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Gulf War and Health: Volume 2: Insecticides and Solvents (2003)

Chapter: 5. Cancer and Exposure to Insecticides

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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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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.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

“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.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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).

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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).

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

The cohort study of 505 male workers at an Italian chemical production plant described earlier in the gastrointestinal cancer section found an SMR of 0.80 (90% CI=0.27–1.82) for exposure to insecticides and lung cancer on the basis of four exposed cases (Rapiti et al., 1997). The lack of verifiable and specific individual exposure data and the small number of exposed cases limit the value of the findings of this study. No additional associations were found between lung cancer and insecticides in the case-control study in Saskatchewan described above (McDuffie et al., 1990).

Several studies examined the relationship between pesticides and lung cancer among various occupationally exposed populations. As mentioned previously, the committee reviewed this literature as supplementary evidence in drawing its conclusion about associations. Studies of pesticide applicators and agricultural workers (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) provide inconsistent measures of effect and often use job titles as surrogates of exposure. The lack of exposure specificity limits the findings of these studies in determining an association between exposure to insecticides used in the Gulf War and lung cancer risk.

Summary and Conclusion

A number of epidemiologic studies have examined the relationship between lung cancer and exposure to the broad group of pesticides, but few examine the association with specific insecticides. One study (Pesatori et al., 1994) reported positive associations between some specific insecticides and lung cancer but the associations were not strong, were based on small numbers of exposed cases, and were not consistent with respect to analyses of living versus deceased controls. Other studies that contain relevant exposure estimates yield inconsistent associations (such as with carbamates) or negative associations (such as with insecticides in general). Table 5.3 identifies the body of literature reviewed and the 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 lung cancer.

TABLE 5.3 Selected Epidemiologic Studies—Lung Cancer and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Specific Insecticides

Cohort Study

Pesatori et al., 1994

Pest-control workers in Florida

 

 

 

Living controlsa

 

 

 

Diazinon

17

1.3 (0.6–3.1)

 

Malathion

11

1.0 (0.4–2.6)

 

Chlorpyrifos

3

0.6 (0.1–2.4)

 

Carbaryl

3

4.2 (0.6–27.2)

 

Propoxur

5

1.4 (0.4–5.5)

 

Deceased controlsa

 

 

 

Diazinon

17

2.0 (0.7–5.5)

 

Malathion

11

1.6 (0.5–4.6)

 

Chlorpyrifos

3

1.3 (0.2–7.1)

 

Carbaryl

3

NA

 

Propoxur

5

12.4 (1.5–100.3)

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Classes of Insecticide

Cohort Study

Pesatori et al., 1994

Pest-control workers in Florida

 

 

 

Living controlsa

 

 

 

Organophosphorous agents

23

2.0 (0.8–5.0)

 

Carbamates

7

1.8 (0.5–6.4)

 

Deceased controlsa

 

 

 

Organophosphorous agents

23

2.2 (0.8–5.8)

 

Carbamates

7

16.3 (2.2–122.5)

Case-Control Study

McDuffie et al., 1990

Male cases from Saskatchewan Cancer Foundation Registry

 

 

 

Carbamates

9

0.46a

Insecticides

Cohort Study

Rapiti et al., 1997

Male workers at Italian chemical production plant

4

0.80 (0.27–1.82)b

Case-Control Study

McDuffie et al., 1990

Male cases from Saskatchewan Cancer Foundation registry

 

 

 

Other insecticidesc

19

0.95a

aResults are adjusted for smoking.

b90% CI.

cInsecticides other than chlorinated hydrocarbons, arsenic, carbamates, or phosphodithioate

BONE CANCER

Of the several forms of primary bone and joint cancer (ICD-9 170.0–170.9), osteosarcoma is the most common primary bone cancer, accounting for about 35% of all cases. Occurring more frequently in males, osteosarcoma is found mostly in people 10–30 years old and rarely during middle age. About 10% of cases develop in people 60 years old and older. Other, rare forms of primary bone cancer include chondrosarcoma (cancer of cartilage cells), Ewing’s tumor (cancer of the bone cavity), chordoma (cancer of the skull base and spinal bones), and malignant fibrous histiocytoma and fibrosarcoma (cancer of the connective tissues). The 5-year survival rate can be as high as 80%, but the prognosis for people with primary bone cancer varies greatly, depending on the specific type of cancer and the stage at which it is diagnosed (ACS, 2000e; NCI, 2002i).

Risk factors for bone cancer are exposure to ionizing radiation, particularly at an early age or at high doses; a history of bone disorders, such as Paget’s disease; and the presence of multiple exostoses (overgrowths of bone tissue), multiple osteochondromas (benign bone tumors formed by bone and cartilage), multiple enchondromas (benign cartilage tumors), and some genetic factors (such as mutation of the p53 tumor-suppressor gene) (ACS, 2000e; NCI, 2002i).

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Epidemiologic Studies of Exposure to Insecticides

Several studies have examined the risk of bone cancer among farmers and agricultural workers (e.g., Blair et al., 1993; Brownson et al., 1989; Reif et al., 1989), but no studies provided an analysis of exposure to the specific insecticides under review or insecticides in general and bone cancer.

An evaluation of any association between insecticides and bone cancer cannot be made until research with greater specificity of exposure is conducted.

SOFT TISSUE SARCOMA

An uncommon form of cancer, soft tissue sarcoma (STS) (ICD-9 171.0–171.9, 164.1) makes up less than 1% of incident cancer cases each year, and the 5-year survival rate is about 90% (ACS, 2002e). About 10% of cases occur in children and adolescents under 20 years old (NCI, 2002j).

There have been only a few studies of risk factors for STS, so the risk factors are not well understood. However, people with alterations in the p53 gene (Li-Fraumeni syndrome) or the NF1 gene (neurofibromatosis, or von Recklinghausen disease) and people with family histories of Gardner’s syndrome (colonic polyps) or retinoblastoma are at increased risk for STS. External ionizing radiation is suspected to cause a small percentage of sarcomas (less than 5%), and exposure to some chemicals—such as vinyl chloride, dioxin, and phenoxyacetic acid—may also play a role (ACS, 2002e). Chemotherapeutic agents that cause secondary sarcomas in cancer survivors are also being investigated (Zahm, 1997).

Epidemiologic Studies of Exposure to Insecticides

This section reviews the available literature on exposure to insecticides and STS. The following discussion highlights the key studies reviewed in drawing a conclusion and Table 5.4 provides results from these studies.

Only one study, an ecologic study, investigated exposure to a specific insecticide, diazinon, and the risk of STS (Mills, 1998). Although a specific insecticide is identified, the study is limited by the fact that mortality is correlated with the number of pounds of insecticide used in the state, which means that exposure and outcome are not on an individual level. Exposure and outcome were also contemporaneous, so no latency period existed between time of exposure and diagnosis of cancer. Thus, as is indicated at the beginning of the chapter, the study was not considered to be useful for the purpose of this review because of its study design limitations.

One population-based case-control study examined the effect of agricultural exposures and the risk of STS (Zahm et al., 1988). Cases were selected from among white men 21 years old or older living in Kansas in 1976–1982. A total of 133 STS cases of the 139 eligible after pathologic review were interviewed by telephone. Population-based controls were matched 3:1 on age and vital status. On the basis of self-reported exposure information, an increase in STS risk was associated with ever using organophosphorous insecticides on animals (OR=2.1, 95% CI=0.6–6.9), insecticides in general (OR=1.3, 95% CI=0.8–2.2), and insecticides on animals (OR=1.6, 95% CI=0.9–2.5). However, no increased risk of STS was observed in those using insecticides on crops (OR=0.8, 95% CI

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

=0.4–1.6). Farmers were also asked about prior use of carbamates, but no cases reported exposure to this class of insecticide. Use of crop insecticides resulted in no association with STS (OR=0.8, 95% CI=0.4–1.6). The study, however, is limited by the potential for exposure misclassification because exposure levels were based on insecticides in general and the classes organophosphorous insecticides and carbamates.

Several studies examine the relationship between exposure to pesticides in general and STS risk. As indicated in the introduction of this chapter, although studies of pesticides were reviewed, they yielded secondary support for conclusions. Some of the studies on pesticide exposure and STS risk include: Fleming et al., 1999a,b; Franceschi and Serraino, 1992; Kristensen et al., 1996; Wiklund et al., 1989; and Zahm et al., 1988.

Summary and Conclusion

Overall, the value of the body of evidence on exposure to insecticides and the risk of STS was limited by the lack of studies. In the one case-control study providing evidence for conclusions, there was not a clear relationship between classes of insecticides known to be present in the Gulf War and STS.

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 soft tissue sarcomas.

TABLE 5.4 Selected Epidemiologic Studies—Soft Tissue Sarcomas and Exposure to Insecticides

 

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Class of Insecticides and Insecticides

Case-Control Study

Zahm et al., 1988

Residents of Kansas

 

 

 

Organophosphorous agents

5

2.1 (0.6–6.9)

 

Animal insecticides

46

1.6 (0.9–2.5)

 

Crop insecticides

14

0.8 (0.4–1.6)

 

Insecticides

50

1.3 (0.8–2.2)

SKIN CANCER

Cancers of the skin are divided into two general types: melanoma and nonmelanoma skin cancers. Together, they are the most common form of cancer in the United States, accounting for more than 40% of all cancers diagnosed each year (ACS, 2001c).

Nonmelanoma skin cancers (ICD-9 173.0–173.9) are the most prevalent form of skin cancer. They are highly curable, with a 5-year survival rate of 95–99% (ACS, 2001c). Risk factors associated with the development of nonmelanoma skin cancer include excessive exposure to ultraviolet radiation (particularly from sunlight but also from tanning lamps and booths); fair complexion; chemical exposure to such substances as arsenic, industrial tar, coal, and some oils; and exposure to ionizing radiation, usually during the course of medical treatment. Sex is also an important risk factor: men are twice as likely as women to develop

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

basal cell cancers and 3 times as likely to develop squamous cell carcinomas (ACS, 2001c; NCI, 2002k).

The most serious form of skin cancer is melanoma (ICD-9 172.0–172.9), which accounts for only 4% of all skin cancers, but nearly 79% of all skin cancer deaths. If it is diagnosed early, the 5-year relative survival rate is more than 90% (ACS, 2001d, 2002a; NCI, 20021). The risk of developing melanoma increases with age, but it is one of the most common cancers in people under 30 years old. Other risk factors include excessive exposure to ultraviolet radiation, sunburn, fair complexion, family history of melanoma, immune suppression, and the presence of dysplastic or congenital melanocytic nevi (moles) (ACS, 2001d; NCI, 20021).

Epidemiologic Studies of Exposure to Insecticides

No epidemiologic studies were identified in the committee’s literature review on the relationship between exposure to specific insecticides and skin cancer, and only one study on insecticides in general was identified. The insecticide study reviewed by the committee is discussed below and Table 5.5 provides the results.

The only study on exposure to insecticides and skin cancer reviewed was a case-control study of 226 male basal cell carcinoma cases and 180 male squamous cell carcinoma cases conducted in Alberta, Canada, in 1983–1984 (Gallagher et al., 1996). Controls (n=406) were randomly selected from insurance subscriber files and frequency matched on 5-year age groups. Trained personnel interviewed all participants to determine skin, hair, and eye pigmentation; medical history; and past occupational exposures, including exposures to insecticides. Interviewers were blinded to the study hypothesis and the disease status of each participant. An increased risk of basal cell carcinoma (OR=1.3, 95% CI=0.9–2.1) and squamous cell carcinoma (OR=1.7, 95% CI=1.1–2.7) was associated with self-reported exposure to insecticides. Insecticide use was further stratified by high and low exposure in relation to squamous cell carcinoma risk. An increased risk (OR=2.8, 95% CI=1.4–5.6) was found for squamous cell carcinoma and high exposure to insecticides. Odds ratios were adjusted for age, skin color, hair color, mother’s ethnic origin, and occupational sunlight exposure but not for recreational sunlight exposure, herbicides, fungicides, or other occupational exposures. The study’s findings, however, are subject to recall bias, and other studies on exposure to insecticides and nonmelanoma skin cancers would be needed to substantiate an association.

Several studies examined the relationship between exposure to pesticides in general and risk of skin cancer; some of those studies are: Corrao et al., 1989; Fleming et al., 1999b; Holly et al., 1996; Morgan et al., 1980; Torchio et al., 1994; Wang and MacMahon, 1979; and Wesseling et al., 1999.

Summary and Conclusion

Given that only one study was available that examines exposure to insecticides in general and skin cancer, there is not sufficient evidence for drawing a conclusion regarding association for skin cancer risk. Additional studies on the exposure to insecticides under review in this report and the risk of skin cancer are needed before a conclusion can be drawn.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

TABLE 5.5 Selected Epidemiologic Studies—Skin Cancers and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Insecticides

Case-Control Study

Gallagher et al., 1996

Residents of Alberta, Canada

 

 

 

Basal cell carcinoma

50

1.3 (0.9–2.1)

 

Squamous cell carcinoma

57

1.7 (1.1–2.7)

 

Low insecticide exposure

21

0.7 (0.3–1.4)

 

High insecticide exposure

36

2.8 (1.4–5.6)

 

p trend=0.02

FEMALE REPRODUCTIVE CANCERS

Female reproductive cancers include cancers of the breast, cervix, uterus, and ovaries. Breast cancer (ICD-9 174.0–174.9 for females) is the most common form of cancer among women and the second most common cause of death from cancer in women, exceeded only by lung cancer (ACS, 2001e). ACS estimates that nearly one in eight women in the United States will have breast cancer. If the tumor is diagnosed while still localized, however, the 5-year survival rate is 96% (ACS, 2002a).

Although considerable efforts have been made, little is known about the etiology of breast cancer. Risk factors generally include family history, mutations in the BRCA1 or BRCA2 (tumor-suppressor) genes, atypical breast hyperplasia, early menarche, late menopause, late childbearing or nulliparity, high breast density, exposure to ionizing radiation, hormone use, obesity, and alcohol use (ACS, 2001e; NCI, 2002m). However, many women who develop breast cancer do not have any of those risk factors.

Most cancers of the cervix (ICD-9 180.0–180.9) are squamous cell carcinomas, and the 5-year survival rate is about 70%. Women are at greater risk for cervical cancer if they or their partners began having sexual intercourse before the age of 18 years or if they have had many sexual partners. That is because of the correlation of cervical cancer and human papilloma viruses, which are believed to initiate abnormal cervical growth (NCI, 2002n).

About one in 57 US women will develop ovarian cancer (ICD-9 183.0) (NCI, 2002o). In contrast with the high 5-year survival rates for other female reproductive cancers, the survival rate for ovarian cancer is 52%. However, if diagnosed early and treated while localized, the 5-year survival rate is 95%. Because of its vague signs and symptoms (such as enlargement of the abdomen and digestive disturbances), ovarian cancer is not always detected early (ACS, 2002a). Risk factors for ovarian cancer include family history, age, childbirth, and the use of fertility drugs, hormone replacement therapy, or talc powder in the genital region (ACS, 2002a).

The 5-year survival rate for cancer of the uterus (ICD-9 179.0–182.8) is a relatively high at 84%. The incidence is higher among white women than among black women, but the case-fatality rate is reversed with black women having nearly twice as high fatality as white women. A major risk factor for uterine cancer is high cumulative exposure to estrogen. Use of estrogen-replacement therapy or tamoxifen, early menarche, late menopause, never having children, and lack of ovulation over long times are risk factors associated with the development of cancer of the corpus, or body, of the uterus. In contrast, pregnancy and the

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

use of oral contraceptives appear to provide some protection against endometrial cancer, or cancer of the lining of the uterus (ACS, 2002a; NCI, 2002p).

Epidemiologic Studies of Exposure to Insecticides

A number of epidemiologic studies have investigated breast cancer risk and exposure to pesticides, with particular attention to the role of specific organochlorine pesticides, including dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), oxychlordane, mirex, hexachlorobenzene, and lindane. However, unlike other classes of insecticides (such as organophosphorous insecticides and carbamates), which share mechanisms and metabolic properties, lindane differs substantially from other organochlorine insecticides in its toxicity, absorption, metabolism, and other characteristics (see Chapter 3). The committee therefore focused its review on lindane and its isomers specifically and not on the larger class of organochlorines (see Chapter 2). Table 5.6 provides the key data points from the critical studies that the committee evaluated in making its conclusions.

Some studies have investigated the relationship between household and occupational exposures to pesticides and female reproductive cancers other than cancer of the breast, but no studies focused specifically on exposure to insecticides. Studies that do examine the risk of cervical, ovarian, or uterine cancer lack specific exposure information on insecticides and often involve extremely small numbers of cases (e.g., Fleming et al., 1999a,b; Wesseling et al., 1999).

Results of three nested case-control studies of serum concentrations of organochlorines, including lindane and its isomers, that were collected before breast cancer diagnosis, and breast cancer risk were primarily negative. Ward and colleagues (2000) conducted a nested case-control study in Norway of breast cancer risk and serum organochlorines in a cohort of 25,431 female serum bank donors in 1973–1991. They measured 71 organochlorine compounds, including γ-1,2,3,4,5,6-hexachlorocyclohexane (HCH), otherwise known as lindane. The study found no evidence of higher serum concentrations of any of these compounds in cases or any trend of increasing risk associated with higher quartiles of exposure to lindane (OR=0.7, 95% CI=0.1–4.0).

Another nested case-control study evaluated the association between serum organochlorine insecticides—including lindane and β-HCH (an isomer of HCH)—and breast cancer risk by using the Columbia, Missouri Breast Cancer Serum Bank, where samples for 7224 women diagnosed with breast cancer in 1977–1987 had been stored (Dorgan et al., 1999). The study found no increased risk of breast cancer in women with higher serum organochlorine insecticides (OR=0.6, 95% CI=0.3–1.3 for β-HCH).

In a third nested case-control study, Hoyer and colleagues (1998) compared serum concentrations of 18 organochlorine pesticides in baseline blood samples from 240 breast cancer cases and 477 controls selected from participants in the Copenhagen City Heart Study. They found no association with lindane or other organochlorines, such as DDT, DDE, and polychlorinated biphenyls; however, breast cancer risk was increased with higher β-HCH levels (OR=1.36, 95% CI=0.79–2.33).

Zheng and colleagues (1999) directly compared benzene hexachloride (BHC) in breast adipose tissue from 304 incident breast cancer cases and 186 benign breast disease cases as controls, and found no association between BHC isomers (including lindane) and

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

risk of breast cancer. An inverse association with breast cancer risk was observed among all study subjects (ORβ-BHC=0.6, 95% CI=0.3–1.1) and among premenopausal and postmenopausal women when the highest quartiles of adipose tissue BHC were compared with the lowest.

Other hospital-based case-control studies of breast cancer risk and organochlorines, including lindane and its isomers, in breast tissue have reported inconsistent results (Dewailly et al., 1994; Falck et al., 1992; Guttes et al., 1998; Mussalo-Rauhamaa et al., 1990). Measurement of the compound in tissue does not allow for a latency period or exposure in the past. Another important issue that must be considered when evaluating studies on lindane or related isomers in breast fat tissue is the degree of control for confounding by other risk factors, such as parity and dietary fat.

A number of studies have focused on subjects considered to have been exposed to an undefined mixture of pesticides on the basis of their occupations or job titles, such as farmers or agricultural workers. However, those studies do not provide the specific information on exposure to insecticides needed for this review. Such studies of pesticides and breast cancer include those by Fleming and colleagues (1999a,b) and Cocco and colleagues (1998b).

Summary and Conclusion

In summary, the studies reviewed do not support an association between environmental exposure to lindane or any of its isomers and breast cancer risk. Caution must be exercised in interpreting the results of the studies because they have several limitations, including very small numbers of participants and the fact that tissue samples in hospital-based studies were collected after diagnosis of the disease. It is unknown whether concentrations of the compounds in question reflect exposures at the time of disease onset or whether the disease process itself or treatment affected the body burden of the compounds. Internal measures of dose are generally considered superior to external measures or job titles used as crude surrogates of exposure. A favorable feature of the nested case-control studies was the prospective design. The studies reviewed by the committee and the relevant data points are identified in Table 5.6. No studies examined exposure to specific insecticides, classes, or insecticides in general and cancer of the cervix, ovary, or uterus; therefore, the committee cannot draw a conclusion regarding association between exposure to insecticides and these female reproductive cancers.

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 lindane or its isomers and breast cancer.

TABLE 5.6 Selected Epidemiologic Studies—Breast Cancer and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Lindane and Related Isomers

Cohort Studies

Ward et al., 2000

Female serum bank donors in Norway

 

 

 

γ-HCH

7

0.7 (0.1–4.0)a

 

β-HCH, highest quartile of lipid-adjusted data

144

0.7

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Dorgan et al., 1999

Female serum bank donors in Columbia, Missouri

 

 

 

Highest quartile of serum β-HCH

27

0.6 (0.3–1.3)

Hoyer et al., 1998

Female serum samples from Copenhagen City Heart Study

 

 

 

Highest quartile of serum β-HCH

63

1.36 (0.79–2.33)b

Case-Control Studies

Zheng et al., 1999

Breast adipose tissue from women in Connecticut

 

 

 

Highest quartile of serum β-BHC

77

0.6 (0.3–1.1)

Mussalo-Rauhamaa et al., 1990

Breast tissue from women in Helsinki

 

 

β-HCH

24

10.51 (2.00–55.26)c

aOR calculated from discordant pairs.

bAdjusted analysis.

cControlled for age and parity.

UROLOGIC CANCERS

Cancers of the genitals or urinary tract include tumors of the prostate, testes, bladder, kidneys, and urinary tract. Urologic cancers account for about 41% of all cancers in men and 4% in women (ACS, 2002a).

Prostate cancer (ICD-9 185) accounts for nearly 30% of all male cancers, making it the most common cancer, excluding skin cancers, in American men (ACS, 2002a). The greatest risk factor is age; most cases occur in men over 65 years old. Other factors include family history of prostate cancer, race (prostate cancer occurs almost 70% more often in black men than in whites), and a high-fat diet (NCI, 2002q).

Although accounting for only about 1% of all cancers in men, testicular cancer (ICD-9 186.0–186.9) is the most common form of cancer in men 15–35 years old. It is one of the most curable types of cancer, with an average 5-year survival rate of more than 90%. In addition to age, risk factors are race (testicular cancer is more common in white men than in black or Asian American men), an undescended testis (cryptorchidism), abnormal testis development, Klinefelter syndrome (XXY chromosomal makeup), and family history of testicular cancer (ACS, 2000f; NCI, 2002r).

Bladder cancer (ICD-9 188.0–188.9) is the sixth most common form of cancer in the United States, excluding nonmelanoma skin cancers (ACS, 2002a). Smoking is considered the most widespread and modifiable risk factor for bladder cancer; smokers are about twice as likely as nonsmokers to develop the disease. Other risk factors include race (whites are twice as likely as blacks to be affected), sex (men are 3 times more likely to be affected than women), increasing age, and history of chronic bladder inflammation (ACS, 2001f; NCI, 2002s). Occupational exposure to carcinogens—such as benzidine and beta-naphthylamine, as seen among dye and rubber industry workers—has also been associated with significantly increased risks of bladder cancer (Miyakawa et al., 2001). Other occupations considered to pose a risk include working in the leather, textile, paint, and printing industries (ACS, 2001f).

Kidney cancer (ICD-9 189.0–189.9) shares some of the risk factors of bladder cancer, including smoking and occupational exposures, such as to asbestos, cadmium, dyes, and some organic solvents. Increased weight has been associated with kidney cancer. Genetic and hereditary factors—such as von Hippel-Lindau disease, papillary renal cell

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

carcinoma, and hereditary renal oncocytoma (benign kidney tumors)—may increase the risk of kidney cancer. Other risk factors are advancing age, pre-existing kidney disease, and sex; men are twice as likely as women to be affected (ACS, 2001g; NCI, 2002t).

Epidemiologic Studies of Exposure to Insecticides

A number of studies have examined the increased risk of urologic cancers—including bladder, kidney, prostate, and testicular cancer—among farmers and agricultural workers, but very few have examined the risk in relation to specific insecticides or to insecticides in general. The studies that have been able to investigate specific insecticide exposures often rely on small numbers of exposed cases and cannot validate the exposure.

Prostate Cancer

Only one insecticide exposed case of prostate cancer was found in the Italian chemical production plant cohort noted above (SMR=1.01, 90% CI=0.05–4.79) (Rapiti et al., 1997) for exposure to insecticides. A PMR study of farmers identified with death certificates in Wisconsin found an association between prostate cancer and a surrogate of exposure to insecticides based on agricultural activity in the farmers’ county (Saftlas et al., 1987). However, the lack of direct exposure measures at the individual level and the use of a PMR analysis, in which high or low ratios for some causes of death may result from decreases or increases in the numbers of deaths from other causes, are limitations of this study. Finally, an ecologic study by Mills (1998) found mixed correlations by ethnicity between age-adjusted incidences of prostate cancer and use of specific pesticides including diazinon, in California.

Testicular Cancer

Hardell and colleagues (1998) conducted a case-control study of testicular cancer among men 30–75 years old and diagnosed in 1989–1992 in the northern and middle parts of Sweden. The 148 cases and 314 population controls were given self-administered comprehensive questionnaires regarding occupational exposures and histories, including exposure to insect repellents and insecticides. Use of insecticides in general revealed no association with testicular cancer (OR=0.7, 95% CI=0.4–1.4); an increase in risk was observed for insect repellents (OR=1.7, 95% CI=1.03–2.8), most of which have DEET as their active ingredient.

The authors conducted both univariate and multivariate analyses on exposure to insect repellents for less than 115 days versus 115 days or more. It appears that the authors included use of video display units, the occupation of plastics worker, and polyvinylchloride exposure with insect repellent use in the model, although it is not explicitly stated. An increased risk of testicular cancer was associated with both categories of exposure in both the univariate and multivariate analyses; larger estimates of effect were associated with exposure to insect repellents for at least 115 days (ORunivariate=2.3, 95% CI=1.2–4.4; ORmultivariate=2.1, 95% CI=1.1–4.2). There may be a potential for recall bias, but it seems unlikely, because relative risks for many of the exposures under study were not increased. A weakness of the findings, however, is that the study authors did not explain whether the exposure occurred within 1 year (rate) or over a lifetime (cumulative). Additionally, the

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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authors did not state how they got the information and why 115 days was set as the threshold.

An ecologic study by Mills (1998) found no correlation between age-adjusted incidence of testicular cancer and specific pesticide use, including diazinon, in California.

Bladder Cancer

Rapiti and colleagues (1997) studied risk factors for a number of cancers in a cohort of 505 male workers at an Italian chemical production plant. A worker was considered exposed to insecticides if he had ever worked in the insecticide production process. On the basis of three exposed cases of bladder cancer, an SMR of 3.53 (90% CI=0.96–9.12) was observed for exposure to insecticides. The extremely small number of exposed cases and the lack of verifiable individual exposure data limit the value of the findings of this study and do not provide the committee with evidence of an association.

Kidney Cancer

Mellemgaard and colleagues (1994) conducted a case-control study on the possible occupational risk factors associated with kidney cancer. Histologically confirmed cases (n=365) were identified through the Danish Cancer Registry and matched on sex and age to controls (n=396) from the Central Population Register. Study participants were interviewed in their homes to determine lifetime occupation and exposure histories. Risk of kidney cancer was increased in men (OR=2.2, 95% CI=0.8–6.3) and women (OR=5.7, 95% CI =0.6–58) who reported insecticide exposure of at least 1 year’s duration occurring 10 years or more earlier. An increased risk of kidney cancer—adjusted for age, body mass index, and smoking—was observed among men who reported exposure to insecticides or herbicides for less than 20 years (OR=1.3, 95% CI=0.4–4.1) and for 20 years or more (OR=3.9, 95% CI=1.0–15.0). The authors indicated that the potential for recall bias was negligible. The risk of kidney cancer was increased with increasing years of exposure to insecticides or herbicides, on the basis of a small number of exposed cases; however, the exposures included exposure to herbicides, which cannot be separated from insecticide exposure.

Urologic Cancers

Several studies examine the relationship between pesticide exposure and urologic cancers. These studies did not contribute substantially to the committee’s conclusions because of the lack of specificity of exposure to insecticides and the use of job title as a surrogate of exposure. The studies on pesticide exposure and the risk of urologic cancers include: Alavanja et al., 1987; Aronson et al., 1996; Cantor and Booze, 1991; Dich and Wiklund, 1998; Fincham et al., 1992; Fleming et al., 1999a,b; Schlehofer et al., 1995; Sharpe et al., 2001; Viel and Challier, 1995; Wang and MacMahon, 1979; Wesseling et al., 1999; and Wiklund et al., 1989.

Summary and Conclusion

The body of literature on individual urologic cancers and exposure to insecticides is small and mostly includes studies of exposure to insecticides in general. Only one study focused on a specific product, the insect repellent DEET. Furthermore, for each urologic cancer, there is no more than one study that provides primary evidence for a conclusion, and

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

these studies involve small numbers of exposed cases. Table 5.7 identifies the key studies reviewed by the committee for each cancer type—prostate, testicular, bladder, and kidney—and exposure to insecticides.

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 prostate, testicular, bladder, and kidney cancers.

TABLE 5.7 Selected Epidemiologic Studies—Urologic Cancers and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Prostate Cancer:

Insecticides

Cohort Study—Mortality

Rapiti et al., 1997

Male workers in Italian chemical production plant

1

1.01 (0.05–4.79)a

Testicular Cancer:

Specific Insecticides

Case-Control Study

Hardell et al., 1998

Residents of Sweden

 

 

 

Insect repellent (DEET)

39

1.7 (1.03–2.8)

 

Univariate analysis

 

 

 

1–115 days

NA

1.2 (0.6–2.5)

 

≥115 days

NA

2.3 (1.2–4.4)

 

Multivariate analysis

 

 

 

1–115 days

NA

1.1 (0.6–2.3)

 

≥115 days

NA

2.1 (1.1–4.2)

Insecticides

Case-Control Study

Hardell et al., 1998

Residents of Sweden

12

0.7 (0.4–1.4)

Bladder Cancer:

Insecticides

Cohort Study—Mortality

Rapiti et al., 1997

Male workers in Italian chemical production plant

3

3.53 (0.96–9.12)a

Kidney Cancer:

Insecticides

Case-Control Study

Mellemgaard et al., 1994

Renal cell carcinoma cases in Denmark

 

 

 

Insecticide exposure

 

 

 

Males

11

2.2 (0.8–6.3)

 

Females

3

5.7 (0.60–58.0)

 

Insecticide/herbicide exposure

 

 

 

Males

7

1.3 (0.4–4.1)

 

<20 years

10

3.9 (1.0–15.0)

 

≥20 years

 

 

 

Females

2

0

 

<20 years

2

2.3b

 

≥20 years

 

 

NOTE: NA=not available.

a90% CI

bRisks of cancer at specific site for category of high pesticide use versus category of low pesticide use.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

BRAIN AND OTHER CENTRAL NERVOUS SYSTEM TUMORS

Brain and other central nervous system (CNS) tumors (ICD-9 191.0–191.9, 192.0–192.3, 192.8–192.9) are among the most deadly adult cancers (ACS, 2002a). Prognosis and treatment depend heavily on the location of the tumor in the CNS and the type of cell in which it develops. Survival rates vary with age. The 5-year relative survival rate of people 15–44 years old is close to 55%. Those 45–64 years old, however, have a 5-year survival rate of 16%, and those over 65 years old have a 5-year survival rate of 5%.

Histologic types of brain and other CNS cancers in the United States vary in their incidence and mortality by age, sex, and race. Rates are higher in males than in females, and whites have higher rates than blacks, followed by Hawaiians, Chinese, Japanese, and Filipino Americans, and Alaskan natives. Age-specific incidences show a peak under the age of 10 years, an exponential rise from the early 20s to 70 years, and then a decline with increasing age thereafter (Inskip et al., 1995).

The only established environmental risk factor for the development of brain and CNS cancers is exposure to radiation, which usually occurs during treatment for other cancers. Other people at risk include those with impaired immune systems or those with a family history of such disorders as neurofibromatosis type 2, tuberous sclerosis, and Von Hippel-Lindau disease. However, the risk factors for brain and CNS cancers remain largely unknown (ACS, 2002f; NCI, 2002u).

Epidemiologic Studies of Exposure to Insecticides

As pointed out by others (Blair and Zahm, 1995; Bohnen and Kurland, 1995), a major limitation in investigation of insecticides and brain cancer risk has been that most of the studies lack information regarding agents of exposure. Often, no specific exposure determination is undertaken, and analyses are based on job title or industry, such as farmer or agriculture. Another limitation is that many studies relied on death certificates to identify both exposure and disease (as reviewed by Khuder et al., 1998), and pathologic confirmation of the specific type of cancer is lacking. Brain and other CNS cancers can take many forms (such as meningioma, anglioblastoma, astrocytoma, and ganglioglioma), and most epidemiologic studies do not identify the histologic type, because of the lack of pathologic review. As a result, studies often analyze the broader category of “brain or CNS cancers.” Epidemiologic studies of brain and other CNS cancers must also address and consider the relatively low survival rate that limits the number of cases to interview and the aggressive nature of the disease, which adversely affects memory and the recall ability of patients. The key studies reviewed by the committee are discussed below, and relevant results are included in Table 5.8.

An ecologic study by Mills (1998) found no correlation between age-adjusted incidences of brain cancer and specific insecticide use, including diazinon, for all 58 California counties. The greatest limitation of this study is the lack of individual measurement of exposure and outcome, as well as the lack of information on other exposures and confounding variables, which could provide alternative explanations for the findings.

A few studies have examined the relationship between insecticide use and brain and other CNS cancers among farmers and agricultural workers. However, most studies are

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

limited by the lack of specific and validated exposure information, small numbers of exposed cases, potential recall bias in interview studies, and lack of control for potential confounding by other exposures. Morrison and colleagues (1992) conducted a cohort mortality study of 156,242 male Canadian prairie farmers in 1971–1987 and found an increase in brain cancer among farmers who treated their lands (150 or more acres) with insecticides. However, the exposure information was based on self-reports from proxies or next of kin and the number of brain cancer deaths observed in this population was extremely small (n=5).

A hospital-based case-control study by Musicco and colleagues (1988) in Milan, Italy, reported an increased risk of brain gliomas among those who used insecticides and fungicides (relative risk [RR]=2.1, 95% CI=1.27–3.58) compared with nonglioma brain tumor controls. Results were similar when the total control population (tumor controls and neurologic controls) was used for the comparison (RR=2.0, 95% CI=1.22–3.23). However, exposure information was based on self-reports, and the use of insecticides cannot be separated from the use of fungicides, which are not a part of the committee’s review.

Another case-control study evaluated the relationship between all CNS cancers and exposure to insecticides and fungicides. On the basis of death certificates from 24 US states, Cocco and colleagues (1998c) found that agricultural exposure to pesticides other than herbicides was associated with an increased risk of CNS cancer among white women (OR=1.4, 95% CI=1.0–1.8) and white men (OR=1.3, 95% CI=1.2–1.4). Controls were selected from subjects who died from nonmalignant diseases, excluding neurologic disorders. Industrial hygienists reviewed the occupation and industry combinations presented on the death certificates and developed a job-exposure matrix in which each combination was assigned a binary exposure value (exposed or unexposed). In their later analyses of the same dataset with a more detailed job-exposure matrix, in which each occupation-industry combination was assigned to one of four probability and intensity levels of exposure, the authors (Cocco et al., 1999b) again found an increased risk of CNS cancer among women (OR=1.3, 95% CI=1.1–1.5). However, there was no clear pattern of CNS cancer risk with increasing probability or intensity of exposure to insecticides and fungicides. Furthermore, the studies were not able to separate the specific role of insecticide exposure versus fungicide exposure and the risk of CNS cancer in this population.

Several studies examined the relationship between exposure to pesticides in general and brain and other CNS cancers among various occupationally exposed populations. Although several studies demonstrate an increase in brain and other CNS cancers, including studies of nonwhite farmers in North Carolina (Delzell and Grufferman, 1985), farmers in Sweden (Rodvall et al., 1996), and women in China (Heineman et al., 1994), the exposure information is based on self-reports, and the studies are not able to identify the specific agent responsible for the cancer risk increase. Issues of exposure misclassification, potential recall bias, and lack of control for confounding variables limit the value of these studies for drawing a conclusion. Studies on pesticide applicators and farmers licensed to use pesticides also found an increased risk of brain and other CNS cancers but used job titles as surrogates of exposure to pesticides (Alberghini et al., 1991; Corrao et al., 1989; Figa-Talamanca et al., 1993b; Godon et al., 1989; Pesatori et al., 1994; Viel et al., 1998; and Wiklund et al., 1989). The lack of specific information on exposure to insecticides limits the usefulness of these findings for the purposes of this report.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Summary and Conclusion

A number of epidemiologic studies have examined the relationship between brain and other CNS cancers and exposure to pesticides in general, but there is a paucity of evidence to determine whether insecticides or the specific insecticides that are the subject of the committee’s review were responsible for the observed increases in risk, especially among pesticide applicators, farmers, and agricultural workers. Those occupational groups are exposed to a multitude of chemicals other than insecticides, depending on the nature of their work, including organic dusts, solvents, other agricultural chemicals, fuels and engine exhausts, and infectious microorganisms. Table 5.8 identifies the body of literature reviewed and the 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 brain and other central nervous system cancers.

TABLE 5.8 Selected Epidemiologic Studies—Brain and Other CNS Tumors and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Insecticides

Cohort Study

Morrison et al., 1992

Canadian prairie farmers

5a

1.34 (0.55–3.25)

Case-Control Studies

Cocco et al., 1999b

Female CNS deaths in 24 US states

 

 

 

Insecticides and fungicides

210

1.3 (1.1–1.5)

Cocco et al., 1998c

CNS deaths in 24 US states

 

 

 

Pesticides other than herbicides

 

 

 

White men

1079

1.3 (1.2–1.4)

 

White women

62

1.4 (1.0–1.8)

Musicco et al., 1988

Brain glioma patients in Milan, Italy

 

 

 

Insecticide and fungicide users

37

2.1 (1.27–3.58)

aPrairie farmers who treated at least 150 acres with insecticides.

NON-HODGKIN’S LYMPHOMA

Cancers that originate in the lymphoid tissues—which include the lymph nodes, spleen, thymus, tonsils and adenoids, and bone marrow—are classified as lymphomas and account for about 5% of all new cancer cases in the United States. Lymphomas are divided generally into two categories according to cell histology: Hodgkin’s disease (discussed in the next section) and non-Hodgkin’s lymphoma (NHL), which includes all other types of lymphomas.

The incidence of NHL (ICD-9 200.0–200.8, 202.0–202.2, 202.8–202.9) has nearly doubled since the early 1970s but has stabilized among most demographic groups. The average age at diagnosis is the early 40s, but the incidence continues to increase dramatically with age, with the elderly at highest risk. Survival varies according to the

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

specific type of lymphoma; the average 5-year survival rates range from 30% to over 70% (ACS, 2002g).

Men have slightly higher incidences than women, and whites are affected more often than blacks or Asian Americans. In addition to age and race, risk factors for NHL include undergoing radiation therapy or chemotherapy for other cancers and a weakened immune system because of autoimmune disease, genetic immune deficiency, or use of immunosuppressant drugs. Infections with the human T-cell leukemia/lymphoma virus, human immunodeficiency virus, Helicobacter pylori bacteria, malaria, and the Epstein-Barr virus are also considered to be risk factors (ACS, 2002g; NCI, 2002v).

Epidemiologic Studies of Exposure to Insecticides

The relationship between agriculture-related occupations and NHL has been examined for many years. A number of well-conducted studies have focused on specific risk factors related to agricultural work, including use of insecticides and herbicides. The key studies reviewed by the committee are described below and summarized in Table 5.9.

The potential for increased risk of NHL with exposure to specific organophosphorous insecticides has been examined in several studies. The studies were generally case-control studies in which participants were interviewed about various types of pesticide use. Cantor and colleagues (1992) were among the first to use case-control studies to investigate the relationship between specific insecticides and NHL. Their subjects were 622 white men with NHL in Iowa (1981–1983) and Minnesota (1980–1982); NHL diagnosis was histologically confirmed. The authors interviewed cases and population-based controls, or close relatives or friends of deceased or incompetent subjects, to determine exposure to specific pesticides, including 23 animal insecticides and 34 crop insecticides. Although use was separated by crop or animal application, most of the agents were used on both.

NHL risk increased with the use of several agents; however, risk was not increased for ever handling dichlorvos and various other insecticides that were not considered in this report. Risk of NHL increased with the use of malathion as an animal or crop insecticide; and the risk was also greater for each type of application when exposure occurred without the use of protective equipment (ORanimal insecticide=1.4, 95% CI=0.8–2.2; ORcrop insecticide=1.9, 95% CI=0.9–4.1). Use of carbaryl on crops without personal protective equipment was also associated with increased NHL risk (OR=2.2, 95% CI=1.2–4.2). For several of the insecticides studied, use before 1965 resulted in higher risk estimates for NHL: malathion (ORcrops=2.9, 95% CI=1.1–7.4), diazinon (ORcrops=2.6, 95% CI=1.2–5.9) and carbaryl (ORcrops=3.8, 95% CI=1.1–13.6). The overall positive findings might indicate either a longer exposure timeframe or an adequate latency period for the development of lymphoma.

Risk of NHL was also associated with ever handling lindane as an animal insecticide (OR=1.4, 95% CI=1.0–2.1) and using it as a crop insecticide (OR=2.0, 95% CI=1.0–3.7). In supplemental interviews, Iowa farmers were asked about the number of days per year that they had used the insecticides. The resulting analysis did not show a trend of increased risk with increased use of lindane (1–4 days/year, OR=3.3; 5–9 days/year, OR=0.4; 10 or more days/year, OR=0.5), but this was based on small numbers of exposed cases (Cantor et al., 1993).

Although the authors conducted multiple comparisons in the study of Iowa and Minnesota cases, there was an increase in NHL risk with exposure to a number of insecticides. ORs were adjusted for vital status, age, state, cigarette smoking, family history

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

of lymphopoietic cancer, high-risk occupations, and high-risk exposures in a logistic analysis (OR>1.5). Exposure misclassification is a potential limitation of the study because of the high proportion of proxy respondents (28.9% of cases and 34.2% of controls), but, if nondifferential misclassification exists, it would bias the results to show no association.

Blair and colleagues (1998) pooled data from population-based case-control studies of NHL among white men in Kansas (Hoar et al., 1986), Nebraska (Zahm et al., 1990), and Iowa and Minnesota (Cantor et al., 1992) to investigate the association with exposure to lindane in greater detail than in the original studies while controlling for potential confounders, including other insecticides or herbicides such as 2,4-dichlorophenoxyacetic acid (2,4-D). Some 987 cases of NHL and 2895 population-based controls participated in the study and provided information on exposure to lindane, farm practices, and use of other agricultural chemicals through telephone interviews. Compared with nonfarmer controls, risk of NHL was increased in farmers who ever used lindane (OR=1.5, 95% CI=1.1–2.0); the risk was similar if use began more than 20 years before lymphoma diagnosis (OR=1.7, 95% CI=1.1–2.5). The findings were adjusted for age, proxy or direct interview, and state of residence but not for other pesticide use. Increased risk of NHL with lindane use was observed whether or not subjects wore protective equipment when lindane was used for fewer than 4 days/year and when it was used on more than 4 days/year. When exposures to carbaryl, diazinon, carbamates, and organophosphorous insecticides were controlled for in the analysis, the relative risk of NHL with lindane use was 1.2 to 1.5. Although the methodologies of the three case-control studies pooled are similar, differences may limit the interpretation of this study; but the study authors do not consider such differences in their discussion. Another limitation of this study is the use of proxy respondents; the risk of lindane use was higher in subjects with proxy respondents than in index subjects, and this suggests differential misclassification.

Zheng and colleagues (2001) further examined the pooled NHL data to look for any effect of carbamate pesticides on NHL risk with particular attention to carbaryl (Sevin). Exposure to carbaryl was ascertained through interviews with study participants or proxies, regarding exposure to carbaryl from farm use, personal handling, and length and frequency of use. Risk of NHL was increased with personal handling (OR=1.8, 95% CI=1.1–2.8), farm use (OR=1.6, 95% CI=1.0–2.4), use on less than 5 days/year (OR=2.4, 95% CI=1.0–5.9), and use on 5 or more days/year (OR=1.5, 95% CI=0.3–10.0). Analyses adjusted for age, type of respondent (proxy or index subject), state of residence, first-degree family history of cancer, use of hair dye, use of private wells, tobacco smoking, and exposure to other pesticides. Risk of NHL was also increased with 20 years or more since carbaryl exposure and with increasing duration of exposure.

Unlike some of the studies of insecticides and NHL, the Zheng study (2001) attempted to control for confounding by other pesticides. The authors indicated that they reached the same conclusions when limiting analyses to index respondents only; that indicates that the potential for recall bias was low. The lack of verified exposure information and the presence of nonoccupational sources of exposure are limitations of the study. However, the response rate was high, the sample was large, and possible confounders—such as exposure to other insecticides or pesticides, smoking, and family history of cancer—were controlled for in the analysis.

A case-control study conducted by Hardell and Eriksson (1999) included cases of NHL, 25 years old or older, and diagnosed in 1987–1990 in seven northern and middle

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

counties of Sweden. Comprehensive questionnaires were administered to 404 cases and 741 controls and followed up with supplemental telephone interviews. To decrease the potential for recall bias, deceased controls were used for deceased cases. Increased NHL risk was associated with exposure to pyrethrin (OR=1.3, 95% CI=0.5–3.4). Because only a univariate analysis was conducted for insecticides, confounding by other pesticides or agents cannot be ruled out. The large number of cases and the use of detailed questionnaires to estimate exposures are strengths of this study.

In a followup study of workers in the grain and flour industry, flour millers with more than 20 years of followup since first employment demonstrated an age-adjusted increased risk of NHL mortality (SMR=2.31, 95% CI=1.19–4.04) (Alavanja et al., 1990). Exposure to malathion was inferred from records and questionnaires. A nested case-control study of 21 cases of NHL in this cohort study found that the NHL risk increased with duration of followup since first employment in flour mills, from an OR of 1.5 (95% CI=0.2–13.9) for those followed less than 15 years to an OR of 9.4 (95% CI=1.4–61.5) for workers followed for 25 years or more. Work histories were available for only a small proportion of the cases and controls, and this limited the analyses by department and job. Also, the number of NHL cases in the cohort was small.

Most studies on agricultural chemical use and NHL risk have focused on men. Zahm and colleagues (1993) conducted a case-control study of the risk of NHL and exposure to insecticides among female agricultural pesticide workers in 66 counties in Nebraska. Increased risk of NHL was observed for diazinon (ORuse on farms=1.9; ORpersonal handling=4.1), malathion (ORuse on farms=1.9; ORpersonal handling=3.6), lindane (ORuse on farms=1.8), and carbaryl (ORuse on farms=2.6). All ORs were adjusted for age. Limitations of the study include the small number of exposed cases and the lack of information on activities most likely to result in exposure to the agents of concern among women.

Studies reviewed but not considered primary evidence in drawing conclusions included a PMR study among grain-industry workers who were probably exposed to malathion (Alavanja et al., 1987) and an ecologic study previously described, which correlated cancer rates, including NHL, with the number of pounds of diazinon used in California (Mills, 1998). Those studies are limited by the lack of individual exposure measurement and other characteristics of their designs, as discussed in Chapter 2.

Weisenburger (1990) conducted a case-control study of men in eastern Nebraska to examine the effect of agricultural exposure on NHL risk. Histologically confirmed NHL cases (n=201) and population-based controls (n=725) were interviewed by telephone to determine individual exposure to specific agricultural chemicals. On the basis of self-reported exposure, several classes of insecticides were associated with increased risk of NHL among men, including organophosphorous insecticides (OR=1.9, 95% CI=1.1–3.1). Recall bias and confounding by other pesticides and unidentified exposures are limitations of this study.

Using the Centers for Disease Control and Prevention Selected Cancers Study, Tatham and colleagues (1997) identified NHL cases in eight population-based registries in Atlanta, Connecticut, Iowa, Kansas, Miami, San Francisco, Detroit, and Seattle. Cases (n=1048) were diagnosed in 1984–1988 and confirmed by pathologic slide review. Controls (n =1659) were enrolled with random-digit dialing and were matched on registry location and age. No increased NHL risk was observed for exposure to organophosphorous insecticides (OR=0.66, 95% CI=0.43–1.00), carbamates (OR=0.93, 95% CI=0.56–1.50), or

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

pyrethroids (OR=0.52, 95% CI=0.14–1.90). Although the committee reviewed the relevant data points for all NHL cases combined, the primary focus of the Tatham study was risk factors related to different groups of NHL subtypes. The authors concluded that the lack of positive findings may indicate that the subgroups chosen are not etiologically distinct.

Several of the studies described above for specific insecticides also found NHL risk increased with exposure to classes of insecticides. Cantor and colleagues (1992) found an association between NHL and use of organophosphorous insecticides on crops or animals (OR=1.5, 95% CI=1.1–2.0), as did Zahm and colleagues (1993) with organophosphorous insecticides use on farms (OR=1.2, 95% CI=0.6–2.5). The association was stronger for personal handling of organophosphorous agents (OR=4.5, 95% CI=1.1–17.9).

NHL risk associated with use of carbamates (OR=1.1, 95% CI=0.8–1.7) was evaluated in the study by Cantor and colleagues (1992) described earlier; however, the study by Zahm and colleagues (1993) did not include enough cases exposed to carbamates to derive any estimated risk. Increased NHL risk was found in the study of men in eastern Nebraska exposed to carbamates (OR=1.8, 95% CI=1.0–3.2) (Weisenburger, 1990) and in the study by Zheng and colleagues (2001) of farmers who reported using carbamates as an insecticide (OR=1.6, 95% 1.2–2.2), as described above.

A study by Nanni and colleagues (1996) of combined cases of chronic lymphocytic leukemia (CLL) and NHL in a population-based case-control study in agricultural areas in Italy reported an increased risk of low-grade NHL and CLL (combined) with exposure to carbamates (OR=3.08, 95% CI=1.05–9.0). However, the value of the study’s findings is limited in that it combines two types of cancer cases that may have different risk factors and etiologies.

Several studies have examined the risk of NHL with exposure defined to encompass insecticides in general. The role of farm use of insecticides in the development of NHL and other diseases was examined by Hoar and colleagues (1986), who conducted a case-control study of 200 white men living in Kansas and diagnosed with NHL in 1979–1981. Cases were histologically confirmed. Three population-based controls, matched for age and vital status, were selected for each case. Insecticide use of greater than 3 days/year and adjusted for herbicide use showed an increase in NHL risk (OR=1.4, 95% CI=0.6–3.1). Exposure misclassification in this study resulting from vague questions concerning agents and errors in recall by the study subjects were likely to affect cases and controls in a similar manner.

Use of any insecticides on farms by female pesticide workers (study described above) showed a slightly decreased risk of NHL (OR=0.8, 95% CI=0.5–1.3), whereas personal handling of insecticides resulted in an increased risk (OR=1.3, 95% CI=0.7–2.3) (Zahm et al., 1993).

Scherr and colleagues (1992) reported on 303 cases of NHL diagnosed in 1980–1982 in the Boston metropolitan area; cases were histologically confirmed. Population-based controls were matched to cases on age and sex and interviewed directly or by proxy regarding exposure to agricultural chemicals. Among those reporting exposure to pesticides or insecticides, risk of NHL was increased (OR=1.8, 95% CI=0.9–3.7). However, the study is limited by the inclusion of exposure to pesticides in general and insecticides combined. Other studies with similarly broad exposure measures had inconsistent findings regarding NHL risk (Hardell and Eriksson, 1999; Settimi et al., 1999; Zhong and Rafnsson, 1996).

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Using death certificates to identify occupation and cases of NHL and other causes of death to use as controls, Cantor (1982) considered people listed as farmer to have been exposed to insecticides. NHL risk was increased in the 15 counties with highest insecticide use (OR=2.4, 95% CI=1.04–5.7) and to a smaller extent in all other counties (OR=1.53, 95% CI=1.00–2.3). The study is limited by its indirect and nonspecific exposure determination and by the use of death certificates for identifying cause of death and the use of occupation as a surrogate of exposure.

The potential relationship between working in agriculture or other occupations related to pesticides in general and increased risk of NHL has been examined in a number of studies. The studies provide supportive information for the discussion of insecticide exposure, but the agents measured were broadly defined.

Mortality studies investigating deaths from NHL among occupational groups likely to be exposed to pesticides, such as farmers and agricultural workers, have yielded inconsistent findings (e.g., Alavanja et al., 1988; Kross et al., 1996; Littorin et al., 1993; Ritter et al., 1990; Sathiakumar et al., 1992; Sperati et al., 1999). Studies of the incidence of NHL have also found mixed results among farmers and other populations likely to be exposed to pesticides in general (e.g., Corrao et al., 1989; Hansen et al., 1992; Waterhouse et al., 1996; Wiklund and Dich, 1994, 1995; Wiklund et al., 1989; Zahm, 1997).

Several case-control studies have examined the relationship between NHL and exposure defined as farming or pesticide use. Many of these studies have found a positive association between employment in such occupations or agricultural groups and NHL (e.g., Balarajan, 1988; Brownson and Reif, 1988; Burmeister et al., 1983; Cantor, 1982; Costantini et al., 2001; Pasqualetti et al., 1991; Pearce et al., 1985, 1987); other published case-control studies found no relationship between pesticide-associated occupations and NHL (e.g., Franceschi et al., 1989; Fritschi and Siemiatycki, 1996; Schumacher and Delzell, 1988).

Although those studies of pesticide users provide supportive data, no specific insecticide or class of insecticides can be implicated from such broadly defined surrogate exposure measures. In general, the studies could not measure the numerous potential confounders of pesticide-related occupations, including fuel emissions from agricultural equipment, herbicides or fungicides, or a number of other chemicals. Many studies appear to support a relationship between NHL and herbicide exposures, but there is a great potential for confounding between insecticide and herbicide use.

Summary and Conclusion

A number of well-conducted case-control studies show an increased NHL risk associated with exposure to specific organophosphorous and carbamate insecticides respectively. By design, such studies assign specific exposures to individual subjects albeit without direct workplace or environmental measurements; in these studies, increased risks were observed with exposure to organophosphorous agents and carbamates in general and malathion, diazinon, lindane, and carbaryl exposure in particular. However, there are too few studies with exposure measurements at the individual insecticide level to draw conclusions on any specific insecticide. The increase in risk estimates, especially those related to organophosphorous insecticides and carbamates, lend support to a possible association. Those associations are consistently increased across various categorizations of the type of use or the source of the exposure information (self-report or proxy respondent). In addition, the studies that have examined insecticide and pesticide use in general have

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

shown increased NHL risks. The potential for downward bias resulting from a healthy worker effect inherent in studies with occupationally exposed cases and population controls also underscore the positive results. Table 5.9 identifies the critical studies reviewed by the committee and the relevant data used in drawing its conclusion.

The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to organophosphorous insecticides or to carbamates and non-Hodgkin’s lymphoma.

TABLE 5.9 Selected Epidemiologic Studies—Non-Hodgkin’s Lymphoma and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Specific Insecticides

Case-Control Studies

Zheng et al., 2001

Pooled analysis of NHL cases

 

 

 

Carbaryl (farm use based on all subjects)

45

1.6 (1.0–2.4)

 

Carbaryl (farm use based on all subjects, adjusted for other pesticides)

45

1.4 (0.9–2.2)

Hardell and Eriksson, 1999

Residents of northern and middle Sweden

 

 

 

Pyrethrins

10

1.3 (0.5–3.4)

Blair et al., 1998

Pooled analysis of NHL cases

 

 

 

Lindane (used by farmer, index respondents)

93

1.5 (1.1–2.0)

Zahm et al., 1993

Female residents of eastern Nebraska

 

 

 

Diazinon (farm use)

7

1.9

 

Diazinon (personally handled)

2

4.1 (0.4–43.2)

 

Malathion (farm use)

9

1.9

 

Malathion (personally handled)

3

3.6 (0.5–23.9)

 

Carbaryl (farm use)

5

2.6

 

Lindane (farm use)

5

1.8

Cantor et al., 1992

Residents of Iowa and Minnesota, ever handled:

 

 

 

Diazinon (crop insecticide)

27

1.5 (0.9–2.5)

 

Dichlorvos (animal insecticide)

20

1.2 (0.7–2.2)

 

Malathion (animal insecticide)

43

1.3 (0.9–2.1)

 

Malathion (crop insecticide)

21

1.5 (0.8–2.7)

 

Carbaryl (crop insecticide)

21

1.7 (0.9–3.1)

 

Lindane (animal insecticide)

55

1.4 (1.0–2.1)

 

Lindane (crop insecticide)

21

2.0 (1.0–3.7)

 

Dichlorvos (animal insecticide)

20

1.2 (0.7–2.2)

Classes of Insecticides

Case-Control Studies

Zheng et al., 2001

Pooled analysis of NHL cases

 

 

 

Carbamates (insecticide use based on all subjects)

89

1.6 (1.2–2.2)

Tatham et al., 1997

CDC Selected Cancers Study

 

 

 

Organophosphorous agents

37

0.66 (0.43–1.00)

 

Carbamates

27

0.93 (0.56–1.50)

 

Pyrethroids

3

0.52 (0.14–1.90)

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Zahm et al., 1993

Female residents of eastern Nebraska

 

 

 

Carbamates (farm use)

7

1.6 (0.6–4.4)

 

Organophosphorous agents (farm use)

14

1.2 (0.6–2.5)

 

Organophosphorous agents (personally handled)

6

4.5 (1.1–17.9)

Cantor et al., 1992

Residents of Iowa and Minnesota, ever handled:

 

 

 

Organophosphorous agents (either use)

96

1.5 (1.1–2.0)

 

Carbamates (crop or animal)

43

1.1 (0.8–1.7)

Weisenburger et al., 1990

Male residents of eastern Nebraska

 

 

 

Organophosphorous agents

NA

1.9 (1.1–3.1)

 

Carbamates

NA

1.8 (1.0–3.2)

Insecticides

Case-Control Studies

Hardell and Eriksson, 1999

Residents of northern and middle Sweden

 

 

 

Insecticides

90

1.2 (0.8–1.7)

Zahm et al., 1993

Female residents of eastern Nebraska

 

 

 

Insecticides (farm use)

56

0.8 (0.5–1.3)

 

Insecticides (personally handled)

22

1.3 (0.7–2.3)

Hoar et al., 1986

Residents of Kansas

 

 

 

Insecticides (adjusted for herbicide use)

 

 

 

3+ days/year

14

1.4 (0.6–3.1)

NOTE: NA=not available.

HODGKIN’S DISEASE

Hodgkin’s disease (HD) (ICD-9 201.0–201.9) differs from NHL in cellular origin and can be identified by the presence of Reed-Sternberg cells in biopsied tissue. HD is far less common than NHL (ACS, 2002a). In the United States, incidence and mortality have been decreasing since the early 1970s, and the 5-year survival rate has increased to 82%. The highest rates of HD are found among persons 15–35 years old and over 55 years old. People infected with the Epstein-Barr virus or having weakened immune systems seem to be at greater risk for HD. Some cases in which members of the same family have developed HD suggest a genetic predisposition, common environmental exposures, or both, but no major risk factors have been discovered (ACS, 2002h; NCI, 2002w).

Epidemiologic Studies of Exposure to Insecticides

 

Few studies have examined the relationship between HD and exposure to specific insecticides thought to have been used during the Gulf War. The literature reviewed by the committee and its strengths and limitations are discussed below, and relevant results are presented in Table 5.10.

Although the risk of HD has been investigated among farmers, agricultural workers, and others known to be exposed to pesticides, only one case-control study (Zahm and colleagues, 1988) specifically examined the effect of insecticides on the risk of HD. Cases were selected from among white men, 21 years old or older who were diagnosed in 1976–1982 in Kansas. A total of 121 HD cases remained in the analysis after initial diagnosis,

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

pathology review and confirmation, and completion of telephone interview. Population-based controls were matched 3:1 on age and vital status. No association with HD was observed for farming-related exposure to general insecticides (OR=0.8, 95% CI=0.5–1.4) and animal insecticides (OR=0.9, 95% CI=0.5–1.5). Use of crop insecticides also resulted in no excess risk of HD (OR=1.1, 95% 0.6–1.9). The study is limited by nonspecific exposure information and the possibility of nondifferential misclassification of exposure.

A PMR study by Alavanja and colleagues (1987) examined the risk of lymphatic and hematopoietic malignancies, including HD, among workers in the grain industry; exposure was inferred from employment information, union records, and responses to questionnaires from some of the subjects. On the basis of one death, a PMR of 1.74 was found for HD among all grain-mill workers. However, the lack of individual exposure data and the fact that only one case of HD was observed are limitations of this study. Given the inherent limitations in the design of a PMR study, such results were considered only as supportive evidence.

The possible association between HD and work in agricultural professions has been explored in numerous studies. The studies provide some background for the committee’s discussion but do not provide the specificity of exposure to insecticides needed to draw conclusions of association for this review. The relevant mortality studies have had inconsistent findings; increased risk of HD was found in some studies (Alavanja et al., 1988; Balarajan, 1988; Franceschi et al., 1991; Persson et al., 1993; Waterhouse et al., 1996; Wiklund and Dich, 1994, 1995; Wiklund et al., 1989) but not in others (Brownson and Reif, 1988; Costantini et al., 2001; Fritschi and Siemiatycki, 1996; Pearce et al., 1985; Zahm, 1997).

Summary and Conclusion

Most of the relevant studies on HD have characterized exposure broadly and have examined increased risks related to agricultural occupations or pesticides in general. The results, including those of the few studies on insecticide exposure, have been inconsistent with regard to a relationship between exposure to pesticides or insecticides and the risk of HD. There is insufficient evidence to examine the potential effects of exposure to insecticides on this health outcome. Table 5.10 highlights the key study reviewed by the committee and the relevant data considered in drawing its conclusion.

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 Hodgkin’s disease.

TABLE 5.10 Selected Epidemiologic Studies—Hodgkin’s Disease and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Insecticides

Case-Control Study

Zahm et al., 1988

Residents of Kansas

 

 

 

Insecticides (ever use)

38

0.8 (0.5–1.4)

 

Insecticides (crop use)

25

1.1 (0.6–1.9)

 

Insecticides (animal use)

32

0.9 (0.5–1.5)

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

MULTIPLE MYELOMA

Multiple myeloma (MM) (ICD-9 203.0, 203.2–203.8) is a relatively rare cancer, accounting for only about 1% of all new cancers diagnosed per year in the United States (ACS, 2002a). It is characterized by excessive proliferation and disordered function of plasma cells (a type of white blood cell formed from B-cell differentiation). The causes of MM are not known, but age and race are considered risk factors. Incidence increases dramatically with age; nearly 98% of all new cases occur in people over 40 years old, and MM occurs twice as often in blacks as in whites. Exposure to ionizing radiation, family history of cancer, occupational exposure in petroleum-related industries, and the presence of other plasma cell diseases are other possible risk factors. In many cases, MM does not cause noticeable symptoms until it is well advanced. However, if it is detected in Stage 1 of its development, the 5-year survival rate is about 50% (ACS, 2002i; NCI, 2000).

Epidemiologic Studies of Exposure to Insecticides

There are few studies in the literature of exposure to insecticides and the risk of MM. The studies that were reviewed included small numbers of exposed cases, lacked specific and validated exposure information, and did not control for potential covariates in the analysis. The key studies reviewed by the committee, including the strengths and limitations of the data, are discussed below with results shown in Table 5.11.

A case-control study conducted by Brown and colleagues (1993) examined MM in 173 white males diagnosed in 1981–1984 in Iowa and exposure to a number of insecticides, including malathion, dichlorvos, lindane, and carbaryl. A pathologist confirmed all diagnoses, which were identified through the Iowa Health Registry. To determine past exposures to specific insecticides, the authors interviewed cases (or close relatives) and population-based controls (n=650) about specific exposure to 24 animal insecticides and 34 crop insecticides. An increased risk of MM was associated with use of dichlorvos (OR=2.0, 95% CI=0.8–5.0) as an animal insecticide, malathion (OR=1.9, 95% CI=0.8–4.6) as a crop insecticide, and handling, mixing, or applying carbaryl for crop use (OR=1.5, 95% CI =0.6–3.9). No risk was observed in persons mixing, handling, or applying malathion as an animal insecticide (OR=0.8, 95% CI=0.3–1.9). Although the study shows a slightly increased risk of MM with exposure to a number of specific insecticides, the risk was greater among deceased cases (interviewed by proxy through the closest relatives) than among living cases indicating the potential for recall bias.

Brown and colleagues’ study was an expansion of Burmeister’s (1990) earlier case-control study on the same set of Iowa males. Although Brown and colleagues were able to identify specific animal and crop insecticides, Burmeister focused on the classes of insecticides. Increased odds ratios were evident for animal and crop use of organophosphorous insecticides (OR=1.22 and 1.31, respectively) and for carbamates used on crops (OR=1.83) but not on livestock (OR=1.00). No association was found between MM and pyrethrins used as livestock insecticides. As in the Brown and colleagues study, small numbers of exposed cases and the potential for differential recall bias between proxy and living cases are limitations.

Nanni and colleagues (1998) conducted a case-control study in the largely agrarian province of Forli, Italy. The Romagna Cancer Registry was used to identify 46 MM cases

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

diagnosed in 1987–1990 for study inclusion. On the basis of three exposed cases, a multivariate analysis revealed a slightly increased risk of MM with exposure to carbamate insecticides (as a class) for those reporting exposure at any point in time and for those who used the insecticides in their profession. Although an a priori matrix was used in assessing exposure, which probably reduced recall bias, there is still the potential for nondifferential misclassification of exposure, which would tend to reduce the risk estimate. The authors also stated that the MM diagnosis may have been less accurate among residents who lived farther from the main specialized hospitals in Italy. The small number of exposed cases also limits the value of the findings of this study.

Two studies of MM mortality and occupation as farmer obtained from death certificates in Iowa (Burmeister et al., 1983) and Wisconsin (Cantor and Blair, 1984) used regional production of crops or livestock as the basis of estimating relative amounts of insecticide use by county. Although the risk of MM was increased in both studies in areas where insecticide use was estimated to be high, the committee did not consider those two studies critical in forming their conclusions, because exposure and disease outcome data were based on death certificates only and there was no further specification or validation of exposure or disease status. Furthermore, the exposure estimates used are approximations of county-wide agricultural practices and do not apply to all residents of every county.

Possible sex-related differences in MM risk were examined by Zahm and colleagues (1992) in a case-control study of agricultural exposures in eastern Nebraska. Exposure to insecticides yielded no association in men (OR=0.6, 95% CI=0.2–1.4) on the basis of 11 cases, but women experienced an increased MM risk (OR=2.8, 95% CI=1.1–7.3) on the basis of 21 cases. The increased MM risk among women is difficult to explain but could have been due to chance or to confounding by other exposures.

The Brown and colleagues study described above found a slightly increased risk of MM among persons reporting exposure to and use of insecticides (OR=1.2, 95% CI=0.9–1.8) (Brown et al., 1993).

A number of studies have looked at MM risk among workers potentially exposed to pesticides. Exposures were broadly characterized, and separate analyses are not provided on more relevant exposures of concern, such as exposure to insecticides. Cohort mortality studies (Ritter et al., 1990; Sperati et al., 1999; Viel and Richardson, 1993), incidence studies (Kristensen et al., 1996; Wiklund and Dich, 1994, 1995; Wiklund et al., 1989), and case-control studies (Brownson and Reif, 1988; Costantini et al., 2001; Demers et al., 1993; Eriksson and Karlsson, 1992; Fritschi and Siemiatycki, 1996; Pearce et al., 1985) of MM and exposure to pesticides have shown mixed results. Although some studies show an increased MM risk with pesticide use, they do not evaluate the specific agents of interest needed to draw conclusions for the purposes of this review.

Summary and Conclusion

Several studies that have examined the association between MM risk and exposure to specific insecticides, classes of insecticides, and insecticides in general show small positive associations. However, this body of evidence is limited by the lack of specific or valid exposure determinations, small numbers, and the likelihood that the small associations are due to bias and chance. It is interesting that a number of studies show slight increases in risk; future research to explore the relationship between exposure to insecticides and MM needs additional statistical power—larger numbers of subjects and better measures of

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

exposure. Table 5.11 highlights the key studies reviewed by the committee and the relevant data considered in drawing its conclusion.

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 multiple myeloma.

TABLE 5.11 Selected Epidemiologic Studies—Multiple Myeloma and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Specific Insecticides

Case-Control Study

Brown et al., 1993

Male residents of Iowa

 

 

 

Dichlorvos (animal use)

7

2.0 (0.8–5.0)

 

Lindane (animal use)

16

1.1 (0.6–2.0)

 

Lindane (crop use)

5

1.2 (0.4–3.4)

 

Malathion (animal use)

6

0.8 (0.3–1.9)

 

Malathion (crop use)

8

1.9 (0.8–4.6)

 

Carbaryl (crop use)

6

1.5 (0.6–3.9)

Classes of Insecticides

Case-Control Studies

Nanni et al., 1998

Residents of Forli, Italy

 

 

 

Carbamates (total exposed)

3

1.2 (0.6–2.3)

 

Carbamates (professionals only)

3

1.7 (0.4–6.9)

Burmeister, 1990

Male residents of Iowa

 

 

 

Organophosphorous agents (crops)

NA

1.31

 

Organophosphorous agents (livestock)

NA

1.22

 

Carbamates (crops)

NA

1.83

 

Carbamates (livestock)

NA

1.00

 

Pyrethrins (livestock)

NA

1.00

Insecticides

Case-Control Studies

Brown et al., 1993

Male residents of Iowa

 

 

 

Insecticides

91

1.2 (0.9–1.8)

Zahm et al., 1992

Residents of Nebraska

 

 

 

Insecticides (male)

11

0.6 (0.2–1.4)

 

Insecticides (female)

21

2.8 (1.1–7.3)

ADULT LEUKEMIA

The four main types of leukemia—acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML) (ICD-9 204.0, 204.1, 205.0, 205.1)—are grouped by the developmental pace of the disease and the type of blood cell affected. Therefore, the disease can be either acute or chronic and can affect either myeloid or lymphocytic cells (ACS, 2002j).3

3  

The ICD codes for all types of leukemia include ICD-9 202.4, 203.1, 204.0–204.9, 205.0–205.9, 206.0–06.9, 207.0–207.2, 207.8, 208.0–208.9.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

AML is the most common type of leukemia in adults; it is evenly distributed between sexes and occurs in both adults and children, but CLL almost never occurs in children. CML is mostly limited to adults and is the third most common type of leukemia. ALL, the most common form of leukemia in children, accounts for the smallest number of adult cases of leukemia (ACS, 2002a; NCI, 2002x). (Conclusions regarding exposure to insecticides and childhood cancers are discussed at the end of this chapter.) A fifth type of leukemia—hairy cell leukemia (HCL) (ICD-9 202.4)—is similar to CLL in that it is a slowly progressing cancer of the lymphocytes. However, because the cells have a different morphology, HCL is often considered separately. Accounting for an estimated 2% of all leukemia cases diagnosed in adults each year, HCL most often affects adults over 50 years old (ACS, 2002j).

Overall, the 5-year survival rate of leukemia patients is 44%—a rate that has tripled in the last 40 years. The survival rates for the types of leukemia differ markedly: 14% for AML, 32% for CML, 58% for ALL, and 71% for CLL. Leukemia is known to be associated with exposure to benzene, high doses of radiation, chemical drugs used to treat other cancers, and smoking. One factor currently under investigation is exposure to electromagnetic fields. However, none of those exposures can explain the majority of leukemia cases diagnosed each year. Rare inherited diseases—such as Fanconi’s anemia, Wiskott-Aldrich syndrome, Bloom’s syndrome, Li-Fraumeni syndrome, Down’s syndrome, and ataxia telangiectasia—also increase the risk of acute leukemia (ACS, 2002j; NCI, 2002x).

Epidemiologic Studies of Exposure to Insecticides

Several studies examined the relationship between exposure to specific insecticides, classes of insecticides, and insecticides in general and the risk of adult leukemia. The discussion below describes the key studies evaluated by the committee in making its conclusion of associaiton, and results of these studies are found in Table 5.12.

Of the studies that examined the relationship between exposure to insecticides and the risk of adult leukemia, only one evaluated the role of specific insecticides—a case-control study by Brown and colleagues (1990) of confirmed leukemias in 578 men in Minnesota (1980–1982) and Iowa (1981–1983). The authors interviewed cases or close relatives to determine exposures and the use of 112 pesticides, including 58 insecticides. Risk of leukemia with ever handling specific animal insecticides was evaluated for carbaryl (OR=1.3, 95% CI=0.5–3.2), dichlorvos (OR=2.0, 95% CI=1.2–3.5), lindane (OR=1.1, 95% CI=0.7–1.7), and malathion (OR=1.2, 95% CI=0.8–2.0). Risk of leukemia with ever handling crop insecticides was evaluated for carbaryl (OR=0.9, 95% CI=0.4–2.1), diazinon (OR=1.2, 95% CI=0.6–2.1), lindane (OR=1.6, 95% CI=0.8–3.2), and malathion (OR=0.9, 95% CI=0.4–1.9). The authors also conducted supplemental interviews of self-identified Iowa pesticide users to obtain information about the usual number of days per year that insecticides were handled. No clear exposure-response patterns were found between leukemia risk and increasing number of days per year of insecticide use. The study authors acknowledge the role of nondifferential exposure misclassification (including difficulty in recalling information by self-respondents and next of kin) and recall bias in the findings and note that the multiple statistical comparisons make it likely that some findings may be due to chance alone. Uncontrolled confounding by exposure to other insecticides or pesticides, such as herbicides, is also a limitation of the study.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

A case-control study by Clavel and colleagues (1996) examined HCL and exposure to various classes of insecticides, including organophosphorous insecticides, carbamates, and pyrethrins. The investigators included 226 histologically confirmed cases of HCL in hospitals in France in 1980–1990 and 425 hospital-based controls hospitalized in the same hospitals at about the same time as the cases. Patients admitted for cancer or for work-related diseases or accidents were not eligible to serve as controls. All cases and controls were sent self-administered questionnaires to ascertain occupational and leisure time exposures, sociodemographic characteristics, smoking, and other behaviors. All persons who identified themselves as farmers were interviewed at home by occupational physicians who specialized in agricultural work. Among farmers, risk of HCL was increased with exposure to organophosphorous insecticides (OR=2.6, 95% CI=1.1–5.7) and pyrethrins (OR=1.6, 95% CI=0.7–3.9) but not carbamates (OR=0.7, 95% CI=0.2–2.8). Limitations of the study include the potential for nondifferential misclassification due to recall difficulties and the grouping of insecticides into broad categories. Because data on exposure to the classes of insecticides were missing for more than 50% of the self-identified farmers, results were interpreted cautiously.

The case-control study by Brown and colleagues (1990) described above found an increased risk of all leukemias with ever handling pyrethrins (ORanimal=3.7, 95% CI=1.3–10.6), carbamates (ORanimal=1.5, 95% CI=0.6–3.6; ORcrops=1.4, 95% CI=0.9–2.2) and organophosphorous insecticides (ORanimal=1.5, 95% CI=1.0–2.1; ORcrops=1.2, 95% 0.8–1.8).

Nanni and colleagues (1996) conducted a population-based case-control study in agricultural areas in Italy to examine the relationship between CLL and NHL and exposure to insecticides, which was discussed earlier in this chapter. The odds ratios for all CLL and low-grade NHL cases were elevated for exposure to carbamates based on recall data (OR=3.08, 95% CI=1.05–9.00) and the matrix (OR=2.95, 95% CI=1.01–8.60). The odds ratios were also increased for exposure to insecticides based on both recall data and the matrix, but only the odds ratio based on recall was statistically precise. Since the study combined cases of CLL and low-grade NHL in its analysis, the study’s findings are limited and the true effect of exposure on CLL cannot be determined and the results are not captured in Table 5.12.

Two of the studies described above examined the association between leukemia and exposure to insecticides in general. Brown and colleagues found an increase in CLL with use of any insecticide (OR=1.3, 95% CI=1.0–1.8), as well as increases with overall animal or crop use. An increased HCL risk with exposure to insecticides in general was reported by Clavel and colleagues (OR=1.8, 95% CI=1.1–3.0) (1996).

Nordstrom and colleagues (1998) conducted a population-based case-control study of 121 men with HCL identified from the Swedish Cancer Registry and diagnosed in 1987–1992 and 484 matched controls. Study participants completed mailed questionnaires, and a trained interviewer followed up by telephone with supplementary questions. Although an association was found when adjusting for age only, (OR=2.0, 95% CI=1.1–3.5), controlling for other variables not explicitly stated eliminated any association (OR=0.7, 95% CI=0.3–1.7).

Richardson and colleagues (1992) reported on a case-control study of confirmed acute leukemia cases and hospital-based controls (not leukemia or lymphoma) identified in departments other than the department from which the cases were selected (hematology).

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Exposure to insecticides was determined through interviews of the cases and controls and independently assessed by an industrial hygienist. Risk of acute leukemia was increased with exposure to insecticide (OR=1.7, 95% CI=1.0–3.1); the magnitude of the risk increased with 10 years or more of exposure (OR=4.0, 95% CI=1.2–13.2). The authors also examined the relationship between exposure to insecticides and the two cytologic types of acute leukemia—ALL and AML. Both increased with exposure to insecticides (ORALL=3.29, 95% CI=1.16–9.36; ORAML=1.51, 95% CI=0.79–2.89).

Only one case of leukemia was observed in the study of male chemical workers (Rapiti et al., 1997). Semenciw and co-workers (1994) assembled a cohort of 155,547 farmers from the population of Alberta, Saskatchewan, and Manitoba, Canada, by linking the 1971 Canadian Censuses of Agriculture and Population. Diagnosis of leukemia was determined from death certificates filed in 1971–1987 and linked to the cohort. Exposure was considered to be the number of acres sprayed with insecticides in 1970; risk of leukemia was not increased by spraying of 90 acres or more with insecticides (RR=1.08, 95% CI=0.51–2.28) on the basis of seven cases. Extremely small numbers and lack of individual exposure data limit the value of the findings of both studies.

Two studies identified leukemia cases and usual occupation as farmers from death certificates (Blair and Thomas, 1979; Burmeister et al., 1982); insecticide exposure was estimated from quantity of use in the county of usual residence. The studies are of little value for supporting conclusions because neither leukemia diagnosis nor the agents were verified, and both are probably subject to nondifferential misclassification, which would tend to move associations toward the null value.

A few studies already discussed above (Clavel et al., 1996; Richardson et al., 1992) and others (Ciccone et al., 1993; Johnson et al., 1993; Kristensen et al., 1996; Pasqualetti et al., 1991; Viel and Richardson, 1993; Zhong and Rafnsson, 1996) examined the relationship between exposure to pesticides and adult leukemia among various, occupationally exposed populations, but do not provide exposure specificity beyond the broad grouping of pesticides. In addition, studies of pesticide applicators (Cantor and Booze, 1991; Fleming et al., 1999a,b; Sperati et al., 1999), farmers (Brownson et al., 1989; Rafnsson and Gunnarsdottir, 1989), and agricultural workers (Hansen et al., 1992; Linet et al., 1994) use job titles as surrogates for exposure. As a result, the lack of specific and validated exposure measurements limits the contributions of these studies toward determining an association between exposure to insecticides under review and leukemia risk.

Summary and Conclusion

Although specific and accurate exposure information on insecticide use is difficult to ascertain in epidemiologic studies, most populations studied involve workers who use insecticides on a regular basis over the course of many years. A majority of the studies discussed above reported an increased risk of leukemia, especially among those exposed to organophosphorous insecticides. The studies on specific organophosphorous agents, such as diazinon, dichlorvos, and malathion, as well as on the broader category of insecticides provided additional support to a conclusion on exposure to organophosphorous compounds. Most of the findings were of sufficient statistical power to detect a precise estimate of risk. Given that most studies included all types of leukemia and that more specific cell types were identified in only a limited number of studies, the committee focused its conclusion on adult leukemia broadly. Table 5.12 provides a description of the population, the number of

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

exposed cases, the estimated risk, and the confidence interval for the studies reviewed by the committee in making its conclusion regarding association.

The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between chronic exposure to organophosphorous insecticides and adult leukemia.

TABLE 5.12 Selected Epidemiologic Studies—Adult Leukemia and Exposure to Insecticides

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Specific Insecticides

Case-Control Studies

Brown et al., 1990

Residents of Iowa and Minnesotaa

 

 

 

Carbaryl

 

 

 

Animal insecticide, ever handled

7

1.3 (0.5–3.2)

 

Animal insecticide, 20 years ago

4

3.0 (0.7–12.4)

 

Crop insecticide, ever handled

9

0.9 (0.4–2.1)

 

Diazinon

 

 

 

Crop insecticide, ever handled

17

1.2 (0.6–2.1)

 

Crop insecticide, 1–4 days/year

8

2.1 (0.8–5.6)

 

Crop insecticide, 5–9 days/year

2

0.5 (0.1–2.4)

 

Crop insecticide, 10+ days/year

0

 

Dichlorvos

 

 

 

Animal insecticide, ever handled

26

2.0 (1.2–3.5)

 

Animal insecticide, 1–4 days/year

5

1.3 (0.4–4.0)

 

Animal insecticide, 5–9 days/year

0

 

Animal insecticide, 10+ days/year

5

3.8 (1.0–14.8)

 

Lindane

 

 

 

Animal insecticide, ever handled

38

1.1 (0.7–1.7)

 

Animal insecticide, 20 years ago

28

1.4 (0.8–2.3)

 

Animal insecticide, 1–4 days/year

15

1.1 (0.5–2.0)

 

Animal insecticide, 5–9 days/year

3

1.1 (0.3–4.1)

 

Animal insecticide, 10+ days/year

10

1.6 (0.7–3.7)

 

Crop insecticide, ever handled

14

1.6 (0.8–3.2)

 

Crop insecticide, 1–4 days/year

6

3.5 (0.9–12.6)

 

Crop insecticide, 5–9 days/year

2

1.2 (0.2–6.9)

 

Crop insecticide, 10+ days/year

3

1.3 (0.3–5.3)

 

Malathion

 

 

 

Animal insecticide, ever handled

30

1.2 (0.8–2.0)

 

Animal insecticide, 20 years ago

15

1.5 (0.8–2.9)

 

Animal insecticide, 1–4 days/year

5

0.5 (0.1–1.3)

 

Animal insecticide, 5–9 days/year

0

 

Animal insecticide, 10+ days/year

7

3.2 (1.0–10.0)

 

Crop insecticide, ever handled

10

0.9 (0.4–1.9)

 

Crop insecticide, 1–4 days/year

4

1.2 (0.3–3.9)

 

Crop insecticide, 5–9 days/year

2

0.8 (0.2–4.4)

 

Crop insecticide, 10+ days/year

0

 

Pyrethrins

 

 

 

Animal insecticide, ever handled

8

3.7 (1.3–10.6)

 

Animal insecticide, 20 years ago

5

3.8 (1.0–14.8)

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Reference

Study Population

Exposed Cases

Estimated Relative Risk (95% CI)

Case-Control Studies

Clavel et al., 1996

HCL cases in France

 

 

 

Organophosphorous agents

14

2.6 (1.1–5.7)

 

Pyrethrins

10

1.6 (0.7–3.9)

 

Carbamates

3

0.7 (0.2–2.8)

Brown et al., 1990

Residents of Iowa and Minnesota

 

 

 

Carbamates (animal insecticide)

8

1.5 (0.6–3.6)

 

Carbamates (crop insecticide)

44

1.4 (0.9–2.2)

 

Organophosphorous agents (animal insecticide)

55

1.5 (1.0–2.1)

 

51

1.2 (0.8–1.8)

 

Organophosphorous agents (crop insecticide)

 

 

Insecticides

Cohort Studies—Mortality

Rapiti et al., 1997

Chemical workers in Italy

1

2.00 (0.10–9.49)

Semenciw et al., 1994

Canadian farmers who sprayed 90+ acres

7

1.08 (0.51–2.28

Case-Control Studies

Clavel et al., 1996

HCL cases in France

37

1.8 (1.1–3.0)

Nordstrom et al., 1998

HCL cases in Sweden

 

 

 

Univariate analysis

22

2.0 (1.1–3.5)

 

Multivariate analysis

22

0.7 (0.3–1.7)

Richardson et al., 1992

Residents near Paris, France

 

 

 

Insecticides

22

1.7 (1.0–3.1)

 

≤10 years

1

0.5 (0.1–4.1)

 

>10 years

7

4.0 (1.2–13.2)

 

Insecticides and ALL

6

3.29 (1.16–9.36)

 

Insecticides and AML

16

1.51 (0.79–2.89)

Brown et al., 1990

Residents of Iowa and Minnesota

 

 

 

Used any insecticide (all types)

250

1.1 (0.9–1.3)

 

Animal insecticide (all types)

238

1.1 (0.8–1.3)

 

Crop insecticide (all types)

134

1.1 (0.8–1.4)

 

CLL (any insecticide)

122

1.3 (1.0–1.8)

aFor all data points, risk estimates for specific animal and crop insecticides are taken from analysis of ever having handled these insecticides.

CHILDHOOD CANCER

Childhood cancer is defined by ACS as cancer diagnosed between birth and the age of 14 years. The causes of most childhood cancers are not well known, especially with regard to potential environmental risk factors. Some of the suggested risk factors are genetics, advanced maternal age, birthweight of more than 4000 g, prenatal viral exposure, prenatal radiation exposure, parental cigarette smoking, and parental occupation (Ross and Swensen, 2000).

Childhood cancers are rare. Developments in treatment and supportive care for some types have enabled 75% of afflicted children to survive 5 years or more, and mortality from all childhood cancers combined has declined by 50% since 1973. Nevertheless, cancer is still the leading cause of death from disease in children age up to 14 years old (ACS, 1999).

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Leukemia is the most common cancer in children and accounts for almost one-third of all childhood cancers. ALL is the most common leukemia in children, accounting for nearly 75% of all leukemia cases (ACS, 2002k). Slightly more prevalent among white children and among boys, ALL generally occurs in early childhood, particularly at the age of 2–3 years. The 5-year survival rate for ALL among children has increased to nearly 80%, primarily because of advances in treatment (ACS, 2002k).

Most of the remaining childhood leukemia cases are categorized as AML, which occurs most often in the first 2 years of life and is less common among older children. However, the incidence of AML increases during the teenage years to adult rates. Developments in treatment have improved the survival rate for children with AML, which has a 5-year survival rate of about 40% (ACS, 2002k).

Prenatal exposure to radiation is known to be associated with the development of ALL. Some genetic disorders—such as Li-Fraumeni syndrome, Down syndrome, and Klinefelter syndrome—also are associated with ALL, and chemotherapeutic agents are associated with secondary leukemias later in childhood or in adulthood. Paternal occupational exposure to chemicals and solvents, radiation, and chemical contamination of ground water have also been hypothesized to be associated with childhood leukemia (ACS, 2002k).

CNS cancers include malignant brain and spinal cord tumors. Brain tumors are the second most common group of cancers affecting children, accounting for about 20% of all childhood cancers. Common types of childhood brain tumors include astrocytomas (tumors originating in the brain cells), primitive neuroectodermal tumors (PNETs) (tumors that develop from primitive stem cells), and germ cell tumors. Neuroblastoma, a type of CNS tumor derived from embryonic neural crest cells, is the third most common form of cancer in children and accounts for 7–10% of all childhood cancers. Neuroblastoma is the most common cancer in children under 1 year old, accounting for 50% of all cancers in infants (ACS, 2002l).

The etiology of childhood brain cancer appears to be multifactorial, with no clear primary cause. Such genetic syndromes as Li-Fraumeni syndrome and von Recklinghausen’s disease are known to be associated with a modest fraction of these tumors, and it is suspected that other risk factors are also involved. One well-established risk factor for the development of brain tumors is exposure to ionizing radiation, which occurs during the treatment of other cancers. Other factors—such as exposure to nitrates, aspartame, and electromagnetic fields—have been studied, but no conclusive evidence clearly implicates them as causal factors. More than 50% of children with brain tumors (all types combined) survive over 5 years (ACS, 2002l).

Lymphomas have two major categories based on cell histology: HD and NHL, both of which are relatively rare in children, but which together are the third most common cancer in children. Representing about 4% of all childhood cancers, NHL occurs about 1 1/2 times as often as HD in children. NHL is 3 times more common in boys than in girls and twice as common in white children as in black children; its incidence peaks at the age of 7–11 years. Little is known about the etiology of childhood NHL. Known risk factors include genetic diseases that cause abnormal or deficient immune system development and radiation exposure (usually during the course of cancer therapy). The 5-year survival rate of children diagnosed with NHL in its early stages is more than 90% (ACS, 2002m).

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

Epidemiologic Studies of Exposure to Insecticides

Most of the studies on childhood cancers are case-control that use cancer registries with well-characterized, pathologically confirmed diagnoses as a basis for selection of cases. However, exposure assessment generally relies on questionnaires or interviews with parents to recall exposures to various agents before, during, or after birth. As a result, the specificity of the agents and the actual period of exposure are subject to recall and misclassification bias.

In making conclusions of association on childhood cancers and other reproductive outcomes (Chapter 8), the committee focused on studies that examine the agents of concern during preconception rather than during or after gestation. That approach was taken to make the conclusions as relevant as possible to Gulf War veterans. It is the committee’s understanding that if a pregnancy occurred during the Gulf War, the pregnant woman would have been removed from the Persian Gulf (Neish and Carter, 1991). However, if evidence to the contrary becomes available, future Gulf War studies will consider studies of gestational exposures.

It should be noted that the majority of childhood cancer studies focus on exposure to agents during pregnancy. The committee discusses several of those studies below and indicates whether they also assessed preconception exposure. If they did not, they were not considered primary evidence in making conclusions of association.

Childhood Leukemia

Only a few studies have elicited information about specific insecticides or classes of insecticides and the risk of developing childhood leukemia. A number of studies examined exposure to pesticides in general, but they were not useful for drawing conclusions for the purposes of this review as they lacked specific information on the types of pesticides used. The following discussion describes the key studies that led to the committee’s conclusion.

Leiss and Savitz (1995) studied all cases of leukemia among 252 in children 0–14 years old diagnosed with cancer in Denver in 1976–1983 and compared them with community controls (n=222). The three exposure periods assessed were 3 months before birth to birth, birth to 2 years before diagnosis, and 2 years before diagnosis to diagnosis. No risk of childhood leukemia was found for cases whose homes underwent insect extermination during the last 3 months of pregnancy (OR=0.4, 95% CI=0.1–1.2, based on four cases) whereas a positive relationship was observed for yard treatment (OR=1.1, 95% CI=0.6–1.9) and the use of pest strips (OR=3.0, 95% CI=1.6–5.7) for the same exposure period. The study authors identified diazinon, chlorpyrifos, and other pesticides as the ingredients most likely to be used in home extermination, and the herbicide 2,4-D, carbaryl, diazinon, and others as most likely ingredients used in yard treatments. Pest strips contain the active ingredient dichlorvos. The study found an increased risk of childhood leukemia in children whose mothers used pest strips during the last 3 months of pregnancy. Limitations acknowledged by the authors include the crude measures of exposure, non-response (about 29% of cases and 21% of controls), and the method of control selection. In addition, the study did not consider exposure during preconception, the time period of interest for this report.

Infante-Rivard and colleagues (1999) studied 491 children, 0–9 years old, with ALL diagnosed in 1980–1993 in Quebec, Canada. Cases were identified on the basis of a clinical

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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diagnosis by an oncologist or hematologist in a tertiary care center. Population-based controls were matched one-to-one on age, sex, and region of residence at the time of diagnosis. Exposure information on home use of pesticides and insecticides was assessed with telephone interviews based on a standardized questionnaire. The mother and father of each case and control were interviewed separately, but the questions regarding pesticide and insecticide exposure were directed only at the mothers. The study provided an analysis of two exposure periods: 1 month before conception to the end of pregnancy and during childhood. The analysis did not report separately on the 1 month before conception. When the mothers were asked about insecticide use during pregnancy in the home by specific type of insect, the ORs ranged from 1.37 for insecticides used against mites and spiders (95% CI =0.73–2.58) to 2.47 for moths (95% CI=1.43–4.28). Use of plant insecticides also showed an increased risk of ALL (OR=1.97, 95% CI=1.32–2.94), whereas use of repellents and sprays for outdoor insects revealed no risk (OR=0.70, 95% CI=0.45–1.09). The risk of childhood ALL showed an exposure-response relationship for increasing use of plant insecticides during pregnancy, although the higher frequency category was based on a small number of exposed cases: OR1–5 times=1.89 (95% CI=1.20–2.97) based on 60 exposed cases, and ORmore than 5 times=4.01 (95% CI=1.12–14.32) based on three cases. One limitation of this study is the lack of information on the specific insecticides used to control or eliminate the pests identified in and around the home. The authors do, however, suggest that chlorpyrifos, diazinon, dichlorvos, malathion, and carbaryl are likely to have been used indoors and around the home by the mothers interviewed. For the purpose of this report, another limitation is the lack of analysis on preconception exposures.

For the same 491 cases of childhood ALL, Infante-Rivard and Sinnett (1999) reported on paternal occupational exposures to insecticides that occurred before conception only. Exposures were coded by industrial hygienists on the basis of occupational job titles and industry type. For children of fathers exposed to insecticides in the workplace before conceiving a child, an increased risk of ALL was found (OR=1.38, 95% CI=0.87–2.18). An increased risk was also observed for exposure to pesticides in general, which included insecticides, herbicides, rodenticides, fungicides, molluscicides, and nematodicides. In this study, there was a possibility of confounding by various types of pesticides. Given that the odds ratio for insecticides was lower than for pesticides in general, one cannot rule out the possibility of confounding by exposure to another class of pesticides.

Several studies examined childhood leukemia with broader measures of exposure to pesticides. Although informative, those studies do not provide separate data on exposure to insecticides. Buckley and colleagues (1989) reported an increased risk of acute nonlymphocytic leukemia (ANLL) with maternal or paternal occupational exposure to pesticides before pregnancy (paternal exposure OR=1.7; maternal exposure OR=3.0, 0.05 <p<0.10), as did Meinert and colleagues (1996, 2000) for childhood leukemia and paternal or maternal occupational exposure to insecticides, herbicides, or fungicides in the year before pregnancy and during pregnancy. Two other studies of exposure to pesticides during pregnancy found increased risks of childhood leukemia (Lowengart et al., 1987; Shu et al., 1988).

Childhood Brain and Other Central Nervous System Tumors and Lymphomas

The committee reviewed the available literature on exposure to insecticides and the risk of brain and other nervous system tumors, including neuroblastoma, astrocytic glioma,

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

primitive PNET, malignant germ-cell tumors, and lymphoma (such as NHL). The literature on other childhood cancers (such as Wilms’ tumor and Ewing’s bone sarcoma) did not examine the insecticides under review.

Few studies have attempted to evaluate the relationship between parental exposure to insecticides before conception and the risk of other childhood cancers. The following discussion highlights the issues of concern and the key studies reviewed by the committee in making its conclusion.

No studies addressed exposure to specific insecticides only before conception in relation to childhood cancers other than leukemia. Davis and colleagues (1993) reported on a study of 45 children 0–10 years old with brain cancer diagnosed in 1985–1989. They found a higher risk in children whose mothers used No-Pest-Strips (containing dichlorvos) during pregnancy than in friend controls (OR=5.2, 95% CI=1.2–22.2, based on eight cases) or cancer controls (OR=1.9, 95% CI=0.6–5.9). When the mothers used carbaryl, diazinon, or any insecticide in the garden or orchard, an increased risk of childhood brain tumors was found in comparison to friend and cancer controls. When the mothers reported using pesticides on pets and being directly exposed to the agents, a lower risk of childhood brain tumors was found than in friend and cancer controls. However, the study did not assess preconception exposures.

In the study discussed above, Leiss and Savitz (1995) compared all cases of brain tumors among 252 children 0–14 years old diagnosed with cancer in Denver in 1976–1983 with community controls (n=222). An increased risk of brain tumors was found in cases whose homes underwent insect extermination during the last 3 months of pregnancy (OR=1.3, 95% CI=0.7–2.1) or used pest strips (OR=1.5, 95% CI=0.9–2.4), whereas no relationship was observed for yard treatment (OR=0.6, 95% CI=0.3–1.1). The authors also found an increased, but imprecise, risk of childhood lymphoma in cases whose homes underwent extermination during the last 3 months of pregnancy (OR=1.2, 95% CI=0.4–3.9) or used pest strips (OR=1.4, 95% CI=0.7–2.5). No risk was observed in cases whose yards were treated with herbicides and insecticides during pregnancy (OR=0.5). There were no separate analyses for preconception exposures.

Daniels and colleagues (2001) conducted a case-control study of neuroblastoma in children diagnosed in 1992–1994 and identified through the Children’s Cancer Study Group and the Pediatric Oncology Group, collaborative clinical trial groups in the United States and Canada. The groups confirmed the diagnosis of the 538 cases in children 0–5 years old at the time of diagnosis. Mothers of cases and controls provided information on parental job histories, occupational exposure, residential use of insecticides, and other factors; fathers were asked to participate only if the mothers completed the interviews. Parents were interviewed separately about exposures that occurred 1 month before conception to the date of diagnosis. The authors stated that the pesticides used in the home by parents and professional exterminators were mostly insecticides. When both parents reported having professional insect extermination in the home 1 month before or during pregnancy, no risk of neuroblastoma was found (OR=1.0, 95% CI=0.5–2.1). An increased risk was observed when both parents reported using pesticides at home (OR=1.3, 95% CI=0.8–3.3). Most parents in the study were asked to recall exposures over periods that occurred 1–5 years earlier. As a result, although the large sample and confirmation of exposure by both parents separately are strengths, it is difficult to say whether the small association indicates or

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

reflects imprecise exposure measurement. The study did not provide a separate analysis of preconception exposures.

Histologically confirmed cases of neuroblastoma in children 0–14 years old and diagnosed were included in a case-control study conducted by Kerr and colleagues (2000). The 372 controls were matched by year of birth to the 183 cases diagnosed in New York state (excluding New York City) between 1976 and 1987. The mothers provided data on parental occupations held during pregnancy. An increased risk of neuroblastoma was observed among children whose mothers reported exposure to insecticides during pregnancy (OR=2.3, 95% CI=1.4–3.7) and whose fathers reported the same exposure (OR=1.7, 95% CI=1.0–2.7). Limitations acknowledged by the authors include potential misclassification due to job-coding errors, the large number of multiple comparisons, interviewer bias, self-reported exposure (of both mothers and fathers) by mothers, and recall bias. Additionally, information regarding occupation prior to conception was not collected..

Pogoda and Preston-Martin (1997) reported a case-control study of childhood brain tumors diagnosed in 1984–1991 in Los Angeles County, California, in children up to 19 years old at diagnosis. Mothers of the 224 cases and 218 controls were interviewed regarding childhood exposure to insecticides and prenatal parental exposure. An OR of 1.3 (95% CI=0.7–2.4) was found between prenatal exposure to insecticides and the risk of pediatric brain tumors on the basis of 26 exposed cases. An increased risk was also observed for prenatal use of flea and tick products (OR=1.7, 95% CI=1.1–2.6) on the basis of 76 exposed cases. However, preconception exposure was not assessed separately, and the case series included subjects older than those in most other childhood cancer studies.

Bunin and colleagues (1994) conducted a case-control study of children with astrocytic glioma and PNET and maternal exposure to insect sprays or pesticides during pregnancy. An increased risk of astrocytoma was observed if mothers used insect sprays or other pesticides at some point during pregnancy (OR=1.5, 95% CI=0.8–2.7), but there was not an increased risk of PNET (OR=0.7, 95% CI=0.4–1.4); furthermore, if mothers used such pesticides weekly during their pregnancy, an increased risk was observed for astrocytoma but not for PNET (OR=2.2 and 1.0, respectively). No information was available on preconception exposure.

Malignant germ-cell tumors (MGCTs) are rare childhood brain cancers derived from primordial germ cells. Shu and colleagues (1995) conducted an exploratory case-control study of 105 cases of MGCT identified through the Children’s Cancer Study Group and 639 community controls identified through random-digit dialing and matched by age. The cases were diagnosed in 1982–1989 and were less than 15 years old at the time of diagnosis. Parents of cases were asked to complete a 22-page self-administered questionnaire regarding occupational and home exposure that occurred during the preconception, prenatal, and postnatal periods. When the three periods of exposure were combined, an increased risk of MGCT was observed for reported maternal and paternal exposure to insecticides or herbicides (OR=2.4, 95% CI=0.9–6.9 for mothers; OR=1.8, 95% CI=0.7–5.0 for fathers). However, the lack of data on timing of exposure with respect to pregnancy limits the usefulness of the data for the committee’s purposes, as does the fact that exposure to insecticides and herbicides are combined. Although an increased risk was reported for domestic exposure to insecticides or herbicides before, during, and after pregnancy, the authors did not report the results for those exposure intervals separately, because the estimates were less stable.

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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)

Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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)

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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
×

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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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Suggested Citation:"5. Cancer and Exposure to Insecticides." Institute of Medicine. 2003. Gulf War and Health: Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. doi: 10.17226/10628.
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