In this large nested case-control study with biomarkers of organochlorine pesticide exposure collected prospectively some 2 decades before disease, we found little evidence for increased odds of PD with increasing serum organochlorines, except for dieldrin. The association between dieldrin and increased odds of PD was strongest in analyses restricted to never smokers, possibly because of strong residual confounding by cigarette smoking among the smokers, biasing the OR down. Although we cannot rule out differences by sex, this did not seem to drive the results among never smokers because the interaction between dieldrin and smoking was more significant than that between dieldrin and sex. The association with dieldrin was also much stronger among the older half of our study subjects. This is consistent with the theory that genetic factors play a greater role in earlier-onset PD,15
and also with another recent study implicating organochlorine exposure in PD risk.16
The association with dieldrin was independent of age, BMI, sex, region, serum cholesterol, and triglycerides.
Organochlorine pesticides have been implicated in the development of PD,1,3
although there are no human studies with prospective biomarkers of exposure. Based on chemical properties, toxicokinetics, and use patterns, a recent review concluded that the cyclodienes—of which dieldrin, but not the others we analyzed, is one—are among the more likely candidates to contribute to the development of PD.3
Dieldrin has perhaps the best documented toxicity on dopaminergic cells, including the generation of oxygen radicals, aggregation and fibrillation of α-synuclein, disruption of the ubiquitin-proteasome system and the mitochondrial membrane potential, induction of dopamine release leading to intracellular dopamine depletion, and activation of caspases.17,18
Mice exposed to dieldrin show many pathologic effects similar to those seen in PD, such as increased oxidative stress, increased α-synuclein expression, and altered dopamine homeostasis.19
Although dopamine neurons seem to be particularly vulnerable to dieldrin neurotoxicity,17
the exposure does not seem to lead to dopaminergic cell loss or motor deficits characteristic of PD. In a few small studies, dieldrin has been found at higher levels in postmortem PD brains than in those of age-matched controls.20–22
However, the same studies identified several other organochlorine pesticides present at higher levels in postmortem PD brains, including p,p'-DDT and p,p'-DDE, for which we saw no association with PD. DDT and DDE can have dopaminergic effects in vitro, but they seem to be less toxic—at least in mice—to the dopaminergic system than dieldrin, and exposure in mice does not seem to produce nigrostriatal damage or behavioral abnormalities.23
There is no data linking the fungicide HCB to PD.
Several studies have used self-reported exposure to pesticides or estimates from occupational histories and found associations between PD and exposure to organochlorine pesticides as a class16,24,25
or, in a recent study, the specific organochlorine herbicide 2,4-dichlorophenoxyacetic acid (2–4-D).26
In the Agricultural Health Study (AHS), no association with 2–4-D was found, but one was found with the related 2,4,5-trichlorophenoxyacetic acid (2,4,5-T).27
In a recent study in France, phenoxy compounds were associated with PD, although this only reached statistical significance among men older than 65 years.16
In the AHS, there was no association between PD and either DDT or dieldrin,27
nor was there with self-reported DDT in a previous study in Finland.28
Only 3 studies, all case-control, have examined serum organochlorine levels in relation to PD, all with samples collected several years after PD onset.29–31
Two of these found statistically significant increases in odds of PD with higher serum β-HCH concentrations,30,31
whereas the other found a significant association with DDE.29
In only 1 of these did they report on dieldrin,31
but all subjects had nondetectable levels.
The exposure profile of FMC participants, in comparison with more recent NHANES data, suggests that chlordane and heptachlor—of which oxychlordane, transnonachlor, and heptachlor epoxide are more persistent metabolites—were not widespread in Finland at the time of FMC blood collection, which is consistent with pesticides sales data.32,33
Mirex concentrations were even lower in FMC samples compared with NHANES, consistent with no known use of mirex in Finland, whereas mirex was used in the United States until its ban in 1978.32,34
In contrast, the other organochlorine pesticides analyzed were at levels much higher than the NHANES data. This is consistent with the fact that FMC blood was collected before bans on these pesticides in Finland, whereas NHANES samples were collected many years after use stopped in the United States.35–37
The lack of association with age in FMC data is likely largely the result of FMC blood collection having occurred at most approximately 3 decades after the introduction of the pesticides into commercial use. Given the average age of FMC participants at baseline (53 years, SD 10 years), most FMC participants would have had the same number of years of exposure to the pesticides regardless of their age. The majority of organochlorine pesticides sales in Finland between 1953 and 1972 went toward use in households, warehouses, and shelters for domestic animals,33
which may partially account for why farmers did not necessarily have higher serum levels of these compounds. Because of this, the pattern of exposures (e.g., frequency of use, dose, other chemicals used concurrently) in our setting may differ from settings where the pesticide exposures are more driven by farming use patterns.
An important limitation to our study is that, although organochlorine pesticides are persistent and therefore serum levels are a reasonable biomarker for past cumulative exposure, ours were 1-time measures decades before disease. Variations in exposure to the different pesticides after FMC blood collection are not captured and could introduce measurement error to the extent that past exposures do not predict future exposures. This possible misclassification is least likely for dieldrin because dieldrin use was banned in Finland in 1969 (except for some later use for wood preservation).32,38
Thus, our measures of blood levels in 1968–1972 should closely reflect total exposure because there was little exposure possibility after that time. This would also apply, although to slightly lesser degrees, to DDT and DDE (DDT was banned in 1976), β-HCH (registered use as a pesticide cancelled in 1977), and HCB (use ceased on a voluntary basis in 1977).38
We also did not have follow-up data on confounders. Unmeasured confounding by cigarette smoking is unlikely to explain our positive findings, however, first because the bias in baseline data from cigarette smoking was against our results, and second because our significant findings were found in analyses restricted to never smokers. The majority of smokers take up smoking at early ages; thus, there would be few never smokers at baseline who later started smoking.
We were limited to examining persistent compounds because of the long time between blood collection and analysis. Some less persistent pesticides have been implicated in the development of PD, such as paraquat, rotenone, and maneb1,3,39
; hence, we cannot rule out the possibility that our dieldrin results stem from exposure correlations with these other compounds. Finally, our PD case definition could not involve physical examination. Instead, we relied on reports from the treating neurologist submitted for the patient to obtain reimbursement for PD medications. In addition, our study neurologist rereviewed these files to further confirm the cases. Although some diagnostic misclassification may have occurred, error from this source is probably modest; recent clinicopathologic studies show approximately 90% accuracy of clinical PD diagnosis made by neurologists.40
Furthermore, diagnostic errors are probably unrelated to serum organochlorine pesticide concentration, and would thus tend to attenuate any true association. Last, although the results are restricted to the Finnish population, we have no reason to expect that the results would not apply to other similarly exposed populations.