Is Pesticide Use Related to Parkinson Disease?
Is Pesticide Use Related to Parkinson Disease?
The search in Embase and Medline yielded 883 publications, of which 52 publications met the inclusion criteria. We excluded 3 publications (Fong et al. 2005; Menegon et al. 1998; Smargiassi et al. 1998) where the study population had been included in subsequent publications (De Palma et al. 1998; Fong et al. 2007; McCann et al. 1998). Lastly, one study (Taylor et al. 1999) was excluded because the reported data showed risk per year of pesticide exposure, which was not comparable with reported risk ratios of other studies. Among the remaining 48 publications, there were two studies for which the relevant results were reported in two separate publications each (Firestone et al. 2005, 2010; Semchuk et al. 1992, 1993). Thus, results of a total of 46 studies were used in the meta-analysis.
An overview of the study characteristics of the included studies can be found in Table 1. There were 39 case–control studies, 4 cohort studies, and 3 cross-sectional studies; 40 publications reported on pesticides, 15 on herbicides, 15 on insecticides, and 9 on fungicides. Three studies included all parkinsonism (Duzcan et al. 2003; Engel et al. 2001a; Tanner et al. 2009); the rest studied idiopathic PD. Four studies showed only results in men (Engel et al. 2001a; Fall et al. 1999; Petersen et al. 2008; Petrovitch et al. 2002). One study included only cases with a disease diagnosis before 51 years of age (Butterfield et al. 1993), which is much lower than the average age of disease onset in all other studies (generally ~ 60 years of age). Information about participation rates was provided for only 13 of the 39 case–control studies. Studies that reported participation rates had rates between 69% and 100% for cases and between 41% and 100% for controls.
Figure 1 shows PD relative risk estimates for any pesticide exposure based on studies of occupational and/or nonoccupational exposures, and studies of occupational exposures only. The summary risk ratios (sRRs) between these two groups were very similar, with sRRs of 1.69 (95% CI: 1.38, 2.06) and 1.52 (95% CI: 1.23, 1.89), respectively, and an overall sRR for all studies combined of 1.62 (95% CI: 1.40, 1.88). The I for all studies combined was 63.7%. Only three studies estimated effects of nonoccupational exposure only (Chaturvedi et al. 1995; Elbaz et al. 2009; Firestone et al. 2005), with an sRR of 1.18 (95% CI: 0.86, 1.63).
(Enlarge Image)
Figure 1.
Forest plot for study-specific RRs and sRRs (95% CIs) of PD associated with the use of pesticides. The studies are ordered by publication year and stratified by studies that did or did not include nonoccupational exposure in the exposed group. Studies were pooled with the random effects method. The size of the squares reflects the statistical weight of the study in the meta-analyses.
Meta-analyses by herbicide, insecticide, and fungicide exposure are shown in Figure 2. In line with the results for any pesticide exposure, we did not observe noticeable differences between studies of occupational exposures only and studies of nonocccupational and occupational exposures combined. The sRR for exposure to fungicides did not indicate an association with PD (overall sRR = 0.99; 95% CI: 0.71, 1.40; Figure 2C), in contrast with positive sRRs for exposure to herbicides (overall sRR = 1.40; 95% CI: 1.08, 1.81; Figure 2A) and insecticides (overall sRR = 1.50; 95% CI: 1.07, 2.11; Figure 2B).
(Enlarge Image)
Figure 2.
Forest plots for study-specific RRs and sRRs (95% CIs) of PD associated with the use of herbicides (A), insecticides (B), and fungicides (C). The studies are ordered by publication year and stratified by studies that did or did not include nonoccupational exposure in the exposed group. Studies were pooled with the random effects method. The size of the squares reflects the statistical weight of the study in the meta-analyses.
(Enlarge Image)
Figure 3.
Funnel plots of effect estimates for exposure to pesticides and pesticide subcategories were suggestive of small study effects, with a tendency for smaller studies to report higher relative risks compared with larger studies (Figure 3), with Egger's test p-values of 0.057, 0.338, 0.208, and 0.680 for pesticide, herbicide, insecticide, and fungicide effect estimates, respectively.
Funnel plots of studies included in the meta-analysis for the risk of PD associated with the use of pesticides (A), herbicides (B), insecticides (C), and fungicides (D). Circles represent studies that included nonoccupational exposure in the exposed group, and triangles represent studies that were based on occupational exposure only. Egger's test p-values were 0.057, 0.338, 0.208, and 0.680 for pesticide, herbicide, insecticide, and fungicide effect estimates, respectively.
Figure 4 presents subgroup sRR estimates for those factors a priori hypothesized to be related to the observed heterogeneity in study results. The only study characteristic that was suggestive of contributing to heterogeneity was the exposure assessment method, with the lowest summary estimates observed for self-reported exposures (n = 36) and highest sRR for studies with exposures estimated based on reported job titles (n = 3). However, these differences were not statistically significant (p = 0.30). There was no evidence for a difference in summary estimates by adjustment of results for potential confounders, type of control population source, geographical area, or by study design. We also investigated whether adjustment for smoking had an effect on the summary risk estimate. Almost identical results were found for studies that did or did not correct for smoking (data not shown). Similar analyses for the subcategories herbicides and insecticides rendered similar results as for all pesticides (data not shown).
(Enlarge Image)
Figure 4.
sRRs (95% CIs) for strata of exposure assessment method, statistical analysis, source of controls, study area, and study design. The p-value from meta-regression represents the p-value of the F-test in case of more than two categories, whereas it represents the p-value for the t-test in the case of the two statistical analysis strata.
Results
The search in Embase and Medline yielded 883 publications, of which 52 publications met the inclusion criteria. We excluded 3 publications (Fong et al. 2005; Menegon et al. 1998; Smargiassi et al. 1998) where the study population had been included in subsequent publications (De Palma et al. 1998; Fong et al. 2007; McCann et al. 1998). Lastly, one study (Taylor et al. 1999) was excluded because the reported data showed risk per year of pesticide exposure, which was not comparable with reported risk ratios of other studies. Among the remaining 48 publications, there were two studies for which the relevant results were reported in two separate publications each (Firestone et al. 2005, 2010; Semchuk et al. 1992, 1993). Thus, results of a total of 46 studies were used in the meta-analysis.
An overview of the study characteristics of the included studies can be found in Table 1. There were 39 case–control studies, 4 cohort studies, and 3 cross-sectional studies; 40 publications reported on pesticides, 15 on herbicides, 15 on insecticides, and 9 on fungicides. Three studies included all parkinsonism (Duzcan et al. 2003; Engel et al. 2001a; Tanner et al. 2009); the rest studied idiopathic PD. Four studies showed only results in men (Engel et al. 2001a; Fall et al. 1999; Petersen et al. 2008; Petrovitch et al. 2002). One study included only cases with a disease diagnosis before 51 years of age (Butterfield et al. 1993), which is much lower than the average age of disease onset in all other studies (generally ~ 60 years of age). Information about participation rates was provided for only 13 of the 39 case–control studies. Studies that reported participation rates had rates between 69% and 100% for cases and between 41% and 100% for controls.
Figure 1 shows PD relative risk estimates for any pesticide exposure based on studies of occupational and/or nonoccupational exposures, and studies of occupational exposures only. The summary risk ratios (sRRs) between these two groups were very similar, with sRRs of 1.69 (95% CI: 1.38, 2.06) and 1.52 (95% CI: 1.23, 1.89), respectively, and an overall sRR for all studies combined of 1.62 (95% CI: 1.40, 1.88). The I for all studies combined was 63.7%. Only three studies estimated effects of nonoccupational exposure only (Chaturvedi et al. 1995; Elbaz et al. 2009; Firestone et al. 2005), with an sRR of 1.18 (95% CI: 0.86, 1.63).
(Enlarge Image)
Figure 1.
Forest plot for study-specific RRs and sRRs (95% CIs) of PD associated with the use of pesticides. The studies are ordered by publication year and stratified by studies that did or did not include nonoccupational exposure in the exposed group. Studies were pooled with the random effects method. The size of the squares reflects the statistical weight of the study in the meta-analyses.
Meta-analyses by herbicide, insecticide, and fungicide exposure are shown in Figure 2. In line with the results for any pesticide exposure, we did not observe noticeable differences between studies of occupational exposures only and studies of nonocccupational and occupational exposures combined. The sRR for exposure to fungicides did not indicate an association with PD (overall sRR = 0.99; 95% CI: 0.71, 1.40; Figure 2C), in contrast with positive sRRs for exposure to herbicides (overall sRR = 1.40; 95% CI: 1.08, 1.81; Figure 2A) and insecticides (overall sRR = 1.50; 95% CI: 1.07, 2.11; Figure 2B).
(Enlarge Image)
Figure 2.
Forest plots for study-specific RRs and sRRs (95% CIs) of PD associated with the use of herbicides (A), insecticides (B), and fungicides (C). The studies are ordered by publication year and stratified by studies that did or did not include nonoccupational exposure in the exposed group. Studies were pooled with the random effects method. The size of the squares reflects the statistical weight of the study in the meta-analyses.
(Enlarge Image)
Figure 3.
Funnel plots of effect estimates for exposure to pesticides and pesticide subcategories were suggestive of small study effects, with a tendency for smaller studies to report higher relative risks compared with larger studies (Figure 3), with Egger's test p-values of 0.057, 0.338, 0.208, and 0.680 for pesticide, herbicide, insecticide, and fungicide effect estimates, respectively.
Funnel plots of studies included in the meta-analysis for the risk of PD associated with the use of pesticides (A), herbicides (B), insecticides (C), and fungicides (D). Circles represent studies that included nonoccupational exposure in the exposed group, and triangles represent studies that were based on occupational exposure only. Egger's test p-values were 0.057, 0.338, 0.208, and 0.680 for pesticide, herbicide, insecticide, and fungicide effect estimates, respectively.
Figure 4 presents subgroup sRR estimates for those factors a priori hypothesized to be related to the observed heterogeneity in study results. The only study characteristic that was suggestive of contributing to heterogeneity was the exposure assessment method, with the lowest summary estimates observed for self-reported exposures (n = 36) and highest sRR for studies with exposures estimated based on reported job titles (n = 3). However, these differences were not statistically significant (p = 0.30). There was no evidence for a difference in summary estimates by adjustment of results for potential confounders, type of control population source, geographical area, or by study design. We also investigated whether adjustment for smoking had an effect on the summary risk estimate. Almost identical results were found for studies that did or did not correct for smoking (data not shown). Similar analyses for the subcategories herbicides and insecticides rendered similar results as for all pesticides (data not shown).
(Enlarge Image)
Figure 4.
sRRs (95% CIs) for strata of exposure assessment method, statistical analysis, source of controls, study area, and study design. The p-value from meta-regression represents the p-value of the F-test in case of more than two categories, whereas it represents the p-value for the t-test in the case of the two statistical analysis strata.
Source...