Pesticides and Parkinson’s disease – a critical review IEH Web Report W21 OCTOBER 2005 The Institute for Environment and Health was established by the Medical Research Council at the University of Leicester in 1993. The Institute is principally funded by UK Government Departments and Agencies by way of specific research and consultancy contracts. This report was prepared by the MRC Institute for Environment and Health for the Department for Environment, Food and Rural Affairs and issued in February 2004. The views expressed here do not necessarily represent those of any Government Department or Agency. Written by Terry Brown, Paul Rumsby, Alexander Capleton, Lesley Rushton and Leonard Levy Edited by Linda Shuker and Philip Holmes Web Report edited by Jean Emeny IEH will continue to make this document available at this Web site (or by a link to a different site). Any changes to its contents will be clearly recorded, either by a note of corrigenda or the issue of a new edition, identified by an amended report reference number and date. A copy of this document is also held at the British Lending Library. Please cite as: IEH (2005) Pesticides and Parkinson’s Disease — A Critical Review (Web Report W21), Leicester, UK, MRC Institute for Environment and Health, available at http://www.le.ac.uk/ieh/ ©Institute for Environment and Health, 2005 ISBN 1 899110 87 9 MRC Institute for Environment and Health University of Leicester 94 Regent Road Leicester LE1 7DD UK http://www.le.ac.uk/ieh/ Contents Executive summary _________________________________________________________ 5 1 Introduction ______________________________________________________________ 11 2 Background______________________________________________________________ 13 2.1 Introduction _______________________________________________________ 13 2.2 Parkinson’s disease ________________________________________________ 13 2.3 Pesticides _________________________________________________________ 24 3 Methodology_____________________________________________________________ 27 3.1 Literature search___________________________________________________ 27 3.2 Criteria for selecting papers for review ______________________________ 28 4 Epidemiological review ___________________________________________________ 29 4.1 Case studies_______________________________________________________ 29 4.2 Descriptive studies _________________________________________________ 29 4.3 Cohort studies _____________________________________________________ 33 4.4 Case–control studies _______________________________________________ 38 4.5 Meta-analyses_____________________________________________________ 60 4.6 Discussion of epidemiological findings ______________________________ 63 4.7 Summary of epidemiology studies __________________________________ 70 4.8 Conclusions from epidemiology studies _____________________________ 71 5 Toxicological review ______________________________________________________ 74 5.1 Potential mechanisms of Parkinson’s disease ________________________ 74 5.2 Potential involvement of pesticides _________________________________ 78 5.3 Summary of toxicology studies______________________________________ 89 5.4 Conclusions from toxicology studies_________________________________ 90 6 Overall summary _________________________________________________________ 92 6.1 Introduction _______________________________________________________ 92 6.2 Epidemiology _____________________________________________________ 92 6.3 Toxicology ________________________________________________________ 94 6.4 Conclusions _______________________________________________________ 95 7 Areas for further research _________________________________________________ 96 7.1 Epidemiological research __________________________________________ 96 7.2 Toxicology ________________________________________________________ 96 Acknowledgements ________________________________________________________ 98 References _______________________________________________________________ 100 Abbreviations _____________________________________________________________ 113 Annex 1 __________________________________________________________________ 114 Literature database descriptors _______________________________________ 114 Executive summary Introduction Parkinson’s disease (PD), first described by James Parkinson as the ‘shaking palsy’, is an idiopathic disease of the nervous system characterised by chronic progressive tremor, bradykinesia, rigidity and postural instability, as a result of loss of dopaminergic neurons in the substantia nigra. In 1983, it was observed that the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in the development of acute parkinsonism, similar in nearly all clinical, pathological, and biochemical features to the idiopathic disease, in a small group of drug addicts in northern California. This led to an interest in the possible role of environmental toxins in the development of PD and parkinsonism generally and, in particular, to an interest in pesticides, given the close structural similarity of the MPTP metabolite, 1-methyl-4-phenylpyridine (MPP+), to the herbicide paraquat. Since then, numerous epidemiological and toxicological studies have been published, looking at pesticides as a risk factor for PD and parkinsonism and possible mechanisms by which pesticides may act. However, many of these studies present conflicting results and some are of uncertain relevance to humans. In addition, a number of other risk factors have been associated with the development of PD, such as rural living and consumption of well-water. As a result of the uncertainties of the potential role of pesticides in the development of PD and parkinsonism, the Department for the Environment, Food and Rural Affairs (Defra) commissioned the Institute for Environment and Health (IEH) to undertake a critical review of the epidemiological and toxicological literature, summarising the current state of knowledge, and to provide a critical evaluation of the possible role of pesticides in the development of PD and parkinsonism. A comprehensive literature search was conducted in December 2002 and updated in April 2003 to identify published literature pertaining to the potential role of pesticides in the development of PD and parkinsonism. From this literature search 336 papers were obtained for further review. Additional papers were identified from the reference lists of these papers, current issues of relevant journals and ad hoc searches of the Internet. Epidemiology The review of the epidemiological literature identified ten descriptive studies, five cohort studies, 38 separate case–control studies and one meta-analysis that investigated the relationship between PD and pesticide exposure. An association between PD and pesticide exposure was tested for in eight of the ten pesticide-related descriptive studies (two case-series studies, three mortality studies, four prevalence studies and one incidence study). Of these eight, all the mortality studies (one of which was reported only as an abstract) and one prevalence study found a significant association between PD and a marker of pesticide use. One case-series study, two prevalence studies, one looking at hexachlorobenzene exposure, and an incidence study (reported only as an abstract) found no association between PD and pesticide use/exposure. Of the five cohort studies identified (including one reported only as an abstract), three showed an increased risk of PD amongst farming occupations of which two inferred an increased risk of PD from pesticide exposure. One study also identified several other occupational groups with an increased risk of PD. An increased risk of PD following pesticide exposure was observed in the majority of the 38 case–control studies identified, with a majority of those showing a significantly increased risk. The excess risks reported in these studies varied from 1.01 to 7.00, although confidence intervals were wide in many studies, partly due to small numbers. From the epidemiological studies reviewed, there appears to be a fairly consistent association between prior pesticide exposure and an increased risk of developing PD; this relationship appears to be 5 IEH Web Report W21, posted October, 2005, at http://www.le.ac.uk reasonably consistent in different populations and countries, although some studies present conflicting results. The heterogeneity between studies may be a result of exposure misclassification. The exposure category, ‘pesticides,’ represents many hundreds of chemicals and, as a result, one cohort exposed to ‘pesticides’ may be exposed to a different group of chemicals compared with another cohort said to be exposed to ‘pesticides’. It may be that exposure to only a few pesticide compounds results in an increased risk of developing PD; however, differences in exposure to these compounds would be masked by the use of broad ‘pesticide’ exposure categories in the studies, possibly resulting in the observed heterogeneity. The level of increased risk identified in different studies is variable, although a meta-analysis focusing on pesticide exposure as a risk factor for PD reported a combined odds ratio of 1.94 (95% confidence interval (CI) 1.49–2.53; Priyadarshi et al., 2000). However, only 19 of the 34 comparable case–control studies (excluding autopsy studies and conference abstracts) identified were included in the analysis; hence, the limited nature of the dataset might have influenced the overall risk estimate. In all the studies reviewed,