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1.  Non-Hodgkin Lymphoma Risk and Insecticide, Fungicide and Fumigant Use in the Agricultural Health Study 
PLoS ONE  2014;9(10):e109332.
Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993–97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999–2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.
PMCID: PMC4206281  PMID: 25337994
2.  Pesticide Exposure and Self-Reported Incident Depression among Wives in the Agricultural Health Study 
Environmental research  2013;126:31-42.
Depression in women is a public health problem. Studies have reported positive associations between pesticides and depression, but few studies were prospective or presented results for women separately.
We evaluated associations between pesticide exposure and incident depression among farmers’ wives in the Agricultural Health Study, a prospective cohort study in Iowa and North Carolina.
We used data on 16,893 wives who did not report physician-diagnosed depression at enrollment (1993-1997) and who completed a follow-up telephone interview (2005-2010). Among these wives, 1,054 reported physician diagnoses of depression at follow-up. We collected information on potential confounders and on ever use of any pesticide, 11 functional and chemical classes of pesticides, and 50 specific pesticides by wives and their husbands via self-administered questionnaires at enrollment. We used inverse probability weighting to adjust for potential confounders and to account for possible selection bias induced by the death or loss of 10,639 wives during follow-up. We used log-binomial regression models to estimate risk ratios and 95% confidence intervals.
After weighting for age at enrollment, state of residence, education level, diabetes diagnosis, and not dropping out of the cohort, wives’ incident depression was positively associated with diagnosed pesticide poisoning, but was not associated with ever using any pesticide. Use of individual pesticides or functional or chemical classes of pesticides was generally not associated with wives’ depression. Among wives who never used pesticides, husbands’ ever use of individual pesticides or functional or chemical classes of pesticides was generally not associated with wives’ incident depression.
Our study adds further evidence that high level pesticide exposure, such as pesticide poisoning, is associated with increased risk of depression and sets a lower bound on the level of exposure related to depression, thereby providing reassurance that the moderate levels of pesticide exposure experienced by farmers’ wives likely do not increase risk.
PMCID: PMC3805780  PMID: 23916637
depression; female; incidence; pesticides; spouses
4.  Pesticide exposure and inherited variants in vitamin D pathway genes in relation to prostate cancer 
Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D’s anti-carcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants.
We evaluated interactions between 41 pesticides and 152 single nucleotide polymorphisms (SNPs) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of Caucasian pesticide applicators within the Agricultural Health Study. We assessed interaction P-values using likelihood ratio tests from unconditional logistic regression and a False Discovery Rate (FDR) to account for multiple comparisons.
Five significant interactions (P<0.01) displayed a monotonic increase in prostate cancer risk with individual pesticide use in one genotype and no association in the other. These interactions involved parathion and terbufos use and three vitamin D genes (VDR, RXRB and GC). The exposure-response pattern among participants with increasing parathion use with the homozygous CC genotype for GC rs7041 compared to unexposed participants was noteworthy (low versus no exposure: odds ratio (OR)=2.58, 95% confidence interval (CI)=1.07–6.25; high versus no exposure: OR=3.09, 95%CI=1.10–8.68; P-interaction=3.8×10−3).
In this study, genetic variations in vitamin D pathway genes, particularly GC rs7041, a SNP previously linked to lower circulating vitamin D levels modified pesticide associations with prostate cancer risk.
Because our study is the first to examine this relationship, additional studies are needed to rule out chance findings.
PMCID: PMC3773544  PMID: 23833127
pesticide; vitamin D; prostate cancer; VDR; RXR
5.  Pesticide Exposure and Depression among Male Private Pesticide Applicators in the Agricultural Health Study 
Environmental Health Perspectives  2014;122(9):984-991.
Background: Pesticide exposure may be positively associated with depression. Few previous studies have considered the episodic nature of depression or examined individual pesticides.
Objective: We evaluated associations between pesticide exposure and depression among male private pesticide applicators in the Agricultural Health Study.
Methods: We analyzed data for 10 pesticide classes and 50 specific pesticides used by 21,208 applicators enrolled in 1993–1997 who completed a follow-up telephone interview in 2005–2010. We divided applicators who reported a physician diagnosis of depression (n = 1,702; 8%) into those who reported a previous diagnosis of depression at enrollment but not follow-up (n = 474; 28%), at both enrollment and follow-up (n = 540; 32%), and at follow-up but not enrollment (n = 688; 40%) and used polytomous logistic regression to estimate odds ratios (ORs) and 95% CIs. We used inverse probability weighting to adjust for potential confounders and to account for the exclusion of 3,315 applicators with missing covariate data and 24,619 who did not complete the follow-up interview.
Results: After weighting for potential confounders, missing covariate data, and dropout, ever-use of two pesticide classes, fumigants and organochlorine insecticides, and seven individual pesticides—the fumigants aluminum phosphide and ethylene dibromide; the phenoxy herbicide (2,4,5-trichlorophenoxy)acetic acid (2,4,5-T); the organochlorine insecticide dieldrin; and the organophosphate insecticides diazinon, malathion, and parathion—were all positively associated with depression in each case group, with ORs between 1.1 and 1.9.
Conclusions: Our study supports a positive association between pesticide exposure and depression, including associations with several specific pesticides.
Citation: Beard JD, Umbach DM, Hoppin JA, Richards M, Alavanja MCR, Blair A, Sandler DP, Kamel F. 2014. Pesticide exposure and depression among male private pesticide applicators in the Agricultural Health Study. Environ Health Perspect 122:984–991;
PMCID: PMC4154212  PMID: 24906048
6.  Sun Exposure, Vitamin D Receptor Genetic Variants, and Risk of Breast Cancer in the Agricultural Health Study 
Environmental Health Perspectives  2013;122(2):165-171.
Background: Epidemiologic evidence suggests a negative relation between sunlight exposure and breast cancer risk. The hypothesized mechanism is sunlight-induced cutaneous synthesis of vitamin D.
Objectives: Our goal was to examine sun exposure and its interaction with vitamin D receptor (VDR) gene variants on breast cancer risk.
Methods: We examined sun exposure and breast cancer incidence among 31,021 private pesticide applicators’ wives, including 578 cases, enrolled in the prospective Agricultural Health Study cohort and followed 8.6 years on average. We estimated interactions between sun exposure, VDR variants, and breast cancer in a nested case–control study comprising 293 cases and 586 matched controls. Information on sun exposure was obtained by questionnaire at cohort enrollment. Relative risks were estimated using Cox proportional hazards regression for the cohort data and conditional logistic regression for the nested case–control data.
Results: We observed a small decrease in breast cancer risk in association with usual sun exposure of ≥ 1 hr/day (versus < 1 hr/day) 10 years before the start of follow-up among all participants [hazard ratio (HR) = 0.8; 95% CI: 0.6, 1.0]. The association appeared to be slightly stronger in relation to estrogen receptor–positive tumors (HR = 0.7; 95% CI: 0.5, 0.9) than estrogen receptor–negative tumors (HR = 1.1; 95% CI: 0.6, 2.1). The HR for joint exposure ≥ 1 hr/day of sunlight and one VDR haplotype was less than expected given negative HRs for each individual exposure (interaction p-value = 0.07).
Conclusion: Our results suggest that sun exposure may be associated with reduced risk of breast cancer, but we did not find clear evidence of modification by VDR variants. Larger studies are warranted, particularly among populations in whom low levels of usual sun exposure can be more precisely characterized.
Citation: Engel LS, Satagopan J, Sima CS, Orlow I, Mujumdar U, Coble J, Roy P, Yoo S, Sandler DP, Alavanja MC. 2014. Sun exposure, vitamin D receptor genetic variants, and risk of breast cancer in the Agricultural Health Study. Environ Health Perspect 122:165–171;
PMCID: PMC3915256  PMID: 24252436
7.  Pesticide Exposure and Self-Reported Gestational Diabetes Mellitus in the Agricultural Health Study 
Diabetes care  2007;30(3):529-534.
To examine the association between pesticide use during pregnancy and gestational diabetes mellitus (GDM) among wives of licensed pesticide applicators.
Using data from the Agricultural Health Study (AHS), we estimated the association between self-reported pesticide-related activities during the first trimester of the most recent pregnancy and GDM among 11,273 women whose pregnancy occurred within 25 years of enrollment.
A total of 506 (4.5%) women reported having had GDM. Women who reported agricultural pesticide exposure (mixing or applying pesticides to crops or repairing pesticide application equipment) during pregnancy were more likely to report GDM (odds ratio [OR] 2.2 [95% CI 1.5–3.3]). We saw no association between residential pesticide exposure (applying pesticides in the home and garden during pregnancy) and GDM (1.0 [0.8–1.3]). Among women who reported agricultural exposure during pregnancy, risk of GDM was associated with ever-use of four herbicides (2,4,5-T; 2,4,5-TP; atrazine; or butylate) and three insecticides (diazinon, phorate, or carbofuran).
These findings suggest that activities involving exposure to agricultural pesticides during the first trimester of pregnancy may increase the risk of GDM.
PMCID: PMC3902103  PMID: 17327316
8.  Risk of Total and Aggressive Prostate Cancer and Pesticide Use in the Agricultural Health Study 
American Journal of Epidemiology  2012;177(1):59-74.
Because pesticides may operate through different mechanisms, the authors studied the risk of prostate cancer associated with specific pesticides in the Agricultural Health Study (1993–2007). With 1,962 incident cases, including 919 aggressive prostate cancers among 54,412 applicators, this is the largest study to date. Rate ratios and 95% confidence intervals were calculated by using Poisson regression to evaluate lifetime use of 48 pesticides and prostate cancer incidence. Three organophosphate insecticides were significantly associated with aggressive prostate cancer: fonofos (rate ratio (RR) for the highest quartile of exposure (Q4) vs. nonexposed = 1.63, 95% confidence interval (CI): 1.22, 2.17; Ptrend < 0.001); malathion (RR for Q4 vs. nonexposed = 1.43, 95% CI: 1.08, 1.88; Ptrend = 0.04); and terbufos (RR for Q4 vs. nonexposed = 1.29, 95% CI: 1.02, 1.64; Ptrend = 0.03). The organochlorine insecticide aldrin was also associated with increased risk of aggressive prostate cancer (RR for Q4 vs. nonexposed = 1.49, 95% CI: 1.03, 2.18; Ptrend = 0.02). This analysis has overcome several limitations of previous studies with the inclusion of a large number of cases with relevant exposure and detailed information on use of specific pesticides at 2 points in time. Furthermore, this is the first time specific pesticides are implicated as risk factors for aggressive prostate cancer.
PMCID: PMC3590039  PMID: 23171882
aggressive prostate cancer; cohort study; farming; organophosphate insecticides; pesticide exposure; prostate cancer
9.  Cancer incidence among pesticide applicators exposed to butylate in the agricultural health study (AHS) 
Environmental research  2009;109(7):860-868.
Although limited, epidemiologic studies suggest possible associations between butylate use and cancer risk, specifically prostate cancer and non-Hodgkin lymphoma (NHL). We examined butylate use and cancer risk more broadly in the AHS, a cohort of licensed pesticide applicators in Iowa and North Carolina. Pesticide use information was collected using self-administered questionnaires. Poisson regression was used to calculate rate ratios(RR) and 95% confidence intervals(CI). Two exposure metrics were used: lifetime exposure days(LD) and intensity-weighted lifetime exposure days(IWLD). We used two referent groups: unexposed to butylate and the lowest butylate usage category. This analysis included 19,655 applicators with complete butylate use information; 5,297 applicators were exposed to butylate, making this the largest study of butylate to-date. The mean follow-up time since enrollment was 9 years. Prostate cancer risk was significantly elevated among applicators in the highest LD category in both referent groups (low exposed referent: RRLD=2.09,95%CI=1.27–3.44). We observed a significantly elevated joint effect of prostate cancer family history and high butylate usage across both exposure metrics and both referent groups (low exposed referent: RRLD=2.00, 95%CI=1.07–3.74), and a non-significant, elevated interaction between butylate use and prostate cancer family history, similar to a previous AHS finding. Statistically significant increased risks and exposure-response trends were seen for all lymphohematopoietic cancers (AL) and NHL for both exposure metrics and referent groups (low exposed referent: AL:RRLD =2.27, 95%CI = 1.18–4.37; NHL: RRLD=3.44, 95%CI =1.29– 9.21). Our analysis did not find meaningful associations for other cancers analyzed. Further study is warranted for AL, NHL and prostate cancers.
PMCID: PMC3799990  PMID: 19615679
butylate; pesticide; cancer; agricultural health study
10.  Vitamin D receptor gene haplotypes and polymorphisms and risk of breast cancer: a nested case-control study 
Observational and experimental studies suggest that vitamin D may influence breast cancer etiology. Most known effects of vitamin D are mediated via the vitamin D receptor (VDR). Few polymorphisms in the VDR gene have been well studied in relation to breast cancer risk and results have been inconsistent.
We investigated VDR polymorphisms and haplotypes in relation to breast cancer risk by genotyping 26 single nucleotide polymorphisms (SNPs) that i) had known/suspected impact on VDR function, ii) were tagging SNPs for the three VDR haplotype blocks among whites, or iii) were previously associated with breast cancer risk. We estimated odds ratios (OR) and 95% confidence intervals (CI) in relation to breast cancer risk among 270 incident cases and 554 matched controls within the Agricultural Health Study cohort.
In individual SNP analyses, homozygous carriers of the minor allele for rs2544038 had significantly increased breast cancer risk (OR=1.5; 95% CI: 1.0, 2.5) and homozygous carriers of the minor allele for rs11168287 had significantly decreased risk (OR=0.6; 95% CI: 0.4, 1.0). Carriers of the minor allele for rs2239181 exhibited marginally significant association with risk (OR=1.4; 95% CI: 0.9, 2.0). Haplotype analyses revealed three haplotype groups (blocks “A”, “B”, and “C”). Haplotype GTCATTTCCTA in block B was significantly associated with reduced risk (OR=0.5; 95% CI: 0.3, 0.9).
These results suggest that variation in VDR may be associated with breast cancer risk.
Our findings may help guide future research needed to define the role of vitamin D in breast cancer prevention.
PMCID: PMC3483029  PMID: 22892281
vitamin D receptor; VDR; haplotype; genotype; breast cancer; nested case-control study
11.  Pesticide Use and Fatal Injury among Farmers in the Agricultural Health Study 
To assess whether pesticide use practices were associated with injury mortality among 51,035 male farmers from North Carolina and Iowa enrolled in the Agricultural Health Study.
We used Cox proportional hazards models adjusted for age and state to estimate fatal injury risk associated with self-reported use of 49 specific pesticides, personal protective equipment, specific types of farm machinery, and other farm factors collected 1–15 years preceding death. Cause-specific mortality was obtained through linkage to mortality registries.
We observed 338 injury fatalities over 727,543 person-years of follow-up (1993–2008). Fatal injuries increased with days per year of pesticide application, with the highest risk among those with 60+ days of pesticide application annually (Hazard Ratio (HR) =1.87; 95% Confidence Interval (CI) = 1.10, 3.18). Chemical-resistant glove use was associated with decreased risk (HR=0.73; 95%CI=0.58, 0.93), but adjusting for glove use did not substantially change estimates for individual pesticides or pesticide use overall. Herbicides were associated with fatal injury, even after adjusting for operating farm equipment, which was independently associated with fatal injury. Ever use of five of 18 herbicides (2,4,5–T, paraquat, alachlor, metribuzin, and butylate) were associated with elevated risk. In addition, 2,4–D and cyanazine were associated with fatal injury in exposure-response analyses. There was no evidence of confounding of these results by other herbicides.
The association between application of pesticides, particularly certain herbicides, and fatal injuries among farmers should be interpreted cautiously but deserves further evaluation, with particular focus on understanding timing of pesticide use and fatal injury.
PMCID: PMC3515737  PMID: 22419121
pesticides; mortality; wounds; injuries
12.  Lifetime Pesticide Use and Telomere Shortening among Male Pesticide Applicators in the Agricultural Health Study 
Environmental Health Perspectives  2013;121(8):919-924.
Background: Telomere length (TL) in surrogate tissues may be influenced by environmental exposures.
Objective: We aimed to determine whether lifetime pesticides use is associated with buccal cell TL.
Methods: We examined buccal cell TL in relation to lifetime use of 48 pesticides for 1,234 cancer-free white male pesticide applicators in the Agricultural Health Study (AHS), a prospective cohort study of 57,310 licensed pesticide applicators. Participants provided detailed information on lifetime use of 50 pesticides at enrollment (1993–1997). Buccal cells were collected from 1999 to 2006. Relative telomere length (RTL) was measured using quantitative real-time polymerase chain reaction. We used linear regression modeling to evaluate the associations between specific pesticides and the logarithm of RTL, adjusting for age at buccal cell collection, state of residence, applicator license type, chewing tobacco use, and total lifetime days of all pesticide use.
Results: The mean RTL for participants decreased significantly in association with increased lifetime days of pesticide use for alachlor (p = 0.002), 2,4-dichlorophenoxyacetic acid (2,4-D; p = 0.004), metolachlor (p = 0.01), trifluralin (p = 0.05), permethrin (for animal application) (p = 0.02), and toxaphene (p = 0.04). A similar pattern of RTL shortening was observed with the metric lifetime intensity-weighted days of pesticide use. For dichlorodiphenyltrichloroethane (DDT), we observed significant RTL shortening for lifetime intensity-weighted days (p = 0.04), but not for lifetime days of DDT use (p = 0.08). No significant RTL lengthening was observed for any pesticide.
Conclusion: Seven pesticides previously associated with cancer risk in the epidemiologic literature were inversely associated with RTL in buccal cell DNA among cancer-free pesticide applicators. Replication of these findings is needed because we cannot rule out chance or fully rule out bias.
PMCID: PMC3734498  PMID: 23774483
Agricultural Health Study; cancer-free subjects; occupational exposures; pesticides; telomere length
13.  Fungal and Atopic Sensitization are Low among Farmers in the Agricultural Health Study 
Clinical Summary
Prevalence of fungal sensitization and atopy was lower among farmers than the US population. Fungal sensitization was related to growing specific agricultural commodities.
PMCID: PMC3387290  PMID: 22633325
fungal sensitization; atopy; agriculture; farmers; specific and total IgE
14.  High pesticide exposure events and central nervous system function among pesticide applicators in the Agricultural Health Study 
While acute pesticide poisoning can be associated with persistent adverse central nervous system (CNS) effects, little is known about the effect of episodic and unusually high pesticide exposure events (HPEEs) that typically do not result in acute poisoning. The objective of this investigation was to examine the association between HPEEs and CNS function among licensed pesticide applicators enrolled in the Agricultural Health Study (AHS).
In 2006–2008, 693 male participants, with no history of a physician-diagnosed pesticide poisoning, completed nine neurobehavioral tests to assess memory, motor speed, sustained attention, verbal learning, and visual scanning and processing. Information on HPEEs and pesticide poisonings was obtained from previous AHS interviews. Associations between HPEEs and neurobehavioral outcomes were estimated with linear regression controlling for age and outcome-specific covariates.
A history of at least one HPEE was reported by 156 (23%) participants. Adverse associations were observed between HPEEs and two of the nine neurobehavioral tests. On a test of visual scanning and processing (Digit-Symbol), participants with HPEEs were 4.2 seconds slower (95% CI: −7.27, −1.11) than those without HPEEs, equivalent to the effect of 3.9 years of age in this population. On a test of visual scanning and motor speed (Sequences A), participants with HPEEs were 2.5 seconds slower (95% CI: −4.53, −0.41) than those without HPEEs, equivalent to the effect of 3.9 years of age. No significant associations were observed between HPEEs and the other neurobehavioral tests.
HPEEs may contribute to adverse CNS outcomes independent of diagnosed pesticide poisoning.
PMCID: PMC3595011  PMID: 21927986
agricultural workers; epidemiology; neurobehavioral testing; pesticide exposure
Neurotoxicology  2012;33(3):457-462.
Our objectives were to summarize literature on the association of amyotrophic lateral sclerosis (ALS) with pesticides as a group and to evaluate associations of ALS with specific pesticides. We conducted a meta-analysis of published studies of ALS and pesticides as a group and investigated the association of ALS with specific pesticides, using data from the Agricultural Health Study (AHS), a cohort including 84,739 private pesticide applicators and spouses. AHS participants provided information on pesticide use at enrollment in 1993-1997. In mortality data collected through February, 2010, ALS was recorded on death certificates of 41 individuals whom we compared to the remaining cohort (controls), using unconditional logistic regression adjusted for age and gender to calculate odds ratios (ORs) and 95% confidence intervals. In the meta-analysis, ALS was associated with use of pesticides as a group (1.9, 1.1-3.1). In the AHS, ALS was not associated with pesticides as a group, but was associated with use of organochlorine insecticides (OCs) (1.6, 0.8-3.5), pyrethroids (1.4, 0.6-3.4), herbicides (1.6, 0.7-3.7), and fumigants (1.8, 0.8-3.9). ORs were elevated for ever use of the specific OCs aldrin (2.1, 0.8-5.1), dieldrin (2.6, 0.9-7.3), DDT (2.1, 0.9-5.0), and toxaphene (2.0, 0.8-4.9). None of these associations was statistically significant. Similar results were observed in an analysis restricted to men. In conclusion, the meta-analysis suggests that ALS risk is associated with use of pesticides as a group, and our analysis of AHS data points to OC use in particular. The latter results are novel but based on a small number of cases and require replication in other populations.
PMCID: PMC3358481  PMID: 22521219
amyotrophic lateral sclerosis; motor neuron disease; cohort study; meta-analysis; pesticides; organochlorine insecticides
16.  EGFR Somatic Mutations in Lung Tumors: Radon Exposure and Passive-smoking in Former- and Never-smoking U.S. Women 
Lung cancer patients with mutations in EGFR tyrosine kinase have improved prognosis when treated with EGFR inhibitors. We hypothesized that EGFR mutations may be related to residential radon or passive tobacco smoke.
This hypothesis was investigated by analyzing EGFR mutations in seventy lung tumors from a population of never and long-term former female smokers from Missouri with detailed exposure assessments. The relationship with passive-smoking was also examined in never-smoking female lung cancer cases from the Mayo clinic.
Overall, the frequency of EGFR mutation was 41% [95% Confidence Interval (CI): 32-49%]. Neither radon nor passive-smoking exposure was consistently associated with EGFR mutations in lung tumors.
The results suggest that EGFR mutations are common in female, never-smoking, lung cancer cases from the U.S, and EGFR mutations are unlikely due to exposure to radon or passive-smoking.
PMCID: PMC3372599  PMID: 22523180
EGFR mutations; never-smokers; lung cancer; radon; passive-smoking; second hand smoke; tobacco smoke
17.  Methyl bromide exposure and cancer risk in the Agricultural Health Study 
Cancer causes & control : CCC  2012;23(6):807-818.
Methyl bromide is a genotoxic soil fumigant with high acute toxicity, but unknown human carcinogenicity. Although many countries have reduced methyl bromide use because of its ozone depleting properties, some uses remain in the United States and other countries, warranting further investigation of human health effects.
We used Poisson regression to calculate rate ratios (RR) and 95% confidence intervals (CI) for associations between methyl bromide use and all cancers combined and 12 specific sites among 53,588 Agricultural Health Study (AHS) pesticide applicators with follow-up from 1993–2007. We also evaluated interactions with a family history for four common cancers (prostate, lung, colon, and lymphohematopoietic). We categorized methyl bromide exposure based on lifetime days applied weighted by an intensity score.
A total of 7,814 applicators (14.6%) used methyl bromide, predominantly before enrollment. Based on 15 exposed cases, stomach cancer risk increased monotonically with increasing methyl bromide use (RR=1.42; 95% CI: 0.51–3.95 and RR=3.13; 95% CI: 1.25–7.80 for low and high use compared with no use; ptrend=0.02). No other sites displayed a significant monotonic pattern. Although we previously observed an association with prostate cancer (follow-up through 1999), the association did not persist with longer follow-up. We observed a non-significant elevated risk of prostate cancer with methyl bromide use among those with a family history of prostate cancer, but the interaction with a family history did not achieve statistical significance.
Our results provide little evidence of methyl bromide associations with cancer risk for most sites examined; however, we observed a significant exposure-dependent increase in stomach cancer risk. Small numbers of exposed cases and declining methyl bromide use might have influenced our findings. Further study is needed in more recently exposed populations to expand on these results.
PMCID: PMC3430844  PMID: 22527160
methyl bromide; fumigant; pesticide; cancer
18.  Poultry and Livestock Exposure and Cancer Risk among Farmers in the Agricultural Health Study 
Cancer causes & control : CCC  2012;23(5):663-670.
The purpose of this study is to evaluate cancer risk associated with raising animals as commodities, which is associated with a variety of exposures, such as infectious agents and endotoxins.
Information was available for 49,884 male farmers in the Agricultural Health Study, who reported livestock and poultry production at enrollment (1993–1997). Cancer incidence data were obtained through annual linkage to state registries. Using Poisson regression analyses, we evaluated whether the number and type of animals raised on the farm impacted cancer risk.
Overall, 31,848 (63.8%) male farmers reported raising any animals. Lung cancer risk decreased with increasing number of livestock on the farm (p-trend=0.04) and with raising poultry (Relative Risk (RR)= 0.6; 95% Confidence Interval (CI): 0.4–0.97). Raising poultry was associated with an increased risk of colon cancer (RR=1.4; 95% CI: 0.99–2.0) with further increased with larger flocks (p-trend=0.02). Risk of non-Hodgkin lymphoma was also elevated in those who raised poultry (RR=1.6; 95% CI: 1.0–2.4), but there was no evidence of increased risk with larger flocks (p-trend=0.5). Raising sheep was associated with a significantly increased risk of multiple myeloma (RR=4.9; 95% CI: 2.4–12.0). Performing veterinary services increased the risk of Hodgkin lymphoma (RR=12.2; 95% CI: 1.6–96.3).
We observed an inverse association between raising poultry and livestock and lung cancer risk and some evidence of increased risk of specific lymphohematopoietic malignancies with specific types of animals and performing veterinary services. Further research into associations between raising animals and cancer risk should focus on identification of etiologic agents.
PMCID: PMC3337970  PMID: 22407136
livestock; poultry; cancer; cohort study; agriculture
19.  Lifetime Organophosphorous Insecticide Use among Private Pesticide Applicators in the Agricultural Health Study 
Organophosphorous insecticides (OPs) are the most commonly used insecticides in US agriculture, but little information is available regarding specific OP use by individual farmers. We describe OP use for licensed private pesticide applicators from Iowa and North Carolina in the Agricultural Health Study (AHS) using lifetime pesticide use data from 701 randomly selected male participants collected at three time periods. Of 27 OPs studied, 20 were used by >1%. Overall, 95% had ever applied at least one OP. The median number of different OPs used was 4 (maximum=13). Malathion was the most commonly used OP (74%) followed by chlorpyrifos (54%). OP use declined over time. At the first interview (1993–1997), 68% of participants had applied OPs in the past year; by the last interview (2005–2007), only 42% had. Similarly, median annual application days of OPs declined from 13.5 to 6 days. While OP use was common, the specific OPs used varied by state, time period, and individual. Much of the variability in OP use was associated with the choice of OP, rather than the frequency or duration of application. Information on farmers’ OP use enhances our ability to characterize and understand the potential health effects of multiple OP exposures.
PMCID: PMC3478402  PMID: 22854518
pesticide use; farming; organophosphorous insecticide
20.  Urinary Biomarker, Dermal, and Air Measurement Results for 2,4-D and Chlorpyrifos Farm Applicators in the Agricultural Health Study 
Epidemiologic studies increasingly rely on improved exposure assessments to characterize pesticide exposures in agricultural populations. A subset of private pesticide applicators in the AHS epidemiological cohort was monitored around the time of their agricultural use of 2,4-D and chlorpyrifos to assess exposure levels and potential exposure factors. Measurements included pre- and post-application urine samples, and patch, hand wipe, and personal air samples. Broadcast or hand spray application methods were used by applicators for 2,4-D products. Chlorpyrifos products were applied using spray applications and in-furrow application of granular products. Geometric mean (GM) values for 69 2,4-D applicators were 7.8 and 25 µg/L in pre- and post-application urine, respectively (p < 0.05 for difference); 0.39 mg for estimated hand loading; 2.9 mg for estimated body loading; and 0.37 µg/m3 for concentration in personal air. Significant correlations were found between all media for 2,4-D. GM values for 17 chlorpyrifos applicators were 11 µg/L in both pre- and post-application urine for the 3,5,6-trichloro-2-pyridinol metabolite, 0.28 mg for body loading, and 0.49 µg/m3 for air concentration. Only 53% of the chlorpyrifos applicators had measureable hand loading results; their median hand loading was 0.02 mg. Factors associated with differences in 2,4-D measurements included application method and glove use; and, for hand spray applicators, use of adjuvants, equipment repair, duration of use, and contact with treated vegetation. Spray applications of liquid chlorpyrifos products were associated with higher measurements than in-furrow granular product applications. This study provides information on exposures and possible exposure determinants for several application methods commonly used by farmers in the cohort and will provide information to assess and refine exposure classification in the Agricultural Health Study. Results may also be of use in pesticide safety education for reducing exposures to applied pesticides.
PMCID: PMC3633453  PMID: 19240759
2, 4-D; chlorpyrifos; exposure measurement; pesticide exposure; agricultural exposure; farm applicator; occupational exposure; Agricultural Health Study
21.  Genetic Susceptibility Loci, Pesticide Exposure and Prostate Cancer Risk 
PLoS ONE  2013;8(4):e58195.
Uncovering SNP (single nucleotide polymorphisms)-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. We evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. After correction for multiple tests using the False Discovery Rate method, two interactions remained noteworthy. Among men carrying two T alleles at rs2710647 in EH domain binding protein 1 (EHBP1) SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use (95% CI: 1.44–8.15) (P-interaction  = 0.003). Among men carrying two A alleles at rs7679673 in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use (95% CI: 1.43, 9.41) (P-interaction  = 0.006). In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer.
PMCID: PMC3617165  PMID: 23593118
22.  Central nervous system function and organophosphate insecticide use among pesticide applicators in the Agricultural Health Study 
Neurotoxicology and teratology  2011;34(1):168-176.
Acute organophosphate (OP) pesticide exposure is associated with adverse central nervous system (CNS) outcomes, however, little is known about the neurotoxicity of chronic exposures that do not result in acute poisoning. To examine associations between long-term pesticide use and CNS function, neurobehavioral (NB) tests were administered to licensed pesticide applicators enrolled in the Agricultural Health Study (AHS) in Iowa and North Carolina. Between 2006 and 2008, 701 male participants completed nine NB tests to assess memory, motor speed and coordination, sustained attention, verbal learning and visual scanning and processing. Data on ever-use and lifetime days of use of 16 OP pesticides were obtained from AHS interviews conducted before testing between 1993 and 2007 and during the NB visit. The mean age of participants was 61 years (SD = 12). Associations between pesticide use and NB test performance were estimated with linear regression controlling for age and outcome-specific covariates. NB test performance was associated with lifetime days of use of some pesticides. Ethoprop was significantly associated with reduced performance on a test of motor speed and visual scanning. Malathion was significantly associated with poor performance on a test of visual scanning and processing. Conversely, we observed significantly better test performance for five OP pesticides. Specifically, chlorpyrifos, coumaphos, parathion, phorate, and tetrachlorvinphos were associated with better verbal learning and memory; coumaphos was associated with better performance on a test of motor speed and visual scanning; and parathion was associated with better performance on a test of sustained attention. Several associations varied by state. Overall, our results do not provide strong evidence that long-term OP pesticide use is associated with adverse CNS-associated NB test performance among this older sample of pesticide applicators. Potential reasons for these mostly null associations include a true absence of effect as well as possible selective participation by healthier applicators.
PMCID: PMC3601543  PMID: 21907279
agricultural workers; epidemiology; organophosphates; neuropsychological testing; pesticide exposure
23.  Impact of Pesticide Exposure Misclassification on Estimates of Relative Risks in the Agricultural Health Study 
The Agricultural Health Study (AHS) is a prospective study of licensed pesticide applicators (largely farmers) and their spouses in Iowa and North Carolina. We evaluate the impact of occupational pesticide exposure misclassification on relative risks using data from the cohort and the AHS Pesticide Exposure Study (AHS/PES).
We assessed the impact of exposure misclassification on relative risks using the range of correlation coefficients observed between measured post-application urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) and chlorpyrifos metabolite and exposure estimates based on an algorithm from 83 AHS pesticide applications.
The correlations between urinary levels of 2,4-D and chlorpyrifos metabolite and estimated exposure intensity scores from the expert-derived algorithm were about 0.4 for 2,4-D (n=64), 0.8 for liquid chlorpyrifos (n=4), and 0.6 for granular chlorpyrifos (n=12). Correlations of urinary levels with individual exposure determinants (e.g., kilograms of active ingredient used, duration of application, or number of acres treated) were lower and ranged from −0.36 to 0.19. These findings indicate that scores from an a priori expert-derived algorithm developed for the AHS were more closely related to measured urinary levels than the several individual exposure determinants evaluated here. Estimates of potential bias in relative risks observed in the AHS based on the correlations from the AHS/PES and the proportion of the AHS cohort exposed to various pesticides indicate that nondifferential misclassification of exposure using the algorithm would bias some estimates toward the null, but less than the misclassification associated with individual exposure determinants.
Based on these correlations and the proportion of the AHS cohort exposed to various pesticides, the potential bias in relative risks from nondifferential exposure misclassification is reduced when exposure estimates are based on an expert algorithm compared to estimates based on separate individual exposure determinants often used in epidemiologic studies. Although correlations between algorithm scores and urinary levels were quite good (i.e., correlations between 0.4 and 0.8), exposure misclassification would still bias relative risk estimates in the AHS towards the null and diminish study power.
PMCID: PMC3566632  PMID: 21257983
24.  Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk 
Carcinogenesis  2011;33(2):331-337.
Previous research demonstrates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, human biomonitoring studies indicate increased genetic damage (e.g. chromosomal aberrations) with pesticide exposure. Given that the nucleotide excision repair (NER) pathway repairs a broad range of DNA damage, we evaluated interactions between pesticide exposure and 324 single-nucleotide polymorphisms (SNPs) tagging 27 NER genes among 776 prostate cancer cases and 1444 male controls in a nested case–control study of white Agricultural Health Study pesticide applicators. We determined interaction P values using likelihood ratio tests from logistic regression models and three-level pesticide variables (none/low/high) based on lifetime days of use weighted to an intensity score. We adjusted for multiple comparisons using the false discovery rate (FDR) method. Of the 17 interactions that met FDR <0.2, 3 displayed a monotonic increase in prostate cancer risk with increasing exposure in one genotype group and no significant association in the other group. Men carrying the variant A allele at ERCC1 rs2298881 exhibited increased prostate cancer risk with high versus no fonofos use [odds ratio (OR) 2.98; 95% confidence interval (CI) 1.65–5.39; Pinteract = 3.6 × 10−4; FDR-adjusted P = 0.11]. Men carrying the homozygous wild-type TT genotype at two correlated CDK7 SNPs, rs11744596 and rs2932778 (r2 = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31–3.10 for rs11744596; Pinteract = 7.2 × 10−4; FDR-adjusted P = 0.09). In contrast, we did not observe associations among men with other genotypes at these loci. While requiring replication, our findings suggest a role for NER genetic variation in pesticide-associated prostate cancer risk.
PMCID: PMC3271261  PMID: 22102698
25.  Joint Associations Between Genetic Variants and Reproductive Factors in Glioma Risk Among Women 
American Journal of Epidemiology  2011;174(8):901-908.
In a pooled analysis of 4 US epidemiologic studies (1993–2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12–13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.
PMCID: PMC3218628  PMID: 21920947
genes; glioma; menstrual cycle; polymorphism, single nucleotide; reproduction; women

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