5
CANCER AND EXPOSURE TO INSECTICIDES

Unlike the following health outcome chapters that discuss health effects of insecticides and solvents in the same chapter, the cancer outcomes have been divided into two chapters. Chapter 5 focuses on the studies that examined cancer outcomes related to insecticide exposure, and Chapter 6 focuses on cancer outcomes related to solvent exposure. The issues encountered by the committee during its review of the relevant literature and the criteria it established in drawing conclusions about associations are discussed in the introduction of each chapter. Each chapter also presents a brief overview of the pertinent toxicologic information and findings from other organizations charged with evaluating the carcinogenicity of insecticides or solvents.

A general introduction to cancer and to cancer epidemiology that applies to both the insecticide and solvent literature is provided here. Furthermore, for each cancer type reviewed by the committee, an overview of the cancer, its risk factors, and 5-year survival rates, as identified by the National Cancer Institute (NCI) and the American Cancer Society (ACS), are presented in this chapter as background information.

The order of specific cancer sites reviewed by the committee in Chapters 5 and 6 is based on the ninth revision of the International Classification of Disease (ICD-9)1 coding system.

CANCER OVERVIEW

Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Men in the United States have slightly less than a 50% lifetime risk of developing cancer, and women slightly more than a 33% lifetime risk (ACS, 2002a).

Cancer is characterized by the uncontrolled growth and spread of abnormal cells and can be caused by either external factors (chemicals, radiation, and viruses) or by internal factors (hormones, immune conditions, and inherited mutations) or both. Causal factors may act together or in sequence to initiate or promote the growth of abnormal cells. For adult

1  

ICD codes are revised and updated by the World Health Organization. Although ICD-10 codes have been published, ICD-9 codes remain the most widely recognized and used. ICD codes were established by the World Health Organization to promote international comparability in the collection, processing, classification, and presentation of mortality statistics. The codes group cancers according to their organ or tissue of origin and their histologic features.



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Gulf War and Health: Insecticides and Solvents, Volume 2 5 CANCER AND EXPOSURE TO INSECTICIDES Unlike the following health outcome chapters that discuss health effects of insecticides and solvents in the same chapter, the cancer outcomes have been divided into two chapters. Chapter 5 focuses on the studies that examined cancer outcomes related to insecticide exposure, and Chapter 6 focuses on cancer outcomes related to solvent exposure. The issues encountered by the committee during its review of the relevant literature and the criteria it established in drawing conclusions about associations are discussed in the introduction of each chapter. Each chapter also presents a brief overview of the pertinent toxicologic information and findings from other organizations charged with evaluating the carcinogenicity of insecticides or solvents. A general introduction to cancer and to cancer epidemiology that applies to both the insecticide and solvent literature is provided here. Furthermore, for each cancer type reviewed by the committee, an overview of the cancer, its risk factors, and 5-year survival rates, as identified by the National Cancer Institute (NCI) and the American Cancer Society (ACS), are presented in this chapter as background information. The order of specific cancer sites reviewed by the committee in Chapters 5 and 6 is based on the ninth revision of the International Classification of Disease (ICD-9)1 coding system. CANCER OVERVIEW Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Men in the United States have slightly less than a 50% lifetime risk of developing cancer, and women slightly more than a 33% lifetime risk (ACS, 2002a). Cancer is characterized by the uncontrolled growth and spread of abnormal cells and can be caused by either external factors (chemicals, radiation, and viruses) or by internal factors (hormones, immune conditions, and inherited mutations) or both. Causal factors may act together or in sequence to initiate or promote the growth of abnormal cells. For adult 1   ICD codes are revised and updated by the World Health Organization. Although ICD-10 codes have been published, ICD-9 codes remain the most widely recognized and used. ICD codes were established by the World Health Organization to promote international comparability in the collection, processing, classification, and presentation of mortality statistics. The codes group cancers according to their organ or tissue of origin and their histologic features.

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Gulf War and Health: Insecticides and Solvents, Volume 2 cancers, a latency period of 10 years or more may elapse between exposure and the detection of cancer (ACS, 2002a). Lifestyle factors and environmental or occupational exposures—including smoking, diet, infectious diseases, and exposures to chemicals and radiation—are associated with an estimated three-fourths of all cancer deaths in the United States. On a population level, tobacco use, unhealthy diet, and physical inactivity are more likely to affect cancer risk than are trace amounts of pollutants in food, drinking water, and air. However, the degree of risk posed by pollutants depends on the dose and duration of exposure. For example, workers exposed to high concentrations of ionizing radiation, some chemicals, metals, and other substances have been shown to be at increased risk for cancer (ACS, 2002a). Cancer Epidemiology and Insecticide Literature Cancer is most likely the result of a multifactorial process over a lifetime, so it is difficult to establish definitive causal relationships. When investigating the factor or factors that may contribute to the development of cancer, epidemiologists must address several different issues, including environmental and occupational exposures, past lifetime activities (such as smoking), long latency periods, high fatality rates, and the need for accurate diagnoses; all of these issues are discussed in Chapter 2. Exposure determination, the role of confounding, and other broad epidemiologic issues considered by epidemiologists and the committee in evaluating the studies are also presented in Chapter 2. Issues germane to the cancer literature on exposure to insecticides and the decisions made by the committee in reviewing this literature are discussed below. Issues specific to the cancer literature and solvent exposure are discussed in the introduction of Chapter 6. The pesticides identified by the US Congress, the Department of Defense, and the Department of Veterans Affairs as potentially being used during the Gulf War were all insecticides except for one insect repellent (N,N-diethyl-3-methylbenzamide [DEET]) (see Appendix D for complete list of insecticides reviewed by the committee). Therefore, the committee focused its review on exposure to insecticides in general, to classes of insecticides, and to specific insecticides. However, the literature on insecticides and cancer outcomes includes studies of occupations or populations—such as farmers, agricultural workers, and pesticide applicators—with exposure to numerous agricultural chemicals including insecticides. Most of those studies focus on exposure to pesticides as a broad group of chemical compounds. The term pesticide is often used in studies when the specific agents are not known or when a mixture of insecticides and other pest-control agents are thought to have been used. Use of pesticides could involve exposure to all types of pest-control agents—including insecticides, herbicides, fungicides, and other agents—and it is not possible to determine whether the reported associations with pesticide exposure are related to the specific insecticides of interest in this report. Most of the studies are occupational and use farmers, agricultural workers, or pesticide applicators as surrogates of exposure to the broad group of chemical agents known as pesticides. As a result, the potential for exposure misclassification bias is a limitation of those studies. The committee did not make conclusions of association on the broad category of pesticides because it includes herbicides, fungicides, and other agents not known to have been used during the Gulf War. Another limitation of the literature is the small number of study subjects, which is due to the specificity of the exposure and the rarity of individual cancers. Although the

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Gulf War and Health: Insecticides and Solvents, Volume 2 studies on exposure to pesticides and cancer outcomes are limited by sample size and lack of exposure specificity, the committee reviewed these studies and provides a brief discussion of their strengths and limitations at the end of each cancer section. However, the studies on exposure to pesticides are not considered primary evidence for the committee’s conclusions and are not included in the data analysis tables in the cancer sections. It should be noted that for cancer sites on which no published studies of exposure to insecticides were available, the committee acknowledged the lack of data and did not draw a conclusion regarding association. Conclusions were drawn for all cancers in which a body of literature was available. The committee focused its review of cancer outcomes on human studies that had comparison or control groups (cohort and case-control studies). Case reports, case series, review articles, and meta-analyses related to cancer were excluded from the committee’s review. Studies that by design could not provide valid exposure assessment information or estimates of risk—such as ecologic, cross-sectional, proportionate mortality ratio (PMR), and mortality odds ratio studies—were reviewed by the committee but were not considered critical to its conclusions. The committee describes those studies in the relevant sections of Chapter 5 as supplementary evidence and identifies the limitations related to drawing conclusions about associations. However, the studies are not identified in the tables that accompany each cancer section, because they were not critical to the committee’s conclusions. The specific limitations of ecologic, cross-sectional, PMR, and mortality odds ratio studies are described in Chapter 2. Toxicity and Carcinogenicity Toxicologic studies examine the direct effects of various agents on natural processes in organisms. They can determine whether a specific chemical is carcinogenic in animals (such as rodents or other animals). Some studies in rodents have demonstrated carcinogenic and tumorigenic effects following long-term or high-dose oral exposure to several insecticides under review in this report, although some have inconsistent results. For example, exposure to dichlorvos has led to leukemia, pancreatic adenoma, and squamous cell papilloma of the forestomach in certain experimental studies (ATSDR, 1997). The International Agency for Research on Cancer (IARC)2, which is charged with evaluating and determining whether a chemical agent is carcinogenic in humans on the basis of evidence from studies on both humans and animals, has determined that dichlorvos is “possibly carcinogenic to humans.” That classification is based on IARC’s finding of “inadequate evidence” in humans and “sufficient evidence” in experimental animals of the carcinogenicity of dichlorvos (IARC, 1991). With regard to malathion and lindane, hepatic cancers have been observed in studies on animals exposed to each (ATSDR, 1999, 2001a). IARC has reviewed hexachlorocyclohexanes, which include the gamma isomer known as lindane, and has determined that the insecticide is “possibly carcinogenic to humans” on the basis of “inadequate evidence” in humans and “limited evidence” in animals. IARC also found 2   It is important to note the differences in the objective of the IARC program and the charge of this committee. The objective of the IARC program is to determine whether agents or occupational exposures are carcinogenic, whereas this committee is charged with determining whether or not there is an association between exposure to a specific agent or agents and a specific health outcome, such as a particular cancer.

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Gulf War and Health: Insecticides and Solvents, Volume 2 “sufficient evidence” of carcinogenicity of technical grade lindane and the alpha isomer in studies conducted on animals (IARC, 1987). The National Toxicology Program has concluded in its most recent report on carcinogens that lindane and hexachlorocyclohexanes are “reasonably anticipated to be human carcinogens” (NTP, 2001). IARC determined that exposure to malathion is not classifiable as to human carcinogenicity because the available animal studies did not provide evidence and no human studies were available to support a conclusion of carcinogenicity (IARC, 1983). IARC has stated that exposure to carbaryl or permethrin insecticides are not classifiable as to human carcinogenicity, because of a lack of human studies and inadequate experimental evidence in animals (IARC, 1976, 1991). ATSDR has identified one pyrethroid, cypermethrin, as having produced lung tumors in animals (ATSDR, 2001b), but IARC has determined that permethrin, a related insecticide, is not classifiable as to human carcinogenicity, because animal studies yielded inadequate evidence and no human studies were available (IARC, 1991). No carcinogenic effects of long-term, high-dose exposure to the other insecticides reviewed in this report have been reported in the experimental literature. The committee uses experimental evidence only in those instances as required by the definitions of the categories of association. Only the category of “Sufficient Evidence of a Causal Association” requires support from experimental evidence. For each conclusion of causality, animal and other experimental data are described that might provide a plausible mechanism for the outcome being discussed. None of the conclusions of association for exposure to insecticides and cancer outcomes are causal; however, a detailed discussion of the experimental evidence on the insecticides under review is provided in Chapter 3. ORAL, NASAL, AND LARYNGEAL CANCERS The cancers under review here are those of the lip (ICD-9 140.0–140.9), tongue (ICD-9 141.0–141.9), mouth (including the lining of the lips and cheeks) (ICD-9 144.0–145.9), pharynx (ICD-9 146.0–146.9), nasal or sinus cavity (ICD-9 160.0–160.9), nasopharynx (ICD-9 147.0–147.9), and larynx (ICD-9 161.0–161.9). Men are more likely than women to develop these cancers, and tobacco use, especially smoking, is a risk factor for both oral and laryngeal cancers. In addition to sex and smoking, other risk factors include alcohol consumption, vitamin A deficiency, exposure to ultraviolet radiation (sunlight), increasing age, a weakened immune system, and occupational exposure to glues and such other substances found in industry as petroleum, plastics, wood, textile, and leather working (ACS, 2000a, 2002b,c; NCI, 2002a,b). Epidemiologic Studies of Exposure to Insecticides The committee could not draw a conclusion regarding association between exposure to insecticides and oral, nasal, or laryngeal cancer, because of the lack of studies that examine exposure to insecticides and the risk of these cancers. Several studies evaluated the risk of those cancers among occupational groups—such as farmers, agricultural workers, and agricultural chemical workers (e.g., Blair et al., 1993; Franceschi et al., 1993; Reif et al., 1989; Sathiakumar et al., 1992; Wiklund and Steineck, 1988)—but none identified specific insecticide exposures.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Until research with greater specificity of exposure is conducted, it is not possible to make a conclusion regarding association between exposure to insecticides and oral, nasal, or laryngeal cancers. GASTROINTESTINAL TRACT CANCERS Gastrointestinal tract tumors include some of the most common cancers in the United States: esophageal (ICD-9 150.0–150.9), stomach (ICD-9 151.0–151.9), colon (ICD-9 153.0–153.9), rectal (ICD-9 154.0–154.1), and pancreatic (ICD-9 157.0–157.9). On the basis of data collected between 1992 and 1997, the 5-year relative survival rate for esophageal cancer is 14%. That rate has steadily increased over the last 20 years; in 1974–1976, it was 5% (ACS, 2002a). With nearly 3 times as many men affected as women, sex is a known risk factor for esophageal cancer. Furthermore, for unknown reasons, blacks are 2–3 times more likely to develop esophageal cancer than whites. The use of tobacco products and long-term heavy drinking are considered important risk factors. Other risk factors are advancing age; medical history of other head and neck cancers; long-standing gastric reflux or peptic ulcer of the esophagus (Barrett’s syndrome); a diet lacking fruits, vegetables, and some minerals and vitamins; and pre-existing conditions, including achalasia of the cardia (failure of the lower esophageal sphincter to relax and allow food to pass) and esophageal webs (abnormal protrusions of tissue into the esophagus) (ACS, 2000b; NCI, 2002c). The incidence of and mortality from stomach cancer in the United States have decreased over the last 60 years; the 5-year relative survival rate is 22% (ACS, 2002a). The disease is found most often in people over 50 years old and is more common in men and in blacks. Although the cause of stomach cancer is unknown, several studies have indicated that the presence of Helicobacter pylori bacteria, which can cause stomach inflammation and ulcers, may be a major risk factor. Other suggested risk factors are tobacco and alcohol abuse, stomach surgery, family history, stomach polyps, and diet, particularly diets high in smoked foods, high in salted fish and meat, and low in fiber (ACS, 2000c; NCI, 2002d). Cancers of the colon and rectum, sometimes referred to together as colorectal cancer, are the third most common cancers in the United States, excluding skin cancers. The 5-year relative survival rate is 61% (ACS, 2002a). Colorectal cancer screening tests and improvements in nutrition and physical activity have decreased the development of these cancers (Frazier et al., 2000). Researchers have identified several risk factors, namely: family history of colorectal cancer or familial colorectal cancer syndromes; personal history of colorectal cancer, intestinal polyps, or chronic inflammatory bowel disease; physical inactivity; obesity; smoking; a diet high in animal fat; and age (most cases occur in people more than 50 years old) (ACS, 2001a; NCI, 2002e). Although mortality from pancreatic cancer among men has declined somewhat over the last 20 years, men are still nearly 3 times more likely than women to develop this cancer. Risk increases with age; most cases occur in people 60–80 years old. Other potential risk factors are smoking, diabetes mellitus, chronic pancreatitis, family history, a diet high in animal fat, and occupational exposures, including those to some pesticides, dyes, and gasoline-related chemicals (ACS, 2000d; NCI, 2002f).

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Gulf War and Health: Insecticides and Solvents, Volume 2 Epidemiologic Studies of Exposure to Insecticides A few studies investigated the risk of gastrointestinal tract tumors among farmers and agricultural workers, but no critical studies examined the risk associated with specific insecticides. Studies that have attempted to do so are limited by poor exposure determination, small numbers of exposed cases, lack of consideration of potential confounders, and possible recall bias in interview data. Results of the studies considered for evidence of association are presented in Table 5.1. Stomach Cancer No studies meeting the committee’s criteria for critical studies were available that evaluated the risk of stomach cancer associated with exposure to the specific insecticides or classes of insecticides used in the Gulf War. One proportional cancer mortality study of Wisconsin farmers evaluated the risk of stomach cancer after insecticide exposure and reported an increased proportional cancer mortality ratio (Saftlas et al., 1987). However, as is explained in the introduction to this chapter, PMR studies were not considered primary evidence for the purpose of this evaluation because of the inherent limitations in that study design (see Chapter 2). Colorectal Cancer A cross-sectional study of serum concentrations of 19 organochlorines, including lindane, looked at exposure to specific insecticides and colorectal cancer (Soliman et al., 1997). However, of the insecticides examined in the study, only lindane is of interest for this report. The half-life of lindane in the body is short enough that a measure of contemporaneous exposure does not provide adequate evidence of exposure before the development of cancer, so this study did not consider a latency period between exposure and cancer outcome and therefore was not considered a critical study. In addition, the Wang and colleagues study (1988) of specific organochlorine exposure on a countywide level (using earwax) and colorectal cancer was not considered a critical study for drawing conclusions because exposure of individual subjects was not determined. Rapiti and colleagues (1997) examined occupational risk factors for cancer mortality in a cohort of 505 men employed at any time from February 17, 1954, to August 31, 1970, in an Italian chemical production plant. Vital status was obtained through June 1991. A subject who had ever worked in insecticide production was considered exposed to insecticides. On the basis of one exposed case, the standard mortality ratio (SMR) was 0.75 (90% confidence interval [CI]=0.04–3.54) for exposure to insecticides and colon and rectal cancer. The lack of verifiable individual exposure data and the fact that only one exposed case was identified severely limit the findings of this study, and the study was not considered to be critical to this review. Although the proportional cancer mortality study by Saftlas and colleagues (1987) mentioned above found an increased risk of rectal cancer associated with insecticide use in Wisconsin, it is not useful in supporting the body of evidence, as noted in the section above on stomach cancer. Pancreatic Cancer Alguacil and colleagues conducted a case-control study (2000) in five hospitals in eastern Spain to analyze the relationship between occupational exposure and pancreatic

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Gulf War and Health: Insecticides and Solvents, Volume 2 cancer. Histologically confirmed incident cases of pancreatic cancer (n=185) and hospital-based controls (n=264) were identified in 1992–1995. Trained personnel conducted interviews with cases and controls to assess lifetime history of disease, occupation, and lifestyle risk factors; industrial hygienists used this information to categorize exposure to 22 suspected carcinogens. A slight increase in pancreatic cancer risk (odds ratio [OR]=1.27, 95% CI=0.57–2.83) was observed in association with exposure to organophosphorous insecticides. The magnitude of risk varied with intensity and duration of exposure: OR=1.8 (95% CI=0.75–4.30) for cases exposed to high concentrations of organophosphorous insecticides for at least 6 months; OR=1.2 (95% CI=0.39–3.68) for those exposed to high concentrations of organophosphorous agents for at least 10 years, 10 years before diagnosis. However, all the findings related to pancreatic cancer and exposure to organophosphorous insecticides are weak, only a small number of cases were exposed, and the study is limited by the potential for selection bias due to the inclusion of controls with chronic (n=93) or acute (n=34) pancreatitis, other benign pathologic conditions (n=70, mainly biliary), and other cancers (n=41). Ji and colleagues (2001) conducted a population-based case-control study on 484 pancreatic cancer cases diagnosed in 1986–1989 in Atlanta, Detroit, and New Jersey. Diagnosis was verified through review of medical charts, and both cases and 2095 population-based matched controls were interviewed to determine past occupations, history of disease, and lifestyle factors. A job-exposure matrix was used to classify each occupation’s potential for and level of exposure to insecticides. No risk of pancreatic cancer was found to be associated with moderate to high exposure to insecticides (OR=1.0, 95% CI=0.4–2.5), on the basis of 10 exposed cases. Although this was a fairly large study, the use of occupational titles and categories of exposure as surrogates of exposure constitutes a limitation. Furthermore, because the job-exposure matrix was based exclusively on experience pertaining to the subject’s usual occupation instead of the subject’s total exposure, the potential for misclassification bias is another limitation that the committee considered in reviewing the evidence provided by the study. Gastrointestinal Cancers Many studies have investigated the relationship between pesticide exposure and the risk of cancers of the gastrointestinal tract. However, the term pesticides often includes exposure to different types of pest agents, such as insecticides, herbicides, fungicides, and other compounds that are not of specific interest in this review. Overall, the studies indicate a slight increase in gastrointestinal tumors among people exposed to pesticides, but most of the studies use industry type and job title, such as pesticide applicator, as surrogates of exposure. The lack of specificity of exposure of interest for this review and the potential for selection and recall bias are limitations of the studies, and the committee reviewed them as supplementary evidence in reaching its decision about associations. Some of the studies on exposure to pesticides and gastrointestinal cancers include: Alavanja et al., 1987, 1990; Cantor and Booze, 1991; Cocco et al., 1998a, 1999a; Fredriksson et al., 1989; Fryzek et al., 1997; Kauppinen et al., 1995; Paldy et al., 1988; Wesseling et al., 1999; Wiklund et al., 1989; and Zhong and Rafnsson, 1996.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Summary and Conclusion Overall, very few studies on exposure to insecticides and specific gastrointestinal tract tumors were available and met the criteria for this review. In fact, only studies on pancreatic cancer were of sufficient specificity and quality to make a conclusion regarding association. Most studies were limited by study design and the lack of specific and individual exposure information. As a result, the committee did not draw a conclusion regarding association for esophageal cancer, stomach cancer, or colorectal cancer, because of the lack of pertinent studies of exposure to the insecticides under review. Based on the studies identified in Table 5.1, the committee was able to make a conclusion of inadequate/insufficient between exposure to insecticides and risk of pancreatic cancer. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between chronic exposure to the insecticides under review and pancreatic cancer. TABLE 5.1 Selected Epidemiologic Studies—Pancreatic Cancer and Exposure to Insecticides Reference Study Population Exposed Cases Estimated Relative Risk (95% CI) Class of Insecticides—Organophosphorous agents Case-Control Study Alguacil et al., 2000 Residents of Spain       All exposed patients 17 1.27 (0.57–2.83)   Highly exposed (6+ months) 16 1.80 (0.75–4.30)   Highly exposed (10+ years, 10 years before diagnosis) 9 1.20 (0.39–3.68) Insecticides Case-Control Study Ji et al., 2001 Residents of United States       Low exposure 45 0.5 (0.3–0.9)   Moderate/high exposure 10 1.0 (0.4–2.5) HEPATOBILIARY CANCERS Hepatobiliary cancers comprise cancers of the liver, bile duct, gallbladder, and biliary tract (ICD-9 155.0–156.9). The overall 5-year survival rate for liver cancer is relatively low at 6% (ACS, 2002a). More cases of gallbladder and other biliary tract cancers occur in men than in women. Other reported risk factors related to hepatobiliary cancers are chronic infection with the hepatitis B virus (alone and in combination with aflatoxin) or hepatitis C virus and cirrhosis of the liver. Cirrhosis is usually due to excessive alcohol consumption but can also be caused by hepatitis B, hepatitis C, or hemochromatosis, a hereditary disease in which too much iron is absorbed from food. Exposure to aflatoxin, vinyl chloride, thorium dioxide, or arsenic in drinking water and long-term anabolic steroid use have also been linked to hepatobiliary cancers (ACS, 2001b; NCI, 2002g).

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Gulf War and Health: Insecticides and Solvents, Volume 2 Epidemiologic Studies of Exposure to Insecticides No well-conducted studies have examined the risk of hepatobiliary cancers in relation to specific insecticide exposure. The studies that are available on classes of insecticides or unspecified insecticides are few, lack consistency of effect, and often do not adequately control for confounding (from alcohol consumption or hepatitis B or C infection). Most studies examine the risk of liver cancer broadly; those that identify more specific cancers are identified below. The key studies reviewed by the committee are discussed below and results are in Table 5.2. No studies involving specific insecticides were considered critical for review by the committee. An ecologic study by Wang and colleagues (1988) conducted in China correlated concentrations of organochlorines (including lindane) in earwax in a sample of adults in a county with county liver cancer mortality data. As discussed in the introduction to this chapter, the committee determined that ecologic study design is of little value in drawing conclusions of association due to its limitations. A case-control study conducted by Cordier and colleagues (1993) examined the effects of organophosphorous insecticides and other pesticides on the risk of hepatocellular carcinoma (HCC). The investigators identified 152 HCC cases in two hospitals in northern Vietnam diagnosed in 1989–1992. Hospital controls (n=241) were frequency matched on the basis of sex, age, hospital, and residence. Patients with a history of cancer were excluded from both the case and control groups. Self-reported agricultural use of organophosphorous insecticides (at least 30 L/year) was strongly associated with risk of HCC (OR=4.7, 95% CI=1.1–20.1); there were 13 exposed cases. However, the risk did not increase with increased insecticide use; no positive associations were observed with use below 30 L/year. A strength of this study is that the authors adjusted for hepatitis B status and alcohol consumption (two known risk factors for HCC and potential confounders) with unconditional logistic regression. However, it is limited by the self-reporting of exposure (which is subject to recall bias), the use of other pesticides, and the small number of exposed cases. In particular, the lack of an exposure-response relationship suggests that the reported exposure to organophosphorous agents could have been confounded by other exposures possibly associated with liver cancer. Cases included in the study were only a subset of all HCC cases, and histologic information was not available on most of the cases included. Bias may also have occurred because of the high proportion of controls with gastroduodenal ulcers, which have been related to higher tobacco consumption and lower alcohol use. Forty-four liver and biliary tract cancer cases were identified from 6259 death certificates among a cohort of 21,437 male Dow chemical-plant workers in Michigan in 1940–1982 (Bond et al., 1990). A control group of 1888 nonexposed workers was chosen randomly from the original cohort of hourly employees. Exposure to insecticides was determined from company work-history records; workers with either a major or a minor work assignment in the insecticide manufacturing unit were considered exposed. No association was observed between work in insecticide production areas and risk of liver or biliary tract cancer (OR=0.6, 95% CI=0.1–2.4) on the basis of two cases. Work area was used as a surrogate of exposure, and the number of exposed cases was small, limiting the interpretation of the findings of this study. The study of Italian chemical production plant workers described previously reported an SMR of 2.04 (90% CI=0.36–6.42) for work in the insecticide production process and

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Gulf War and Health: Insecticides and Solvents, Volume 2 liver cancer (Rapiti et al., 1997). The lack of verifiable individual exposure data and the fact that only two cases were exposed are limitations of this study. Several studies examined the relationship between exposure to the broader category pesticides (which includes insecticides, fungicides, herbicides, and other pest agents) and hepatobiliary cancers among various occupationally exposed populations. Although several studies demonstrated an increase of hepatobiliary cancers among pesticide applicators and manufacturers (e.g., Amoateng-Adjepong et al., 1995; Figa-Talamanca et al., 1993a,b; Fleming et al., 1999a,b; Pesatori et al., 1994; Thomas et al., 1996), the use of job titles as surrogates of exposure does not provide specific or validated exposure information at the individual level. Furthermore, depending on the nature of the work, the various occupational groups are exposed to a multitude of chemicals other than insecticides, including organic dusts, solvents, other agricultural chemicals, fuels and engine exhausts, and infectious microorganisms; such exposure limits the value of these findings in supporting an association between exposure to insecticides and hepatobiliary cancers. Summary and Conclusion No studies reviewed examined specific insecticide use and the risk of hepatobiliary cancers. The studies that do contain relevant exposure data provide inconsistent measures of association across exposure classifications, no increasing risk with increasing exposure, and small numbers of exposed cases. Table 5.2 identifies the literature with relevant findings. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between chronic exposure to the insecticides under review and hepatobiliary cancers. TABLE 5.2 Selected Epidemiologic Studies—Hepatobiliary Cancers and Exposure to Insecticides Reference Study Population Exposed Cases Estimated Relative Risk (95% CI) Class of Insecticide—Organophosphorous agents Case-Control Study Cordier et al., 1993 Residents of northern Vietnam       1–9 L/year 19 1.1 (0.4–2.9)   10–19 L/year 4 0.7 (0.1–3.9)   20–29 L/year 3 0.4 (0.1–2.5)   ≥30 L/year 13 4.7 (1.1–20.1) Insecticides Cohort Study Rapiti et al., 1997 Male workers at Italian chemical production plant 2 2.04 (0.36–6.42)a Case-Control Study Bond et al., 1990 Male chemical workers in Michigan 2 0.6 (0.1–2.4) a90% CI LUNG CANCER Lung cancer (carcinoma of the lung and bronchus, ICD-9 162.2–162.9) is the leading cause of cancer death among both men and women in the United States, and smoking is the

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Gulf War and Health: Insecticides and Solvents, Volume 2 strongest risk factor. Other environmental risk factors for lung cancer are exposure to asbestos, radon gas, second-hand tobacco smoke, such radioactive ores as uranium, and chemicals, including arsenic, vinyl chloride, coal products, and mustard gas. People with tuberculosis, some types of pneumonia, silicosis, or berylliosis may also be at increased risk for lung cancer (ACS, 2002d; NCI, 2002h). Although great strides have been made in treating lung cancer, the 5-year relative survival rate is only 15% (ACS, 2002a). Epidemiologic Studies of Exposure to Insecticides As with several of the other cancer sites, very few studies examine the risk of lung cancer in relation to specific insecticides. Studies that do provide some specificity—whether examining exposure to a specific compound, a class, or the general category of insecticides—are few and do not show a consistent effect. The studies reviewed also did not specify the type of respiratory cancer but focused broadly on lung cancer. The key studies reviewed by the committee are discussed below, including their strengths and limitations. The results are provided in Table 5.3. The committee assessed whether each study adequately controlled for smoking, a major risk factor for lung cancer and an important potential confounder (see Chapter 2 and Appendix E). Pesatori and colleagues (1994) conducted a nested case-control study of 65 deceased pest-control workers with lung cancer recorded on death certificates as an underlying or contributing cause of death and pest-control worker controls (122 deceased and 172 living) selected from a cohort of Florida pest-control workers whose companies applied for licenses to the Florida Department of Health and Rehabilitative Services in 1965–1966. Exposure to specific insecticides was determined from interviews with next of kin for all subjects, including the living controls. Higher risks of lung cancer than in living controls were reported in association with exposure to diazinon, carbaryl, and propoxur; no association was seen with exposure to malathion or chlorpyrifos, as shown in Table 5.3. Almost all the associations were weak, and the CIs were generally wide, probably because of the small numbers of exposed cases. The ORs using dead controls were consistently somewhat higher than when living controls were used in the analysis; given that all interviews were with proxies, this is difficult to explain. The study was limited by the use of proxy interviews to determine exposure, which could introduce a number of biases. Using the Saskatchewan Cancer Foundation registry, McDuffie and colleagues (1990) identified 273 primary lung cancer cases diagnosed in 1983–1986. Population-based control subjects (n=187) were identified from records of the Saskatchewan Hospital Services Plan. All participants were interviewed to determine occupational exposure, medical history, and smoking status. The smoking-adjusted OR for lung cancer and exposure to carbamates was less than 1.0 and suggested no risk of lung cancer from exposure. Analysis of the 451 cases who were initially contacted but declined to be interviewed revealed a tendency for younger cases to be more likely to participate than older cases, which led to a potential for selection bias. Pesatori and colleagues (1994) also evaluated exposure to insecticides grouped by class in the study of pest-control workers described above. Risk of lung cancer was increased for organophosphorous insecticides (OR=2.0, 95% CI=0.8–5.0) and carbamates (OR=1.8, 95% CI=0.5–6.4) as reported by next of kin, but results showed considerable uncertainty. Limitations of the study, as noted above, apply to these results as well.

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Gulf War and Health: Insecticides and Solvents, Volume 2 In 2000, Buckley and colleagues reported on a case-control study of cases of NHL and leukemia identified through the Children’s Cancer Study Group. Increased risks of childhood NHL were observed: if mothers used household insecticides 1–2 days per week (OR=2.62) or on most days (OR=7.33) during pregnancy; if mothers reported having professional insect treatments around the home (OR=2.98, 95% CI=1.44–6.16) at the time of pregnancy; or if either parent reported being exposed to pesticides occupationally (OR=1.74, 95% CI=0.82–3.69). Exposure one month prior to conception was assessed, but not analyzed separately. Paternal exposure was not considered. Several studies examined the relationship between exposure to pesticides in general—including insecticides, herbicides, fungicides, and other types of pest agents—and the risk of some childhood cancers, including brain and other CNS cancers and lymphomas. However, the role of insecticides cannot be differentiated from that of herbicides, fungicides, or other pesticides in assessing the risk of childhood cancers. A majority of the studies reviewed show an increased risk of childhood cancers with exposure to pesticides before or during pregnancy. Studies on pesticide exposure include those by Cordier and colleagues (1994), Feychting and colleagues (2001), Holly and colleagues (1998), and McCredie and colleagues (1994) for brain and other nervous system tumors; and Meinert and colleagues (2000) for NHL. Summary and Conclusion The studies of exposure to insecticides and childhood cancers have focused primarily on maternal exposure during pregnancy. Only one study examined the relationship between paternal exposure to insecticides before conception and childhood leukemia (Infante-Rivard et al., 1999). Other studies combined exposures prior to and during pregnancy. Tables 5.13 and 5.14 summarize the results of the most relevant studies reviewed by the committee in assessing exposure to insecticides and the risk of childhood cancers, specifically childhood leukemia, brain and other nervous system tumors, and lymphomas. The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between paternal or maternal preconception exposure to the insecticides under review and certain childhood cancers, including childhood leukemia, brain and other central nervous system cancers, and non-Hodgkin’s lymphoma. TABLE 5.13 Selected Epidemiologic Studies—Childhood Leukemia and Exposure to Insecticides Reference Study Population Exposed Cases Estimated Relative Risk (95% CI) Insecticides Case-Control Studies Infante-Rivard et al., 1999 ALL cases in Quebec, Canada       Maternal domestic exposure 1 month before pregnancy to end of pregnancy       Cockroaches, ants, flies, bees, wasps 168 1.79 (1.34–2.40)   Moths 45 2.47 (1.43–4.28)   Mites and spiders 23 1.37 (0.73–2.58)   Insects 96 1.59 (1.11–2.26)   Termites 8 1.89 (0.56–6.37)   Plant insecticides 78 1.97 (1.32–2.94)   Repellents and sprays for outdoor insects 46 0.70 (0.45–1.09)

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Gulf War and Health: Insecticides and Solvents, Volume 2 Reference Study Population Exposed Cases Estimated Relative Risk (95% CI) Infante-Rivard and Sinnett, 1999 ALL cases in Quebec, Canada     Paternal preconception occupational exposure       Insecticides 50 1.38 (0.87–2.18) TABLE 5.14 Selected Epidemiologic Studies—Other Childhood Cancers and Exposure to Insecticides Reference Study Population Exposed Cases Estimated Relative Risk (95% CI) Brain and Other Nervous System Tumors Case-Control Studies Daniels et al., 2001 Neuroblastoma (Children’s Study Group)       Parental exposure 1 month before conception through pregnancy       Extermination in home 23 1.0 (0.5–2.1)   Home insecticide use 93 1.3 (0.8–3.3) Shu et al., 1995 Malignant germ-cell tumors (Children’s Study Group)       Exposure before, during, and after diagnosis (combined)       Insecticides or herbicide (maternal) 7 2.4 (0.9–6.9)   Insecticides or herbicides (paternal) 7 1.8 (0.7–5.0) Non-Hodgkin’s Lymphoma Case-Control Study Buckley et al., 2000 Childhood NHL (Children’s Study Group)       Maternal exposure 1 month before pregnancy, during pregnancy, or while nursing (combined)       Personal use of insecticides (1–2 days/week) 17 2.62 (0.96–7.18)   Personal use of insecticides (most days) 6 7.33 (0.84–63.85)   Professional insecticide extermination 31 2.98 (1.44–6.16) REFERENCES ACS (American Cancer Society). 1999. Childhood Cancer—General Statement. Available: http://www.cancer.org (choose cancer type) [accessed February 2002]. ACS. 2000a. Nasal Cavity and Paranasal Sinuses Cancer. Available: http://www.cancer.org (choose cancer type), [accessed March 4, 2002]. ACS. 2000b. Esophagus Cancer. Available: http://www.cancer.org (choose cancer type) [accessed March 2002]. ACS. 2000c. Stomach Cancer. Available: http://www.cancer.org (choose cancer type) [accessed March 2002]. ACS. 2000d. Pancreatic Cancer. Available: http://www.cancer.org (choose cancer type) [accessed March 2002]. ACS. 2000e. Bone Cancer. Available: http://www.cancer.org (choose cancer type) [accessed March 2002]. ACS. 2000f. Testicular Cancer. Available: http://www.cancer.org (choose cancer type) [accessed March 2002]. ACS. 2001a. Colorectal Cancer. Available: http://www.cancer.org (choose cancer type) [accessed March 2002]. ACS. 2001b. Liver Cancer. Available: http://www.cancer.org (choose cancer type) [accessed March 2002]. ACS. 2001c. Nonmelanoma Skin Cancer. Available: http://www.cancer.org (choose cancer type) [accessed February 2002]. ACS. 2001d. Melanoma Skin Cancer. Available: http://www.cancer.org (choose cancer type) [accessed February 2002].

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Gulf War and Health: Insecticides and Solvents, Volume 2 Mussalo-Rauhamaa H, Hasanen E, Pyysalo H, Antervo K, Kauppila R, Pantzar P. 1990. Occurrence of beta-hexachlorocyclohexane in breast cancer patients. Cancer 66(10):2124–2128. Nanni O, Amadori D, Lugaresi C, Falcini F, Scarpi E, Saragoni A, Buiatti E. 1996. Chronic lymphocytic leukaemias and non-Hodgkin’s lymphomas by histological type in farming-animal breeding workers: A population case-control study based on a priori exposure matrices. Occupational and Environmental Medicine 53(10):652–657. Nanni O, Falcini F, Buiatti E, Bucchi L, Naldoni M, Serra P, Scarpi E, Saragoni L, Amadori D. 1998. Multiple myeloma and work in agriculture: Results of a case-control study in Forli, Italy. Cancer Causes and Control 9(3):277–283. National Cancer Institute (NCI). 2000. What You Need to Know About Multiple Myeloma: Information About Detection, Symptoms, Diagnosis, and Treatment of Multiple Myeloma. Available: http://www.nci.nih.gov/cancer_information/cancer_type/plasma_cell_neoplasm [accessed March 2002]. NCI. 2002a. What You Need to Know About Oral Cancer: Information About Detection, Symptoms, Diagnosis, and Treatment of Oral Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/head_and_neck [accessed May 2002]. NCI. 2002b. What You Need to Know About Cancer of the Larynx: Information About Detection, Symptoms, Diagnosis, and Treatment of Laryngeal Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/head_and_neck [accessed May 2002]. NCI. 2002c. What You Need to Know About Cancer of the Esophagus: Information About Detection, Symptoms, Diagnosis, and Treatment of Esophageal Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/esophageal [accessed May 2002]. NCI. 2002d. What You Need to Know About Stomach Cancer: Information About Detection, Symptoms, Diagnosis, and Treatment of Stomach Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/stomach [accessed May 2002]. NCI. 2002e. What You Need to Know About Cancer of the Colon and Rectum: Information About Detection, Symptoms, Diagnosis, and Treatment of Colon and Rectal Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/colon_and_rectal [accessed May 2002]. NCI. 2002f. What You Need to Know About Cancer of the Pancreas: Information About Detection, Symptoms, Diagnosis, and Treatment of Pancreatic Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/pancreatic [accessed May 2002]. NCI. 2002g. What You Need to Know About Liver Cancer: Information About Detection, Symptoms, Diagnosis, and Treatment of Liver Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/liver [accessed May 2002]. NCI. 2002h. What You Need to Know About Lung Cancer: Information About Detection, Symptoms, Diagnosis, and Treatment of Lung Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/lung [accessed May 2002]. NCI. 2002i. Bone Cancer: Questions and Answers. Available: http://cis.nci.nih.gov/fact/6_26.htm [accessed May 2002]. NCI. 2002j. Soft Tissue Sarcomas: Questions and Answers. Available: http://cis.nci.nih.gov/fact/6_12.htm [accessed February 2002]. NCI. 2002k. What You Need to Know About Skin Cancer: Information About Detection, Symptoms, Diagnosis, and Treatment of Skin Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/Skin [accessed May 2002]. NCI. 2002l. What You Need to Know About Melanoma: Information About Detection, Symptoms, Diagnosis, and Treatment of Melanoma. Available: http://www.nci.nih.gov/cancer_information/cancer_type/melanoma [accessed May 2002]. NCI. 2002m. What You Need to Know About Breast Cancer: Information About Detection, Symptoms, Diagnosis, and Treatment of Breast Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/breast [accessed March 2002]. NCI. 2002n. What You Need to Know About Cancer of the Cervix: Information About Detection, Symptoms, Diagnosis, and Treatment of Cervical Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/cervical [accessed May 2002]. NCI. 2002o. What You Need to Know About Ovarian Cancer: Information About Detection, Symptoms, Diagnosis, and Treatment of Ovarian Cancer. Available: http://www.nci.nih.gov/cancer_information/cancer_type/ovarian [accessed May 2002].

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