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Journal of Toxicology and Environmental Health, Part

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Occupational Pesticide Exposures and Cancer Risk: AReviewMichael C. R. Alavanja

a& Matthew R. Bonner

b

aDivision of Cancer Epidemiology and Genetics , National Cancer Institute, North Bethesd

Maryland , USAbDepartment of Social and Preventive Medicine , School of Public Health and Health

Professions, State University of New York at Buffalo , Buffalo , New York , USA

Published online: 09 May 2012.

To cite this article:Michael C. R. Alavanja & Matthew R. Bonner (2012) Occupational Pesticide Exposures andCancer Risk: A Review, Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 15:4, 238-263, DOI:

10.1080/10937404.2012.632358

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Journal of Toxicology and Environmental Health, Part B, 15:238263, 2012

ISSN: 1093-7404 print / 1521-6950 online

DOI: 10.1080/10937404.2012.632358

OCCUPATIONAL PESTICIDE EXPOSURES AND CANCER RISK: A REVIEW

Michael C. R. Alavanja

1

, Matthew R. Bonner

2

1Division of Cancer Epidemiology and Genetics, National Cancer Institute, North Bethesda,Maryland, USA2Department of Social and Preventive Medicine, School of Public Health and Health Professions,State University of New York at Buffalo, Buffalo, New York, USA

A review of the epidemiological literature linking pesticides to cancers in occupational studiesworldwide was conducted, with particular focus on those articles published after the releaseofIARC Monograph 53 (1991): Occupational Exposures in Insecticide Applications and SomePesticides. Important new data are now available. Chemicals in every major functional classof pesticides including insecticides, herbicide, fungicides, and fumigants have been observedto have significant associations with an array of cancer sites. Moreover, associations were

observed with specific chemicals in many chemical classes of pesticides such as chlorinated,organophosphate, and carbamate insecticides and phenoxy acid and triazine herbicides.However, not every chemical in these classes was found to be carcinogenic in humans.Twenty-one pesticides identified subsequent to the last IARC review showed significant expo-sure-response associations in studies of specific cancers while controlling for major potentialconfounders. This list is not an exhaustive review and many of these observations need to beevaluated in other epidemiological studies and in conjunction with data from toxicology andcancer biology. Nonetheless, it is reasonable and timely for the scientific community to pro-vide a multidisciplinary expert review and evaluation of these pesticides and their potentialto produce cancer in occupational settings.

Pesticides are a diverse group of chemi-cals used to control pests, including plants,molds, and insects. Pesticides are widely usedin agricultural, and commercial and residentialsettings, making exposure to the general pop-ulation ubiquitous. The National Health andNutrition Survey found that the majority of theUnited States population displayed detectablelevels of various pesticide metabolites in theirurine (Barr et al. 2004; 2005; 2010), addingevidence that the general population is read-ily exposed, primarily through ingestion of food

treated with pesticides and other indirect expo-sure routes.Pesticides are broadly known to exert

adverse toxic effects to humans following high-dose acute exposure; however, knowledge

This article not subject to US copyright law.This work was funded, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute

(Z01CP010119).Address correspondence to Michael C. R. Alavanja, Senior Investigator, Division of Cancer Epidemiology and Genetics, National

Cancer Institute, 1620 Executive Blvd., North Bethesda, MD 20892, USA. E-mail: [email protected]

about chronic low-dose adverse effects to spe-cific pesticides is more limited. Although themajority of pesticides currently registered foruse in the United States are neither overtlygenotoxic nor carcinogenic in rodent studies,human cancer possibly resulting from expo-sures is an area of public concern and growingscientific interest.

In the past 10 years, an increasing num-ber of case-control and cohort studies aswell as meta-analyses (Akhtar 2004; Alavanja2003; 2004a; Andreotti et al. 2009; Band

et al. 2010; Beane Freeman et al. 2005;Bonner et al. 2005; Chamie et al. 2008; Chiuet al. 2006; Chiu and Blair 2009; Christensenet al. 2010; Dennis et al. 2010; Erikssonet al. 2008; Hou et al. 2006; Knopper and

238


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PESTICIDES AND CANCER IN HUMANS 239

Lean 2004; Koutros et al. 2009; Lee et al.2004a; 2004b; 2007; Mahajan et al. 2006a;2006b; Miligi et al. 2006; Multigner et al.2010; Orsi et al. 2009; Purdue et al. 2007;Rusiecki et al. 2006; 2009; Samanic, 2006;Schroeder et al. 2001; Spinelli et al. 2007;Van Bemmel 2008; Van Maele-Fabry et al.2006; 2008; Van Maele-Fabry and Willems2003; 2004) with exposure information on pes-ticides and other etiologically relevant factorshave investigated hypotheses linking occupa-tional pesticide exposures to a number of dif-ferent cancers. Moreover, evidence is emerg-ing that chronic low-dose exposure to variouspesticides perturbs a number of biologic path-ways, including oxidative stress (Abdollahi et al.

2004; Akhgari et al. 2003) and immunotoxicity(Galloway and Handy 2003), that have beenlinked with carcinogenesis.

Because a comprehensive review of all theextant literature on this topic is beyond thescope of this review, this review only evaluatesoccupational exposures to pesticides becauseworkers in certain occupational environmentshave higher cumulative exposures than do indi-viduals in the general environment and it issometimes possible to better document expo-sures to specific pesticides. Higher exposures

in occupational studies may result in larger risksthat are more readily detectable epidemiologi-cally while permitting control of important con-founders. Once an accurate identification of ahuman carcinogen is made in the occupationalenvironment, the relevance to the general pop-ulation may be largely the same other than thesize of the cancer risk, which is determinedby the size of the exposure if a linear, no-threshold exposure-response pattern of cancerrisk is assumed.

METHODS

Relevant literature was identified bysearching PUBMED using the searchterm Human Cancer Epidemiology ANDPesticides. The result of this research pro-duced 774 articles, of which 602 were researcharticles and 172 were reviews and/or com-mentaries. The list was reduced to 721 articles

when the search was restricted to articlespublished on or after 1990, which representsthe bulk of the literature published subsequentto the publication of IARC monograph 53(1991). The list was further restricted to cancerstudies among adults in which there was someexposure-response information and narrowedthe list to 103 studies. Based on these studieswe compiled a list of selected pesticides(Table 1) that have sufficient evidence to war-rant a comprehensive and systematic reviewfor human carcinogenicity. The pesticides listedin Table 1 were selected based on the followingguidelines: (1) Pesticide-specific exposure datawere reported by the study, (2) there wasevidence of an exposure-response gradient

across exposure levels, and (3) there wasadjustment for potential confounders. We rec-ognize that replication of epidemiologic resultsis important, but such data are not yet availablefor many pesticides. We refrained from usingstrict criteria, such as Hills criteria, becausea comprehensive evaluation of the evidencenecessary for making causal inference, whichwould include comprehensively assessingbiological effects of exposure, is beyond thescope of this review. This review is focusedon epidemiologic developments since the last

comprehensive IARC evaluation of pesticidesfor human carcinogenicity.While the predominant focus of this review

is directed toward suggestive positive associa-tions between occupational pesticide use andcancer incidence if the inclusion guidelines aremet, it is important to note that most pesti-cides have not been found to be associatedwith cancer in epidemiologic studies. Furtherwinnowing of the list will be made whenthe biological effects of exposure are evalu-ated. Further expansion of the list would be

warranted as new epidemiological finding arepublished.

EPIDEMIOLOGIC STUDIES WITHEXTERNAL COMPARISONS GROUPS

Studying the health experience of farm-ers and pesticide applicators has provided theprimary opportunity to evaluate the effect of


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240 M. C. R. ALAVANJA AND M. R. BONNER

TABLE 1. Pesticides for Which Postmarket Surveillance Data Suggests Human Carcinogenicity

Cancer site Pesticide

Exposed cases(exposuremetric) Relative risk estimate pfor trend Reference

Prostate Butylate, herbicide,thiocarbamate

37 (LD) RR = 1.0 (NE.Ref), 0.95 (0.61.6),1.7 (1.02.8) [among studysubjects with a family history ofprostate cancer]

.04 (Lynch et al.2009)

Clordecone, insecticide,cyclodiene

41 (g/L inplasma)

OR = 1.0 (NE.Ref), 0.97(0.332.83), 3.2 (1.010.1), 3.0(1.18.1) [among study subjectswith a family history of prostatecancer]


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TABLE 1. (Continued)

Cancer site Pesticide

Exposed cases(exposuremetric) Relative risk estimate pfor trend Reference

EPTC, herbicide,thiocarbamate

14 (IWLD) OR = 1.0 (NE.Ref), 1.8 (0.74.3),2.5 (1.12.2)

.01 Andreotti et al.2009)

Pendimethalin,herbicide,dinitroaniline

14 (IWLD) OR = 1.0 (NE.Ref), 1.4 (0.53.9),3.0 (1.37.2)

.01 Andreotti et al.2009)

Melanoma Carbaryl, insecticide,carbamate

76 (LD) OR = 1.0 (NE.Ref), 1.3 (0.92.1),1.7 (1.12.5)

.013 (Dennis et al.2010)

Maneb/mancozeb,fungicide, polymericdithiocarbamate

17 (LD) OR = 1.0 (NE.Ref), 1.3 (0.92.1),1.7 (1.12.5)


Parathion, insecticide,organothio phosphate

21 (LD) OR = 1.0 (NE.Ref), 1.6 (0.83.1),2.4 (1.34.4)


Toxaphene, insecticide,organochlorine

8 (LD) RR = 1.0 (NE.Ref), 0.7 (0.22.3),2.9 (1.18.1)

.03 (Purdue et al.2007)

Leukemia Chlordane, insecticide,

cyclodiene

18 (LD) RR = 1.0 (NE.Ref), 1.2 (0.43.3),

2.6 (1.26.0)

.02 (Purdue et al.

2007)Diazinon, insecticide,

organothiophosphate11 (LD) RR = 1.0 (NE.Ref), 1.1 (0.33.7),

2.6 (0.97.8), 3.4 (1.110.5).026 (Beane Freeman

et al. 2005)

Non-Hodgkinslymphoma

Chlordane(asoxychlordane),insecticide, cyclodiene

329 (bloodlevelsoxychlor-dane)

OR = 1.0 (LE), 1.36 (0.88-2.08),1.39 (0.88-2.08), 1.39(0.88-2.19), 2.68 (1.69-4.24)

.009 (Spinell i et al.2007)

Lindane, herbicide,nitrophenyl ether

12 (IWLD) RR = 1.0 (NE.Ref), 1.6 (0.64.1),2.6 (1.16.4)

.04 (Purdue et al.2007)

Bladdercancer

Imazethapyr, herbicide,imidazolinone

41 (IWLD) RR = 1.0 (NE.Ref), 1.0 (0.51.8),0.9 (0.51.8), 1.3 (0.62.9), 2.4(1.24.7)

.01 (Koutros et al.2009)

Note. LD = lifetime days; IWLD = intensity-weighted life days; NE.Ref= no exposure reference group; LE.Ref = low exposurereference group. Asterisk indicates that when multiple papers from the same study were reported (and consistent), only the latest paper

was cited.

pesticides directly in humans. In the UnitedStates and other developed countries, farmersexperience a lower mortality and cancer inci-dence rate compared to the general population(Alavanja et al. 2005; Blair et al. 1993; Dichand Wiklund 1998; Koutros 2010a; Morrisonet al. 1993; Saftlass et al. 1987; Wigle et al.1990). Lower risks of lung and bladder can-cer have been attributed to a relatively low

tobacco use (Alavanja et al. 2004a; 2004b;2005; Blair et al. 1985; 1993; 2009), whilelower colorectal cancer risk may be influencedby the higher prevalence of physical activityassociated with agricultural work (Neugut et al.1996; Thune and Furberg, 2001). Excess risksfor specific cancers were also noted in many(Acquavella et al. 1998; Blair et al. 1992) stud-ies of agricultural populations, including cancer

of the lymphatic and hematopoietic system,connective tissue, skin, brain, prostate, stom-ach, and lip. More recently a significantly ele-vated risk was also observed for ovarian canceramong female pesticide applicators (Koutroset al. 2010a).

Studies, using standardized incidence ratio(SIR) analysis, or standardized mortality ratio(SMR) analysis, all relied on external compar-

isons to estimate associations between farmersand a general population. Necessarily, thesestudies offer only limited information regard-ing the potential for causality because spe-cific exposure data to individuals are notavailable. Nonetheless, these types of stud-ies provide some insight into the nature ofthe relationship between pesticides and cancerrisk.


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OCCUPATIONAL EXPOSURE TOPESTICIDES AND SELECT CANCER SITES

Prostate Cancer

Prostate cancer risk among farmers and

other pesticide users has been evaluated inmore than 100 studies worldwide. Meta-analyses indicate that farming is more fre-quently associated with an increased risk ofprostate cancer in North America than inEurope (Van Maele-Fabry and Wilems 2004).

A total of 8 of 15 studies in North Americafound a modestly increased risk among famerscompared to nonfarmers, with effect estimatesranging from 1.1 to 4.3, although 7 stud-ies reported no such association. Results frommeta-analyses based on these studies are con-sistent with a weak, positive association thatis difficult to distinguish from the null (VanMaele-Fabry et al. 2006; Van Maele-Fabry andWilhems 2004).

In a population-based case-control studyof prostate cancer in South Carolina, farming-related exposures were determined for405 incident prostate cancer cases obtainedfrom the South Carolina Central CancerRegistry, 392 controls matched for age, race,and region were obtained from the Health

Care Financing Administration MedicareBeneficiary Files, and occupational informa-tion was collected using computer-assistedtelephone interviewing. Farming was associ-ated with elevated risk of prostate cancer inCaucasians (in terms of odds ratio [OR] andconfidence interval [CI]: ORadjusted = 1.8 [95%CI: 1.32.7]) but not in African-Americans(ORadjusted = 1.0 [95% CI: 0.61.6]). Racialdifferences in the association between farmingand prostate cancer may be explained bydifferent farming activities or different gene

environment interactions by race (Meyerset al. 2007). These cancer incidence findingsfrom South Carolina are not reflective of a38% excess prostate cancer mortality rateamong African-American men from threestates from the southeastern United States (i.e.,North Carolina, South Carolina, and Georgia)engaged in farming, compared to the experi-ence of African-American farmers in 21 states

in other parts of the country (Dosemeci et al.1994).

A significant association between prostatecancer risk and exposure to DDT (OR = 1.68[95% CI: 1.042.70 for high exposure]),simazine (OR = 1.89 [95% CI: 1.083.33 forhigh exposure]) and lindane (OR = 2.02[95% CI: 1.153.55 for high exposure]) wasobserved among 1516 prostate cancer casesand 4994 age-matched controls consisting of allother cancer sites other than lung and cancersof unknown primary sites in a population-based case-control study in British Columbia,Canada. The study also reported more prelim-inary associations of prostate cancer risk fordichlone, dinoseb amine, malathion, endosul-

fan, 2,4-D, 2,4-DB, carbaryl, captan, dicamba,and diazinon (Band et al. 2010). Carbaryl(Mahajan et al. 2007), captan (Greenberget al. 2007), diazinon (Beane Freeman et al.2005), dicamba (Samanic et al. 2006), andmalathion (Bonner et al. 2007) were not asso-ciated with prostate cancer risk in the U.S.

Agricultural Health Study (AHS), a prospectivecohort study of certified pesticide applicatorsand the spouses of farmer applicators in Iowaand North Carolina (Alavanja et al. 2003;2005; Koutros et al. 2010a). Dichlone, dinoseb

amine, endosulfan, 2,4-D, and 2,4-DB werenot evaluated in pesiticide-specific analyses inthe AHS.

A significant excess risk of prostate can-cer was observed in the U.S. AgriculturalHealth Study (AHS). This excess may bedue in part to pesticide use. In the AHS,an age-adjusted excess prostate cancer riskwas observed with specific pesticide use (i.e.,butylate, coumaphos, fonofos, phorate, per-methrine for animal use) among those with afamily history of prostate cancer and methyl

bromide among those with and without a fam-ily history of prostate cancer (Alavanja et al.2003). Similar findings were noted a few yearslater in the same cohort for butylate (Lynchet al. 2009), coumaphos (Christensen et al.2010), fonofos (Mahajan et al. 2006a), phorate(Mahajan et al. 2006b), permethrin (Rusieckiet al. 2009), and terbufos (Bonner et al. 2010)with the accumulation of additional prostate


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cancer cases. These observed interactions werefollowed up with a gene-by-environment asso-ciation study of 776 cases and 1444 con-trols from the AHS. In one of the analysesresulting from this project, the 8q24 regionof the genome, which was previously associ-ated with prostate cancer risk as a main effect(Yeager et al. 2009), showed significant inter-action with fonofos (p-interaction adjusted formultiple comparisons = .02) and an expo-sure response pattern of enhanced risk withincreased use (ORnonexposed = 1.17 [95% CI:0.931.48], ORlow = 1.3 [95% CI: 0.752.27],OR high = 4.46 [95% CI: 2.179.17]); otherpositive interactions were also observed forcoumaphos, phorate, terbufos, and permethrin

(Koutros et al. 2010b), providing some biolog-ical context for the original link between thesepesticides and prostate cancer (Alavanja et al.2003).

In a case-control study of prostate can-cer conducted on 709 consecutive casesof histologically confirmed prostate canceridentified between June 2004 to December2007 in Guadeloupe, a French archipelagoin the Caribbean, prostate cancer risk rosewith increasing plasma chlordecone concen-tration (i.e., Kepone) (Multigner et al. 2010).

Chlordecone is an estrongenic insecticide thatwas used extensively in the French West Indiesfor more than 30 years. An odds ratios of1.77 (95% CI: 1.212.58) was observed inthe highest tertile of values above the limitof detection, p trend = .002. Stronger asso-ciations were observed among those witha positive family history of prostate can-cer. Among subjects with plasma chlordeconeconcentrations above the limit of detec-tion and two single-nucleotide polymorphisms(rs3829125 and rs171345920) the risk of

prostate cancer was elevated (OR = 5.23 [95%CI: 0.8233.32]). These polymorphisms con-trol chlordecone reductase in the liver andmay lead to lower levels of biliary excre-tion of chlordecone clearance from circula-tion (Multigner et al. 2010) Chlorodecone alsobinds the estrogen receptor alpha (ER alpha)and beta (ER beta); ER alpha mediates theadverse effects of estrogen on the prostate,

such as aberrant proliferation, inflammation,and malignancy (Multigner et al. 2010). Thisstudy provides some additional support for thehypothesis that estrogens increase the risk ofprostate cancer.

In a second analysis from the AHSproject, pesticides and single-nucleotidepolymorphisms (SNP) in genes in xenobiotic-metabolizing enzymes (XME) that havebeen independently associated with prostatecancer were evaluated currently for statis-tical interaction. A significant interactionwas observed between petroleum oilherbicides and rs1883633, in the glutamate-cysteine, ligase catalytic subunit (GCLC)(p-interaction = 1.0 104 after controlling

for multiple comparisons). Among men car-rying at least one variant allele, the risk ofprostate cancer associated with high petroleumoil herbicide was 3.7-fold higher than thosewith no use (OR = 3.7 [95% CI: 1.97.3])(Koutros et al. 2011). To rule out the possibilitythat these results are due to chance, replicationin other studies is necessary. To our knowledgeattempts to duplicate the link between specificpesticide exposures, genetic polymorphisms,and prostate cancer risk in other studies havenot yet been made.

In summary, the epidemiologic evidencefrom a number of different studies nowmore convincingly shows that prostate can-cer is related to pesticide use. The cancerrisk observed after exposure to certain pes-ticides revealed disparities among races andbetween those with and those without a fam-ily history of prostate cancer. These differencesmay be explained by chance or by (1) dif-ferences in pesticide use patterns or (2) dif-ferences in genetic susceptibility. Evaluatingthese disparities more intensively may pro-

vide important biological insights concerningmechanisms of action that will help moreclearly identify links between specific pes-ticides and prostate cancer. The exposure-response evidence from British Columbia link-ing simazine, DDT, and lindane to prostatecancer is important etiological information thatneeds to be replicated, while the prostate can-cer effect-modification observed among those


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with selected polymorphisms and chloredoneexposure in Guadeloupe and the effect mod-ification among those with selected polymor-phisms and exposures to fonofos and butylateexposures among applicators in Iowa andNorth Carolina are important mechanistic datathat needs to be replicated and extended.The evidence for other pesticides with interest-ing preliminary geneenvironment analyses isnow being completed. Ongoing evaluations oftelomere shortening and epigenetic aberrationsare additional biomarkers that may be usefulfor etiological studies of pesticides and prostatecancer risk.

Lung Cancer

More than 85% of all lung cancer inWestern countries results from cigarette smok-ing (IARC 2004). Farmers, as a group, smokeless than the general population and usu-ally experience significantly less lung cancerand other chronic disease compared with thegeneral population (Alavanja et al. 2004a;Blair et al. 1985). In the AHS, for example,the respiratory cancer incidence among pri-vate applicators (mostly farmers) was only 47%(SIR = 0.47 [95% CI: 0.410.52]) of the general

population of Iowa and North Carolina. Amongthe farmers spouses the rate was only 41%(SIR = 0.41 [95% CI: 0.320.51]) and amongcommercial pesticide applicators only 61%(SIR = 0.61 [95% CI: 0.331.02]) (Alavanjaet al. 2005). The strong influence of smok-ing on lung cancer rates can mask the effectof pesticides on lung cancer rates in Westernagricultural populations, if smoking is not ade-quately controlled in the analysis. An excessrisk of lung cancer was found among vine-yard workers exposed to arsenic-based pesti-

cides (Luchtrath 1983; Mabuchi et al. 1979;1980). Among licensed pesticide applicators inFlorida, the risk of lung cancer rose with thenumber of years licensed and a standardizedmortality ratio greater than 2 was observedamong applicators licensed for 20 or moreyears (Pestori et al. 1994); this excess wasattributed to exposure to organophosphate andcarbamate insecticides and phenyoxyacetic

acid herbicides. Phenoxy herbicides or con-taminants of phenoxy herbicides (dioxin andfurans) and excess lung cancer mortality werealso observed in a cohort of workers fromfour manufacturing plants in Germany (Becheret al. 1996). Similar results were observed in apooled analyses of 36 cohorts from 12 coun-tries (Kogevinas et al. 1997). These positivefindings were not observed in a number of ear-lier studies of pesticide applicators (Mac Mahonet al. 1988; Wang and Mac Mahon 1979) andpesticide manufacturers (Coggon et al. 1986;Ott et al. 1987).

In the AHS, two widely used herbi-cides, metolachlor (OR = 1, 1.6, 1.2, 5:

ptrend = .0002) pendimethalin (1.0, 1.6, 2.1,

4.4;ptrend=

.003, respectively) and two widelyused insecticides, chlorpyrifos (OR = 1, 1.1,1.7, 1.9; ptrend = .03) and diazinon (OR = 1,1.6,2.7, 3.7;ptrend = .04, respectively) showedsome evidence of exposure response for lungcancer (Alavanja et al. 2004a) in a nested case-control study that controlled for tobacco useand age. These associations were later repli-cated in the same study using a cohort analy-sis for diazinon (Beane Freeman et al. 2005),chlorpyrifos (Lee et al. 2004a), pendimethlin(Hou et al. 2006), and metolachlor (Rusiecki

et al. 2006). An association was also observedfor dicamba and lung cancer risk in the high-est tertile of lifetime exposure days (RR = 2.16[95% CI: 0.974.82, ptrend = .02] (Samanicet al. 2006); for dieldrin and lung cancer risk(RR = 2.8 [95% CI: 1.17.2, prend = .02](Purdue et al. 2007); and for carbofuranand lung cancer risk (RR = 3.05 [95% CI:0.949.87]) among those in the highest tertileof exposure (Bonner et al. 2005).

In summary, a large number of studiespublished subsequent to IARC Monograph

53 (1991) noted associations between sev-eral widely used classes of insecticides, her-bicides, and herbicide contaminants and lungcancer. Significant exposure-response gradientswere also observed between specific pesticidesand lung cancer in studies that carefully con-trolled for smoking, age, and some other lungcancer determinants. Arsenical insecticides area recognized cause of human cancer (IARC


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Monograph 53). While epidemiologic datalinking chlorpyrifos, diazinon, and dieldrin tolung cancer are relatively new, they are of par-ticular interest because they are unlikely to beattributed to uncontrolled confounding or dif-ferential exposure misclassification. Observedassociations for carbofuran, dicamba, meto-lachlor, and pendimethalin and lung cancerare of interest, but the associations were notquite as strong as the other pesticides identi-fied. The link between specific phenoxy acidherbicides and lung cancer is not chemical spe-cific and the link needs to be examined inother studies where associations with specificpesticides and the mechanisms through whichthese pesticides may increase cancer risk can

be studied.

Colorectal Cancer

Colorectal cancer is the third most com-mon incident cancer in the United States, andcolorectal cancer is not commonly associatedwith an occupational etiology. As with lungcancer, colorectal cancer incidence rates aregenerally found to be lower among farmers ascompared with the general population. Whilethe reason for this lower rate is not known, it is

suspected that lower smoking rates and higherlevels of occupational physical activity may beinvolved (Garabrant et al. 1984). A few epi-demiological studies found a link between pes-ticides and increased risk of colorectal cancer.The risk of rectal cancer mortality was elevatedamong farmers in Italy (Forastiere et al. 1993)and Iceland (Zhong and Rafnsson 1996). In theNetherlands, the risk of rectal cancer amongpesticide manufacturing workers was approx-imately threefold higher among those withexposure to two chlorinated pesticides dieldrin

and aldrin but the highest risk was not associ-ated with the highest exposure (Swaen et al.2002; Van Amelsvoort et al. 2009). Althoughquantitatively elevated colorectal cancer riskswere observed in American cohorts of man-ufacturing workers exposed to the herbicidealachlor (Acquavella et al. 2004), no dis-cernable exposure-response relationship wasobserved for any cancer.

Aldicarb is an oxime carbamate insecticidethat was associated with a significantlyincreased risk of colon cancer with the highexposure category resulting in a 4.1-foldincreased risk in the highest exposure group[95% CI: 1.312.8 with ptrend = .001] (Leeet al. 2007)

Dicamba is a benzoic acid herbicide thatwas used by 22,036 (52.5%) AHS cohortapplicators. Exposure was not associated withoverall cancer incidence; however, a significanttrend of increasing risk for colon cancer withtotal lifetime days of exposure was observed(risk ratio [RR] = 1.76 [95% CI: 1.003.07,

ptrend = .002]). (Samanic et al. 2006). Theseresults were largely due to elevated risk at the

highest exposure levelEPTC (s-ethyl-N,N-diproylthiocarbamate) isa thiocarbamate herbicide used in every regionof the United States. It was used by 9878 pes-ticide applicators in the Agricultural HealthStudy, and these applicators were observedto have an excess risk of colon cancer atthe highest cumulative number of days of use(RR = 2.05 [95% CI: 1.343.14,ptrend < .01])(Van Bemmel et al. 2008). No excess risk wasnoted for rectal cancer.

Imazethapyr, a heterocyclic aromatic

amine, is a widely used crop herbicide firstregistered for use in the United States in 1989.Among 20,646 applicators who reported useof imazethapyr, a significant trend in excessrisk for colon cancer was observed but limitedto proximal colon cancers (RR = 2.73 [95% CI:1.42, 5.25, p for trend .001]) (Koutros et al.2009).

Trifluralin is a 2,6-dinitro herbicide usedby 25,712 pesticide applicators in the AHS.Trifluralin exposure was not associated withcancer incidence overall; however, there was

an excess of colon cancer in the highest expo-sure category (RR =1.76 [95% CI: 1.052.95,

p for trend = .036] compared to the non-exposed applicators as a referent (Kang et al.2008).

Chlordane is an organochlorine insecticidethat was widely used for termite control. It wasintroduced in 1948 and was phased out inthe 1970s. A statistically significant increase in


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rectal cancer risk among AHS pesticide userof 2.7 [95% CI: 1.16.8] was observed with asignificant trend of increasing use and increas-ing exposure (ptrend = .02) (Purdue et al.2007).

Chlorpyrifos use showed significant expo-sure response trend (ptrend = .008) for rectalcancer with a relative risk of 2.7, [95% CI:1.26.4] in the highest exposure category (Leeet al. 2007).

Pendimethalin, a widely used dinitroani-line herbicide, has been classified as a pos-sible human carcinogen (Group C) by theU.S. Environmental Protection Agency (EPA).The compound was used by 9089 pesticideapplicators in the Agricultural Health Study, and

these applicators were observed to be at a sig-nificant excess risk of rectal cancer comparedto nonusers in the AHS (RR = 4.3 [95% CI:1.512.7]) for the highest exposed subjects; pfor trend = .007 (Hou et al. 2006).

In summary, colon cancer and rectal cancerhad not been widely thought to be associ-ated with farming or pesticide exposures atthe time of IARC Monograph 53. Subsequentstudies among farmers in Italy (Forastiere et al.1993) and Iceland (Zhong and Rafnsson 1996)observed significant excesses in rectal cancer

mortality. In the AHS, chlordane, chlorpyrifos,and pendimethalin were linked to rectal can-cer, and aldicarb, dicamba, EPTC, imazethapyrand trifluralin were linked to colon cancer, afteradjustment for age, smoking, and total daysof pesticide exposure. Based on AHS data itseems that the pesticides associated with coloncancer are distinct from those associated withrectal cancer, but excesses in colon cancer andrectal cancer are associated with herbicidesand insecticides.

While the biological explanations for

these epidemiological relationships are lacking,exposure-response patterns for these chemi-cals tend to strengthen the epidemiologic evi-dence relating pesticide exposure and colonand rectal cancer. Further evaluations of thesefindings in independent samples and otherstudies are important next steps in assess-ing the potential carcinogenicity of thesechemicals.

Pancreatic Cancer

Pancreatic cancer is the fourth leadingcause of cancer death in the United States(American Cancer Society 2008) and the sixth

leading cause of cancer death in Europe (Brayet al. 2002). Smoking is the only firmly estab-lished modifiable risk factor, but unlike lungcancer, smoking only accounts for approxi-mately 25% of pancreatic cancer cases inWestern countries (Silverman et al. 1994;International Agency for Research on Cancer2004). Occupationally, exposure to chlori-nated hydrocarbon solvents (CHS) seems themost consistent occupational association withpancreatic cancer (Ojajarvi et al. 2001), whilechlorinated pesticides and pancreatic cancer

yielded mixed results. Garabrant et al. (1992)found statistically significant pancreatic cancerexcess among chemical manufacturing workers(28 exposed cases) exposed to DDT (OR = 4.8[95% CI: 1.317.6]), DDD (OR = 4.3 [95%CI: 1.512.4]), and ethylan (OR = 5.0 [95%CI: 1.418.2]). In a population-based case-control study, Fryzek et al. (1997) observedsignificant excesses of pancreatic cancer amongworkers exposed to ethylan, DDT, and overallorganochlorine pesticides among 66 exposedcases. An excess risk of pancreatic cancer was

associated with high serum levels of DDE, butthe risk was diminished after adjustment forpolychlorinated biphenyls (PCB) (Hoppin et al.2000). Another study used a job-exposure-matrix to estimate the level of occupationalexposure to pesticides among 484 cases and2095 controls (Ji et al. 2001) and informa-tion on potential confounders was obtainedby questionnaire. Excess risks were found foroccupational exposure to fungicides (OR = 1.5[95% CI: 0.37.6]) and herbicides (OR = 1.6[95% CI: 0.73.4]) in the moderate/high level

after adjustment for potential confounding fac-tors, but specific chemicals were not identified.

An increased risk for insecticides exposure dis-appeared after adjustment for fungicides andherbicide exposures.

In the AHS, 93 incident pancreatic can-cer cases were diagnosed subsequent to com-pleting a detailed questionnaire. Risk esti-mates were calculated controlling for age,


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smoking, and diabetes. Two herbicides (EPTCand pendimethalin) of the 13 pesticides exam-ined for intensity-weighted lifetime exposureuse showed a statistically significant exposure-response association with pancreatic can-cer. Applicators in the top half of lifetimependimethalin use had a threefold higher [95%CI: 1.37.2, p trend = .01] risk comparedwith never users, and those in the top halfof lifetime EPTC use had a 2.56-fold [95%CI: 1.15.4, p trend = .01]) risk comparedwith never users (Andreotti et al. 2009) afteradjustment for age, smoking, and a historyof diabetes. Since pendimethalin and EPTCare able to form N-nitroso-compounds, thesefindings are consistent with evidence suggest-

ing a carcinogenic effect of nitosoamines onthe pancreas (Andreotti et al. 2009). Becausethis was the first study to observe an asso-ciation between these two herbicides andpancreatic cancer, the possibility exists that thiswas a chance finding. Organochlorine pesti-cides were not associated with an excess risk ofpancreatic cancer in the study, but a real asso-ciation may have been missed in this cohortsince DDT and many other chlorinated pesti-cides were banned in the 1970s and exposureswere greatly diminished after that time (Purdue

et al. 2007).

Melanoma

The incidence of cutaneous melanoma hassteadily increased over recent decades andthere is striking risk variation by geographiclocation (Mackie et al. 2009). Ultraviolet radi-ation (UVR) exposure and individual pheno-type (common nevi, atypical nevi, familialmelanoma, fair eye and skin color, inability totan, high-density freckles, premalignant, and

skin cancer lesions) are well-known major etio-logic risk factors for cutaneous melanoma, butdata have suggested that the combination ofthese factors is not sufficient to explain themelanoma risk (Fortes et al. 2007; Fortes andde Vries 2008; Mackie et al. 2009).

An Italian case-control study observed thatmelanoma patients had a higher use of pes-ticides in a residential setting compared with

controls (Fortes et al. 2007). A study ofwhite, Ranch Hand Vietnam veterans found anincreased risk of melanoma related to dioxinexposure and herbicide exposure (Akhtar et al.2004). An additional report of an elevated SIRfor melanoma among Pan Britannica indus-trys pesticide workers suggests that pesticidesare related to the development of melanoma(Wilkinson et al. 1997).

In the AHS, specific pesticide exposuresascertained by questionnaire prior to the onsetof disease were found to be significantly asso-ciated with cutaneous melanoma. No signifi-cant associations were seen with overall her-bicide, insecticide, fungicide, or fumigant use,or with chemical classes of pesticides includ-

ing phenoxy herbicides, triazine herbicides,organochlorine insecticides, or organophos-phate insecticides. However melanoma wassignificantly associated with the fungicidemaneb/mancozeb (OR = 2.4 [95% CI:1.24.9 for those with more than 63 d ofexposure, trend p = .006]), the insecticidesparathion (OR = 2.4 [95% CI: 1.34.4 formore than 56 d of exposure, trend p = .003]),and carbaryl (OR = 1.7 [95% CI: 1.12.5 formore than 56 d of exposure, trend p = .013])(Dennis et al. 2010; Mahajan et al. 2007) after

adjustment for age and measures of skin pig-mentation. While the evidence linking specificpesticides to melanoma is growing, specificlinks have yet to be replicated.

Multiple Myeloma

Multiple myeloma (MM) is a malignancyarising from mature plasma B-cells in thebone marrow producing a serum immuno-protein. Among hematopoietic malignancies,MM has the poorest prognosis and lowest sur-

vival rates (i.e., 5-yr survival, 1530%) (Groganet al. 2001). According to the American CancerSociety, approximately 20,000 new cases and11,000 multiple myeloma deaths are expectedin the United States in 2010 (American CancerSociety 2008).

Farming has been consistently associatedwith an increased risk of MM since the1970s when Milham (1971) reported a higher


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than expected number of MM deaths amongAmerican farmers. Khuder and Mutgi (1997)published a meta-analysis of farm employ-ment and MM and assessed 32 case-controland cohort studies done between 1981 and1996. The pooled analysis of the OR fromindividual papers showed a relative risk of1.23 with 95% CI 1.14 to 1.32 for the associa-tion between MM and farming. Most recently,a systematic review of case-control studiesof multiple myeloma of occupational expo-sure to pesticides showed a pooled odds ratio(OR) for working farmers of 1.39 (95% CI:1.181.65) and for pesticide exposure 1.47(95% CI: 1.111.94). For working on a farmfor more than 10 years OR was 1.87 (95% CI:

1.153.16) (Merhi et al. 2007).Monoclonal gammopathy of undeterminedsignificance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma.In a prospective study, Landgren et al. (2009a)found that virtually all MM cases are precededby MGUS 2 yr or more prior to MM diagno-sis, establishing a key role for MGUS in thepathway to MM.

In the AHS, a 1.34-fold (95% CI:0.971.81) risk of multiple myeloma was

observed (Alavanja et al. 2005). Comparedwith men from Olmsted County, Minnesota,the age-adjusted prevalence of MGUS was 1.9-fold (95% CI, 1.32.7-fold) higher among malepesticide applicators in the AHS (Landgrenet al. 2009b). Among applicators, a 5.6-fold(95%CI: 1.9 to 16.6-fold), 3.9-fold (95% CI:1.5- to 10.0-fold), and 2.4-fold (95% CI: 1.1-to 5.3-fold) increased risk of MGUS prevalencewas observed among users of the chlorinatedinsecticide dieldrin, the fumigant mixturecarbon-tetrachloride/carbon disulfide, and the

fungicide chlorthalonil, respectively. A previousAHS examination determined that a relation-ship between exposure and disease is notlikely confounded by farming or nonfarmingactivities (Coble et al. 2002), increasing thelikelihood that pesticides and not confoundingfactors are responsible for these associations.

In the same study statistically significantrisks for multiple myeloma were associated

with lifetime exposure-days (RR = 5.72 [95%CI: 2.7611.87;ptrend =.01]), compared withapplicators reporting that they never used per-methrin (Rusiecki et al. 2009) in analysis withadjustment for age, gender, family history ofcancer, cigarette smoking, state of residence,and enrollment year. The elevated risk was lim-ited to the highest exposure category that had10 cases of MM. These findings were similaracross a variety of alternative exposure metrics,exposure categories, and reference groups.

In summary, although the evidence link-ing pesticide exposure to multiple myelomahas increased in recent years, additional epi-demiological evidence is needed to test thehypothesis that specific pesticides are positively

associated with multiple myeloma. The signifi-cant association between MM and permethrinexposure needs to be carefully evaluated inother studies. The use of preclinical biomarkersof multiple myeloma (i.e., MGUS) may be apowerful approach to test etiological hypothe-ses concerning MM, since pesticide exposureseems to give rise to more cases of MGUSthan MM.

Leukemia

Leukemia is a heterogeneous categoryof hematopoietic malignancies, includingchronic and acute subtypes that have com-plicated the identification of etiologic factors.Moreover, pesticides include large numbersof diverse chemicals and formulations thatalso exacerbates the difficulty in identifyingassociations between specific pesticides activeingredients and specific subtypes of leukemia.Notwithstanding, causal associations withleukemia were demonstrated for two agents:benzene and ionizing radiation. Other sus-

pected occupational causes include pesticides,infectious agents, electromagnetic fields, andsolvents and aromatic hydrocarbons (Descathaet al. 2005; Rukkala et al. 2002).

Since the various subtypes of leukemia arerelatively infrequent and since they are likelyto have different etiologies (Greaves 1997;Keller-Byrne et al. 1995), identifying a clearlink to specific pesticides has been challenging.


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A recent meta-analysis of 14 cohort studiesof workers in plants manufacturing pesticidesand leukemia was published (Van Maele-Fabryet al. 2008) and a meta-rate ratio was estimatedat 1.43 (95% CI: 1.051.94). A recent meta-analysis of 13 case-control studies examiningthe association between occupational expo-sures and hematopoietic cancers observed anOR of 1.35 (95% CI: 0.92.0) (Merhi et al.2007). Epidemiological evidence was insuffi-cient to permit identification of a specific pesti-cide or chemical class that would be respon-sible for the increased risk in either cohortor case-control studies. With limited exposuredata, it is impossible to assess the contributionof the active ingredient or other ingredients and

to distinguish the diversity of leukemia.Organophosphates have been associatedwith leukemia and other immunologicallyrelated cancers in the epidemiological litera-ture (Brown et al. 1990; Cantor et al. 1992;Clavel et al. 1996; De Roos et al. 2003; Waddelet al. 2001). The leukemogenic effects oforganophosphates may be related to immunefunction perturbation. In the AHS, leukemiarisk was elevated for the high category ofintensity-weight exposure-days for fonofos, anorganophosphate insecticide applied to corn,

sugar cane, tobacco, and several other crops(RR =2.67 [95% CI: 1.066.70, ptrend =.04])(Mahajan et al. 2006a). Diazinon, anothercommon organophosphate insecticide, is reg-istered for a variety of uses on plants andanimals. In the AHS, diazinon was associ-ated with leukemia (RR = 3.36 [95% CI:1.0810.49, ptrend = .026]) (Beane Freemanet al. 2005). A positive association was alsoobserved between the use of alachlor in the

AHS cohort and an elevated risk of leukemia(Lee et al. 2004b) and between EPTC and

leukemia (Van Bemmel et al. 2008), althoughthe risk associated with both pesticides waslimit to the highest exposure group and furtherfollow-up will be necessary. All leukemia riskestimates in AHS cohort analyses are adjustedfor age and other pesticides that are potentiallyconfounders.

Organochlorine (OC) insecticides are aclass of insecticides characterized by their

cyclic structure, number of chlorine atoms, andlow volatility. Chlordane and heptachlor arestructurally related organochlorine insecticidesand the technical grade of each compoundcontains approximately 1020% of the othercompound (IARC 2001). IARC has judged thatthe weight of evidence suggests that chlordaneand heptachlor as well as DDT and toxapheneare possible human carcinogens (IARC-2B)with excesses observed for lung cancer,leukemia, non-Hodgkins lymphoma, and soft-tissue sarcoma, but aldrin, dieldrin, and lindaneare not classifiable as to their carcinogenicity(IARC and Cancer 2001). In the AHS,chemical-specific associations with leukemiawere observed for chlordane/heptachlor 2.1

(95% CI: 1.13.9) and lindane 2 (95% CI:1.13.5) (Purdue et al. 2007), although the evi-dence for lindane was considered equivocal bythe authors.

Metribuzin is a selective triazinone herbi-cide that is used to control broadleaf weedsand grasses in vegetable and field crops. Theresults from this study suggest a potential asso-ciation between metribuzin use as measuredby intensity-weighted lifetime exposure daysand certain lymphohematopoietic malignan-cies. The highest exposure tertiles for lympho-

hematopoietic malignancies were 2.09 (95%CI: 0.994.29; ptrend = .02) and for leukemia2.42 (95% CI: 0.827.19;ptrend = 0.08); how-ever, with these having not been observed pre-viously, caution needs to be used to interpretthe data (Delancey et al. 2009)

In a prospective study, in peripheral bloodobtained up to 77 mo before a diagnosis ofchronic lymphocytic leukemia (CLL), prediag-nostic B-cell clones were present in 44 of45 patients with CLL (Landgren et al. 2009c).Use of B-cell clones as prediagnostic markers

of CLL may be a valuable tool in evaluating thelink between specific pesticides and CLL.

In summary, leukemia is not one diseasebut many related diseases with varying eti-ologies. While the evidence linking pesticideexposure in general to leukemia is abun-dant, the evidence linking specific pesticidesto leukemia is limited and the evidence link-ing a specific pesticide to a specific leukemia


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subtype is largely nonexistent. Recent epi-demiological evidence linking specific pesti-cides to leukemia has established hypothesesthat need to be evaluated in other studies;the associations between leukemia overall anddiazinon (an organophosphate insecticide) andchlordane (an OC insecticide) are statisticallysignificant and are of particular interest. Theuse of preclinical biomarkers for monoclonalB-cell lymphocytosis (MBL) to study the etiol-ogy of chronic lymphcytic leukemia may be apowerful approach for this leukemia subtype(Landgren et al. 2009a).

Non-Hodgkin Lymphoma (NHL)

Non-Hodgkin lymphoma is a diverse groupof over 20 different malignancies affecting theimmune system/lymphatic system (Jaffe et al.2001). The classification system of specific sub-types is now based on immunohistochemistry,cytogenetics, and evolving knowledge in clini-cal presentation (Jaffe et al. 2001). Interest inthe etiology of NHL has increased since therehas been a substantial rise in the incidence ofthe disease from the 1960s through the 1980swith a leveling off in the 1990s. The estab-lished risk factors for NHL include different

immunosuppressive states, including humanimmunodeficiency virus (HIV), and autoim-mune diseases such as Sjogrens syndrome, sys-temic lupus, erythematosis, rheumatoid arthri-tis, psoriasis, and celiac disease (Grulich andVajdic 2005). These conditions cannot accountfor the increases observed (Grulich and Vajdic2005). A meta-analysis of case-control stud-ies focusing on 13 case-control studies pub-lished between 1993 and 2005 observed anoverall significant meta-odds ratio betweenoccupational exposure to pesticides and NHL

(OR = 1.35 [95% CI: 1.21.5]). When obser-vations were limited to those that had morethan 10 years of exposure there is risk eleva-tion (OR = 1.65 [95% CI: 1.081.95]) (Merhiet al. 2007). While the meta-analyses sup-port the hypothesis that pesticides are associ-ated with NHL, they collectively lack sufficientdetail about pesticide exposure and otherinformation on risk factors for hematopoietic

cancers to identify specific causes (Merhi et al.2007).

Since the publication of the meta-analysisby Merhi et al. (2007), several new studiesadd weight to the evidence linking pesticidesto NHL. A new population-based case-controlstudy in Sweden with 910 cases and 1016 con-trols observed a significant excess risk ofNHL associated with the phenoxyherbicideMCPA (OR = 2.81 [95% CI: 1.276.22]) andglyphosate (OR = 2.02 [95% CI: 1.163.71]).Glyphosate was observed to have an exposure-response association with NHL when com-paring NHL risk for those with no expo-sure, 10 d of exposure, and >10 dof exposure (OR = 1.0 ref, OR = 1.69

[95% CI: 0.704.07], OR =

2.36 [95%CI: = 1.045.37], respectively), but MCPAusers did not show a monotonic exposure-response pattern. Glyphosate users had morethan a fivefold excess risk of unspecified non-Hodgkin lymphoma (OR = 5.63 [95%. CI:1.4422.0]), and MCPA had more than a nine-fold excess risk with unspecified non-Hodgkinlymphoma (OR = 9.31 [95% CI: 2.1141.2]).Insecticides overall gave OR of 1.28 (95% CI:0.961.72) and impregnating agents OR of1.57 (95% CI: 1.072.30). 2,4-D and 2,4,5,T

(2,4,5-trichlorophenoxyacetic acid) have beenbanned from Sweden and could not be eval-uated (Eriksson et al. 2008). No excess risk ofNHL was observed among glyphosate users inany exposure category in the AHS, even amongthose with 57 d or more of occupational expo-sure, although a nonsignificant twofold excessof myeloma was observed (De Roos et al.2005).

A new hospital-based case-control studyconducted in 6 centers in France examined theassociation between pesticides and 244 cases

of NHL and other lymphoid neoplasms(Hodgkin lymphoma, lymphoproliferative syn-dromes [LPS], and multiple myeloma). Whileincreased odds ratios for NHL were observedfor users of organochlorine and organophos-phate insecticides, carbamate fungicides, andtriazine herbicides, the study was too small toevaluate the association with specific pesticides(Orsi et al. 2009).


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Collins et al. (2009) noted there were8 deaths from non-Hodgkin lymphoma (stan-dardized mortality ratios = 2.4, 95% CI:1.04.8) among workers exposed to diox-ins in pentachlorophenol (PCP) manufactur-ing. No trend of increasing risk for anycause of death with rising dioxin exposurewas observed. However, the highest rates ofnon-Hodgkin lymphoma were found in thehighest exposure group (standardized mortalityratios = 4.5, 95% CI: 1.211.5).

In a population-based NHL case-controlstudy in British Columbia, significant exposure-response trends were observed for sixpesticides includingp,p-DDE, hexachloroben-

zene (HCB), beta-hexachlorocyclohexane

(beta-HCCH), mirex, oxychlordane, cis-nonachlor, and trans-nonachlor. The strongestassociation was found for oxychlordane, whichis a metabolite of chlordane. The OR for quar-tiles of exposure of oxychlordane in blood was1 (ref), 1.36 (95% CI: 0.882.08), 1.39 (95%CI: 0.882.19), 2.68 (95% CI: 1.694.24),

p-trend = .001 (Spinelli et al. 2007).In a population-based case-control study

conducted in six Canadian provinces includingQuebec, Ontario, Manitoba, Saskatchewan,

Alberta, and British Columbia with cases diag-

nosed between September 1, 1991, andDecember 31, 1994, a positive family his-tory of cancer both with (OR = 1.72 [95%CI 1.212.45]) and without pesticide exposure(1.43 [95% CI: 1.121.83]) increased risk toNHL (McDuffie et al. 2009).

Two epidemiological studies reported thatthe association of NHL with pesticides waslargely limited to NHL cases with chromoso-mal translocations t(14;18) (Schroeder et al.2001; Chiu et al. 2006). In the Schroeder et al.(2001) study conducted in Iowa and Minnesota,

NHL with t(14:18) translocations were signifi-cantly elevated for dieldrin (OR = 3.7 [95% CI:1.97.0]), lindane (OR=2.3 [95%CI: 1.33.9]),toxaphene (OR =3.0 [95% CI: 1.56.1]), andatrazine (OR = 1.7 [95% CI: 1.02.8]). In theChiu et al. (2006) study conducted in Nebraskathe results for NHL witht(14:18) translocationswere significant elevated for dieldrin (OR = 2.4[95% CI: 0.87.9]), toxaphene (OR = 3.2

[95% CI: 0.812.5]), and lindane (OR = 3.5;[95% CI:1.48.4]) compared with nonfarmers.

Atrazine was not reported in this study, buttriazine herbicide users were at a significantlyelevated risk fort(14:18)-positive NHL. A directconnection between agricultural pesticide use,t(14:18) in blood, and malignant progressionto follicular lymphoma (FL) was found in aprospective cohort study of farmers (Agopianet al. 2009). This study provides a molecu-lar connection between agricultural pesticides,t(14:18) frequency in blood, and clonal pro-gression but links to specific pesticides was notpossible.

In summary, non-Hodgkin lymphoma(NHL) is not one disease but many related

diseases with seemingly varying etiologies.New evidence linking pesticide exposures (i.e.,dieldrin, lindane, toxaphene, and atrazine)to NHL subtypes with t(14:18) translocationssuggests an etiological link. These studies areimportant in further refining understanding ofthe link between pesticides and NHL, but theywere too small to assess exposure-responserelationships. A large case-control study inSweden linked use of glyphosate and MCPAto NHL. While glyphosate was observed tohave an exposure-response association, MCPA

did not. No excess risk of NHL was observedamong glyphosate users in the AHS with evena greater number of exposure days. With tworelatively strong studies giving inconsisitentresults, glyphosate is included in Table 1pending evaluation of the biological effects ofexposure and additional epidemiological data.

Another large case-control study in BritishColumbia provided further evidence thatorganochlorine pesticides contributed to NHLrisk. The risk was particular strong for oxychlor-dane, a metabolite of chlordane.

Soft-Tissue Sarcoma

Soft-tissue sarcoma (STS) is a rare malignantneoplasm affecting supporting tissue other thanbone and cartilage. An association betweenSTS and dioxin (2,3,7,8-tetrachlorodibenzo-

p-dioxin or TCDD) was examined in anumber of studies with somewhat inconsistent


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results. A positive association was observedbetween soft tissue sarcoma and TCDD among5,172 men at 12 different chemical plants(Fingerhut et al. 1991). Among workers with1 yr or more of exposure and 20 yr of latency,3 STS cases were observed and only 0.3 wereexpected (SMR = 922 [95% CI: 1902695]).

In an international cohort study,21,863 male and female workers exposedto phenoxy herbicides and dioxin had anexcess risk of STS with an SMR equal to 2.03(95% CI: 0.754.43) (Kogevinas et al. 1997).In contrast, Fleming et al. (1999) found nocases of STS in a cohort of 33,658 pesticideapplicators in Florida who were followed from

January 1, 1975, through December 31, 1993,

and Becher et al. (1996) found no cases ofSTS in a cohort of 2479 German workersexposed to phenoxy herbicides and dioxinwith 54,063 person-years of observation.In Seveso, Italy, the health consequences of anindustrial accident resulting in dioxin exposureto the surrounding community were studiedby Bertazzi et al. (2001). No STS cases werefound in the two areas nearest the accident,but in an area further from the highest contam-ination a nonsignificant excess of STS RR = 2.1(95% CI: 0.65.4) was observed. IARC clas-

sified 2,3,7,8-tetrachlorodibenzo-p-dioxin ahuman carcinogen in 1997 based on exposureresponse with cancers overall, but not basedon an exposure-response association with aspecific cancer. This decision met with somecriticism in the literature (Cole et al. 2003).Since IARC designated dioxin a human car-cinogen, a review of the literature (Steenlandet al. 2004) provided additional support forthe IARCs classification. More recently, astudy following the morality experience of1615 workers during 19422003 who had

occupational exposure to dioxin in a plantin Midland, MI, observed 4 deaths from STS(SMR = 4.1[95% CI: 1.110.5]), but no excessdeaths from other cancers (Collins et al. 2009).

Other Organs

Ovarian cancer is the fifth most com-mon type of cancer among North American

women, and it is a leading cause of gyne-cological cancer death. Since hormones andreproductive factors are so influential in theetiology of ovarian cancer, several investigators(Garry et al. 2002; Salehi et al. 2010) sug-gested that certain pesticides with estrogenicand anti-estrogenic activity may also play a rolein the etiology. Two case-control studies fromItaly suggested a possible role for the triazineherbicides atrazine, simazine, and cyanazinein the etiology of ovarian cancer. The initialobservation was made in a hospital-based studywith a relative risk of 4.4 for ovarian canceramong women with definite or probable expo-sure to triazine herbicides (Donna et al. 1984).

A follow-up population-based study observed

a significant relative risk of 2.7 for ovariancancer among those exposed to triazine her-bicides (Donna et al. 1986). In a centralCalifornia population-based case-control studyof incident cases (n =256) and random digit-dialed control subjects (n = 1122), the anal-ysis of ever versus never occupational expo-sure to triazines demonstrated that cases werenumerically more likely to be exposed thancontrol subjects (ORadjusted = 1.34 [95% CI:0.772.33]) (Young et al. 2004; 2005). Therewas no evidence of a dose-response rela-

tionship between triazines and ovarian cancer(p = .22). In the AHS, a significant excessrisk of ovarian cancer was observed amongfemale applicators (i.e., 8 observed and only1.9 expected) but not among female spouses ofmale farmers (Alavanja et al. 2005), and it wasnot possible to identify an exposure responsi-ble for this association. The total evidence isnot persuasive as to the presence or absenceof an association between ovarian cancer andtriazine exposure, but the issue is importantand unresolved and more research is necessary.

DDT (1,1-dichloroethenylidene)-bis (4-chlorobenzene) and other organochlorinepesticides have received considerable atten-tion as possible causes of breast cancer.

A pooled analysis of five large studies in theUnited States, however, found no significantassociation between DDE levels (a metaboliteof DDT) or PCBs (polychlorinated biphenyls)and breast cancer risk (Laden et al. 2001).


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Recently, data from the 19942004 NationalHealth and Nutritional Examination Surveywas used to examine the association betweenserum concentrations of organochlorine andbreast cancer, but no positive association wasobserved, casting doubt on the hypothesizedassociation (Xu et al. 2010). However, theSeveso Womens Health Study observed anexposure-response relationship between breastcancer and serum TCDD levels in women inthe highest dioxin exposure zone after adjust-ing for other major risk factors such as parity,lactation, age at first pregnancy, smoking, andother factors (Pesatori et al. 2009). Althoughmuch of the recent data does not supportan association between pesticides and breast

cancer, some positive observations keep theissue alive but unresolved.A significant excess risk of bladder cancer

was observed among pesticide applicators inthe AHS cohort who were exposed to the het-erocylic aromatic amine pesticide imazethapyr.Rate ratios (RRs) were increased by 137%in the highest exposure group (RR = 2.37,95% CI: 1.204.68), with a significant trendof rising risk with elevated imazethapyr expo-sure (ptrend = .01) (Koutros et al. 2009).

Although there is no experimental evidence

linking imazethapyr to cancer in laboratory ani-mals and no prior epidemiological evidenceof carcinogenicity, this newly emerging class ofherbicides deserves careful postmarket surveil-lance and biological testing.

Thyroid cancer is relatively uncommon,but it is the most common neoplasm of theendocrine system. Associations between pesti-cides and thyroid cancer have not been wellstudied. Since some pesticides have endocrine-disrupting properties and at least one studyhas shown an association between agricul-

tural chemicals and thyroid cancer (Sokic et al.1994), the question of an etiological linkbetween specific pesticides and thyroid can-cer is one that needs to be more completelyexamined.

Malignant neoplasms of the brain accountfor approximately 2% of the annual cancerdeaths in the United States. Meta-analyses in1998 (Khuder et al. 1998) and in 1992 (Blair

et al. 1992; Blair and Beane Freeman 2009)found consistent positive findings that sug-gested there was a weak association betweenbrain cancer and farming. The analysis in1998 reported a relative risk equal to 1.30[95% CI: 1.091.56], while the analysis in1992 reported an elevated quantitative risk ofbrain cancer OR =1.05 [95% CI: 0.991.12].The epidemiologic literature found only equiv-ocal results linking specific pesticides and braincancer (Bohnen and Kurland 1995), but someevidence suggests insecticides and fungicideexposure in women in the Unites States may beassociated with a small increased risk for braincancer (Cocco et al. 1999). A major limitationof the studies published to date is the lack of

details regarding exposure. Analyses by job titlealone often result in misclassification of expo-sure, resulting in an underestimation of braincancer risk by occupation. No firm, specificpesticide link to brain cancer has been made,but additional studies are warranted.

Testicular cancer is relatively uncommon inthe United States with an age-adjusted inci-dence rate of 4.5 per 100,000 men (AmericanCancer Society 2008). While studies fromSouth Africa (Aneck-Hahn et al. 2007) andMexico (de Jager et al. 2006) have indicated

impaired semen quality associated with DDTexposure among people living in endemicmalarias areas, a link with testicular cancerhas not been established, nor has a link beenestablished with any other pesticide.

DISCUSSION AND CONCLUSIONS

Currently, more than 800 active ingredi-ents and thousands of pesticide formulationsare on the market in the United States and

other countries, but only arsenical insecticides(International Agency for Research on Cancer1991) and TCDD (a contaminant of thephenoxy herbicide 2,4,5-T) are identified ashuman carcinogens by the IARC (category 1)(International Agency for Research on Cancer1997). In IARC Monograph 53 published in1991, occupational exposures in sprayingand application of non-arsenical insecticides


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as a group are classified as probable humancarcinogens (category 2A) (IARC and Cancer1991). A major challenge to epidemiology isthe identification of whether specific com-pounds are responsible for specific humancancer risks. Such determinations are cru-cial for precise and effective public healthaction. As new scientific evidence emerges,linking specific pesticides with specific cancers,the precautionary principal would indi-cate that a multidisciplinary reevaluation ofhuman carcinogenicity of certain pesticides isnecessary.

While new epidemiologic data will addimportant data on the veracity of the emerg-ing associations, a number of conclusions can

be gleaned from the existing epidemiologicevidence regarding the role of occupationalpesticide exposure in the etiology of variouscancers.

Chemicals in every major functional class ofpesticides (i.e., insecticides, herbicides, fungi-cides, and fumigants) were noted to havesignificant associations with an array of can-cer sites. Moreover, associations have beenobserved with specific chemicals in manychemical classes of pesticides (e.g., chlorinated,organophosphate, and carbamate insecticides

and phenoxy acid and triazine herbicides).However, not every chemical in these classeshas been observed to be associated withcancer in humans. This has likely dilutedthe apparent exposure-response associationsbetween pesticides and cancer in many pre-vious studies that focused on chemical classrather than specific pesticides. Focusing etio-logic studies on exposures to individual pesti-cides and specific health endpoints is neces-sary to identify which specific pesticides arehuman carcinogens and promote cancer inci-

dence among occupationally exposed popula-tions. The adverse health effect of concurrentexposures to multiple pesticides is of consid-erable toxicological interest, but it has beeneven more methodologically challenging forepidemiological studies. Methodological chal-lenges, such as small numbers of exposedcases, and crude and imprecise exposureassessments that lack specificity on specific

active ingredients have hampered many previ-ous epidemiologic studies. Additionally, inad-equate ascertainment of lifestyle factors andtheir control in the analysis in studies that useSMRs and SIRs have distorted the etiologicalpicture of some earlier studies masking theeffect of pesticide exposure on lung, colon,rectal, pancreas, and bladder cancer.

Evidence is accumulating that suggestsgenetic susceptibility to the carcinogenic effectsof certain pesticides may vary in a popula-tion, and assessing the impact of this varia-tion may be important to hazard identifica-tion. The use of biomarkers to identify pre-clinical disease and early biologic effects suchas MGUS, MBL, telomere length (TL) anal-

ysis, and t(14:18) translocations can provideimportant additional compelling informationto identifying which specific active ingredientscontribute to the etiology of specific cancersites. Moreover, the use of these biomarkersmay be informative with regards to the mech-anisms through which pesticides potentiatecarcinogenesis in humans.

In conclusion, the published epidemiolog-ical literature linking specific pesticides to spe-cific cancers has grown steadily since IARCMonograph 53, published in 1991, and IARC

Monograph 69, published in 1997. Importantnew data are now available, but the informa-tion from many disciplines is scattered throughthe scientific literature. Informed selection ofpesticides by users may mitigate cancer riskto both those occupationally and those notoccupationally exposed to pesticides. Since useof pesticides worldwide results in exposure tomillions of workers occupationally and to hun-dreds of millions of people through nonoccu-pational routes of exposure, identifying poten-tial carcinogens among these chemicals should

be an important public health priority. Otherthan arsenical insecticides and TCDD (a pesti-cide contaminant), which are now categorizedby IARC as human carcinogens, 21 chemi-cals were selected from the literature emergingsubsequent to the last IARC review, becausethey have shown significant exposure-responseassociations in studies of specific cancer, whilecontrolling for major potential confounders


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(Table 1). This list is not exhaustive, and othercandidate chemicals are likely to emerge asthe literature assessing the link between spe-cific chemicals and specific cancers expands.It is recognized that many of these observationsneed to be evaluated in other epidemiologi-cal studies, and important data from toxicologyand cancer biology need to be consideredin conjunction with the epidemiologic data,before a final evaluation of the epidemiologicdata can be made. Nonetheless, it is nowreasonable and timely to engage the scien-tific community and regulatory agencies in anexpert review and evaluation of pesticides andtheir potential to induce cancer in occupa-tional setting.

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