The Geoparkinson study is one of the largest case–control studies to date of genetic, environmental and occupational risk factors for Parkinson's disease or other degenerative parkinsonian syndromes. The genetic analyses (reported separately) have examined 15 candidate polymorphisms as potential modifiers of chemical toxicity. We have used an unusually detailed method to estimate exposure, integrating data on both occupational and hobby exposure to produce estimates of total exposure to the target agents. The advantage of this approach is that it provides a quantitative measure of exposure and can provide useful information about the adequacy of current exposure standards to prevent Parkinson's disease. The results suggest that relatively low intensity exposures to pesticides may increase risks. On the contrary, they suggest that, in general, risks from solvents and metals are less important in this respect. However, we return to this in the accompanying paper, where we examine exposure–gene interactions.
A major problem in case–control studies is that of recall bias. We have tried to deal with this by the use of lifetime occupational histories, the use of prompts (“In this job was there use of…?”) and the production of detailed exposure estimates. Recall bias is most likely to lead to differential reporting for brief exposures. Under‐reporting of short‐term exposures among controls would have little impact on our quantitative exposure estimates. This is in contrast to the large effect recall bias might have in studies that use exposure metrics such as ever/never exposed. More cases than controls had the assistance of a relative or friend in completing the interview. This, together with the proportion of cases whose interview responses were held to be poor/confused but plausible (18% of Parkinson's disease cases vs 13% of controls), suggests that cognitive impairment was commoner among cases. This would tend to lead to under‐reporting of exposures among cases and so bias the study downwards. However, cases may have been more likely than controls to reflect on past exposures because of concern about their illness, so leading to over‐reporting of exposures among cases.
In this study some subjects clinically held to have Parkinson's disease were classified as having parkinsonism when the UK PDS Brain Bank criteria were applied. As a result, the category parkinsonism comprised a mixture of patients with Parkinson's disease and other degenerative parkinsonian syndromes. The numbers of subjects, classified as parkinsonism, with a Parkinson's plus condition such as progressive supranuclear palsy or multisystem atrophy was too small for further study. The variation in the numbers of subjects with parkinsonism across the five centres may, in part, reflect differing methods of case ascertainment (neurologist review versus note‐based classification).
We found an increased odds ratio for work with pesticides, with a significant exposure–response relationship. Many previous studies have found such an association, but few have established an exposure–response relationship,17
perhaps owing to small sample size6
or poor exposure assessment. One limitation of this study (and in most previous retrospective case–control studies) was our inability to establish which pesticides subjects had been exposed to, as most participants were unable to provide this information. Our estimates were generated for typical pesticides used for the agricultural class or activity described. For example, we used paraquat dichloride (OES: 0.1 mg/m3
8 hour time‐weighted average exposure) for herbicidal tasks in gardening hobbies or jobs. We acknowledge that many pesticides do not have UK occupational exposure limits and that our method of using a generic “pesticide” metric to describe exposure to a diverse range of chemicals is based on the assumption that all pesticides act in an additive manner with respect to Parkinson's disease. While we recognise the limitations of this approach, we believe that the quantitative values assigned to pesticide exposures represent a considerable improvement on simpler classification systems.
- Pesticide use is associated with Parkinson's disease and this has implications for occupational and, perhaps, recreational users of these agents. Further research is needed to establish which pesticides are associated with this effect.
- Head injury, as measured by episodes of being knocked unconscious, is associated with Parkinson's disease. This finding, if confirmed, has implications for all contact sports and, in particular, combat sports such as boxing.
Our use of the AAI as our exposure metric allows us to classify exposure according to intensity and is much less prone to exposure misclassification than cruder metrics such as ever/never exposed or number of years of exposure. We acknowledge that the AAI is not a cumulative metric and will not differentiate between a person who works at 50% of the OEL for 1 year or 20 years. However, the AAI quantifies exposure intensity and we believe that this is a more useful measure than cruder metrics when setting exposure standards.
- Parkinson's disease is associated with pesticide use.
- A positive family history of Parkinson's disease is associated with an increased odds ratio of developing the disease.
- A history of ever having been knocked unconscious is associated with Parkinson's disease and this shows an exposure–response relationship, but it is unclear whether such head injuries predates disease onset.
- Use of psychoactive medication is associated with Parkinson's disease, although it is unclear whether this use predates disease onset.
A specific weakness of our exposure metric (AAI) is that it tends to underestimate pesticide exposure owing to the seasonal nature of pesticide use. We found that pesticide exposure was generally intermittent, both for recreational (4–8 days a year for an hour or less) and occupational applications (10–40 days a year; 4–8 hours a day). In contrast, solvent and metal exposures typically arose from regular and often, daily, occupational use. As a result, caution must be exercised in interpreting the pesticide results in comparison with those for solvents and metals. A recreational user with an AAI of 0.0004 OEL units is likely to have been exposed to pesticides at about 10% of the OEL for 1 hour in each of 6 days per year. A farmer with an AAI of 0.05 OEL units, exposed to pesticides for 20 days per year, will have been exposed to approximately 50% of the OEL for that pesticide on each of those 20 days.
No associations were found with solvent exposure; however, we report our finding of gene–solvent interactions in our accompanying paper. Evidence that metal exposures were risk factors for parkinsonism or Parkinson's disease was lacking.
Head injury (defined as frequency of ever having been knocked unconscious) showed an exposure–response relationship with Parkinson's disease, and this, if confirmed, has implications for contact sports. Head injury has previously been linked to an increased risk of Parkinson's disease, but the results have been inconsistent.8
Use of antidepressant, anxiolytic or hypnotic drugs also appeared to be associated with Parkinson's disease. One explanation for this finding is that depression has been associated with an increased risk of Parkinson's disease later in life.4,30
However, no information as to the timing of head injury, or use of medication was sought and accordingly we cannot state that these exposures predate symptom onset. Thus, the observed association with head injury may be due to recall bias or to an increased risk of falls in Parkinson disease. Equally, the use of psychotropic medication may simply reflect the well recognised psychiatric effects of Parkinson's disease. The largest odds ratio was for a positive family history of Parkinson's disease. Whether this reflects shared environment or genetic predisposition or even bias is unclear.31
Without neurological examination of family members we cannot comment on the accuracy of self‐reported family history of Parkinson's disease in patients and controls.
This large study confirms the previously described20,21,32
negative association between tobacco smoking and Parkinson's disease, which is probably owing to a true neuroprotective effect of tobacco smoke constituents.33
In agreement with previous studies, we found no evidence that alcohol consumption was associated with disease.34,35
In conclusion, this study has provided important evidence of the increased risk of Parkinson's disease in relation to exposure to pesticides. The exposure–response relationship suggests that pesticide exposure may be a causative and potentially modifiable risk factor.