Residents of agricultural areas experience pesticide exposures from sources other than direct agricultural work. We developed a quantitative, active ingredient-specific algorithm for cumulative (adult, married lifetime) non-occupational pesticide exposure intensity for spouses of farmers who applied pesticides in the Agricultural Health Study (AHS). The algorithm addressed three exposure pathways: take-home, agricultural drift, and residential pesticide use. Pathway-specific equations combined (i) weights derived from previous meta-analyses of published pesticide exposure data and (ii) information from the questionnaire on frequency and duration of pesticide use by applicators, home proximity to treated fields, residential pesticide usage (e.g., termite treatments), and spouse's off-farm employment (proxy for time at home). The residential use equation also incorporated a published probability matrix that documented the likelihood active ingredients were used in home pest treatment products. We illustrate use of these equations by calculating exposure intensities for the insecticide chlorpyrifos and herbicide atrazine for 19,959 spouses. Non-zero estimates for >/=1 pathway were found for 78% and 77% of spouses for chlorpyrifos and atrazine, respectively. Variability in exposed spouses' intensity estimates was observed for both pesticides, with 75th to 25th percentile ratios ranging from 7.1 to 7.3 for take-home, 6.5 to 8.5 for drift, 2.4 to 2.8 for residential use, and 3.8 to 7.0 for the summed pathways. Take-home and drift estimates were highly correlated (>/=0.98), but were not correlated with residential use (0.010.02). This algorithm represents an important advancement in quantifying non-occupational pesticide relative exposure differences and will facilitate improved etiologic analyses in the AHS spouses. The algorithm could be adapted to studies with similar information.

BACKGROUND: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. OBJECTIVE: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. METHODS: From studies in North American agricultural areas published from 1995-2015, we abstracted dust pesticide concentrations reported as summary statistics (e.g., geometric means (GM)). We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). RESULTS: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (inter-quartile range of published data) based on 52 statistics from 7 studies. For the para-occupational pathway, GMs were 2.3 times higher (95% confidence interval [CI]: 1.5-3.3; 15 statistics, 5 studies) in homes of farmers who applied pesticides more versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95%CI: 1.1-1.4) and 1.5 (95%CI: 1.2-1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and ≥20%, respectively (88 statistics, 5 studies). CONCLUSION: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available.

BACKGROUND: Occupational pesticide use is associated with lung cancer in some, but not all, epidemiologic studies. In the Agricultural Health Study (AHS), we previously reported positive associations between several pesticides and lung cancer incidence. OBJECTIVE: We evaluated use of 43 pesticides and 654 lung cancer cases after ten years of additional follow-up in the AHS, a prospective cohort study comprised of 57,310 pesticide applicators from Iowa and North Carolina. METHODS: Information about lifetime pesticide use and other factors was ascertained at enrollment (1993-1997) and updated with a follow-up questionnaire (1999-2005). Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for smoking (smoking status and pack-years), gender, and lifetime days of use of any pesticides. RESULTS: Hazard ratios were elevated in the highest exposure category of lifetime days of use for pendimethalin (1.50; 95% CI = 0.98-2.31), dieldrin (1.93; 95% CI = 0.70-5.30), and chlorimuron-ethyl (1.74; 95% CI = 1.02-2.96), although monotonic exposure-response gradients were not evident. The HRs for intensity-weighted lifetime days of use of these pesticides were similar. For parathion, the trend was statistically significant for intensity-weighted lifetime days (p=0.049) and borderline for lifetime days (p=0.073). None of the remaining pesticides evaluated were associated with lung cancer incidence. CONCLUSIONS: These analyses provide additional evidence for an association between pendimethalin, dieldrin, and parathion use and lung cancer risk. We found an association between chlorimuron-ethyl, a herbicide introduced in 1986, and lung cancer that has not been previously reported. Continued follow-up is warranted.

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 1993-7. 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=5701 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.

Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures.

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.

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.

Pesticide exposures can be reduced by use of personal protective equipment as well as proper mixing and application practices. The authors examined the effects of risk-accepting personality on personal protective equipment (PPE) use and mixing and application practices among private pesticide applicators and their spouses within the Agricultural Health Study (AHS) in Iowa and North Carolina and commercial applicators in Iowa. The AHS follow-up questionnaire included four questions designed to assess attitudes toward risk. Analysis was limited to those who were currently working on a farm or registered as a commercial applicator and indicated current pesticide use (n = 25,166). Respondents who answered three or more questions in the affirmative (private applicators: n = 4160 [21%]; commercial applicators: n = 199 [14%]; spouses: n = 829 [23%]) were classified as having a risk-accepting personality. Logistic regression was used to evaluate specific work practices associated with risk-accepting attitudes. Among private applicators, the likelihood of using any PPE when mixing or loading pesticides was lower among risk-acceptors compared to risk-averse individuals (odds ratio [OR] = 0.72, 95% confidence interval [CI]: 0.65-0.79). A similar relationship was observed among commercial applicators (OR = 0.77, 95% CI: 0.34-1.77) but not among spouses (OR = 1.09, 95% CI: 0.90-1.33). Among private applicators, risk-acceptors were more likely than the risk-averse to apply pesticides within 50 feet of the home (OR = 1.21, 95% CI: 1.01-1.44), compared to further than (1/4) mile. These findings suggest that the decisions to use personal protective equipment and properly handle/apply pesticides may be driven by risk-accepting personality traits. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Agromedicine for the following free supplemental resource: Adjusted odds ratios of PPE use and risk accepting personality traits among participants currently applying pesticides in the Agricultural Health Study (1999-2005)].

The Agricultural Health Study (AHS), a large prospective cohort, was designed to elucidate associations between pesticide use and other agricultural exposures and health outcomes. The cohort includes 57,310 pesticide applicators who were enrolled between 1993 and 1997 in Iowa and North Carolina. A follow-up questionnaire administered 5 years later was completed by 36,342 (63%) of the original participants. Missing pesticide use information from participants who did not complete the second questionnaire impedes both long-term pesticide exposure estimation and statistical inference of risk for health outcomes. Logistic regression and stratified sampling were used to impute key variables related to the use of specific pesticides for 20,968 applicators who did not complete the second questionnaire. To assess the imputation procedure, a 20% random sample of participants was withheld for comparison. The observed and imputed prevalence of any pesticide use in the holdout dataset were 85.7% and 85.3%, respectively. The distribution of prevalence and days/year of use for specific pesticides were similar across observed and imputed in the holdout sample. When appropriately implemented, multiple imputation can reduce bias and increase precision and can be more valid than other missing data approaches.

Prevalence of fungal sensitization and atopy was lower among farmers than the US population. Fungal sensitization was related to growing specific agricultural commodities.

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.

BACKGROUND: Atrazine is a triazine herbicide used widely in the United States. Although it is an animal carcinogen, the mechanism in rodents does not appear to operate in humans. Few epidemiologic studies have provided evidence for an association. METHODS: The Agricultural Health Study (AHS) is a prospective cohort that includes 57,310 licensed pesticide applicators. In this report, we extend a previous AHS analysis of cancer risk associated with self-reported atrazine use with six additional years of follow-up and more than twice as many cancer cases. Using Poisson regression, we calculated relative risk estimates and 95% confidence intervals for lifetime use of atrazine and intensity-weighted lifetime days, which accounts for factors that impact exposure. RESULTS: Overall, 36,357 (68%) of applicators reported using atrazine, among whom there were 3,146 cancer cases. There was no increase among atrazine users in overall cancer risk or at most cancer sites in the higher exposure categories compared with the lowest. Based on 29 exposed cases of thyroid cancer, there was a statistically significant risk in the second and fourth quartiles of intensity-weighted lifetime days. There was a similar pattern for lifetime days, but neither the risk estimates nor the trend were statistically significant and for neither metric was the trend monotonic. CONCLUSIONS: Overall, there was no consistent evidence of an association between atrazine use and any cancer site. There was a suggestion of increased risk of thyroid cancer, but these results are based on relatively small numbers and minimal supporting evidence.

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 approximately 80%, to the right and left thighs and right forearm from wearing a coverall/suit by approximately 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.

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.

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.

Although specific pesticides have been associated with wheeze in farmers, little is known about pesticides and asthma. Data from 19,704 male farmers in the Agricultural Health Study were used to evaluate lifetime use of 48 pesticides and prevalent adult-onset asthma, defined as doctor-diagnosed asthma after the age of 20 yrs. Asthma cases were categorised as allergic (n = 127) and nonallergic (n = 314) based on their history of eczema or hay fever. Polytomous logistic regression, controlling for age, state, smoking and body mass, was used to assess pesticide associations. High pesticide exposure events were associated with a doubling of both allergic and nonallergic asthma. For ever-use, 12 individual pesticides were associated with allergic asthma and four with nonallergic asthma. For allergic asthma, coumaphos (OR 2.34; 95% CI 1.49-3.70), heptachlor (OR 2.01; 95% CI 1.30-3.11), parathion (OR 2.05; 95% CI 1.21-3.46), 80/20 mix (carbon tetrachloride/carbon disulfide) (OR 2.15; 95% CI 1.23-3.76) and ethylene dibromide (OR 2.07; 95% CI 1.02-4.20) all showed ORs of >2.0 and significant exposure-response trends. For nonallergic asthma, DDT (dichlorodiphenyltrichloroethane) showed the strongest association (OR 1.41; 95% CI 1.09-1.84), but with little evidence of increasing asthma with increasing use. Current animal handling and farm activities did not confound these results. There was little evidence that allergy alone was driving these associations. In conclusion, pesticides may be an overlooked contributor to asthma risk among farmers.

The aim was to develop quantitative estimates of farmers' pesticide exposure to atrazine and to provide an overview of background levels of selected non-persistent pesticides among corn farmers in a longitudinal molecular epidemiologic study. The study population consisted of 30 Agricultural Health Study farmers from Iowa and 10 non-farming controls. Farmers completed daily and weekly diaries from March to November in 2002 and 2003 on pesticide use and other exposure determinants. Urine samples were collected at 10 time points relative to atrazine application and other farming activities. Pesticide exposure was assessed using urinary metabolites and diaries. The analytical limit of detection (LOD) ranged between 0.1 and 0.2 microg/l for all pesticide analytes except for isazaphos (1.5 microg/l) and diazinon (0.7 microg/l). Farmers had higher geometric mean urinary atrazine mercapturate (AZM) values than controls during planting (1.1 vs <LOD microg/g creatinine; P<0.05). AZM levels among farmers were significantly related to the amount of atrazine applied (P=0.015). Interestingly, farmers had a larger proportion of samples above the LOD than controls even after exclusion of observations with an atrazine application within 7 days before urine collection (38% vs 6%, P<0.0001). A similar pattern was observed for 2,4-D and acetochlor (92% vs 47%, P<0.0001 and 45% vs 4%, P<0.0001, respectively). Urinary AZM levels in farmers were largely driven by recent application of atrazine. Therefore, the amount of atrazine applied is likely to provide valid surrogates of atrazine exposure in epidemiologic studies. Elevated background levels of non-persistent pesticides, especially 2,4-D, indicate importance in epidemiologic studies of capturing pesticide exposures that might not be directly related to the actual application.