Exposure to pesticides and risk of Hodgkin lymphoma in an international consortium of agricultural cohorts (AGRICOH).

PURPOSE: Some pesticides may increase the risk of certain lymphoid malignancies, but few studies have examined Hodgkin lymphoma (HL). In this exploratory study, we examined associations between agricultural use of 22 individual active ingredients and 13 chemical groups and HL incidence. METHODS: We used data from three agricultural cohorts participating in the AGRICOH consortium: the French Agriculture and Cancer Cohort (2005-2009), Cancer in the Norwegian Agricultural Population (1993-2011), and the US Agricultural Health Study (1993-2011). Lifetime pesticide use was estimated from crop-exposure matrices or self-report. Cohort-specific covariate-adjusted overall and age-specific (< 40 or ≥ 40 years) hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression and combined using random effects meta-analysis. RESULTS: Among 316 270 farmers (75% male) accumulating 3 574 815 person-years at risk, 91 incident cases of HL occurred. We did not observe statistically significant associations for any of the active ingredients or chemical groups studied. The highest risks of HL overall were observed for the pyrethroids deltamethrin (meta-HR = 1.86, 95% CI 0.76-4.52) and esfenvalerate (1.86, 0.78-4.43), and inverse associations of similar magnitude were observed for parathion and glyphosate. Risk of HL at ≥ 40 years of age was highest for ever-use of dicamba (2.04, 0.93-4.50) and lowest for glyphosate (0.46, 0.20-1.07). CONCLUSION: We report the largest prospective investigation of these associations. Nonetheless, low statistical power, a mixture of histological subtypes and a lack of information on tumour EBV status complicate the interpretability of the results. Most HL cases occurred at older ages, thus we could not explore associations with adolescent or young adult HL. Furthermore, estimates may be attenuated due to non-differential exposure misclassification. Future work should aim to extend follow-up and refine both exposure and outcome classification.

Residential proximity to crops and agricultural pesticide use and cause-specific mortality: A prospective census-based cohort study in the Netherlands.

BACKGROUND: There is continued concern about residential proximity to agricultural pesticide use and possible adverse health effects. Studies on this subject have been scarce with inconsistent results. We explored associations between residential proximity to specific crops, pesticide use and cause-specific mortality in a prospective census-based cohort study in The Netherlands. METHODS: Selecting inhabitants aged >30 living in less urbanized areas, at the same address for nine years up to baseline (2004) from a national register-based cohort, we followed ~3.1 million individuals for cause-specific mortality until 2012. We estimated the area of specific crop groups cultivated within buffers of 50 m, 100 m and 250 m around each individual's residence and the amount of fungicides, herbicides and insecticides used within the same buffers for the period 1995-2003. The association between these exposure proxies and 25 primary causes of death was investigated using Cox proportional hazards regression, adjusting for individual and area-level confounders. RESULTS: Residential proximity to crops was associated with decreased mortality risks overall. In contrast to the overall trend an increased risk was observed for chronic lower respiratory diseases and proximity to maize cultivation. We found no evidence of an association between the amount of pesticides used and cause-specific mortality. CONCLUSIONS: In a large prospective census-based cohort study in The Netherlands we found evidence of an increased risk of chronic lower respiratory diseases in relation to maize cultivation which was not reflected in general pesticide use, hinting to specific pesticides or practices in maize cultivation that may lead to the observed increased risk.

Animal farming and the risk of lymphohaematopoietic cancers: a meta-analysis of three cohort studies within the AGRICOH consortium.

OBJECTIVE: Animal farming entails a variety of potential exposures, including infectious agents, endotoxins and pesticides, which may play a role in the aetiology of lymphohaematopoietic cancers (LHCs). The aim of this study was to assess whether farming specific animal species is associated with the risk of overall LHC or its subtypes. METHODS: Data from three prospective cohort studies in the USA, France and Norway which are part of the Agricultural Cohort consortium and which collected information about animal farming and cancer were used. Analyses included 316 270 farmers and farm workers. Adjusted Cox models were used to investigate the associations of 13 histological subtypes of LHC (n=3282) with self-reported livestock (cattle, pigs and sheep/goats) and poultry (ever/never and numbers raised) farming. Cohort-specific HRs were combined using random-effects meta-analysis. RESULTS: Ever animal farming in general or farming specific animal species was not meta-associated with overall LHC. The risk of myeloid malignancies decreased with increasing number of livestock (p trend=0.01). Increased risk of myeloproliferative neoplasms was seen with increasing number of sheep/goats (p trend <0.01), while a decreased risk was seen with increasing number of livestock (p trend=0.02). Between cohorts, we observed heterogeneity in the association of type of animal farmed and various LHC subtypes. CONCLUSIONS: This large-scale study of three prospective agricultural cohorts showed no association between animal farming and LHC risk, but few associations between specific animal species and LHC subtypes were observed. The observed differences in associations by countries warrant further investigations.

Parkinson's disease and long-term exposure to outdoor air pollution: A matched case-control study in the Netherlands.

BACKGROUND: There is some evidence to suggest an association between ambient air pollution and development of Parkinson's disease (PD). However, the small number of studies published to date has reported inconsistent findings. OBJECTIVES: To assess the association between long-term exposure to ambient air pollution constituents and the development of PD. METHODS: Air pollution exposures (particulate matter with aerodynamic diameter <10 µm [PM10], <2.5 µm [PM2.5], between 2.5 µm and 10 µm [PMcoarse], black carbon, and nitrogen oxides [NO2 and NOx]) were predicted based on land-use regression models developed within the "European Study for Air Pollution Effects" (ESCAPE) study, for a Dutch PD case-control study. A total of 1290 subjects (436 cases and 854 controls). were included and 16 years of exposure were estimated (average participant starting age: 53). Exposures were categorized and conditional logistic regression models were applied to evaluate the association between ambient air pollution and PD. RESULTS: Overall, no significant, positive relationship between ambient air pollutants and PD was observed. The odds ratio (OR) for PD associated with an increase from the first quartile of NO2 (<22.8 µg/m3) and the fourth (>30.4 µg/m3) was 0.87 (95% CI: 0.54, 1.41). For PM2.5 where the contrast in exposure was more limited, the OR associated with an increase from the first quartile PM2.5 (<21.2 µg/m3) to the fourth (>22.3 µg/m3) was 0.50 (95% CI: 0.24, 1.01). In a subset of the population with long-term residential stability (n = 632), an increased risk of PD was observed (e.g. OR for Q4 vs Q1 NO2:1.37, 95% CI: 0.71, 2.67). CONCLUSIONS: We found no clear association between 16 years of residential exposure to ambient air pollution and the development of PD in The Netherlands.

Pesticide use and risk of non-Hodgkin lymphoid malignancies in agricultural cohorts from France, Norway and the USA: a pooled analysis from the AGRICOH consortium.

BACKGROUND: Pesticides are commonly used in agriculture, and previous studies endorsed the need to further investigate the possible association between their use and risk of lymphoid malignancies in agricultural workers. METHODS: We investigated the relationship of ever use of 14 selected pesticide chemical groups and 33 individual active chemical ingredients with non-Hodgkin lymphoid malignancies (NHL) overall or major subtypes, in a pooled analysis of three large agricultural worker cohorts. Pesticide use was derived from self-reported history of crops cultivated combined with crop-exposure matrices (France and Norway) or self-reported lifetime use of active ingredients (USA). Cox regression models were used to estimate cohort-specific hazard ratios (HRs) and 95% confidence intervals (CIs), which were combined using random effects meta-analysis to calculate meta-HRs. RESULTS: During follow-up, 2430 NHL cases were diagnosed in 316 270 farmers accruing 3 574 815 person-years under risk. Most meta-HRs suggested no association. Moderately elevated meta-HRs were seen for: NHL and ever use of terbufos (meta-HR = 1.18, 95% CI: 1.00-1.39); chronic lymphocytic leukaemia/small lymphocytic lymphoma and deltamethrin (1.48, 1.06-2.07); and diffuse large B-cell lymphoma and glyphosate (1.36, 1.00-1.85); as well as inverse associations of NHL with the broader groups of organochlorine insecticides (0.86, 0.74-0.99) and phenoxy herbicides (0.81, 0.67-0.98), but not with active ingredients within these groups, after adjusting for exposure to other pesticides. CONCLUSIONS: Associations of pesticides with NHL appear to be subtype- and chemical-specific. Non-differential exposure misclassification was an important limitation, showing the need for refinement of exposure estimates and exposure-response analyses.

Associations of residential exposure to agricultural pesticides with asthma prevalence in adolescence: The PIAMA birth cohort.

BACKGROUND: It has been suggested that children who are exposed to agricultural pesticides have an increased risk of asthma, but evidence for associations betweeen residential pesticide exposure and childhood asthma is inconsistent. OBJECTIVES: To investigate the associations of residential pesticide exposure with the prevalence of asthma and related symptoms within a Dutch birth cohort study. METHODS: In this cross-sectional analysis, we included participants of the PIAMA birth cohort study with data on residential pesticide exposure and asthma from parent-completed questionnaires at age 14, collected in 2012 (N = 1473). We used spatial data on the presence of individual crops (cereals, open field vegetables, commercial crops, open field floriculture/bulbs, corn and potatoes) and pesticide application on these crops to estimate residential exposure to pesticides with known irritant properties for the respiratory system within distances of 100, 500, and 1000 m of the participants' homes. Logistic regression was used to estimate associations between exposure and outcomes, adjusting for potential confounders. RESULTS: No associations were found between living within 100, 500 and 1000 m of agricultural fields likely treated with pesticides and symptoms of asthma. For instance, for participants living within 100 m of fields with any crops likely treated with pesticides, the adjusted odds ratios (95% confidence interval) for the prevalence of asthma, shortness of breath and dry night cough at age 14 were 0.31 (0.07, 1.32), 0.61 (0.23, 1.57) and 1.26 (0.56, 2.80), respectively. No associations were found between estimated exposure to pesticides with known irritant properties for the respiratory system and asthma or related symptoms. CONCLUSIONS: There was no association between living near agricultural fields likely treated with pesticides and asthma and related respiratory symptoms, among our study participants.

Assessment of residential environmental exposure to pesticides from agricultural fields in the Netherlands.

We developed a spatio-temporal model for the Netherlands to estimate environmental exposure to individual agricultural pesticides at the residential address for application in a national case-control study on Parkinson's disease (PD). Data on agricultural land use and pesticide use were combined to estimate environmental exposure to pesticides for the period 1961 onwards. Distance categories of 0-50 m, >50-100 m, >100-500 m and >500-1000 m around residences were considered. For illustration purposes, exposure was estimated for the control population (n=607) in the PD case-control study. In a small validation effort, model estimates were compared with pesticide measurements in air and precipitation collected at 17 stations in 2000-2001. Estimated exposure prevalence was higher for pesticides used on commonly cultivated (rotating) crops than for pesticides used on fruit and bulbs only. Prevalence increased with increasing distance considered. Moderate-to-high correlations were observed between model estimates (>100-500 m and >500-1000 m) and environmental pesticide concentrations measured in 2000-2001. Environmental exposure to individual pesticides can be estimated using relevant spatial and temporal data sets on agricultural land use and pesticide use. Our approach seems to result in accurate estimates of average environmental exposure, although it remains to be investigated to what extent this reflect personal exposure to agricultural pesticides.

Environmental exposure to pesticides and the risk of Parkinson's disease in the Netherlands.

BACKGROUND: Exposure to pesticides has been linked to Parkinson's disease (PD), although associations between specific pesticides and PD have not been well studied. Residents of rural areas can be exposed through environmental drift and volatilization of agricultural pesticides. OBJECTIVES: Our aim was to investigate the association between lifetime environmental exposure to individual pesticides and the risk of PD, in a national case-control study. METHODS: Environmental exposure to pesticides was estimated using a spatio-temporal model, based on agricultural crops around the residential address. Distance up to 100m from the residence was considered most relevant, considering pesticide drift potential of application methods used in the Netherlands. Exposure estimates were generated for 157 pesticides, used during the study period, of which four (i.e. paraquat, maneb, lindane, benomyl) were considered a priori relevant for PD. RESULTS: A total of 352 PD cases and 607 hospital-based controls were included. No significant associations with PD were found for the a priori pesticides. In a hypothesis generating analysis, including 153 pesticides, increased risk of PD was found for 21 pesticides, mainly used on cereals and potatoes. Results were suggestive for an association between bulb cultivation and PD. CONCLUSIONS: For paraquat, risk estimates for the highest cumulative exposure tertile were in line with previously reported elevated risks. Increased risk of PD was observed for exposure to (a cluster of) pesticides used on rotating crops. High correlations limited our ability to identify individual pesticides responsible for this association. This study provides some evidence for an association between environmental exposure to specific pesticides and the risk of PD, and generates new leads for further epidemiological and mechanistic research.

Proximity to agricultural fields as proxy for environmental exposure to pesticides among children: The PIAMA birth cohort.

BACKGROUND: Agricultural pesticides are frequently used for crop protection. Residents living in close proximity to treated fields may be exposed to these pesticides. There is some indication that children living near agricultural fields have an increased risk of developing asthma and decreased lung function. OBJECTIVES: The aim of this study was to assess the proximity of participants' homes to fields likely treated with pesticides as proxy for environmental exposure to agricultural pesticides among participants of a Dutch birth cohort study, and to combine acreage of fields with farmer-reported pesticide use. METHODS: Potential pesticide exposure at the home address at the time of the 14-year follow-up was estimated for 2291 participants of the Dutch PIAMA birth cohort study. We used spatial data on the presence of crops during the year 2012 to calculate the surface area of specific crops relevant for pesticide use in The Netherlands cultivated within 50, 100, 500 and 1000m of the study homes. Farmer-reported pesticides use on specific crops from a national survey performed in 2012 was used to estimate the amount of all pesticides and pesticides with known irritant properties for the respiratory system applied within the aforementioned distances of the study homes. RESULTS: For 3%, 7%, 40%, and 65% of the homes, any relevant crops were present within 50, 100, 500 and 1000m, respectively. Among these, the most frequent crops were corn, cereals, and potatoes. For almost the same percentages of homes, it was estimated that pesticides with known irritant properties for the respiratory system were potentially applied within these distances. CONCLUSIONS: We observed that a small proportion of the study participants lived in close proximity (<50 or <100m) to agricultural fields with crops relevant for pesticide use in The Netherlands. The percentage of study homes within 500 or 1000m of agricultural fields with these crops was much larger.

Assessment of occupational exposure to pesticides in a pooled analysis of agricultural cohorts within the AGRICOH consortium.

BACKGROUND: This paper describes methods developed to assess occupational exposure to pesticide active ingredients and chemical groups, harmonised across cohort studies included in the first AGRICOH pooling project, focused on the risk of lymph-haematological malignancies. METHODS: Three prospective agricultural cohort studies were included: US Agricultural Health Study (AHS), French Agriculture and Cancer Study (AGRICAN) and Cancer in the Norwegian Agricultural Population (CNAP). Self-reported pesticide use was collected in AHS. Crop-exposure matrices (CEMs) were developed for AGRICAN and CNAP. We explored the potential impact of these differences in exposure assessment by comparing a CEM approach estimating exposure in AHS with self-reported pesticide use. RESULTS: In AHS, 99% of participants were considered exposed to pesticides, 68% in AGRICAN and 63% in CNAP. For all cohorts combined (n=316 270), prevalence of exposure ranged from 19% to 59% for 14 chemical groups examined, and from 13% to 46% for 33 active ingredients. Exposures were highly correlated within AGRICAN and CNAP where CEMs were applied; they were less correlated in AHS. Poor agreement was found between self-reported pesticide use and assigned exposure in AHS using a CEM approach resembling the assessment for AGRICAN (κ -0.00 to 0.33) and CNAP (κ -0.01 to 0.14). CONCLUSIONS: We developed country-specific CEMs to assign occupational exposure to pesticides in cohorts lacking self-reported data on the use of specific pesticides. The different exposure assessment methods applied may overestimate or underestimate actual exposure prevalence, and additional work is needed to better estimate how far the exposure estimates deviate from reality.

Occupational exposures and Parkinson's disease mortality in a prospective Dutch cohort.

OBJECTIVES: We investigated the association between six occupational exposures (ie, pesticides, solvents, metals, diesel motor emissions (DME), extremely low frequency magnetic fields (ELF-MF) and electric shocks) and Parkinson's disease (PD) mortality in a large population-based prospective cohort study. METHODS: The Netherlands Cohort Study on diet and cancer enrolled 58,279 men and 62,573 women aged 55-69 years in 1986. Participants were followed up for cause-specific mortality over 17.3 years, until December 2003, resulting in 402 male and 207 female PD deaths. Following a case-cohort design, a subcohort of 5,000 participants was randomly sampled from the complete cohort. Information on occupational history and potential confounders was collected at baseline. Job-exposure matrices were applied to assign occupational exposures. Associations with PD mortality were evaluated using Cox regression. RESULTS: Among men, elevated HRs were observed for exposure to pesticides (eg, ever high exposed, HR 1.27, 95% CI 0.86 to 1.88) and ever high exposed to ELF-MF (HR 1.54, 95% CI 1.00 to 2.36). No association with exposure duration or trend in cumulative exposure was observed for any of the occupational exposures. Results among women were unstable due to small numbers of high-exposed women. CONCLUSIONS: Associations with PD mortality were observed for occupational exposure to pesticides and ELF-MF. However, the weight given to these findings is limited by the absence of a monotonic trend with either duration or cumulative exposure. No associations were found between PD mortality and occupational exposure to solvents, metals, DME or electric shocks.

Occupational exposure to pesticides and endotoxin and Parkinson disease in the Netherlands.

OBJECTIVES: Previous research has indicated that occupational exposure to pesticides and possibly airborne endotoxin may increase the risk of developing Parkinson disease (PD). We studied the associations of PD with occupational exposure to pesticides, specifically to the functional subclasses insecticides, herbicides and fungicides, and to airborne endotoxin. In addition we evaluated specific pesticides (active ingredients) previously associated with PD. METHODS: We used data from a hospital-based case-control study, including 444 patients with PD and 876 age and sex matched controls. Exposures to pesticides from application and re-entry work were estimated with the ALOHA+job-exposure matrix and with an exposure algorithm based on self-reported information on pesticide use. To assess exposure to specific active ingredients a crop-exposure matrix was developed. Endotoxin exposure was estimated with the DOM job-exposure matrix. RESULTS: The results showed almost no significant associations. However, ORs were elevated in the higher exposure categories for pesticides in general, insecticides, herbicides and fungicides, and below unity for endotoxin exposure. The analyses on specific active ingredients showed a significant association of PD risk with the fungicide benomyl. CONCLUSIONS: This study did not provide evidence for a relation between pesticide exposure and PD. However, the consistently elevated ORs in the higher exposure categories suggest that a positive association may exist. The possible association with the active ingredient benomyl requires follow-up in other studies. This study did not provide support for a possible association between endotoxin exposure and PD.

Expert assessment of historical crop specific pesticide use in the Netherlands.

OBJECTIVES: Retrospective assessment of environmental pesticide exposure is challenging. Exposure measurements or information on crop-specific pesticide use are often lacking historically. We applied expert assessment to reconstruct historical pesticide use patterns in the Netherlands, and evaluated reliability and accuracy of this procedure. METHODS: For six main crops in the Netherlands, two experts per crop individually rated the probability (percentage of farmers applying) and frequency of use of authorised active ingredients between 1961 and 2005 per 5-year period. Inter-rater agreement was investigated by the percentage overall agreement and weighted Cohen's κ's (κ(w)). Experts' ratings were compared with self-reported pesticide use from recent farmer surveys to determine accuracy of the ratings. RESULTS: Inter-rater agreement on the probability of use varied between crops (κ(w) 0.25 to 0.69), as well as agreement on the frequency of use (κ(w) 0.32 to 0.64). Inter-rater agreement was marginally higher for herbicides and fungicides than insecticides. Comparisons with survey data indicated fair to good accuracy of the experts' ratings for the probability (κ(w) 0.48 to 0.65) and frequency of use (κ(w) 0.38 to 0.68). For all crops except fruit, the specificity of the experts' ratings was higher than the sensitivity. CONCLUSIONS: Overall inter-rater agreement between experts was fair to good and experts' ratings were reasonably accurate. Results of this study indicate that expert assessment can be used to derive information on historical pesticide use, which is essential for epidemiological studies evaluating the effect of (past) environmental exposure to pesticides on health.

Is pesticide use related to Parkinson disease? Some clues to heterogeneity in study results.

BACKGROUND: Previous systematic reviews have indicated that pesticide exposure is possibly associated with Parkinson disease (PD). However, considerable heterogeneity has been observed in study results. OBJECTIVE: We aimed at providing an update of the literature published on PD and exposure to pesticides by performing a systematic review and meta-analysis. In addition, we investigated whether methodological differences between studies could explain the heterogeneity in study results. METHODS: We identified studies through a systematic literature search. We calculated summary risk ratios (sRRs) for pesticide exposure and subcategories using random effects meta-analyses and investigated sources of heterogeneity by meta-regression and stratified analyses. RESULTS: Thirty-nine case-control studies, four cohort studies, and three cross-sectional studies were identified. An sRR of 1.62 [95% confidence interval (CI): 1.40, 1.88] for pesticide exposure (ever vs. never) was found. Summary estimates for subclasses of pesticides indicated a positive association with herbicides and insecticides, but not with fungicides. Heterogeneity in individual study results was not related to study design, source of control population, adjustment of results for potential confounders, or geographical area. However, results were suggestive for heterogeneity related to differences in the exposure assessment. Job title-based exposure assignment resulted in a higher sRR (2.5; 95% CI: 1.5, 4.1) than did assignment based on self-reported exposure (e.g., for self-reported ever/never exposure, sRR = 1.5; 95% CI: 1.3, 1.8). CONCLUSIONS: This review affirms the evidence that exposure to herbicides and insecticides increase the risk of PD. Future studies should focus on more objective and improved methods of pesticide exposure assessment.