Sadie Costello

Parkinson's Disease and Residential Exposure to Maneb and Paraquat From Agricultural Applications in the Central Valley of California

Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to Parkinsons disease (PD). Human data are insufficient to support this claim for any specific pesticide, largely because of challenges in exposure assessment. The authors developed and validated an exposure assessment tool based on geographic information systems that integrated information from California Pesticide Use Reports and land-use maps to estimate historical exposure to agricultural pesticides in the residential environment. In 1998-2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73). Persons aged < or =60 years at the time of diagnosis were at much higher risk when exposed to either maneb or paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15, 15.16) in 1974-1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at younger ages.

Parkinson’s disease risk from ambient exposure to pesticides

Due to the heavy and expanding agricultural use of neurotoxic pesticides suspected to affect dopaminergic neurons, it is imperative to closely examine the role of pesticides in the development of Parkinson’s disease (PD). We focus our investigation on pesticide use in California’s heavily agricultural central valley by utilizing a unique pesticide use reporting system. From 2001 to 2007, we enrolled 362 incident PD cases and 341 controls living in the Central Valley of California. Employing our geographic information system model, we estimated ambient exposures to the pesticides ziram, maneb, and paraquat at work places and residences from 1974 to 1999. At workplaces, combined exposure to ziram, maneb, and paraquat increased risk of PD three-fold (OR: 3.09; 95% CI: 1.69, 5.64) and combined exposure to ziram and paraquat, excluding maneb exposure, was associated with a 80% increase in risk (OR:1.82; 95% CI: 1.03, 3.21). Risk estimates for ambient workplace exposure were greater than for exposures at residences and were especially high for younger onset PD patients and when exposed in both locations. Our study is the first to implicate ziram in PD etiology. Combined ambient exposure to ziram and paraquat as well as combined ambient exposure to maneb and paraquat at both workplaces and residences increased PD risk substantially. Those exposed to ziram, maneb, and paraquat together experienced the greatest increase in PD risk. Our results suggest that pesticides affecting different mechanisms that contribute to dopaminergic neuron death may act together to increase the risk of PD considerably.

Dopamine Transporter Genetic Variants and Pesticides in Parkinson's Disease

Background Research suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson’s disease (PD) risk. Materials Methods: In 324 incident PD patients and 334 population controls from our rural California case–control study, we genotyped rs2652510, rs2550956 (for the DAT 5′ clades), and the 3′ variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele–pesticide interactions. Results PD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08–2.57] and 3′ VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96–3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88–10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70–12.1). We obtained similar results for occupational pesticide measures. Discussion Using two independent pesticide measures, we a) replicated previously reported gene–environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure. Conclusion Our results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk.

Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease.

Background: Human, animal and cell models support a role for pesticides in the etiology of Parkinson disease. Susceptibility to pesticides may be modified by genetic variants of xenobiotic enzymes, such as paraoxonase, that play a role in metabolizing some organophosphates. Methods: We examined associations between Parkinson disease and the organophosphates diazinon, chlorpyrifos, and parathion, and the influence of a functional polymorphism at position 55 in the coding region of the PON1 gene (PON1-55). From 1 January 2001 through 1 January 2008, we recruited 351 incident cases and 363 controls from 3 rural California counties in a population-based case-control study. Participants provided a DNA sample, and residential exposure to organophosphates was determined from pesticide usage reports and a geographic information system (GIS) approach. We assessed the main effects of both genes and pesticides in unconditional logistic regression analyses, and evaluated the effect of carrying a PON1-55 MM variant on estimates of effects for diazinon, chlorpyrifos, and parathion exposures. Results: Carriers of the variant MM PON1-55 genotype exposed to organophosphates exhibited a greater than 2-fold increase in Parkinson disease risk compared with persons who had the wildtype or heterozygous genotype and no exposure (for diazinon, odds ratio = 2.2 [95% confidence interval = 1.1–4.5]; for chlorpyrifos, 2.6 [1.3–5.4]). The effect estimate for chlorpyrifos, was more pronounced in younger-onset cases and controls (≤60 years) (5.3 [1.7–16]). No increase in risk was noted for parathion. Conclusion: The increase in risk we observed among PON1-55 variant carriers for specific organophosphates metabolized by PON1 underscores the importance of considering susceptibility factors when studying environmental exposures in Parkinson disease.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson’s disease

Background and purpose:  In 1‐methyl‐4‐phenyl 1,2,3,6‐tetrahydropyridine animal models of Parkinson’s disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine–PD association.

Quantitative Exposure to Metalworking Fluids and Bladder Cancer Incidence in a Cohort of Autoworkers

Occupations with mineral oil exposure have been associated with bladder cancer in population-based case-control studies. The authors report results from the first cohort study to examine bladder cancer incidence in relation to quantitative exposures to metalworking fluids (MWFs), based on 21,999 male Michigan automotive workers, followed from 1985 through 2004. Cox regression was used to estimate hazard ratios based on categorical exposure variables for straight, soluble, and synthetic MWFs, as well as duration of exposure to ethanolamines and nitrosamines. Penalized splines were also fit to estimate the functional form of the exposure-response relation. Increased bladder cancer risk was associated with straight MWFs but not with any other exposure. The hazard ratio increased with cumulative exposure to a maximum of 2-fold observed at 75 mg/m(3)-year straight MWF exposure (lagged 20 years). Calendar time windows relevant to polycyclic aromatic hydrocarbon exposure were examined but could not be distinguished from the lagged (10-, 20-year) metrics. No association was observed between any exposure and incident lung cancer, suggesting that smoking is unlikely to confound the associations observed here. The quantitative relation with straight MWFs strengthens the evidence for mineral oils as a bladder carcinogen.

Geographic Model and Biomarker-Derived Measures of Pesticide Exposure and Parkinson’s Disease

Abstract:  For more than two decades, reports have suggested that pesticides and herbicides may be an etiologic factor in idiopathic Parkinsons disease (PD). To date, no clear associations with any specific pesticide have been demonstrated from epidemiological studies perhaps, in part, because methods of reliably estimating exposures are lacking. We tested the validity of a Geographic Information Systems (GIS)‐based exposure assessment model that estimates potential environmental exposures at residences from pesticide applications to agricultural crops based on California Pesticide Use Reports (PUR). Using lipid‐adjusted dichlorodiphenyldichloroethylene (DDE) serum levels as the “gold standard” for pesticide exposure, we conducted a validation study in a sample taken from an ongoing, population‐based case–control study of PD in Central California. Residential, occupational, and other risk factor data were collected for 22 cases and 24 controls from Kern county, California. Environmental GIS–PUR‐based organochlorine (OC) estimates were derived for each subject and compared to lipid‐adjusted DDE serum levels. Relying on a linear regression model, we predicted log‐transformed lipid‐adjusted DDE serum levels. GIS–PUR‐derived OC measure, body mass index, age, gender, mixing and loading pesticides by hand, and using pesticides in the home, together explained 47% of the DDE serum level variance (adjusted r2= 0.47). The specificity of using our environmental GIS–PUR‐derived OC measures to identify those with high‐serum DDE levels was reasonably good (87%). Our environmental GIS–PUR‐based approach appears to provide a valid model for assessing residential exposures to agricultural pesticides.

Incident ischemic heart disease and recent occupational exposure to particulate matter in an aluminum cohort

Fine particulate matter (PM2.5) in air pollution, primarily from combustion sources, is recognized as an important risk factor for cardiovascular events but studies of workplace PM2.5 exposure are rare. We conducted a prospective study of exposure to PM2.5 and incidence of ischemic heart disease (IHD) in a cohort of 11,966 US aluminum workers. Incident IHD was identified from medical claims data from 1998 to 2008. Quantitative metrics were developed for recent exposure (within the last year) and cumulative exposure; however, we emphasize recent exposure in the absence of interpretable work histories before follow-up. IHD was modestly associated with recent PM2.5 overall. In analysis restricted to recent exposures estimated with the highest confidence, the hazard ratio (HR) increased to 1.78 (95% CI: 1.02, 3.11) in the second quartile and remained elevated. When the analysis was stratified by work process, the HR rose monotonically to 1.5 in both smelter and fabrication facilities, though exposure was almost an order of magnitude higher in smelters. The differential exposure–response may be due to differences in exposure composition or healthy worker survivor effect. These results are consistent with the air pollution and cigarette smoke literature; recent exposure to PM2.5 in the workplace appears to increase the risk of IHD incidence.

Association of DRD2 and DRD3 polymorphisms with Parkinson's disease in a multiethnic consortium

OBJECTIVE To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinsons disease (PD). METHODS The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case-control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. RESULTS Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR=1.5, 95% CI 1.0-2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African-Americans, showing an inverse association with PD risk (OR=0.10, 95% CI 0.2-0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR=0.4, 95% CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. CONCLUSIONS DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Epidemiologic challenges for studies of occupational exposure to engineered nanoparticles; a commentary.

Objective: Identify most likely health effects of occupational exposure to engineered nanoparticles (ENP). Recommend analytic approaches to address epidemiologic challenges. Methods: Review air pollution and occupational literature on health effects of fine particulate matter (PM). Provide example of mortality study of exposure to PM composed of metalworking fluid. Apply standard Cox models and g-estimation to adjust for potential healthy worker survival effect (HWSE). Results: In contrast with standard methods, g-estimation suggests that exposure to PM may cause chronic heart and lung disease; longer exposure reduces survival. HWSE appears stronger for chronic disease than for cancer. Conclusions: We recommend hazard surveillance, short-term panel studies of biomarkers, and prospective cohort studies of cardiovascular and respiratory diseases. Building research capacity in g-estimation methods to reduce HWSE is necessary for future studies of chronic disease and ENP.