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Asbestos and Its Diseases$

John E. Craighead and Allen R. Gibbs

Print publication date: 2008

Print ISBN-13: 9780195178692

Published to Oxford Scholarship Online: September 2009

DOI: 10.1093/acprof:oso/9780195178692.001.0001

Nonthoracic Cancers Possibly Resulting from Asbestos Exposure

(p.230) 9 Nonthoracic Cancers Possibly Resulting from Asbestos Exposure
Asbestos and Its Diseases

John E. Craighead

Oxford University Press

Abstract and Keywords

In the 1970s and 1980s, studies of asbestos workers in both Europe and North America suggested on the basis of preliminary epidemiological evidence that cancer in several major organ systems, other than the lungs and pleura, might result from exposure to asbestos. However, many of these early investigations were poorly controlled and both socioeconomic and lifestyle information such as diet, tobacco use, and alcoholic beverage abuse were not available for consideration. During the past two decades, considerable new information has accumulated and the fear that asbestos causes multisystem malignant disease has quelled. This chapter summarizes the available information with respect to the organ systems most often implicated.

Keywords:   asbestos contamination, asbestos workers, nonthoracic cancers, diet, tobacco use, alcoholic beverage abuse


Studies of asbestos workers in the 1970s and 1980s in both Europe and North America suggested on the basis of preliminary epidemiological evidence that cancer in several major organ systems, other than the lungs and pleura, might result from exposure to asbestos. Unfortunately, many of these early investigations were poorly controlled and both socioeconomic and lifestyle information such as diet, tobacco use, and alcoholic beverage abuse were not available for consideration. Nonetheless, evidence gradually accumulated in the medical literature implicating asbestos as a carcinogen or cocarcinogen in many organ systems, even though the relative risks (RR) were usually of a low order. The demonstration of asbestos bodies (AB) and fibers in various tissues by pathologists further served to support the conclusion that asbestos exposure could result in systemic neoplastic disease (Auerbach et al., 1980; Huang et al., 1988; Kanazawa, 1970; Sebastien et al., 1980).

On the basis of these incomplete observations, concerns found their way into governmental regulations and medical review articles, too often in the form of realities, and then into litigation as the foundation for personal injury suits. A flurry of epidemiological and experimental studies followed in an effort to shed further light on the issues and to elucidate the possible pathobiological mechanisms involved. During the past two decades, considerable new information has accumulated and the fear that asbestos causes multisystem malignant disease has quelled. This chapter summarizes the available information with respect to the organ systems most often implicated.

In 1965, Sir Bradford Hill published a list of incisive questions that in his opinion medical scientists should address before considering whether or not an exposure to an extraneous substance in our environment has the capacity to cause a specific disease. Hill’s criteria are now widely accepted as a basis for determining cause and effect relationships. As the information considered in detail below illustrates, associations can occasionally be found in epidemiological studies, but the key question remains how and when can causation be established in an imperfect world when the seemingly obvious may not be the answer to the riddle. The demanding considerations of Hill summarized (p.231) and briefly discussed below are of paramount importance in evaluating the various cancers considered in this chapter.

  1. 1. Strength: The strength of an association can only be established on the basis of a statistical analysis of the results of appropriately designed and conducted epidemiological investigations. Hill emphasized that “no formal tests of significance can answer … questions.” Such tests can, and should, remind us of the effects that the play of chance can create and they will instruct us in the likely magnitude of the (hypothesized) effects. Beyond that, they, that is, statistical analyses, contribute nothing to the “proof” of (a) hypothesis.

  2. 2. Consistency: To paraphrase Hill, one must ask—has the observed association been repeatedly found by different scientists in various locations and populations, as well as under different circumstances and time frames?

  3. 3. Specificity: “If … an association is limited to specific workers and to particular sites and types of disease, and there is no association between the work and other modes of dying, then clearly that is a strong argument in favor of causation.” In more recent years, statisticians have turned to multivariate analyses to exclude confounding factors that commonly influence the health of members of a study group. For example, smoking, alcoholic beverage abuse, and familial patterns of disease inheritance.

  4. 4. Temporality: What is the temporal relationship of the hypothesized association? Which is the cart and which the horse? This question is particularly relevant with diseases of slow development. For example, does a particular diet lead to disease or do the early stages of the disease lead to peculiar dietary habits?

  5. 5. Biological Gradient: “if the association is one that reveals a … dose-response curve, then we should look … carefully for such evidence.”

  6. 6. Plausibility: This concept depends on the biological knowledge of the day. Hill advises caution before dismissing a concept of pathogenesis. It is too early to be shortsighted. The association we observe may be one new to science or medicine and we must not dismiss it too lightheartedly as just too odd. As Sherlock Holmes advised Dr Watson, “when you have eliminated the impossible, whatever remains, however improbable, must be the truth.”

  7. 7. Coherence: “A cause and effect interpretation of … data should not seriously conflict with the generally known facts of the natural history and biology of the disease.”

  8. 8. Experiment: “Occasionally it is possible to appeal to experimental, or semiexperimental, evidence. For example, because of an observed association some preventive action is taken. Does it in fact prevent? The dust in the workshop is reduced, lubricating oils are changed, persons stop smoking cigarettes. Is the frequency of the associated events affected? Here the strongest support for the causation hypotheses may be revealed.”

  9. 9. Analogy: “A search of the medical literature often yields surprising but obscure analogies relevant to our understanding of disease. Just as we must be cautious not to exclude evidence based on the questionable plausibility of a hypothesis, so we can learn much by identifying analogous and insightful biological occurrence of an unrelated nature.”

Oral and Nasopharyngeal Carcinoma

Perhaps no anatomical region where cancer commonly occurs is more difficult to define, and delineate structurally from adjacent topographical areas (Forastiere et al., 2001). For the purpose of categorization, disease is generally assigned a site of origin on the (p.232)

Table 9.1 Upper Respiratory and Digestive Tract Associated Cancers by Anatomical Site *

Rates/1 × 105 Person-Years










Pyriform sinus






(*) US National Cancer Institute: Surveillance, Epidemiology and End Results (SEER) data for 1975–1998.

basis of the International Classification of Causes of Disease, but the potential exists for errors. Thus, inaccuracies of classification, no doubt, often occur. For these reasons, epidemiological studies based on crude mortality data invariably are compromised by potential inaccuracies. More refined incidence estimations of cancer origin by anatomical site have been published in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) reports, summarized in Table 9.1.

Oral and nasopharyngeal cancers display dramatic geographic and regional differences in prevalence, and the incidence also relates to the patient’s sex. Worldwide, these diseases are often associated with tobacco and alcoholic beverage abuse (Craighead, 1995; Nam et al., 1992; Talamini et al., 1998) but geographic difference in incidence might be related in part to nutritional and dietary factors (McLaughlin et al., 1988). The role of viruses in the causation of malignant lesions in the oropharynx is also a subject of contemporary consideration. Papillomaviruses have now been implicated in the causation of some squamous carcinomas of the mouth, including the tongue, and nasopharyngeal carcinomas are strongly associated with Epstein-Barr virus infections in certain regions of the Orient (Craighead, 1999; Mork et al., 2001; Van Houten et al., 2001).

Selikoff et al. (1979) reported a RR of 2.1 for cancer of the oropharynx on a best estimate appraisal of disease in members of a large cohort of asbestos insulation workers. A study from South Africa (Botha et al., 1986) compared the incidence of cancer of the lips, oral cavity, and pharynx in males residing in a crocidolite mining region, with persons living elsewhere in that country. They found a Standardized Mortality Ratio (SMR) of 2.24 for white males, and 2.72 for “colored” males. In these studies no effort was made to address the issues of smoking and alcoholic beverage abuse. In contrast negative results were obtained in systematic epidemiological investigations by Mancuso and Coulter (1963), Puntoni et al. (1979), Blot et al. (1979), Enterline et al. (1987), and Cantor et al. (1986), unfortunately all mortality studies. Several other negative studies have not been cited here either because of the limited size of their study group, or the lack of anatomical detail regarding the original location of the lesions. Since many of the neoplasms in the oropharynx are localized and cured by treatment, morbidity data would prove more valuable for a critical evaluation of risk factors. Reports analyzing the incidence of nonfatal premalignant and malignant diseases in relation to asbestos exposure have not been published.

Laryngeal Carcinoma

Cancer of the larynx is a relatively uncommon disease comprising about 1% of human malignancies. It predominantly occurs in males in the later decades of life (Brownson (p.233) and Chang, 1987; Burch et al., 1981; Elwood et al., 1984; Herity et al., 1982; Luce et al., 1988; Muscat and Wynder, 1992; Rothman et al., 1980; Williams and Horm, 1977). Cancer of the larynx is usually of the squamous cell type and is readily diagnosed with a high degree of specificity by both the clinician and the pathologist. Early disease is readily amenable to treatment; thus, retrospective mortality studies using death certificate data are an unsuitable means of evaluating disease occurrence.

Numerous epidemiological studies and reviews in the literature have documented the strong association of laryngeal carcinoma with cigarette smoking (Tuyns et al., 1988). The disease also occurs in those who use cigars and pipes, but the incidence is substantially lower. The relative prevalence of the disease increases in relation to the intensity of cigarette use. Few cases have been reported in those who do not smoke. Alcoholic beverage abuse is a risk factor, but the association is relatively weak.

Is laryngeal carcinoma causatively associated with asbestos exposure? It should be emphasized at the outset that investigations designed to address this question are difficult to conduct because of the low incidence of the disease and the difficulty documenting exposure. Invariably, the confounding influences of cigarette and alcohol use must be considered. Rarely is adequate information available, yet changes in the cigarette consumption patterns of a study population could have dramatic effects on the occurrence of laryngeal carcinoma.

The possible association of laryngeal carcinoma with asbestos exposure has been examined in several case-control studies published in the last several decades. Investigations of this type are no better than the care with which they are designed and conducted. Retrospective inquiries are fraught with hazard since patients may be reluctant to implicate themselves for such known health abuses as smoking and alcohol use. Furthermore, recollections and documentation of asbestos exposure and particularly, the duration and intensity of such an exposure, is subject to question. This was pointed out in a paper by Stell and McGill (1973) when they stated: “it was often necessary to ask leading questions about exposure to asbestos.” In the studies reported, there is a consistent problem with regard to controlling for alcohol and cigarette abuse. This problem proved to be a deficiency in the publication authored by Shettigara and Morgan (1975). Hillerdal and Lindholm (1980) attempted to associate asbestos exposure with laryngeal carcinoma by considering radiologically detected pleural plaques in patient and control groups as a measure of exposure, ignoring the questions of cigarette and alcohol abuse. The diagnosis of pleural plaques by radiologic means is imprecise and, in certain regions of Scandinavia, where the study was carried out, pleural plaques often occur in the general population in the absence of occupational asbestos exposure (Chapter 6). In a paper by Burch et al. (1981), the following conclusion was reached: “the RR for males exposed to asbestos after the effects of cigarette smoking were controlled was 2.3, and the effect seemed restricted to cigarette smokers.” Findings in the literature implicating asbestos were based on small numbers of cases and controls and consequently were subject to large sampling errors.

In a paper by Rothman et al. (1980), it was concluded that “there seems to be little question that asbestos is a risk factor, probably a strong risk factor in most populations. … Lack of sufficient data and uncontrolled confounding effects of smoking, however, preclude any precise determination of increased risk attributable to asbestos.” These authors also state that “few of the occupational studies … cited here were able to control adequately for tobacco use, but it is evident from the figures … that small differences in tobacco use could account for substantial differences in risk.” Rothman’s survey of published reports is deficient in that it only cites a few case-control studies, but fails to note a number of published reports that do not support their conclusions (Blot et al., 1980; Brown et al., 1988; (p.234) Flanders et al., 1984; Hinds et al., 1979; Newhouse et al., 1980; Olsen and Sabroe, 1984; Parnes, 1990; Rubino et al., 1979; Thomas et al., 1982; Tsai et al., 1996; Zagraniski et al., 1986). Moreover, Rothman et al. (1980) recalculated his data in an attempt to overcome the problems of matching controls with patients by age and smoking background. This reduces the number of individuals included in the analysis substantially, and thus broadened the confidence limits. After considering the methodological problems confounding attempts to assess relationships between asbestos and laryngeal cancer, it is hardly surprising that RR estimates range from 1.4 to 13 in various studies.

In a case-control study by Hinds et al. (1979), it was noted that neither asbestos exposure nor exposure to other toxic substances were found to increase significant risk. The work was undertaken in the Puget Sound area of Washington, where an increased incidence of malignant mesothelioma (MM) had been noted among “blue collar” workers, presumably due to shipyard employment. It is noteworthy that this study tended to have more nonsmokers and light smokers in the control group than in the case group. This imbalance presumably would increase the likelihood that an asbestos effect would be demonstrated if synergism played a role. It was not! In a study of shipyard workers in coastal Virginia (Blot et al., 1980), “no overall excess of laryngeal cancer associated with shipbuilding was found.” In contrast, Puntoni et al. (1979) calculated an elevated RR (1.96) among Genoa, Italy shipyard workers. Newhouse et al. (1980) studied the etiology of carcinoma of the larynx in patients hospitalized in Great Britain. Those in the group with laryngeal carcinomas comprised a larger number of smokers than controls, yet no association was found between asbestos exposure and the occurrence of the disease.

Two cohort investigations have been carried out in an effort to compare the prevalence of laryngeal carcinoma in asbestos workers with members of the general population. These studies are deficient inasmuch as the prevalence of cigarette and alcohol abuse in the control and the exposed populations of workers cannot be assessed and compared accurately. Indeed, it is likely that the use of tobacco products would be greater in the workers than in a control population drawn from all strata of society. A study by McDonald et al. (1980) in Québec, Canada, which included almost 1.1 × 104 men working in the asbestos industry, failed to demonstrate an excess of deaths due to laryngeal cancer.

Analyses by pathologists have demonstrated asbestos fibers and AB in a wide variety of organs in the absence of disease (Auerbach et al., 1980). It is not surprising, therefore, that studies in which laryngeal tissue is digested in lye and examined microscopically have yielded a few AB. When AB were found, “no dysplastic epithelial changes were present in the mucosa.” (Roggli et al., 1980). In a study by Hirsh et al. (1979), asbestos fibers in small numbers were found by electron microscopy in the laryngeal tissue of two men believed to have asbestosis and pleural plaques. Both were smokers. One had a laryngeal polyp and the second, laryngeal carcinoma. This work was not controlled by carrying out parallel analyses on tissue from those without laryngeal diseases. This study, then, provides no definitive information.

A review by Chan and Gee (1988) states that “Available epidemiological evidence does not support a causal association between asbestos and laryngeal cancer.” Another review article by Edelman (1989) concludes that “based on data from 13 cohort and 8 case-control studies … neither case-control nor cohort studies have established an increased risk of laryngeal cancer for asbestos workers.” And, an editorial by Liddell (1990) concludes: “thus, it is my opinion that the evidence of a link between exposure to asbestos and laryngeal carcinoma definitely fails to satisfy the criteria for causation set by Bradford Hill.”

A meta-analysis by Goodman et al. (1999) yielded an overall SMR of 157 (95% confidence limits 95–245) but failed to demonstrate an apparent dosage effect. This study (p.235) displayed a number of inconsistencies not the least of which was an inability to control for smoking. A meta-analysis by Smith et al. (1990) documented modest elevations in SMR in four of seven cohorts, but broad confidence limits for the data shed doubt on the validity of conclusions.

In summary, tobacco smoking is clearly the only established risk factor in the pathogenesis of laryngeal carcinoma. Accordingly, it is not surprising that populations of so-called “blue collar” workers experience more laryngeal carcinoma than members of the general public inasmuch as tobacco abuse occurs more commonly in this category of worker. On the basis of their occupational activities, these individuals would be expected to allege an exposure to asbestos more frequently than members of the general population. However, they also report a higher prevalence of exposure to other foreign materials in the workplace, including nonasbestos dusts and toxic chemicals. For example, in one report, the following substances were listed as suspect etiological agents: mustard gas, nickel, soot, tars and minerals, pesticides, naphthalene, leather, wood dust, and ball bearings. With the possible exception of tars and soot, these materials are not recognized risk factors for laryngeal cancer. The currently published data fails to provide a compelling basis for concluding that asbestos exposure is a risk factor for laryngeal carcinoma. It is not surprising that AB and fibers in small numbers have been demonstrated in laryngeal tissue of some patients, given the role of the larynx as a portal to the respiratory tract. Clearly, the presence of AB in this tissue does not serve as a basis for implicating asbestos in the etiology of laryngeal cancer.

Esophageal Cancer

In the general population, the lifetime risk of esophageal cancer is 0.8% for men and 0.3% for women. Cancer develops throughout the extent of the esophagus from the oral pharynx to the cardia of the stomach (Ries et al., 2002), but the morphological types and the pathogenic features differ by anatomical region. Squamous carcinoma customarily occurs in the proximal and middle esophagus; it has a strong association with tobacco and alcohol abuse (Gao et al., 1994; Yu et al., 1988). In contrast, most neoplasms in the lower esophagus are adenocarcinomas. In this segment, particularly in the distal esophagus and the adjacent cardia of the stomach, the lesions often develop in the wake of Barrett’s esophagitis, often accompanied by hiatus hernia and gastric regurgitation, the so-called gastroesophageal reflux disorder (GERD; Chow et al., 1995; Garewal and Sampliner, 1989; Spechler and Goyal, 1986). In this condition, there is an association with dietary indiscretions and smoking (Wu et al., 2001). The adenocarcinomas arise in the glandular epithelium of the distal esophagus usually developing after a protracted history of GERD and chronic esophagitis (Brown et al., 1994; Chow et al., 1995; Gammon et al., 1997; Jankowski et al., 1999; Lagergren et al., 1999). Currently, for unknown reasons, adenocarcinomas of the distal esophagus are increasingly prevalent in middle-aged men and women, more so in Whites than in African Americans (Blot, 1994; Enzinger and Mayer, 2003).

Extensive epidemiological studies have been carried out on workers in a number of different industries where asbestos exposure has occurred in an effort to determine whether or not asbestos contributes to carcinoma development in the esophagus (Puntoni et al., 1979; Rubino et al., 1979). Some early studies provided positive suggestive results, but these investigations, unfortunately, were not well controlled (Newhouse et al., 1985). In addition, dietary, smoking, and alcohol histories were not obtained. For example, Selikoff cited a RR of 2.5 based on both the investigator’s evaluation of the clinical evidence and (p.236) death certificate data from a 1.78 × 104 cohort of insulation workers (Selikoff et al., 1979). But, these observations are of limited value and do not provide definitive evidence. When more carefully designed epidemiologic investigations were carried out, no increase in prevalence of esophageal tumors was found among occupationally exposed workers (Enterline et al., 1987; Zoloth and Michaels, 1985). Thus, the evidence thus far, including a recent meta-analysis by Goodman et al. (1999), fails to demonstrate an epidemiological association between exposure and the development of esophageal cancer.

Studies have also been carried out in several sites in the United States in an effort to determine whether or not an increased concentration of asbestos in potable water results in the development of cancer of the digestive tract (Marsh, 1983; Sigurdson et al., 1981). These investigations have failed to demonstrate an increased prevalence of esophageal cancer in persons residing in areas where water concentrations of chrysotile and amphibole asbestos are believed to be excessively high, in comparison to North American overall.

Numerous experimental studies have been conducted in an attempt to demonstrate the development of cancers of the digestive tract in animals fed massive amounts of asbestos in their food during the course of their lifetime (Condie, 1983). Postmortem examinations have failed to demonstrate the occurrence of digestive tract cancers that can be attributed to asbestos.

Gastric Carcinoma

A considerable body of information has accumulated on the natural history of gastric carcinomas worldwide, particularly since these cancers were a significant cause of mortality among men in generations past (Graham 1975; Haenszel and Correa, 1975). In more recent years, the number of new cases of gastric carcinoma in developed countries has decreased substantially; in the United States; the incidence has declined by about 75% since 1930.

Epidemiological studies provide insights into the factors that may influence the development of these cancers but the etiology is uncertain in most cases. There are a number of possible etiologies to consider. First, gastric carcinoma is not one disease but several different morphologic and biological entities occurring in different anatomic regions of the stomach. Accordingly, the occurrence of these various cancers may be influenced by different environmental and heritable influences. For example, atrophic gastritis and the associated adenocarcinoma occur in persons with pernicious anemia, whereas nutritional factors may play an etiological role in cancer developing in various localized regions of the world. In some foreign populations, overcooked food and smoked meat products have been associated with an increased prevalence of gastric carcinomas and in some instances, chemicals have been implicated, but proof of a causative relationship is lacking. Of particular note is the unusually high prevalence of gastric carcinoma in Japan, China, Chile, Costa Rica, Iceland, and Finland. In these countries, the disease is two to three times more common than in North America and Western Europe.

It is noteworthy that both in developed and developing countries, the male:female ratios are comparable and there is no consistent gradient in risk between urban and rural populations. The disease process seems to occur more frequently in persons of lower socioeconomic classes and “blue collar” workers (Englund, 1981; Wu-Williams et al., 1990). Nonasbestos miners, fishermen, and agriculture workers have an unusually high prevalence in a few studies. Genetic factors most probably contribute to the development of at least some gastric cancers (Lindor et al., 2005).

(p.237) In recent years, Helicobacter pylori, infection of the gastric mucosa, has been associated with the development of ulcerative disease and cancer in the upper digestive tract of humans. The mechanism(s) accounting for the carcinogenesis of H pyloris in the stomach remains to be determined (Blaser, 1999; Nogueira et al., 2001).

Studies by Selikoff and his associates (1964, 1968, 1979; Doll and Peto, 1987) suggested that insulation workers were at increased risk for developing gastric carcinoma. Unfortunately, this work was not carefully controlled for dietary factors (Weisburger and Raineri, 1975), alcoholic beverage consumption (Gammon et al., 1997; Hoey et al., 1981), and tobacco use (Zhang et al., 1997). A few additional studies (Enterline et al., 1987; Kang et al., 1997) tended to yield data consistent with the conclusion of Selikoff, but more recent investigations have consistently failed to demonstrate an epidemiological relationship between gastric carcinoma and exposure to asbestos. Further, a dose-response relationship has not been demonstrated. A review of 45 published studies by Morgan et al. (1985) and an additional literature review by Edelman (1988) failed to demonstrate an association of gastric carcinomas with asbestos exposure. The work of Hodgson and Jones (1986) documented mortality of more than 3.1 × 104 male asbestos workers in the United Kingdom. No excess of digestive tract cancer was found in this investigation. An unpublished evaluation by Weiss of 17 cohort studies (Tables 9.2 and 9.3) and a recent meta-analysis by Goodman et al. (1999) also failed to demonstrate an association. Assorted additional studies of diverse occupational groups support this conclusion (Acheson et al., 1984; Berry and Newhouse, 1983; Clemmesen and Hjalgrim-Jensen, 1981; Coggon et al., 1990; Gardner et al., 1986; Hughes et al., 1987; McDonald et al., 1984; Ohlson et al., 1984; Peto et al., 1985; Puntoni et al., 1979; Rubino et al., 1979; Sanden and Jarvholm, 1987; Seidman et al., 1986).

Different approaches to this question have been explored. More specifically, epidemiological studies have been carried out to determine whether the asbestos content of potable water in various communities is associated with an increased prevalence with gastric carcinoma. These investigations have not demonstrated an increase in prevalence

Table 9.2 Gastric Cancer Risk in Cohorts of Asbestos Workers

Gastric Cancer

Ref. No.


No. in Cohort

Type of Work

Obs. No.

Exp. No.



Clemmesen and Hjalgrim-Jensen/1981


Asbestos cement factory





Acheson et al./1984


Amosite factory





Ohlson et al./1984


Railroad maintenance





Peto et al./1985


Textile factory





Hilt et al./1985


Chemical plant





Seidman et al./1986


Amosite factory





Gardner et al./1986


Chrysotile asbestos-cement factory





Hughes et al./1987


Asbestos-cement factory









(*) p < .05.


Table 9.3 Gastric Cancer Risk in Cross-sectional Cohorts of Asbestos Workers *

Gastric Cancer



No. in Cohort

Type of Work

Obs. No.

Exp. No.



Mancuso and Coulter/1963







Selikoff et al./1979




New York/

New Jersey










Puntoni et al./1979








et al./1980












Hodgson and



All workers in

England and Wales






et al./1987



production and maintenance






and Jarvholm/1987











(*) Unpublished summaries kindly provided by William Weiss, MD.

() p <.05.

() Number obtained from RD Jones, personal communication, October 13, 1986; representing all workers first employed before 1969.

of gastric cancer in communities where the asbestos content of the water is exceedingly high (Marsh, 1983). Experimental investigations have been carried out in several animal species to determine whether or not cancer can be induced in the digestive tract by the feeding of enormous amounts of asbestos. These studies have also proved to be negative (Condie, 1983), or lacked consistent results (Kogan et al., 1987).

In summary, the medical literature documents a number of factors that seem to influence the occurrences of gastric carcinoma. Overall, the observations reported in epidemiological studies are inconsistent with the notion that asbestos contributes to the development of this disease process. And, experimental studies have proven negative.

Colorectal Carcinoma

Colorectal cancer is the second most common malignancy of older men, and the fourth among women of advancing age. Because of its frequent occurrence, the subject of its causation has been the basis for considerable research during the last several decades. Epidemiological studies demonstrate a strong association of colorectal cancer with dietary influences, particularly, the consumption of large amounts of animal fat and red meat, and a relatively fiber-free diet (Ghadirian et al., 1997; La Vecchia et al., 1988; Slattery et al., 1988; Willett et al., 1990). Some investigations have also found a possible association with smoking and alcoholic beverage consumption (Giovannucci et al., 1994a,b; Hilt et al., 1985; Lieberman et al., 2003; Newcomb et al., 1995; Nyrén et al., 1996; Wu and Henderson, 1995). Individuals with colorectal cancer commonly have a strong family history of this (p.239) disease, and recent studies have documented an autosomal dominant mode of inheritance of a predisposition to colorectal cancer, particularly disease occurring at a relatively young age (Bonelli et al., 1988; Fuchs et al., 1994; Sondergaard et al., 1991). In addition, there are several uncommon, but increasingly well-defined genetic syndromes that predispose one to cancer. Among those that claim an African heritage, there is a 50% greater likelihood of developing colorectal cancer than among Caucasians (Haggitt and Reid, 1986). From these clinical and epidemiological observations, one can conclude that the etiology of colorectal cancer is multifactorial, although the precise mode by which these influences may interact, remains to be defined (Burt et al., 1985; Young and Wolf, 1988).

Detailed studies of the molecular biology and cytogenetics of colorectal cancer indicate that the tumor cells acquire a series of mutational and chromosomal changes that influence the development of the disease. This is reflected in the loss of certain genes and the overexpression of others, ultimately resulting in neoplastic change. It appears that in some cancers, there may be a cumulative influence of several different genetic factors in the development of the tumor.

Can asbestos influence the development of colorectal cancer either as a causative or as a contributory factor? As discussed below, the experimental and epidemiological evidence strongly argues against such a thesis.

From an epidemiological perspective, more than 25 different evaluations of occupationally exposed populations have been carried out to explore this question. These studies have been analyzed in reviews (Demers et al., 1994; Edelman, 1988; Garabrant et al., 1992; Morgan et al., 1985; Weiss, 1995). The latter report evaluates both cohort and case-control studies and considers the estimated intensity of exposure in the analysis. A dosage gradient was not found (Table 9.4).

A meta-analysis by Frumkin and Berlin (1988) suggested that there existed an association of carcinoma of the colorectal tissue with asbestos exposure, but this analysis, in our view, was imperfect because it was based on the notion that the prevalence of lung cancer in a study population is a surrogate for exposure. Rather, the analysis of Frumkin and Berlin can be interpreted to argue for an association of cancer of the colon and rectum with cigarette smoking, a possibility that has not been established, as of yet.

A meta-analysis by Homa et al. (1994) suggested that “exposure to amphibole asbestos may be associated with colorectal cancer, but the findings may reflect an artifact …” An additional recent meta-analysis by Goodman et al. (1999) in which 69 individual cohorts were evaluated, yielded an SMR of 89, a finding that is compellingly negative.

In a death certificate survey conducted in more than half of the United States, Kang et al. (1997) found a small but significant elevation in the proportional mortality ratio among mechanical, electrical, and electronic engineers, but not in occupations where heavy exposures to asbestos might be expected to occur, such as among insulation workers and plumbers.

Table 9.4 SMR for Lung and Colorectal Cancer by Estimated Exposure Intensity *





Lung carcinoma





95% CL




Colorectal carcinoma









(*) Adapted from Demers et al. (1994).

(p.240) Epidemiological studies have also been conducted to evaluate the association of carcinoma of colorectal tissue with environmental exposure to asbestos in potable water supplies. The US Environmental Protection Agency (EPA) has shown that most Americans are exposed to particulates of asbestos in the water, but almost invariably; these particulates are short (<5 µm) fibers of chrysotile. However, in a study conducted among residents of Duluth, Minnesota that derives its potable water from Lake Superior where the concentrations of amphibole asbestos in the water ranged from 1 to 30 million fibers/L, there was no increase in the occurrence of gastrointestinal neoplasms (Sigurdson et al., 1981). In the six communities studied intensively, the prevalence of colorectal carcinoma was not increased in proportion to the relative amounts of asbestos in the drinking water (Kanarek et al., 1980; Levy et al., 1976; Marsh, 1983). This enormous body of data fails to provide compelling evidence that asbestos in drinking water is a contributory factor in the development of cancer of the colon and rectum.

Debate on this issue continues. Studies by de la Provôte et al. (2002) recently suggested a link of asbestos with lower gastrointestinal tumors, and a paper by Jakobsson et al. (1994) records data indicating that right colon malignant lesions are associated with exposure to asbestos-cement dust, but again, the increase in the risk of disease proved to be minimal.

Attempts to identify occupational groups at high risk for colorectal cancer have been carried out by Berg and Howell (1975) and Spiegelman and Wegman (1985). An association of the neoplasm with specific high-risk groups was not found.

Ingested asbestos transmigrates through the colonic mucosa and is transported through the body by lymphatics in rats administered massive doses of chrysotile and amosite asbestos per os (Westlake et al., 1965). In the studies conducted by Sebastien et al. (1980), fibers were detected at relatively high concentrations in the thoracic duct lymph of experimental animals for 16 hours after ingestion of asbestos. Most fibers were short (ie, <5 µm), although a few of the crocidolite fibers recovered were relatively long, and one measured 41 µm in length! Bolton et al. (1982) were unable to reproduce these findings. However, experimental work in animals has shown that the feeding of asbestos to animals does not contribute to the development of cancer in the lower digestive tract (Condie, 1983; Cunningham et al., 1977; Donham et al., 1980; McConnell et al., 1983a,b; Truhaut and Chouroulinkov, 1989). These observations further argue against the notion that occupational exposure to asbestos contributes to the development of colorectal cancer.

AB and fibers have been found in digests of the colonic tissue of asbestos workers who had carcinoma of the colon, but not in the tissues of unexposed persons with the same tumor (Ehrlich et al., 1985, 1991). No information was provided documenting the presence or absence of AB and asbestos fibers in colorectal tissues of asbestos workers without cancer. In some of the positive cases reported by Ehrlich et al. (1985, 1991), large numbers of short fibers (ie, <5 µm) of chrysotile were found in the colonic tissue. Unfortunately, the report did not provide sufficient information to allow one to rule out contamination of the specimen during collection or processing, an ever-present concern.

Using light microscopy, Rosen et al. (1974), failed to find “typical” AB in digests of the colon of 19 patients with carcinoma of the colon. They reported the presence of small numbers of “atypical” bodies and some ferruginous bodies in some of these cases. In a study of this type the investigator is obliged to carefully discriminate between “true” AB and artifacts.

Recently, Dodson et al. (2000) documented the presence of asbestos fibers in mesenteric and omental tissues of noncancer patients. Again, the ever-present potential problems of contamination of the specimens was not excluded. The mechanisms of transport of asbestos to these tissues is unclear and has not been investigated experimentally.

(p.241) Pancreatic Carcinoma

Roughly 3% of cancers in the United States develop in nonendocrine pancreatic tissue. Because of the organ’s subtle location in the retroperitoneal space, and the tendency for this cancer to become symptomatic only after it has become inoperable, the mortality rate is high. The disease almost invariably is an adenocarcinoma that tends to occur in the fifth and sixth decades of life and affects males more often than females. Attempts to establish an etiology based on epidemiological studies have failed, although cigarette smoking is a possible causative or contributory factor. The risk tends to increase in relationship to tobacco consumption, and appears to be reduced after cessation. But the evidence is by no means compelling. Selikoff and his associates (1980) found no increase in risk among heavy smokers who were asbestos factory workers and insulators. Chemicals of several different formulations induce pancreatic carcinoma in laboratory animals, but asbestos has not been shown to be carcinogenic experimentally.

On the basis of the study of Selikoff and Seidman (1981) and a subsequent national survey of disease in insulators, the question arose, does asbestos have a causative or contributory role in pancreatic cancer? Surveys of workers in refineries and petrochemical plants (Tsai et al., 1996), textile factory (Brown et al., 1994; Dement, 1994), railroad shops (Ohlson et al., 1984), an insulation factory (Acheson et al., 1984) and shipyards (Puntoni et al., 1979) have failed to demonstrate an association (Table 9.5). And, a recent meta-analysis by Goodman et al. (1999) came to a similar conclusion. In the absence of compelling epidemiological evidence, one is obliged to conclude that asbestos is not a risk factor for pancreatic carcinoma.

Renal Cell Carcinoma

The etiology and pathogenesis of the commonly occurring renal cell carcinoma of the kidney is obscure, but exposure to cigarette smoke, drugs such as Phenacetin, petrochemical effluents, and heavy metals, including lead and calcium, have been implicated as possible causes (Brownson, 1988; McLaughlin et al., 1984).

In 1979, Selikoff and his associates noted an apparent increase in the prevalence of renal cell carcinoma among North American insulation workers. Studies by Enterline (1987), Puntoni and coworkers (1979), and Maclure (1987) demonstrated a similar increase in risk for asbestos workers. Unfortunately, the Enterline (1987) and Puntoni et al. (1979) investigations failed to consider the prevalence of tobacco use. In addition, the tumors of the renal parenchyma (renal cell carcinoma) were not differentiated in the analysis from transitional cell carcinomas that develop in the renal pelvis. Both of these

Table 9.5 Results of Epidemiological Studies Examining the Possible Association of Asbestos Exposure with Pancreatic Carcinoma



Selikoff et al. (1980)


Acheson et al. (1984)


Putino et al. (1979)


Ohlson et al. (1984)


Dement et al. (1994)


Tsai et al. (1996)


(p.242) malignant lesions are epidemiologically associated with cigarette smoking, and a dosage effect has been documented for the cancers of the urinary drainage system (Hartge et al., 1987; La Vecchia et al., 1990). Thus, the variables of asbestos exposure and tobacco use, accompanied by inattention to considerations of tumor type and latency period, have compromised analyses.

Evaluations of renal parenchymal tissue from nonoccupationally exposed persons at autopsy (Huang et al., 1988) have yielded asbestos fibers and a microscopical survey (Auerbach et al., 1980) documented AB in histologic sections. Rats administered asbestos by lavage similarly had demonstrable asbestos in the renal parenchyma (Patel-Mandlik and Millette, 1983). In a single obscure publication by Gibel et al., 1976, several rats fed high concentrations of chrysotile asbestos developed neoplasms believed to be renal cell carcinomas. The results of this work have not been reproduced.

Cook and Olsen (1979) detected asbestos fibers in the urine of Duluth, MN residents drinking unfiltered Lake Superior water that contained low concentrations of amphibole asbestos fibers. The particles in the drinking water and urine were exceedingly short, that is, mean fiber length and breadth were 0.96 and 0.17 µm. Guillemin et al. (1989) evaluated the urine of employees of an asbestos-cement factory. The mean concentration of chrysotile in the urine of the asbestos-exposed workers was twofold greater than in control subjects, but the number of crocidolite particles in the urine of the controls was greater than in those exposed in the cement factory. Again, the fibers were exceedingly short and of no probable pathogenic importance (Mean geometric length/breadth of chrysotile: 0.47/0.068 µm, and crocidolite: 0.68/0.1 µm). Because of the inevitable problems resulting from extraneous contamination in the laboratory, these results must be evaluated with critical skepticism.

In a case-controlled study of 147 cases of renal cell carcinoma, exposure to asbestos was found to be associated with a RR of 1.62 (95% confidence index (CI) = 1.3–16.6) (McCredie and Stewart, 1993). A link with employment in dry cleaning, the iron and steel industry, and possibly petroleum refinery employment was also found in this study. In a similar investigation of more than 700 male cases of renal cell carcinoma in New Zealand stratified by age and smoking background, an association with asbestos exposure was not detected, although painters, glass workers, and firefighters were claimed to be at increased risk (Delahunt et al., 1995). An association with asbestos exposure was not demonstrated in an evaluation of 26 renal cancer deaths occurring in a Texas chemical plant (Bond, 1985). Work by Auperin et al. (1994) yielded a similar conclusion, and a recent comprehensive meta-analysis by Goodman et al. (1999) failed to demonstrate an association of renal cancer with asbestos exposure. It is important to note that in many of the negative studies, there was a paucity of workers whose trades might have been expected to result in heavy exposure to asbestos.

Although a low order of association of asbestos with renal cell carcinoma has been suggested by some investigators, the bulk of the evidence argues against a causative role for asbestos in kidney cancer. It should be recognized, however, that the difficulties one encounters in conducting a definitive study are imposing, considering all the potentially confounding variables. In the writer’s view, the finding of minute fibers of asbestos in kidney tissue and urine is of doubtful significance with regard to cancer causation, although it vividly shows that asbestos is distributed widely in the tissues of those who are exposed to industrial aerosols (if not all of us).

Lymphoid Malignancies

Non-Hodgkin’s lymphoma, chronic lymphogenous leukemia, and multiple myeloma have as their common denominator an origin in elements of the lymphoid and hematopoietic (p.243) systems. In general, these are diseases of advancing age. This is a heterogeneous family of sporadically occurring malignancies with a nomenclature that is in a state of flux as the various morphologic types are characterized by molecular approaches and immunocytochemistry (Harris et al., 2000). To a large extent, the etiology is unknown, although experimental and some epidemiological evidence implicate viruses, chemicals, and irradiation (Craighead, 2000; Pearce and Bethwaite, 1992). For reasons that are unclear, the overall incidence of these neoplasms in the general population is increasing (Weisenburger, 1994).

Over the past several decades, case reports and surveys of various occupational groups have documented the occurrence of malignant disease of the lymphoid system in patients with the stigmata of an asbestos-associated disease and among those who claim environmental exposure to asbestos (Table 9.6). Non-Hodgkin’s lymphoma of the pleura and lung parenchyma, and immunoblastic lymphadenopathy in the thorax also have been reported in patients with an occupational history of asbestos exposure (Gerber 1970; Maguire et al., 1981; Parisio et al., 1999). And, cases of lymphoblastic leukemia, lymphoma, and

Table 9.6 Literature Review of Malignant Diseases of Lymphoplasmocytic Cells Associated with Asbestos Exposure

Non-Hodgkin’s lymphoma



Dworsky et al.


Elmes and Simpson


Efremidis et al.




Kagan and Jacobson


Kang et al.




Mancuso and El-Attar




Olsson and Brandt


Waxweiler and Robinson


Chronic lymphocytic leukaemia

Bianchi et al.


Epremidis et al.


Kagan and Jacobson




Spanedda et al.


Multiple myeloma





Kagan and Jacobson




Linet et al.


Morris et al.


Spanedda et al.


Schwartz et al.


(p.244) plasmacytoma have been described in a coincidental association with MM presumably caused by asbestos (Efremidis et al., 1985; Perry et al., 1978; Takabe et al., 1997). Many of the reports summarize a cumulated series of cases (Table 9.6; Kagan and Jacobson, 1983; Kagan, 1988). However, in a national survey of more than 1.7 × 104 insulators, Selikoff et al. (1979) found no increase in the incidence of lymphoma or leukemia.

Two case-controlled studies have been carried out. In the report by Schwartz et al. (1988), 4.3 × 102 patients with chronic lymphatic leukemia and almost 7 × 102 with multiple myeloma were studied using controls from the patients’ community. Asbestos exposure was assessed on the basis of the job category of the patient, but a critical individual evaluation of exposure was not done. An estimate of the severity of exposure for the patients with lymphoma and leukemia was made, but even when the exposure to asbestos was thought to be heaviest, the RR was only 1.4 with 95% (CI = 0.8–2.3). An association with asbestos exposure was not found for patients with multiple myeloma. A second case-control study was reported by Ross et al. (1982). Patients with large cell lymphomas of the digestive tract were evaluated using a limited number of control subjects and a pair analytical approach. As with the study of Schwartz et al. (1988), the likelihood of asbestos exposure was estimated on the basis of occupation, inasmuch as little objective information was available. In this investigation, the RR proved to be 12, a highly significant result! Unfortunately, additional epidemiological investigations using contemporary approaches and a more critical appraisal of asbestos exposure were not carried out; thus, these intriguing findings have not been confirmed.

A panoply of reports (de Shazo et al., 1983; Dubois et al., 1989; Dworsky et al., 1982; Garcia et al., 1989; Gaurmer et al., 1981; Hartmann et al., 1984; Kagan et al., 1977; Kouzan et al., 1985; Lange et al., 1978; Miller and Kagan, 1981; Rom and Travis, 1992; Warheit et al., 1985; Wilson et al., 1977) argue that chronic stimulation of the immune system by asbestos might result in malignancy. However, concrete support for this thesis, based on experimental or clinical observations, is lacking. And, no compelling mechanistic explanation for malignant transformation of lymphoid elements (that incorporates these diverse experimental observations) has been proposed. Since lymphomas, chronic lymphogenous leukemia, and multiple myeloma occur commonly in the elderly, and overall comprise about 2% of malignancies in this age group, one would anticipate that an inquisitive physician could elicit a history of an actual or alleged asbestos exposure in a sizable proportion of those so affected. Thus, critical skepticism of claims of a disease association is warranted at this time.


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