Systematic evidence mapping of potential correlates of exposure for per- and poly-fluoroalkyl substances (PFAS) based on measured occurrence in biomatrices and surveys of dietary consumption and product use.

Per- and poly-fluoroalkyl substances (PFAS) are widely observed in environmental media and often are found in indoor environments as well as personal-care and consumer products. Humans may be exposed through water, food, indoor dust, air, and the use of PFAS-containing products. Information about relationships between PFAS exposure sources and pathways and the amounts found in human biomatrices can inform source-contribution assessments and provide targets for exposure reduction. This work collected and collated evidence for correlates of PFAS human exposure as measured through sampling of biomatrices and surveys of dietary consumption and use of consumer products and articles. A systematic evidence mapping approach was applied to perform a literature search, conduct title-abstract and full-text screening, and to extract primary data into a comprehensive database for 16 PFAS. Parameters of interest included: sampling dates and locations, cohort descriptors, PFAS measured in a human biomatrix, information about food consumption in 11 categories, use of products/articles in 11 categories, and reported correlation values (and their statistical strength). The literature search and screening process yielded 103 studies with information for correlates of PFAS exposures. Detailed data were extracted and compiled on measures of PFAS correlations between biomatrix concentrations and dietary consumption and other product/article use. A majority of studies (61/103; 59%) were published after 2015 with few (8/103; 8%) prior to 2010. Studies were most abundant for dietary correlates (n = 94) with fewer publications reporting correlate assessments for product use (n = 56), while some examined both. PFOA and PFOS were assessed in almost all studies, followed by PFHxS, PFNA, and PFDA which were included in >50% of the studies. No relevant studies included PFNS or PFPeS. Among the 94 studies of dietary correlates, significant correlations were reported in 83% of the studies for one or more PFAS. The significant dietary correlations most commonly were for seafood, meats/eggs, and cereals/grains/pulses. Among the 56 studies of product/article correlates, significant correlations were reported in 70% of the studies. The significant product/article correlations most commonly were for smoking/tobacco, cosmetics/toiletries, non-stick cookware, and carpet/flooring/furniture and housing. Six of 11 product/article categories included five or fewer studies, including food containers and stain- and water-resistant products. Significant dietary and product/article correlations most commonly were positive. Some studies found a mix of positive and negative correlations depending on the PFAS, specific correlate, and specific response level, particularly for fats/oils, dairy consumption, food containers, and cosmetics/toiletries. Most of the significant findings for cereals/grains/pulses were negative correlations. Substantial evidence was found for correlations between dietary intake and biomatrix levels for several PFAS in multiple food groups. Studies examining product/article use relationships were relatively sparse, except for smoking/tobacco, and would benefit from additional research. The resulting database can inform further assessments of dietary and product use exposure relationships and can inform new research to better understand PFAS source-to-exposure relationships. The search strategy should be extended and implemented to support living evidence review in this rapidly advancing area.

An algorithm for quantitatively estimating non-occupational pesticide exposure intensity for spouses in the Agricultural Health Study.

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 (0.01‒0.02). 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.

Occupational Exposure to Pesticides and the Incidence of Lung Cancer in the Agricultural Health Study.

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 10 years of additional follow-up in the AHS, a prospective cohort study comprising 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 (HRs) and 95% confidence intervals (CIs), adjusting for smoking (smoking status and pack-years), sex, 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 was 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.

Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data.

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 to 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 (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently 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, five 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. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017. Relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations: meta-regression of published data. Environ Health Perspect 125:296-305; http://dx.doi.org/10.1289/EHP426.

The Biomarkers of Exposure and Effect in Agriculture (BEEA) Study: Rationale, Design, Methods, and Participant Characteristics.

Agricultural exposures including pesticides, endotoxin, and allergens have been associated with risk of various cancers and other chronic diseases, although the biological mechanisms underlying these associations are generally unclear. To facilitate future molecular epidemiologic investigations, in 2010 the study of Biomarkers of Exposure and Effect in Agriculture (BEEA) was initiated within the Agricultural Health Study, a large prospective cohort in Iowa and North Carolina. Here the design and methodology of BEEA are described and preliminary frequencies for participant characteristics and current agricultural exposures are reported. At least 1,600 male farmers over 50 years of age will be enrolled in the BEEA study. During a home visit, participants are asked to complete a detailed interview about recent agricultural exposures and provide samples of blood, urine, and (since 2013) house dust. As of mid-September 2014, in total, 1,233 participants have enrolled. Most of these participants (83%) were still farming at the time of interview. Among those still farming, the most commonly reported crops were corn (81%) and soybeans (74%), and the most frequently noted animals were beef cattle (35%) and hogs (13%). There were 861 (70%) participants who reported occupational pesticide use in the 12 months prior to interview; among these participants, the most frequently noted herbicides were glyphosate (83%) and 2,4-D (72%), and most commonly reported insecticides were malathion (21%), cyfluthrin (13%), and permethrin (12%). Molecular epidemiologic investigations within BEEA have the potential to yield important new insights into the biological mechanisms through which these or other agricultural exposures influence disease risk.

Non-hodgkin lymphoma risk and insecticide, fungicide and fumigant use in the agricultural health study.

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.

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.

Cancer incidence in the agricultural health study.

OBJECTIVES: This large, prospective cohort study of private applicators, commercial applicators, and spouses of farmer applicators was undertaken to ascertain the etiology of cancers elevated in agriculture. METHODS: The participants were matched to cancer registry files in Iowa and North Carolina. Incident cases were identified from enrollment through 31 December 2002. Standardized incidence ratios (SIR) were used to compare the cancer incidence of the participants with that of the total population in the two states. RESULTS: The overall cancer incidence among farmers [SIR 0.88, 95% confidence interval (95% CI) 0.84-0.91] and their spouses (SIR 0.84, 95% CI 0.80-0.90) were significantly lower than expected, particularly for respiratory and urinary cancers. Commercial pesticide applicators had an overall cancer incidence comparable with the expected (SIR 1.01, 95% CI 0.84-1.20). Smoking prevalence was significantly lower than the national average. Prostate cancer was elevated among private applicators (SIR 1.24, 95% CI 1.18-1.33) and commercial applicators (SIR 1.37, 0.98-1.86). Excess ovarian cancer was observed for female applicators (SIR 2.97, 95% CI 1.28-5.85), but not for female spouses (SIR 0.55, 95% CI 0.38-0.78). Female spouses had a significant excess of melanoma (SIR 1.64, 95% CI 1.24-2.09), which was not observed among pesticide applicators. CONCLUSIONS: Low overall cancer incidence rates seem to be a result of low overall smoking prevalence and other lifestyle factors, while excess cancer of the prostate and ovaries among applicators may be occupationally related. The excess risk of melanoma observed among spouses was unexpected.

Mortality among participants in the agricultural health study.

PURPOSE: This analysis of the Agricultural Health Study cohort assesses the mortality experience of licensed pesticide applicators and their spouses. METHODS: This report is based on 52,393 private applicators (who are mostly farmers) and 32,345 spouses of farmers in Iowa and North Carolina. At enrollment, each pesticide applicator completed a 21-page enrollment questionnaire. Mortality assessment from enrollment (1994-1997) through 2000 provided an average follow-up of about 5.3 years, 447,154 person-years, and 2055 deaths. RESULTS: Compared with the general population in the two states, the cohort experienced a very low mortality rate. Standardized mortality ratios (SMRs) for total mortality, cardiovascular disease, diabetes, COPD, total cancer, and cancers of the esophagus, stomach, and lung were 0.6 or lower for both farmers and spouses. These deficits varied little by farm size, type of crops or livestock on the farm, years of handling pesticides, holding a non-farm job, or length of follow up. SMRs among ever smokers were not as low as among never smokers, but were still less than 1.0 for all smoking-related causes of death. No statistically significant excesses occurred, but slightly elevated SMRs, or those near 1.0, were noted for diseases that have been associated with farming in previous studies. CONCLUSIONS: Several factors may contribute to the low mortality observed in this population, including the healthy worker effect typically seen in cohorts of working populations (which may decline in future years), a short follow-up interval, and a healthier lifestyle manifested through lower cigarette use and an occupation that has traditionally required high levels of physical activity.

Pesticides and lung cancer risk in the agricultural health study cohort.

The authors examined the relation between 50 widely used agricultural pesticides and lung cancer incidence in the Agricultural Health Study, a prospective cohort study of 57,284 pesticide applicators and 32,333 spouses of farmer applicators with no prior history of lung cancer. Self-administered questionnaires were completed at enrollment (1993-1997). Cancer incidence was determined through population-based cancer registries from enrollment through December 31, 2001. A lung cancer standardized incidence ratio of 0.44 (95% confidence interval: 0.39, 0.49) was observed overall, due in large part to a low cigarette smoking prevalence. Two widely used herbicides, metolachlor and pendimethalin (for low-exposed groups to four higher exposure categories: odds ratio (OR) = 1.0, 1.6, 1.2, 5.0; p(trend) = 0.0002; and OR = 1.0, 1.6, 2.1, 4.4; p(trend) = 0.003, respectively), and two widely used insecticides, chlorpyrifos and diazinon (OR = 1.0, 1.1, 1.7, 1.9; p(trend) = 0.03; and OR = 1.0, 1.6, 2.7, 3.7; p(trend) = 0.04, respectively), showed some evidence of exposure response for lung cancer. These excesses could not be explained by previously identified lung cancer risk factors. The usage levels in this cohort are considerably higher than those typically experienced by the general population. An excess risk among spouses directly exposed to pesticides could not be evaluated at this time.

Use of agricultural pesticides and prostate cancer risk in the Agricultural Health Study cohort.

The authors examined the relation between 45 common agricultural pesticides and prostate cancer incidence in a prospective cohort study of 55,332 male pesticide applicators from Iowa and North Carolina with no prior history of prostate cancer. Data were collected by means of self-administered questionnaires completed at enrollment (1993-1997). Cancer incidence was determined through population-based cancer registries from enrollment through December 31, 1999. A prostate cancer standardized incidence ratio was computed for the cohort. Odds ratios were computed for individual pesticides and for pesticide use patterns identified by means of factor analysis. A prostate cancer standardized incidence ratio of 1.14 (95% confidence interval: 1.05, 1.24) was observed for the Agricultural Health Study cohort. Use of chlorinated pesticides among applicators over 50 years of age and methyl bromide use were significantly associated with prostate cancer risk. Several other pesticides showed a significantly increased risk of prostate cancer among study subjects with a family history of prostate cancer but not among those with no family history. Important family history-pesticide interactions were observed.