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2 Committee’s Approach to Its Charge and Methods Used in Evaluation GENERAL APPROACH TO EVIDENCE REVIEW The committee was charged with assessing the evidence concerning the causation of selected cancers, other than lung cancer and mesothelioma, by exposure to asbestos fibers. The charge required that the committee com- pile and review the available evidence, attempting to identify all relevant epidemiologic studies, and then evaluate whether the evidence was suffi- cient to infer the existence of a causal relationship. There are now well- established models for meeting the charge, dating as far back as the land- mark 1964 report of the US surgeon general on smoking and health (HEW 1964), which reached the conclusion that smoking causes lung cancer and other diseases. That report assembled the full body of relevant scientific evidence and evaluated it according to formal guidelines. Abundant, com- prehensive reviews of various other agents have since been conducted to gauge whether the sets of evidence associating them with particular health outcomes warrant causal conclusions. Established templates for reviewing scientific evidence set out ap- proaches for gathering evidence and assessing its sufficiency to infer causal- ity of association. With regard to obtaining evidence for review, the ap- proach needs to involve clearly specified search criteria that facilitate collection of all potentially relevant studies for evaluation. For some pur- poses, there may also be an attempt to capture relevant reports in the “gray literature” (non-peer-reviewed or unpublished findings) to obtain the full set of relevant data and to ensure that publication bias does not skew the evidence evaluated, as may occur when datasets are gathered exclusively 18

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19 COMMITTEE’S APPROACH AND METHODS USED from peer-reviewed publications. In the case of an as intensively studied agent as asbestos, however, the committee considered that the findings of most studies would be published. It is possible that only statistically signifi- cant or particularly notable results on nonrespiratory endpoints would be included in the published reports on the cohort studies, and this could lead to reporting bias for cancers at the designated sites. Once germane studies have been identified, they may undergo evalua- tion so that they can be classified according to the quality of the evidence that they provide. They may be evaluated systematically according to a standardized protocol and placed into tiers on the basis of their quality. In a systematic review, results of studies may be qualitatively evaluated and subjected to an overall judgment; additionally, data may be combined to derive a quantitative summary and to explore variation in results among studies. Analyzing aggregated summaries of studies is often referred to as meta-analysis; on occasion, data from studies are obtained at the level of individual participants and jointly analyzed, an approach sometimes re- ferred to as pooled analysis. Statistical approaches for quantitative meta- analysis have been developed (Petitti 2000), as well as methods for detect- ing publication bias in meta-analyses (Peters et al. 2006). Guidelines for causal inference have long been used; perhaps the best- known are those offered in the first report of the US surgeon general on smoking and health (HEW 1964): • The consistency of the association. • The strength of the association. • The specificity of the association. • The temporal relationship of the association. • The coherence of the association. The guidelines provide principles for interpreting epidemiologic evidence in a context set by biologic plausibility and the coherence of different lines of evidence. This committee has used such criteria in meeting its charge. Specificity refers to a unique exposure-disease relationship, which is characteristic of diseases caused by infectious organisms. The concept has also been applied for investigating the contribution of physical and chemi- cal agents to disease (Weiss 2002). The association of asbestos with me- sothelioma constitutes one of the few examples of a high degree of specific- ity for a toxic agent and cancer risk, but the committee gave minimal weight to the criterion of specificity because the cancer sites under consideration have multiple causes and more will likely be identified. From the outset, the committee recognized that asbestos fibers are known to be carcinogenic and that its conclusions with regard to the can- cers specified in its charge would rest heavily on the epidemiologic evi-

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20 ASBESTOS dence. The committee also believed that information on fiber dose to the target organs would be relevant, because the risk of cancer associated with asbestos fibers is known to be dose-dependent. The committee also gath- ered information on mechanisms by which asbestos fibers are carcinogenic. That broad array of evidence was reviewed and synthesized by the com- mittee to make its final determination as to the strength of evidence in support of an inference of causality. A variety of descriptors have been used by committees of the Institute of Medicine (IOM), the National Research Council, and other entities in characterizing the strength of evidence (see NRC 2004 for a review). The classification schemes generally include a category for circumstances in which the data are inadequate for making a judgment and a category for evidence of no association. Most schemes in- clude several categories of evidence indicative of a possible causal associa- tion ranging from uncertain to fully certain; two or three categories gener- ally serve for this purpose. The IOM approach has also distinguished between association and causality. For this report, the committee selected a classification scheme similar to that used in the 2004 report of the US surgeon general on smoking and health (HHS 2004). That report used two categories in reference to evi- dence in support of a causal determination: sufficient and suggestive. Be- cause the legislation mandating this committee’s review requested only a determination of whether asbestos played a causal role in inducing these additional types of cancer, it was the committee’s judgment that insertion of an additional category for evidence more weakly supportive of causation would unnecessarily generate another, most probably arbitrary distinction in classifying the evidence below the threshold for causal inference. There- fore, the committee adopted the four-category scheme of the recent US sur- geon general’s report on smoking and health (HHS 2004) as adequate to meet its charge: • Evidence sufficient to infer a causal relationship. • Evidence suggestive but not sufficient to infer a causal relationship. • Evidence inadequate to infer the presence or absence of a causal rela- tionship, which encompasses evidence that is sparse, of poor quality, or conflicting. • Evidence suggestive of no causal relationship. For the purpose of addressing the charge and the designation of “cause,” the committee required that the evidence be judged sufficient. The category of suggestive “but not sufficient” potentially comprises a range of evidence and uncertainty that does not rise to the level of certainty needed for the designation of causality. For the cancer sites specified in its charge, the committee also needed to

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21 COMMITTEE’S APPROACH AND METHODS USED consider how asbestos fibers could jointly act with other causal agents to affect risk. For cancers of the larynx and esophagus, tobacco and alcohol are well-established carcinogens, and most cases are attributable to their independent and joint actions. Smoking is also a cause of stomach cancer. Various risk factors for cancers of the colon and rectum are under investi- gation, including diet and physical activity. Epidemiologists use the terms effect modification and interaction in referring to the joint consequences of several agents in causing disease. Ef- fect modification in a positive direction, called synergism, increases risk in those exposed to two or more risk factors beyond expectation based on their independent effects. Negative effect modification is called antagonism. To assess the presence of effect modification, stratified and multivariate analytic approaches can be used. The presence of synergism implies that those exposed to one risk factor are at heightened risk when exposed to the additional, interacting factors. Effect modification by tobacco-smoking has been considered in studies of the association between asbestos exposure and lung cancer. For investi- gating such effect modification, information is needed on both asbestos exposure and smoking; this requirement is met by some studies, most often of a case-control design. A recent evaluation of the evidence concerning effect modification by smoking on the risk of lung cancer associated with asbestos exposure by the International Agency for Research on Cancer (IARC 2004) concluded that there is synergism; the pattern has not been precisely characterized, however, in part because of methodologic issues. A related issue is whether asbestos fibers alone can cause cancers at the designated sites. Epidemiologists have conceptually classified causal agents as necessary (presence is required), sufficient (presence is not required, but the agent can cause the disease by itself), and neither necessary nor suffi- cient (Goodman and Samet 2006, Rothman and Greenland 1998). That classification has proved useful in classifying the span of causation from diseases linked to specific agents to diseases with multiple causes, such as coronary heart disease. For example, causal microbial agents are necessary for infectious diseases and tobacco-smoking alone appears sufficient for lung cancer although there may be genetic and other nontoxicologic fac- tors that lead one smoker but not another to develop lung cancer. Simi- larly, asbestos fibers are considered sufficient for mesothelioma. Goodman and Samet (2006) stress that for multifactorial diseases, such as cancer, most risk factors are to be regarded as being in the neither-necessary-nor- sufficient category. Agents that behave as synergens, amplifying the effect of another carcinogen, whether or not they appear to function as carcino- gens by themselves, would be regarded as causal factors. Ultimately, a con- vincing demonstration that the presence compared with absence of asbes- tos exposure, all else being equal, would increase the population risk of

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22 ASBESTOS cancer at one of the sites under review would establish a causal role for asbestos for that type of cancer. Finally, although it considered the precision of measures of association reported by the researchers when interpreting the weight of evidence pro- vided by various epidemiologic studies, the committee does not regard sta- tistical significance as a rigid basis for determining causality. A full evalua- tion needs to consider all types of relevant evidence and take into account uncertainties beyond those of a solely statistical nature. EVIDENCE CONSIDERED Assembly of Literature Database The biomedical literature concerning asbestos is vast (about 25,000 citations in the searchable reference databases MEDLINE and EMBASE), but much of it exclusively addresses asbestos’s role in causing asbestosis, lung cancer, and mesothelioma. Given the committee’s circumscribed task of answering the question of whether this known carcinogen plays a causal role in producing pharyngeal, laryngeal, esophageal, stomach, or colorectal cancer (“selected cancers”), the committee saw no need to revisit the entire body of information on asbestos’s biologic activity or even to review the entire epidemiologic literature on asbestos exhaustively. The subset of epi- demiologic literature referring to the selected cancer sites, however, did need to be identified comprehensively, retrieved when possibly pertinent to the task, and thoroughly reviewed when found to be relevant. MEDLINE and EMBASE are biomedical databases of bibliographic ci- tations and abstracts drawn from biomedical journals (more than 4,600 and 6,500, respectively) published in over 70 countries. Their broad inter- national coverage can be regarded as exhaustive for the developed coun- tries. To ensure the necessary completeness of the desired subset of asbestos literature, those databases were searched by using detailed expansions of synonyms and CAS numbers for asbestos in combination with global search terms for the selected cancers. Before secondary documents and repeated publication of the same material in an English journal and a non-English native language publication were culled, these searches retrieved about 450 English citations and about 100 foreign-language citations. The secondary literature (e.g., ATSDR 2001; Becklake 1979; EPA 1986; IARC 1977, 1987; Kleinfeld 1973; Landrigan et al. 1999; Li et al. 2004; OSHA 1986) was used to identify articles about the cohorts that have served as the basis of conclusions concerning asbestos’s involvement in asbestosis, mesothelioma, and lung cancer. In addition, the reference lists of previous reviews and meta-analyses of asbestos’s possible role in the etiology of the “selected cancers” were also searched to identify the primary citations

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23 COMMITTEE’S APPROACH AND METHODS USED considered. Although the committee would not necessarily accept every study given weight in earlier assessments, the members wanted to be aware of all literature that had been considered. Site-specific reviews were screened for citations on digestive system cancers (Hallenbeck and Hesse 1977, Schneiderman 1974), gastrointestinal cancers (Edelman 1988, Frumkin and Berlin 1988, Goldsmith 1982, Goodman et al. 1999, Kanarek 1989, Miller 1978, Morgan et al. 1985), stomach cancer (Smith 1973), colorectal cancer (Homa et al. 1994, Weiss 1995), colon cancer (Gamble 1994), and laryn- geal cancer (Browne and Gee 2000; Chan and Gee 1988; Edelman 1989; Goodman et al. 1999; Griffiths and Molony 2003; Guidotti et al. 1975; Kraus et al. 1995; Libshitz et al. 1974; Liddell 1990; Parnes 1996, 1998; Smith et al. 1990). The primary publications identified in this manner con- sisted largely of site-specific case-control studies. “Asbestos cohorts” were defined as those having asbestos as a major exposure and as a primary research focus. That excluded studies of cohorts for which asbestos was merely a component of a poorly characterized, com- plex exposure; was a confounder of the exposure of real interest to the researchers; or was mentioned as a hypothesized explanation of an observed excess risk. We sought to gather a comprehensive set of citations concern- ing the asbestos cohorts, but to limit procurement of hard copies to articles most relevant to our mission—the most recent or comprehensive publica- tions on a given cohort and articles specifically addressing the five selected cancers, asbestos exposure, or distribution of asbestos fibers to tissues. All citations related to a given study population were grouped on a spreadsheet to characterize the cohort and how it had been researched over the years. For the cohorts that ultimately provided information on the selected can- cers, information from this spreadsheet is tabled in Appendix B. That pro- cedure facilitated recognition of whether any additional publications per- tained to a pre-existing study cohort and thereby avoided double-counting of evidence. It also aided in identification of which articles should be ob- tained as hard copies. Other search operations were performed manually in PubMed to aug- ment the citations downloaded from MEDLINE and EMBASE into ProCite (2003). PubMed, which contains all MEDLINE citations and an additional 5%, mostly from less prominent foreign journals, is readily accessible for on-line queries and for recovery of citations for importation into ProCite. To capture any other publications related to the cohorts that might contain information about the “selected cancers” (which might have been deemed peripheral to demonstrating the “known health outcomes”), the names of researchers identified in their author lists were manually searched in PubMed for other asbestos-related publications. Special attention was paid to seeking updates of the identified cohorts that superseded those con- sidered for the evaluations of lung cancer and mesothelioma.

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24 ASBESTOS Unless it is found to be associated with the cancer in question, an occu- pational exposure addressed in a case-control study often is not mentioned in the title, abstract, or keyword field scanned during database searches. Therefore, to avoid bias toward positive results and to ensure full retrieval of case-control studies that considered asbestos and that were published through August 2005, PubMed was screened for cancer, occupation, and case-control (and variants) in combination with synonyms for the selected cancer sites without stipulation of an asbestos-related keyword. The final ProCite database contains about 2,500 citations. For some- what more than a fourth of them (754), hard copies were obtained and more closely evaluated for pertinence. Ultimately, about 300 publications directly contributed evidence to our evaluation. Results were abstracted from 36 citations on case-control studies and from about 80 citations on the 40 informative cohort populations for the meta-analyses conducted on epidemiologic findings. Nearly 200 citations contributed asbestos-specific information from animal and in vitro studies, exposure investigations, and mineralogic characterizations. Selection of Studies for Inclusion The citations identified by the search procedure described in the previ- ous section were screened for further consideration on the basis of their abstracts. Copies of reviews, meta-analyses, and other secondary sources were obtained for use in searching as described above and for background information, but the cancer-site-specific content was not considered by the committee members before they conducted their own evaluation. For its evidentiary database, however, the committee was interested only in re- ports of primary investigations. A comprehensive dataset on all asbestos’s potential health effects was not being sought, but a wide net was cast by retrieving copies of reports involving the selected cancer sites that might address asbestos exposure specifically and of asbestos-exposed cohorts that might present information on the selected sites of this review along with data on the health outcomes that are now accepted to be asbestos related. The committee limited the epidemiologic results in its evidentiary data- base to findings of appropriately designed cohort and case-control studies. Cross-sectional studies, ecologic studies, and case series could at most pro- vide supportive evidence. Furthermore, the committee decided that studies of asbestos in drinking water, primarily ecologic in design, did not provide information that was directly pertinent to the charge. Although the committee wanted to be as comprehensive as possible, constraints of time and accessibility prevented securing original articles for a large portion of the foreign-language citations and arranging for their translation. When English abstracts were available, they usually stated ma-

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25 COMMITTEE’S APPROACH AND METHODS USED jor findings and conclusions, but the committee’s consensus was that study methods needed to be addressed in detail if the reliability of a citation’s results were to be evaluated. Therefore, all foreign-language articles were set aside. Consideration of available abstracts and tables did not suggest that the findings reported in those documents differed systematically from findings reported in their English-language counterparts. Articles that were eligible for inclusion in the evidentiary database were evaluated from several perspectives, as set forth below to determine the overall quality of studies and the consequent reliability of estimates of rela- tive risk (RR) derived from them. As discussed in more detail in the follow- ing sections, the design of each study was assessed in terms of how the study sample (cohort members or cases) and comparison group were selected, how the health outcome was determined, how exposure was characterized, and how adequately possible biases and confounders had been addressed. For some of the committee’s analyses, subgroups of studies were selected on the basis of design characteristics. CRITERIA FOR EVIDENCE EVALUATION Fiber Type The committee recognized that there is evidence suggesting that the risk associated with asbestos exposure for development of mesothelioma (and possibly of lung cancer) may vary by fiber type. Controversy continues (for example, Hessel et al. 2004, Rice and Heineman 2003) as to whether there is an absolute difference in the toxicity of amphibole and serpentine (chryso- tile only) forms of asbestos and whether only amphibole fibers have carci- nogenic potential, particularly for mesothelioma, the neoplasm for which a difference seems most apparent. Recent reviews suggest that rather than having no carcinogenic activity, chrysotile has a generally lesser degree of potency than amphibole fibers, and that the various types of amphibole fibera differ in the extent of their biological activity (Britton 2002, IPCS 1998, Roggli 2006, Roggli et al. 1997, Suzuki et al. 2005). In its initial assessment of its charge, the committee evaluated whether its report could address whether associations of asbestos exposure with risk for the desig- nated cancers either depended on the presence of specific type of fibers or varied with type of fiber. With the sole exception of the Montreal study (Dumas et al. 2000; Parent et al. 1998, 2000), the case-control studies did not provide information on fiber type, as self-reported work histories were generally the basis for exposure estimation and the resulting exposure esti- mates were not specific to fiber type. Consequently, the potentially relevant evidence on fiber type came almost exclusively from the cohort studies of asbestos-exposed populations, and specifically from those that have had

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26 ASBESTOS relatively pure exposures to a specific fiber type, such as the crocidolite mining and milling workers in Western Australia. In considering the body of evidence from cohort studies for the designated cancer sites, the commit- tee found only limited literature that was specific as to fiber type. The com- mittee considered the physical and chemical characteristics that distinguish the major fiber types and the potential relevance of these characteristics to relative carcinogenicity of the fiber types. The implications of these physical and chemical differences among fiber types for human carcinogenesis have not been extensively studied, specifically under circumstances of occupa- tional exposure. Current evaluations favor the hypothesis that carcinoge- nicity is not limited to asbestos fibers of the amphibole type (Britton 2002, IPCS 1998, Roggli 2006, Roggli et al. 1997, Suzuki et al. 2005). Conse- quently, the committee’s report describes the level of causal inference in relation to asbestos, without specifying the type. Grouping of Evidence by Cancer Site The cancers that this committee was asked to consider are a diverse group of tumors that develop from the upper portions of the respiratory and digestive tracts to the colon and rectum. Even cancers that occur in tissues contiguous to the mouth and pharynx, and that are conventionally grouped together as “head and neck” cancers, differ markedly in their risk factors and descriptive epidemiology. In many epidemiologic studies that have examined the association of asbestos with the cancers of interest in this report, sites have been grouped into various categories to allow statisti- cal analyses of rather sparse data, even when cancers at the subsites have very different etiologies. Optimally, one would consider the evidence con- cerning these cancers in groupings that reflect generally similar etiology, but extracting what information is available from epidemiologic studies conducted over the last half century under circumstances of evolving under- standing of biologic mechanisms and epidemiologic analysis make this ob- jective unattainable. Given the committee’s intention of considering the available data in a comprehensive and inclusive fashion, however, results were first abstracted with notations as to exactly which anatomic sites the researchers were re- porting on, according to specific International Classification of Disease (ICD) codes for causes of death (ICD-9; although now superseded, version 9 was in effect at the time of most of the deaths recorded in the studies reviewed) or the comparable oncology codes for cancer type (ICD-O-3). Table 2.1 indicates the equivalence between those coding systems for the cancers under consideration, with some of the common phrases used by researchers to report findings on grouped sets of sites, which often are not accompanied by precise designations.

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27 COMMITTEE’S APPROACH AND METHODS USED TABLE 2.1 Standard Codes and Nonstandard Groupings Used to Characterize “Accepted” and “Selected” Cancers ICD-9 ICD-O-3 (for mortality) (for incidence) “Aerodigestive” “Head and Neck” Lip, oral cavity, and pharynx (140-149) (C00-C14) Pharynx Oro- 146 C09.0, C 09.1, C09.8, C09.9, C10.0, C10.1, C10.2, C10.3, C10.4, C10.8, C10.9 Naso- 147 C11.0-C11.9 Hypo- 148 C12.9-C13.9 Ill-defined sites within lip, oral cavity, and pharyx 149 C14.0, C14.1, C14.2, C14.8 Pharynx, unspecified 149.0 Digestive organs and peritoneum (150-159) “Gastrointestinal” (GI) Esophagus 150 C15.0-C15.9 Stomach 151 C16.0-C16.9 Small intestine, including duodenum 152 C17.0-C17.9 Colorectal C18.0-C20.9 Colon 153 C18.0-C18.9 Rectum, rectosigmoid junction, and anus 154 C19.9, C20.9, C21.0-C21.8 “Other digestive” Liver and intrahepatic bile ducts 155 Gall bladder and extrrahepatic bile ducts 156 Pancreas 157 Retroperitoneum and peritoneum 158 C48.0-C48.8 Ill-defined 159 Respiratory and intrathoracic organs (160-165) Nasal cavities, middle ear, and sinuses 160 C30.0-C30.1, (often classified with “Head and Neck”) C31.0-C31.9 Larynx 161 C32.0-C32.9 Glottic 161.0 C32.0 Supraglottic 161.1 C32.1 Subglottic 161.2 C32.2 continues

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28 ASBESTOS TABLE 2.1 Continued ICD-9 ICD-O-3 (for mortality) (for incidence) Trachea, bronchus, and lung 162 C33.9, C34.0-C34.9 Pleura 163 C38.4 Mesothelioma [applies to tissues otherwise coded as 158 or 163] Asbestosis 523.2 or 501 NOTE: “Selected cancers” for consideration as specified by legislation (italicized bold face). “Accepted health outcomes” generally regarded as causally related to asbestos exposure (underlined). The committee did attempt to note whether effects might be associated with more specific classifications that would be more meaningful from an etiologic perspective. The committee also noted that ICD codes do not cap- ture changes in the subsites involved or their histopathologic classification, which was of particular relevance for esophageal and stomach cancers. When the available data were assembled, the committee considered group- ings no broader than “pharynx with oral or buccal cavity,” “larynx with epilarynx” (larynx plus portions of the oropharynx specified as ICD codes 146.4, 146.5, and 148.2), and “rectum with colon or intestines” to be meaningful. Because of the committee’s requirement for relatively specific group- ings of sites, a considerable number of cohorts were judged uninformative for the “selected cancers.” Those cohorts may have been studied intensively with repeated follow-up of vital status, but in most cases the researchers’ primary interest was respiratory disease, both malignant and nonmalignant, and information on the cancers of concern in this review was not reported or analyzed. Study Designs Epidemiologic designs applied in investigations of environmental and occupational risk factors for cancer are primarily of three types: cohort studies of defined groups (such as worker populations), case-control stud- ies, and “ecologic” studies that compare rates in geographic regions defined by exposure characteristics. Epidemiologic studies can also be classified as exposure-based or general-population-based depending on whether the source population is defined as an exposed group (such as workers in a

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38 ASBESTOS founding adjustment. For cohort studies, this was accomplished by using Poisson regression; for case-control studies, the method of DerSimonian and Laird (1986) was applied. Details of how these aggregate estimates were calculated are provided below. Summary Plots for Cohort Studies Organization of Summary Plots Two plots were constructed for each cancer site. The first summarizes the effect of any exposure to asbestos (vs none), and the second summa- rizes the effect of high exposure vs none. Each summary plot includes the RR and 95% CI for each cohort listed, and a summary RR with an associ- ated 95% CI. The template for summaries of cohort studies of cancer at each site is given in Table 2.2. Most of the cohort studies reported results for cancer mortality, but some also, or only, reported on cancer incidence. Incidence is a more com- prehensive statistic because it considers all people in whom cancer was di- agnosed, not just those who ultimately died from it. Therefore, when there was a choice, incidence findings were reported. A study’s caption on a plot indicates when a standardized incidence ratio was reported rather than a standardized mortality ratio. Plot 1 includes every cohort with a reported finding for any exposure vs none without reference to study characteristics (such as exposure quality and confounder adjustment). The committee decided that the reliability of an estimate of risk for a given cancer type from simply being in an occupa- tional cohort in comparison with a standard population (that is, being cat- egorized as having had “any exposure”) would not be affected by a study’s thoroughness in determining exposure gradients. Therefore, unlike what was done for case-control results, the cohort results for “any exposure” were not stratified on how exposure quality was measured in the overall study (in which detailed exposure characterization was most often derived TABLE 2.2 Organization of Summary Plots Used for Cohort Studies Informative for Cancer at Each Site Plot Type of RR Studies Included 1 Any vs none All 2 Most extreme vs none (If more than one Studies reporting RR on a gradient gradient reported, aggregates calculated with smallest and with largest reported RRs)

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39 COMMITTEE’S APPROACH AND METHODS USED for application to respiratory health outcomes). Most cohort studies did not report explicit confounder adjustment, so stratification on this charac- teristic was not part of the analysis. Plot 2 presents RRs for the most extreme category of an exposure gra- dient vs no exposure. We endeavored to capture the estimated effect in the highest reported categories of exposure (vs none) as a means of detecting dose-response relationships; a positive shift of the summary RR on plot 2 relative to plot 1 is viewed as an indicator of a dose-response relationship. One difficulty in capturing a qualitative sense of that phenomenon is the considerable heterogeneity in how “high exposure” was characterized across studies. Several studies reported RRs on multiple exposure gradients (such as cumulative exposure, duration of exposure, and intensity of exposure). To handle the heterogeneity of reporting scales and metrics, we applied the following procedure to generate plot 2 for each selected cancer site: • Only studies that reported RRs over an exposure gradient were in- cluded on plot 2. • The RR and CI corresponding to the most extreme category of each reported gradient were abstracted. For example, if a study reported RRs across both probability of exposure and duration of exposure, RRs corre- sponding to those for whom exposure was most probable and to those with the longest exposure were both abstracted. • For studies reporting RRs across several metrics reflecting an expo- sure gradient, both the highest and lowest reported RRs were presented on plot 2. A pair of summary RRs and 95% CIs was computed, first by includ- ing the lowest RRs and then the highest RRs. We view the resulting sum- mary as being robust to variability in the metrics and scales used to report exposure gradients. Computational Conventions Used for Plot Summaries of Cohort Studies The RR for a cohort study is the ratio of observed to expected events (for example, observed deaths divided by expected deaths). Information needed to compute estimated RRs and 95% CIs was abstracted directly from the published papers. In many cases, an estimated RR and its CI were reported directly. In other cases, CIs were omitted and needed to be com- puted from available information; we used the following conventions: • In several studies, the authors supplied incomplete information (for example, RR and observed cases but not expected cases). Whenever two pieces of information were supplied, we calculated the third. • In many other studies, an RR was given but no CI. However, the CI could be readily obtained from observed and expected counts by using

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40 ASBESTOS Byar’s approximation, which has been shown by Breslow and Day (1987, page 69) to be very accurate. • In the uncommon situation in which the RR was given with only a p- value (without observed or expected cases and without a CI), we used the following procedures to recover the CI: —When only the point estimate and a p-value were given, the CI was computed by inverting the hypothesis test, as follows. Suppose p de- notes the p-value from a two-sided hypothesis test. Let Zp/2 denote the ordinate that cuts off probability p/2 in the right tail of a standard normal distribution. Then se[log(RR)] = log(RR)/Zp/2, and the associ- ated 95% CI for the RR can be computed by exponentiation of log(RR) ± 1.96*se[log(RR)]. —When an upper bound for a p-value was given (such as p < 0.05), we made the conservative assumption that the p-value was equal to its upper limit (such as p = 0.05) and computed the standard error (se) as above. (The true CI is narrower than the one derived here.) —When a lower bound for a p-value was given (such as p > 0.05), we plotted the RR but did not calculate a CI. • In some cases, RR was zero (the number of expected cases was posi- tive, but the number observed was zero). These cases were entered on the plot with an arrow indicating that the lower confidence bound is at nega- tive infinity; confidence limits were not calculated. These cases were in- cluded in the summary RR derived via Poisson regression. Summary Plots for Case-Control Studies Organization of Summary Plot Odds ratios (ORs) were abstracted from the case-control studies as the estimate of cancer risk. Given the relative rarity of the cancers under con- sideration, those estimates of risk may be considered equivalent to RRs (Koepsell and Weiss 2003, Rothman and Greenland 1998), and so a dis- tinction will not be made between ORs and RRs in the remainder of this report. Two sets of plots were constructed for each cancer site. Table 2.3 sum- marizes the organization of plots for the case-control studies at each cancer site. As with the cohort studies, for each of the plots described here, a 95% CI for the weighted average of the RRs is given below the individual study values. For plots with stratification, the aggregate RR and CI are included for each stratum. All the case-control studies that met the committee’s crite- ria for inclusion in the quantitative evidentiary database reported findings exclusively for cancer incidence. The first set of plots characterizes the effects of any exposure vs none.

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41 COMMITTEE’S APPROACH AND METHODS USED TABLE 2.3 Organization of Summary Plots for Case-Control Studies Informative for Cancer at Each Site Plot Type of RR Studies Included Stratification 1a Any vs none All 1b Any vs none All • EAM = 1 • EAM = 2 1c (larynx Any vs none EAM = 1 • Adjusted for alcohol use and pharynx and smoking only) • Not adjusted for alcohol use and smoking 2 Most extreme vs none Those reporting RR (If more than one on an exposure gradient reported, gradient (EAM = 1) aggregates calculated with smallest and with largest reported RRs) Plot 1a includes every study, without reference to study characteristics (ex- posure ascertainment method and confounder adjustment). Plot 1b is strati- fied by EAM, where “EAM = 1” indicates higher quality exposure assess- ment as described previously and “EAM = 2” indicates a lesser quality of exposure assessment. For studies of laryngeal and pharyngeal cancers, we included a third plot (1c) stratified on whether adjustment was made for smoking and alcohol consumption. For other sites, the small number of studies did not permit similar stratification. The second set of plots characterizes extreme exposure vs none with data from those studies that reported exposure effects on a gradient; we used the same approach applied to cohort studies. Computational Conventions Used for Plot Summaries of Case-Control Studies For each study population represented in the plots, its estimated RR and its 95% CI or standard error were abstracted as available from the manuscripts. In most cases, the estimated RR and its CI were obtained directly. In cases in which CIs were not presented in the articles, they were computed if possible from available information: • In the uncommon situation in which the RR was given with only a p-value, we used the procedures described for cohort studies to recover the CI.

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42 ASBESTOS • In the small number of cases in which the estimated RR was zero and no CI was given, we used the standard method of adding 0.5 to each cell in the two-by-two table of case status vs exposure status and calculated the CI by using formulas supplied by Agresti (2002). • A small number of studies reported an adjusted RR, but neither a p- value nor a CI. For those cases, we compared the crude RR (computed from information usually available in a table giving the total number of cases and the number of cases exposed to asbestos) with the adjusted RR. If the crude RR was within 1 standard error of the adjusted RR, we calculated and used the CI for the crude RR. Computation of Summary RRs For each plot (and within each stratum for stratified plots), an esti- mated aggregate or summary RR and its associated 95% CI are given. An outline of the calculation of those values for cohort and case-control studies follows. Cohort Studies In a cohort study, the number of observed events (such as observed deaths) can be assumed to follow a Poisson distribution with the mean equal to the expected number of events in the absence of an exposure effect (such as, expected number of deaths), inflated by the true RR (Armitage et al. 2002). This suggests the model: Yj ~ Poisson[Ej exp(θ)], where for study j, Yj denotes observed number of cases, Ej denotes expected number, and exp(θ) is the average RR across studies. To estimate θ and its confidence interval, we fit the Poisson regression: log µj = log Ej + θ to the observed event counts across studies, treating θ as an offset term. The standard error calculation took into account extra Poisson variation by using the estimated deviance. The resulting summary RR and its CI for each plot are given by: () ˆ ˆ exp θ ± 1.96se θ  .   Case-Control Studies The summary RR and CI for case-control studies was computed with the method of DerSimonian and Laird (1986). That approach assumes that

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43 COMMITTEE’S APPROACH AND METHODS USED the distribution of true log RRs across studies follows a normal distribution with mean θ and variance σ2. The average log RR is computed as a weighted average over studies, where the weights are inversely proportional to the standard error for each estimated log RR (therefore, larger studies contrib- ute more information). Let θj represent the estimated log RR reported from study j, and let sj denote its standard error. The logarithm of the summary RR is computed by using a weighted average: ˆ θ = ∑ Wj θ j ∑j Wj . j The weights are given by: 1 Wj = , s2 + σ 2 ˆ j where σ 2 is an estimator of the between-study variation in the true log RRs ˆ across studies. (The DerSimonian and Laird estimator uses a moment-based ˆ procedure to compute σ 2 .) The standard error of θ is: ˆ −1 2 (∑ W ) . j j Therefore, the lower and upper 95% confidence limits for the summary RR are given by:   ˆ 1.96  expθ ± . ∑j Wj     INTEGRATION OF DATA Previous evaluations of specific agents or exposures as contributing to an increased risk of cancer have been conducted by expert panels convened by national and international agencies. The expert panels review, evaluate, and integrate the scientific evidence based on three sources of information: epidemiologic studies of cancer in humans, studies of cancer in experimen- tal animals, and biologic mechanistic data. The present committee critically reviewed and summarized the strengths and weaknesses of the scientific evidence of those three types, guided by the newly revised principles and procedures described in the preamble to the IARC monographs (IARC 2006). Such guidelines for causal inference are not rigid criteria that can be implemented in a formulaic fashion, so the committee endeavored to achieve comparability across the cancer sites in the application of the criteria it had

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44 ASBESTOS adopted by following a uniform format for the critical, final sections of Chapters 7 through 11. The concluding section for each site documents the extent of the epidemiologic evidence from the comprehensive search that proved informative for that site, the consistency of that evidence, and the strength of association conveyed by it. The epidemiological evidence was integrated with the complementary evidence on dose, mechanisms, and toxicologic research. All conclusions were made in accord with the pre- specified classification for causal inference. Exposure Data and Epidemiologic Evidence The committee considered the geographic distribution, commercial ap- plications of asbestos fibers, and exposure data from occupational and en- vironmental sources. The quality of exposure data and the demonstration of dose-response relationships in human epidemiologic studies were major considerations in evaluating the studies. Other considerations used to assess quality included bias and confounding, as discussed above. In addition to case-control studies and cohort analyses, the committee considered a small number of human case reports that examined biomarkers of potential ad- verse effects of asbestos fibers and dose deposited at target organs that may be relevant for development of cancer at the sites under consideration. The strength of the epidemiologic evidence for a casual relationship between asbestos exposure and development of cancer at each site was distilled, as described above. Studies in Experimental Animals The committee reviewed all animal studies published in the peer- reviewed literature related to asbestos exposure and development of cancer at the sites under consideration. Those studies were evaluated qualitatively and quantitatively according to the criteria outlined in the preamble to the IARC monographs, as summarized in Table 2.4. Biologic Mechanistic Data The committee reviewed the current mechanistic hypotheses regarding asbestos-related diseases of the lung and pleura. From the information on pulmonary diseases, the following properties of asbestos fibers were consid- ered to be most relevant for pathogenicity: fiber length and diameter, sur- face reactivity, cytotoxicity, genotoxicity, and persistence at the target site, in that they might contribute to chronic inflammation and cell prolifera- tion. The evidence for fiber deposition, persistence, and induction of mor-

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45 COMMITTEE’S APPROACH AND METHODS USED TABLE 2.4 Evaluation of Animal Studies Qualitative considerations: 1. Adequacy of experimental design 2. Exposure information-route, dose, and duration 3. Animal survival, duration of follow-up, and description of pathologic lesions 4. Consistency of published results across species, sexes, and target organs Quantitative considerations: 1. Dose-response and time relationships 2. Statistical analysis SOURCE: IARC 2006. phologic, cellular, or molecular changes relevant to carcinogenicity at the sites under consideration was evaluated. The committee evaluated the overall strengths and weaknesses of the scientific evidence based on human epidemiologic studies, animal studies, and biologic mechanistic studies. It then integrated all this information be- fore reaching a conclusion regarding the strength of the evidence for a causal association between asbestos exposure and an increased risk of cancer at each site under consideration. Integration of this evidence—reflecting the consensus reached by the committee—is summarized at the end of each site- specific review. REFERENCES Agresti A. 2002. Categorical Data Analysis. 2nd edition. New York: Wiley. Andrews KW, Savitz DA. 1999. Accuracy of industry and occupation on death certificates of electric utility workers: Implications for epidemiologic studies of magnetic fields and cancer. Bioelectromagnetics 20(8): 512-518. Armitage P, Berry G, Matthews JNS. 2002. Statistical Methods in Medical Research. 4th edi- tion. Oxford, England: Blackwell Science. ATSDR (Agency for Toxic Substances and Disease Registry). 2001. Toxicological Profile for Asbestos. Atlanta, GA: US Department of Health and Human Services. Becklake MR. 1979. Environmental exposure to asbestos: A factor in the rising rate of cancer in the industrialized world? Chest 76(3): 245-247. Breslow NE, Day NE. 1987. Statistical methods in cancer research: The design and analysis of cohort studies. IARC Scientific Publications 82(2): 1-406. Britton M. 2002. The epidemiology of mesothelioma. Seminars in Oncology 29(1): 18-25. Browne K, Gee JB. 2000. Asbestos exposure and laryngeal cancer. Annals of Occupational Hygiene 44(4): 239-250. Chan CK, Gee JB. 1988. Asbestos exposure and laryngeal cancer: An analysis of the epidemio- logic evidence. Journal of Occupational Medicine 30(1): 23-27. D’Amico M, Agozzino E, Biagino A, Simonetti A, Marinelli P. 1999. Ill-defined and multiple causes on death certificates: A study of misclassification in mortality statistics. European Journal of Epidemiology 15(2): 141-148.

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