Increased cancer burden among pesticide applicators and others due to pesticide exposure.

A growing number of well-designed epidemiological and molecular studies provide substantial evidence that the pesticides used in agricultural, commercial, and home and garden applications are associated with excess cancer risk. This risk is associated both with those applying the pesticide and, under some conditions, those who are simply bystanders to the application. In this article, the epidemiological, molecular biology, and toxicological evidence emerging from recent literature assessing the link between specific pesticides and several cancers including prostate cancer, non-Hodgkin lymphoma, leukemia, multiple myeloma, and breast cancer are integrated. Although the review is not exhaustive in its scope or depth, the literature does strongly suggest that the public health problem is real. If we are to avoid the introduction of harmful chemicals into the environment in the future, the integrated efforts of molecular biology, pesticide toxicology, and epidemiology are needed to help identify the human carcinogens and thereby improve our understanding of human carcinogenicity and reduce cancer risk.

Occupational pesticide use and self-reported olfactory impairment in US farmers.

OBJECTIVES: Pesticide exposure may impair human olfaction, but empirical evidence is limited. We examined associations between occupational use of 50 specific pesticides and olfactory impairment, both self-reported, among 20 409 participants in the Agricultural Health Study, a prospective cohort of pesticide applicators (mostly farmers, 97% male). METHODS: We used logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between pesticide use at enrolment (1993-1997) and olfactory impairment reported two decades later (2013-2016), adjusting for baseline covariates. RESULTS: About 10% of participants reported olfactory impairment. The overall cumulative days of any pesticide use at enrolment were associated with a higher odds of reporting olfactory impairment (OR (highest vs lowest quartile): 1.17 (95% CI: 1.02 to 1.34), p-trend = 0.003). In the analyses of 50 specific pesticides, ever-use of 20 pesticides showed modest associations with olfactory impairment, with ORs ranging from 1.11 to 1.33. Of these, higher lifetime days of use of 12 pesticides were associated with higher odds of olfactory impairment compared with never use (p-trend ≤ 0.05), including two organochlorine insecticides (dichlorodiphenyltrichloroethane and lindane), two organophosphate insecticides (diazinon and malathion), permethrin, the fungicide captan and six herbicides (glyphosate, petroleum distillates, 2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxyacetic acid and metribuzin), although many of these did not exhibit clear, monotonic exposure-response patterns. CONCLUSION: Overall, we found relatively broad associations between pesticides and olfactory impairment, involving many individual pesticides and covering several chemical classes, suggesting that pesticides could affect olfaction through multiple pathways. Future epidemiological studies with objective measurement of olfaction are required to confirm these findings.

Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators.

OBJECTIVES: Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. We evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators. METHODS: Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. We used multivariate logistic regression to estimate ORs and 95% CIs for subclinical hypothyroidism (TSH >4.5 mIU/L) compared with normal TSH (0.4-<4.5 mIU/L) and for anti-TPO positivity. We also examined pesticide associations with TSH, T4 and T3 in multivariate linear regression models. RESULTS: Higher exposure to the insecticide aldrin (third and fourth quartiles of intensity-weighted days vs no exposure) was positively associated with subclinical hypothyroidism (ORQ3=4.15, 95% CI 1.56 to 11.01, ORQ4=4.76, 95% CI 1.53 to 14.82, ptrend <0.01), higher TSH (ptrend=0.01) and lower T4 (ptrend=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: ORQ4=2.78, 95% CI 1.30 to 5.95, ptrend=0.02), higher TSH (ptrend=0.04) and anti-TPO positivity (ptrend=0.01). The fumigant methyl bromide was inversely associated with TSH (ptrend=0.02) and positively associated with T4 (ptrend=0.01). CONCLUSIONS: Our results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators.

Industrial hog farming is associated with altered circulating immunological markers.

OBJECTIVES: The previously observed inverse association between hog farming and risk of lung cancer in the Agricultural Health Study (AHS) has been attributed to endotoxin exposure, the levels of which are particularly high in industrial hog confinement facilities. We conducted an investigation to explore the potential biological mechanisms underlying this association, as well as other immunological changes associated with hog farming. METHODS: Serum immune marker levels were measured using a multiplexed bead-based assay in 61 active hog farmers and 61 controls matched on age, phlebotomy date and raising cattle. Both groups comprised non-smoking male AHS participants from Iowa. We compared natural log-transformed marker levels between hog farmers and controls using multivariate linear regression models. RESULTS: Circulating levels of macrophage-derived chemokine (CCL22), a chemokine previously implicated in lung carcinogenesis, were reduced among hog farmers (17% decrease; 95% CI -28% to -4%), in particular for those with the largest operations (>6000 hogs: 26% decrease; 95% CI -39% to -10%; ptrend=0.002). We also found that hog farmers had elevated levels of other immune markers, including macrophage inflammatory protein-3 alpha (MIP-3A/CCL20; 111% increase, 95% CI 19% to 273%), basic fibroblast growth factor (FGF-2; 93% increase, 95% CI 10% to 240%) and soluble interleukin-4 receptor (12% increase, 95% CI 1% to 25%), with particularly strong associations for MIP-3A/CCL20 and FGF-2 in winter. CONCLUSIONS: These results provide insights into potential immunomodulatory mechanisms through which endotoxin or other exposures associated with hog farming may influence lung cancer risk, and warrant further investigation with more detailed bioaerosol exposure assessment.

Cancer incidence and metolachlor use in the Agricultural Health Study: An update.

Metolachlor, a widely used herbicide, is classified as a Group C carcinogen by the U.S. Environmental Protection Agency based on increased liver neoplasms in female rats. Epidemiologic studies of the health effects of metolachlor have been limited. The Agricultural Health Study (AHS) is a prospective cohort study including licensed private and commercial pesticide applicators in Iowa and North Carolina enrolled 1993-1997. We evaluated cancer incidence through 2010/2011 (NC/IA) for 49,616 applicators, 53% of whom reported ever using metolachlor. We used Poisson regression to evaluate relations between two metrics of metolachlor use (lifetime days, intensity-weighted lifetime days) and cancer incidence. We saw no association between metolachlor use and incidence of all cancers combined (n = 5,701 with a 5-year lag) or most site-specific cancers. For liver cancer, in analyses restricted to exposed workers, elevations observed at higher categories of use were not statistically significant. However, trends for both lifetime and intensity-weighted lifetime days of metolachor use were positive and statistically significant with an unexposed reference group. A similar pattern was observed for follicular cell lymphoma, but no other lymphoma subtypes. An earlier suggestion of increased lung cancer risk at high levels of metolachlor use in this cohort was not confirmed in this update. This suggestion of an association between metolachlor and liver cancer among pesticide applicators is a novel finding and echoes observation of increased liver neoplasms in some animal studies. However, our findings for both liver cancer and follicular cell lymphoma warrant follow-up to better differentiate effects of metolachlor use from other factors.

Incidence of solid tumours among pesticide applicators exposed to the organophosphate insecticide diazinon in the Agricultural Health Study: an updated analysis.

OBJECTIVE: Diazinon, a common organophosphate insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon-associated cancer risk. We used updated diazinon exposure and cancer incidence information to evaluate solid tumour risk in the AHS. METHODS: Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment (1993-1997) and follow-up (1998-2005); cancer incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for cancer sites with ≥10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). RESULTS: We observed elevated lung cancer risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; P(trend)=0.02) and IW days of diazinon use (RR=1.41; 95% CI 0.98 to 2.04; P(trend)=0.08). Kidney cancer (N=94) risks were non-significantly elevated (RR(LT) days=1.77; 95% CI 0.90 to 3.51; P(trend)=0.09; RR(IW) days 1.37; 95% CI 0.64 to 2.92; P(trend)=0.50), as were risks for aggressive prostate cancer (N=656). CONCLUSIONS: Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk. Newly identified links to kidney cancer and associations with aggressive prostate cancer require further evaluation.

Pesticide Exposures and Body Mass Index (BMI) of Pesticide Applicators From the Agricultural Health Study.

Endocrine-disrupting chemicals, including pesticides, may be associated with weight gain. This is the first longitudinal study to examine a potential association between weight gain and pesticides using data on 8,365 male pesticide applicators from the Agricultural Health Study (AHS) cohort established in 1993. The relationship between total cumulative days of exposure to pesticide functional/chemical classes and to the four most frequently used individual pesticides was studied in relation to body mass index (BMI) at the time of 5-yr follow-up (beginning in 1998) with the length of the exposure period dating back to age 20 yr. Multiple regression, Spearman correlation, ordinal logistic regression, and logistic regression models all utilized a Bonferroni-adjusted p value, were adjusted for relevant covariates, and were stratified by state of residence (Iowa/North Carolina) and presence/absence of weight-related health conditions. Adjusted multiple regression yielded statistically significant positive parameter estimates for the study sample and Iowa subgroups with consistent findings for triazine herbicides and atrazine: Change in BMI per 100 cumulative pesticide exposure days ranged from 0.07 to 0.11 for triazine herbicides and from 0.10 to 0.19 for atrazine. Ordinal logistic regression compared normal weight with overweight and with obese using the zero exposure category as referent. Statistically significant adjusted odds ratios identified for the study sample and both state subgroups for the highest level of atrazine exposure ranged from 1.4 to 1.7. Further investigation is warranted to evaluate the associations identified here.

Respiratory disease in United States farmers.

OBJECTIVES: Farmers may be at increased risk for adverse respiratory outcomes compared with the general population due to their regular exposures to dusts, animals and chemicals. However, early life farm exposures to microbial agents may result in reduced risk. Understanding respiratory disease risk among farmers and identifying differences between farmers and other populations may lead to better understanding of the contribution of environmental exposures to respiratory disease risk in the general population. METHODS: We compared the prevalence of self-reported respiratory outcomes in 43548 participants from the Agricultural Health Study (AHS), a prospective cohort of farmers and their spouses from Iowa and North Carolina, with data from adult participants in the National Health and Nutrition Examination Survey (NHANES) over the same period (2005-2010). RESULTS: AHS participants had lower prevalences of respiratory diseases (asthma, adult-onset asthma, chronic bronchitis and emphysema), but higher prevalences of current respiratory symptoms (wheeze, cough and phlegm) even after controlling for smoking, body mass index and population characteristics. The overall prevalence of asthma in the AHS (7.2%, 95% CI 6.9 to 7.4) was 52% of that in NHANES (13.8%, 95% CI 13.3 to 14.3), although the prevalence of adult-onset asthma among men did not differ (3.6% for AHS, 3.7% for NHANES). Conversely, many respiratory symptoms were more common in the AHS than NHANES, particularly among men. CONCLUSIONS: These findings suggest that farmers and their spouses have lower risk for adult-onset respiratory diseases compared with the general population, and potentially higher respiratory irritation as evidenced by increased respiratory symptoms.

Risk of total and aggressive prostate cancer and pesticide use in the Agricultural Health Study.

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; P(trend) < 0.001); malathion (RR for Q4 vs. nonexposed = 1.43, 95% CI: 1.08, 1.88; P(trend) = 0.04); and terbufos (RR for Q4 vs. nonexposed = 1.29, 95% CI: 1.02, 1.64; P(trend) = 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; P(trend) = 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.

Pesticide exposure and self-reported incident depression among wives in the Agricultural Health Study.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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, 1054 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. RESULTS: After weighting for age at enrollment, state of residence, education level, diabetes diagnosis, and drop out, 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. CONCLUSIONS: 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.

Pesticide use and fatal injury among farmers in the Agricultural Health Study.

PURPOSE: To assess whether pesticide use practices were associated with injury mortality among 51,035 male farmers from NC and IA enrolled in the Agricultural Health Study. METHODS: 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. RESULTS: We observed 338 injury fatalities over 727,543 person-years of follow-up (1993-2008). Fatal injuries increased with days/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. CONCLUSION: 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.

Genetic variation in nucleotide excision repair pathway genes, pesticide exposure and prostate cancer risk.

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; P(interact) = 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 (r(2) = 1.0), exhibited increased risk with high versus no carbofuran use (OR 2.01; 95% CI 1.31-3.10 for rs11744596; P(interact) = 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.

Methyl bromide exposure and cancer risk in the Agricultural Health Study.

PURPOSE: 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. METHODS: We used Poisson regression to calculate rate ratios (RR) and 95 % confidence intervals (CI) for associations between methyl bromide use and all cancers combined, as well as 12 specific sites, among 53,588 Agricultural Health Study pesticide applicators with follow-up from 1993 to 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. RESULTS: 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; p (trend) = 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 nonsignificant 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. CONCLUSIONS: 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.

Occupational pesticide exposures and cancer risk: a review.

A review of the epidemiological literature linking pesticides to cancers in occupational studies worldwide was conducted, with particular focus on those articles published after the release of IARC Monograph 53 (1991): Occupational Exposures in Insecticide Applications and Some Pesticides. Important new data are now available. Chemicals in every major functional class of pesticides including insecticides, herbicide, fungicides, and fumigants have been observed to 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 exposure-response associations in studies of specific cancers while controlling for major potential confounders. This list is not an exhaustive review and many of these observations need to be evaluated in other epidemiological studies and in conjunction with data from toxicology and cancer biology. Nonetheless, it is reasonable and timely for the scientific community to provide a multidisciplinary expert review and evaluation of these pesticides and their potential to produce cancer in occupational settings.

Mortality in the agricultural health study, 1993-2007.

Comparing agricultural cohorts with the general population is challenging because the general healthiness of farmers may mask potential adverse health effects of farming. Using data from the Agricultural Health Study, a cohort of 89,656 pesticide applicators and their spouses (N = 89, 656) in North Carolina and Iowa, the authors computed standardized mortality ratios (SMRs) comparing deaths from time of the enrollment (1993-1997) through 2007 to state-specific rates. To compensate for the cohort's overall healthiness, relative SMRs were estimated by calculating the SMR for each cause relative to the SMR for all other causes. In 1,198,129 person-years of follow-up, 6,419 deaths were observed. The all-cause mortality rate was less than expected (SMR(applicators) = 0.54, 95% confidence interval (CI): 0.52, 0.55; SMR(spouses) = 0.52, 95% CI: 0.50, 0.55). SMRs for all cancers, heart disease, and diabetes were significantly below 1.0. In contrast, applicators experienced elevated numbers of machine-related deaths (SMR = 4.15, 95% CI: 3.18, 5.31), motor vehicle nontraffic accidents (SMR = 2.80, 95% CI: 1.81, 4.14), and collisions with objects (SMR = 2.12, 95% CI: 1.25, 3.34). In the relative SMR analysis for applicators, the relative mortality ratio was elevated for lymphohematopoietic cancers, melanoma, and digestive system, prostate, kidney, and brain cancers. Among spouses, relative SMRs exceeded 1.0 for lymphohematopoietic cancers and malignancies of the digestive system, brain, breast, and ovary. Unintentional fatal injuries remain an important risk for farmers; mortality ratios from several cancers were elevated relative to other causes.

Xenobiotic-metabolizing gene variants, pesticide use, and the risk of prostate cancer.

BACKGROUND: To explore associations with prostate cancer and farming, it is important to investigate the relationship between pesticide use and single nucleotide polymorphisms (SNPs) in xenobiotic metabolic enzyme (XME) genes. OBJECTIVE: [corrected] We evaluated pesticide-SNP interactions between 45 pesticides and 1913 XME SNPs with respect to prostrate cancer among 776 cases and 1444 controls in the Agricultural Health Study. METHODS: 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. RESULTS: A positive monotonic interaction was observed between petroleum oil/petroleum distillate use and rs1883633 in the oxidative stress gene glutamate cysteine ligase (GCLC; P interaction=1.0×10(-4)); men carrying at least one variant allele (minor allele) experienced an increased prostate cancer risk (OR=3.7, 95% CI: 1.9-7.3). Among men carrying the variant allele for thioredoxin reductase 2 (TXNRD2) rs4485648, microsomal epoxide hydrolase 1 (EPHX1) rs17309872, or myeloperoxidase (MPO) rs11079344, an increased prostate cancer risk was observed with high, compared with no, petroleum oil/petroleum distillate (OR=1.9, 95% CI: 1.1-3.2, P interaction=0.01; OR=2.1, 95% CI: 1.1-4.0, P interaction=0.01), or terbufos (OR=3.0, 95% CI: 1.5-6.0, P interaction=2.0×10(-3)) use, respectively. No interactions were deemed noteworthy at the false discovery rate=0.20 level; the number of observed interactions in XMEs was comparable with the number expected by chance alone. CONCLUSION: We observed several pesticide-SNP interactions in oxidative stress and phase I/II enzyme genes and risk of prostate cancer. Additional work is needed to explain the joint contribution of genetic variation in XMEs, pesticide use, and prostate cancer risk.

Impact of pesticide exposure misclassification on estimates of relative risks in the Agricultural Health Study.

BACKGROUND: The Agricultural Health Study (AHS) is a prospective study of licensed pesticide applicators 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). METHODS: 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 a chlorpyrifos metabolite and exposure estimates based on an algorithm from 83 AHS pesticide applications. RESULTS: Correlations between urinary levels of 2,4-D and a chlorpyrifos metabolite and algorithm estimated intensity scores 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 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 a priori expert-derived algorithm scores were more closely related to measured urinary levels than individual exposure determinants evaluated here. Estimates of potential bias in relative risks based on the correlations from the AHS/PES indicate that non-differential misclassification of exposure using the algorithm would bias estimates towards the null, but less than that from individual exposure determinants. CONCLUSIONS: Although correlations between algorithm scores and urinary levels were quite good (ie, 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.

Determinants of captan air and dermal exposures among orchard pesticide applicators in the Agricultural Health Study.

OBJECTIVES: To identify and quantify determinants of captan exposure among 74 private orchard pesticide applicators in the Agricultural Health Study (AHS). To adjust an algorithm used for estimating pesticide exposure intensity in the AHS based on these determinants and to compare the correlation of the adjusted and unadjusted algorithms with urinary captan metabolite levels. METHODS: External exposure metrics included personal air, hand rinse, and dermal patch samples collected from each applicator on 2 days in 2002-2003. A 24-h urine sample was also collected. Exposure determinants were identified for each external metric using multiple linear regression models via the NLMIXED procedure in SAS. The AHS algorithm was adjusted, consistent with the identified determinants. Mixed-effect models were used to evaluate the correlation between the adjusted and unadjusted algorithm and urinary captan metabolite levels. RESULTS: Consistent determinants of captan exposure were a measure of application size (kilogram of captan sprayed or application method), wearing chemical-resistant (CR) gloves and/or a coverall/suit, repairing spray equipment, and product formulation. Application by airblast was associated with a 4- to 5-fold increase in exposure as compared to hand spray. Exposure reduction to the hands, right thigh, and left forearm from wearing CR gloves averaged ∼80%, to the right and left thighs and right forearm from wearing a coverall/suit by ∼70%. Applicators using wettable powder formulations had significantly higher air, thigh, and forearm exposures than those using liquid formulations. Application method weights in the AHS algorithm were adjusted to nine for airblast and two for hand spray; protective equipment reduction factors were adjusted to 0.2 (CR gloves), 0.3 (coverall/suit), and 0.1 (both). CONCLUSIONS: Adjustment of application method, CR glove, and coverall weights in the AHS algorithm based on our exposure determinant findings substantially improved the correlation between the AHS algorithm and urinary metabolite levels.

Pesticide exposure and incident thyroid cancer among male pesticide applicators in agricultural health study.

BACKGROUND: Many pesticides are known to have thyroid-disrupting properties. However, few studies have evaluated the association between specific pesticide ingredients and risk of thyroid cancer. We investigated self-reported pesticide use and incident thyroid cancer in the Agricultural Health Study (AHS), a large cohort of occupationally-exposed male pesticide applicators. METHODS: The AHS is a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. At enrollment (1993-1997) and follow-up (1999-2005), participants reported use of 50 pesticides. We characterized exposure as ever use (44 pesticides with ≥5 exposed cases) and by cumulative intensity-weighted lifetime days (22 pesticides with ≥10 exposed cases), a metric that accounts for factors that influence exposure. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression for incident thyroid (n = 85 cases) cancer among male participants using follow-up through 2014/2015. RESULTS: Use of the fungicide metalaxyl (HR = 2.03, CI:1.16-3.52) and the organochlorine insecticide lindane (HR = 1.74, CI:1.06-2.84) was associated with increased risk of thyroid cancer. The herbicide chlorimuron-ethyl was inversely associated with risk when we restricted to papillary thyroid cancer, the most common subtype (HR = 0.52, CI:0.28-0.96). High use of the insecticide carbaryl (>median intensity-weighted days) was inversely associated with thyroid cancer (HR = 0.20, CI:0.08-0.53, ptrend = 0.001). CONCLUSIONS: In this large cohort study, we observed increased risk of thyroid cancer associated with use of metalaxyl and lindane, and an inverse association with carbaryl. More work is needed to understand the potential role of these chemicals in thyroid carcinogenesis.