and Hammond 1978, Selikoff and Seidman 1991, Tola et al. 1988) and in the largest study of patients with asbestosis (Karjalainen et al. 1999). Some of the heterogeneity seen in Figure 8.2 reflects the statistical imprecision of subgroup analyses, especially for women. The combined RR associated with any occupational exposure to asbestos (Figure 8.2) was 1.40 (95% CI 1.19-1.64). Further analyses examined whether the association between asbestos exposure and laryngeal cancer was stronger among the most highly ex- posed subjects in a subset of 11 cohorts in which this information was available. The analysis was done in several ways to take account of the multiple indexes used by many of the studies to define the intensity or dura- tion of exposure (duration of employment, cumulative exposure, peak ex- posure, probability of exposure, and so on). We plotted the highest and lowest RRs for subjects who were in one of the “most exposed” categories by any definition. Figure 8.3 presents the plots for the 11 cohorts in which this information was available. In each of the individual cohorts, the RR estimates exceeded 1.0. The aggregate RR estimate in the most highly ex- posed subjects was 2.57 (95% CI 1.47-4.49) for the strongest association reported and 2.02 (95% CI 1.64-2.47) for the weakest association reported; both are higher than the combined estimate associated with any exposure to asbestos 1.40 (95% CI 1.19-1.64). Our last approach in assessing the cohort studies of asbestos exposure in relation to laryngeal-cancer risk was to examine the association in co- horts with extremely high exposure to asbestos, such as the patients with asbestosis studied by Karjalainen et al. (1999). The standardized incidence ratios (SIRs) of mesothelioma (RR = 32, 95% CI 14.4-60.0) and of lung cancer (RR = 6.7, 95%CI 5.6-7.9) were significantly increased in this co- hort, compared with the incidence in the general population of Finland. The SIR of laryngeal cancer was also increased (RR = 4.2, 95% CI 1.4-9.8) in men but not women. In summary, the larger cohort studies consistently show increased risk of laryngeal cancer in asbestos-exposed workers employed in a wide array

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180 ASBESTOS of industries and in a large cohort of workers with asbestosis. There is some evidence of a dose-response relationship in the meta-analyses. Case-Control Studies The case-control studies of laryngeal cancer that were retained for thor- ough evaluation after exclusion of studies that did not assess exposure to asbestos or did not meet other exclusion criteria are listed in Table 6.5 according to quality of their exposure assessment. The details of the design aspects of those studies are presented in Table C.1 and their detailed results are abstracted in Table E.2. The findings of the studies are summarized in Table 8.1 and in the plots presented in Figures 8.4-8.7. The committee identified 18 published case-control studies that pro- vide data on the association between risk of laryngeal cancer and exposure to asbestos or any employment in an occupation or industry where asbestos exposure was known to occur. The studies involved from 20 cases (Luce et al. 2000) to 940 cases (Elci et al. 2002). Seven of the studies had 200 or more subjects (Berrino et al. 2003, Deitz et al. 2002, Elci et al. 2002, Marchand et al. 2000, Olsen and Sabroe 1984, Wortley et al. 1992, Zheng et al. 1992), while seven more included at least 100 (Ahrens et al. 1991, Brown et al. 1988, Burch et al. 1981, De Stefani et al. 1998, Gustavsson et al. 1998, Muscat and Wynder 1992, Stell and McGill 1973). Over 97% of cases in these studies were male. The male predominance reflects the facts that about 80% of laryngeal cancers occur in men and that occupational exposures to asbestos typically occur in trades where nearly all workers have been men. Figure 8.4 provides the RR or odds ratio estimates associated with re- porting “any” exposure to asbestos in 15 studies that compared subjects with any occupational exposure to those with no exposure to asbestos. Three case-control studies are excluded from this analysis (Berrino et al. 2000, Gustavsson et al. 1998, Wortley et al. 1992), because they present results for larynx only in relation to dose. Only one (Luce et al. 2000) of the 15 studies included in Figure 8.5 has an RR estimate below 1.0. The meta- analysis, combining 15 studies, found an RR of 1.43 (95% CI 1.15-1.78) associated with “any” exposure to asbestos. To assess whether the association between asbestos exposure and risk of laryngeal cancer was stronger in studies with higher exposure informa- tion, the committee separated the studies into those with better measures of exposure and those with more limited data, as shown in Figure 8.5. The RR from the combined analysis of 10 studies with higher-quality exposure in- formation was 1.21 (95% CI 1.04-1.40). Among the studies considered to have more limited information on asbestos exposure were two (Shettigara and Morgan 1975, Stell and McGill 1973) in which the association with

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181 LARYNGEAL CANCER AND ASBESTOS Ahrens91 (men) Brown88 (men) Burch81 (men) DeStefani98 (men) Dietz03 (men + women) Elci02 (men) Study Reference Hinds79 (men) Luce00 (men) Marchand00 (men) Muscat92 (men) Olsen84 (men) Shettigara75 (men, p<0.001, RR=infinity) Stell73 (men, RR=14.5) Zagraniski86 (men) Zheng92 (men) Summary 95% Interval 0.01 0.1 0.25 0.5 1 2 3 5 7 10 Relative Risk FIGURE 8.4 Case-control studies: RR of laryngeal cancer in people with “any” exposure to asbestos compared with people with none. asbestos appeared to be the strongest. However, those small studies had a negligible influence on the summary measure of association between asbes- tos exposure and increased risk of laryngeal cancer. The association per- sisted with or without the inclusion of studies with weaker exposure data. Most of the case-control studies made some attempt to control for to- bacco and alcohol consumption in examining the association between as- bestos exposure and laryngeal cancer. Two of the studies whose results are presented in Figure 8.6 with adjustment for those risk factors also gave unadjusted estimates in the citation. In Dietz et al. (2004), the association between asbestos exposure and laryngeal cancer was weakened by control- ling for other covariates; but in Brown et al. (1988), controlling for tobacco

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182 ASBESTOS EAM = 1 Brown88 (men) Burch81 (men) DeStefani98 (men) Dietz03 (men + women) Elci02 (men) Hinds79 (men) Luce00 (men) Study Reference Marchand00 (men) Muscat92 (men) Zagraniski86 (men) Summary 95% Interval EAM = 2 Ahrens91 (men) Olsen84 (men) Shettigara75 (men, p<0.001, RR=infinity) Stell73 (men, RR=14.5) Zheng92 (men) Summary 95% Interval 0.01 0.1 0.25 0.5 1 2 3 5 7 10 Relative Risk FIGURE 8.5 Case-control studies: RR of laryngeal cancer in people with “any” exposure to asbestos compared with people with none, stratified on quality of exposure assessment (top, EAM = 1: higher-quality exposure assessment; bottom, EAM = 2: lower-quality exposure assessment). use and alcohol consumption made little difference. Overall, with adjust- ment for the other two prominent risk factors for laryngeal cancer, an asso- ciation with asbestos exposure appears to persist (RR = 1.18, 95% CI 1.01- 1.37). Given the propensity that has been demonstrated for smoking to act as an effect modifier in lung cancer rather than merely as a simple additive factor, however, it may be more appropriate to consider stratified analyses than adjusted multivariate findings.

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183 LARYNGEAL CANCER AND ASBESTOS Adjusted for SMK and ALC Brown88 (men) DeStefani98 (men) Dietz03 (men + women) Elci02 (men) Marchand00 (men) Study Reference Muscat92 (men) Zagraniski86 (men) Summary 95% Interval Not Adjusted for SMK and ALC Burch81 (men) Hinds79 (men) Luce00 (men) Summary 95% Interval 0.01 0.1 0.25 0.5 1 2 3 5 7 10 Relative Risk FIGURE 8.6 Case-control studies: RR of laryngeal cancer in people with “any” exposure to asbestos compared to people with none, from studies with higher-quality exposure assessment, stratified on quality of confounder assessment (top: adjusted; bottom: unadjusted). Five of the case-control studies presented results stratified by tobacco or alcohol consumption and allowed limited consideration of whether as- bestos exposure might modify the laryngeal carcinogenicity of tobacco or alcohol exposure (Burch et al. 1981, De Stefani et al. 1998, Gustavsson et al. 1998, Marchand et al. 2000, Muscat and Wynder 1992). The informa- tion presented in Burch et al. (1981) did not conform to a tabular presen- tation, but the results from the others are abstracted in Table 8.2.

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184 ASBESTOS TABLE 8.2 Effect Modification for Laryngeal Cancer Associated with Asbestos Exposure and Smoking Asbestos Exposure Smoking History None or Low Intermediate or High Study (pack-years) (cumulative) (cumulative) Marchand et al. (2000) <30 1.0 1.5 (0.9-2.5) (adjusted for age and 30+ 5.3 (3.2-8.8) 6.5 (3.8-10.8) for alcohol consumption) Never Ever De Stefani et al. (1998) ≤ 35 1.0 1.7 (0.2-14.2) 36+ 6.2 (3.5-11.1) 30.6 (8.4-112.1) Never Ever Muscat and Wynder (1992) not current 1.0 1.3 (0.7-2.4) current 5.8 (3.4-10.00 6.3 (3.3-12.2) Never Ever Gustavsson et al. (1998) not current 1.0 1.8 (adjusted for age, region, current 3.9 4.8 [vs 4.7 expected and alcohol consumption) under additive model; or 7.0 under multiplicative model] Gustavsson et al. (1998) found the observed risk (4.8) in the combined exposure category for Swedish men closer to the prediction of an additive model (3.9 + 1.7 – 1.0 = 4.7) than of a multiplicative one (3.9 × 1.7 = 7.0). Marchand et al. (2000), reporting on a hospital-based study of 315 inci- dent cases of laryngeal cancer in France, found risks (also adjusted for age and alcohol consumption) somewhat indicative of interaction of joint ex- posure to asbestos and smoking. Muscat and Wynder (1992) reported simi- lar results in a hospital-based study of 194 white males in the United States. De Stefani et al. (1998), however, found a much stronger association with having “ever” been exposed to asbestos among Uruguayan heavy smokers than in asbestos-exposed men who had not smoked as much. A limitation of all of those studies is that, although the risk was higher among men who were exposed than those who were not unexposed to asbestos, the data were not stratified into narrowly defined combinations of asbestos expo- sure, tobacco-smoking, and alcohol consumption.

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185 LARYNGEAL CANCER AND ASBESTOS As in the analyses of cohort studies, the committee examined the risks in the extreme categories of exposure-related gradients (longest duration, highest probability of exposure, cumulative exposure, and so on) in the case-control studies. As depicted in Figure 8.7, the aggregate results for the weakest (RR = 1.38, 95% CI 1.02-1.86) and the strongest (RR = 1.53, 95% CI 1.21-1.93) reported associations for extreme exposure groups were both higher than the aggregated estimate for subjects with any exposure to as- bestos in the studies with more reliable exposure assessment (top of Figure 8.5), and this a suggests of dose-response relationship. Berrino03 (men) Brown88 (men) DeStefani98 (men) Elci02 (men, largest RR) Study Reference Elci02 (men, smallest RR) Gustavsson98 (men, largest RR) Gustavsson98 (men, smallest RR) Marchand00 (men) Wortley92 (men+women, largest RR) Wortley92 (men+women, smallest RR) Summary 95% Interval (using largest RR) Summary 95% Interval (using smallest RR) 0.01 0.1 0.25 0.5 1 2 3 5 7 10 Relative Risk FIGURE 8.7 Case-control studies: RRs of laryngeal cancer in people in with extreme exposure to asbestos compared with those with none (♦ = more than one exposure gradient reported in citation, so the plot contains both highest and lowest estimates of risk for most extreme category over all gradients).

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186 ASBESTOS EVIDENCE INTERGRATION AND CONCLUSION Evidence Considered The evidence base included a larger number of epidemiologic studies of asbestos exposure and laryngeal cancer, particularly of the case-control de- sign, than were available for other cancer sites. The committee reviewed the results on 35 cohort populations and 18 case-control studies. Subjects in the studies had been exposed to asbestos in a wide array of industries and occupations in North America, South America, Europe, and Japan. Many of the case-control studies collected some data with which to control for confounding by tobacco-smoking and alcohol consumption. Several case- control studies examined the association between asbestos exposure and laryngeal cancer, stratifying on tobacco use. The committee also reviewed four experimental studies in which rodents were exposed over much of their lifetime to high concentrations of asbestos through inhalation. Consistency Asbestos exposure was associated with increased risk of laryngeal can- cer in all nine large cohort studies (those with at least 10 cases of or deaths from laryngeal cancer) and in both the cohort and case-control combined analyses. Some evidence of a dose-response relationship in risk was seen in both the cohort and the case-control studies. There was no consistent evi- dence of confounding in case-control studies that reported both age- adjusted and multivariate-adjusted RR estimates. Several case-control stud- ies that stratified on tobacco-smoking observed higher risk among men who were exposed than in those not exposed to asbestos, although these analy- ses did not simultaneously stratify on asbestos, tobacco, and alcohol. Strength of Association The RR of laryngeal cancer among persons with any occupational ex- posure to asbestos compared with those who reported no exposure was 1.40 (95% CI 1.19-1.64) in the meta-analysis of the cohort populations and 1.43 (95% CI 1.15-1.78) in the case-control studies. There was some evidence from both cohort and case-control studies that risk increased with the intensity, duration, or likelihood of exposure; the aggregate estimates of RR in the most highly exposed subjects in either type of study ranged from 1.38 to 2.57.

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187 LARYNGEAL CANCER AND ASBESTOS Coherence Several factors contribute to the biologic plausibility that asbestos may cause cancer of the larynx. The larynx, like the lung, is anatomically in the direct path of inhaled asbestos fibers. Inflammation or damage of the vocal folds could disrupt laminar airflow and predispose to the deposition and accumulation of asbestos fibers in the larynx. Squamous-cell carcinomas of the lung and larynx have histologic and clinical similarities. Cancers at both sites arise from the respiratory epithelium in regions of squamous metapla- sia and dysplasia. Tobacco-smoking is the most important risk factor for both sites. Asbestos exposure is an established cause of lung cancer. On the basis of theoretical considerations, tobacco-smoking, alone or in combina- tion with alcohol consumption, may predispose to the accumulation of as- bestos fibers in the epithelial lining of the larynx. Aerodynamic turbulence at bifurcations of the large conducting airways is known to contribute to the deposition of long asbestos fibers in the lung (Asgharian and Yu 1988). Bronchogenic carcinomas commonly arise in those areas (Schlesinger and Lippmann 1978). The accumulation of asbestos fibers, together with smok- ing and/or drinking, could produce chronic irritation or inflammation and thus accelerates the progression of neoplasia. The committee identified and considered several limitations in the evi- dence related to biologic plausibility. Foremost were the absence of clinical data documenting that asbestos fibers accumulate and persist in the larynx and the lack of experimental support from animal studies. The presence or absence of asbestos fibers in laryngeal tissue from occupationally exposed people has been investigated in only a few studies, in which contamination from other tissues is always a concern; Roggli et al. (1980) reported asbes- tos bodies and Kambic et al. (1989) reported fibers in this anatomic area. Studies in rats and Syrian hamsters found that asbestos inhalation, at levels sufficient to cause mesothelioma in both species and lung cancer in rats, did not induce chronic inflammation or increase cancer of the larynx (Hesterberg et al. 1993, 1994; McConnell 2005; McConnell et al. 1994a,b, 1999). These rodent models do not, however, reflect exposure to cofactors, such as tobacco-smoking and alcohol consumption, which may affect fiber deposition and/or persistence that may exacerbate local tissue injury and inflammation. Conclusion Considering all lines of evidence, the committee placed greater weight on the consistency of the epidemiologic studies and the biologic plausibility of the hypothesis than on the lack of confirmatory evidence from animal studies or documentation of fiber deposition in the larynx. The committee

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