The available scientific evidence does not support the existence of a causal relationship between Parkinson’s disease and pesticides in general or paraquat in particular. Parkinson’s disease is overwhelmingly associated with old age and it is generally agreed that the development of Parkinson's disease involves both environmental and genetic factors (Obeso et. al., (2010). Missing pieces in the Parkinson’s disease puzzle. Nature Medicine, 16-6, 653-661). The relative contribution of these and other factors is still the subject of considerable scientific debate as evidenced by the significant number of scientific papers examining the association of pesticides, including paraquat, with the development of Parkinson's disease using studies in experimental animals and epidemiological investigations.
An analysis by independent senior medical and epidemiological scientists under the guidance of Professor Sir Colin Berry (Emeritus Professor at Queen Mary, University of London, and former member of the UK Medical Research Council) and Professor Pierluigi Nicotera (Founding Director of the German Center for Neurodegenerative Diseases, Bonn) found no causal link between exposure to paraquat and Parkinson’s disease (Berry, C., La Vecchia, C. & Nicotera, P., (2010). Paraquat and Parkinson’s Disease. Cell Death and Differentiation, 17, 1115–1125). This publication builds on the previous Consensus Statement on Parkinson’s Disease and the Environment in which 29 independent experts concluded that the evidence to date does not permit a conclusion to be drawn regarding the existence of an association between exposure to paraquat and the development of Parkinson’s disease (Bronstein et al., (2008). Consensus Statement Parkinson’s Disease and the Environment: Collaborative on Health and the Environment and Parkinson’s Action Network (CHE PAN) Conference June 26-28, 2007. Environmental Health Perspectives, 117:117-121).
Mandel et al. (2012) reviewed and evaluated two epidemiologic studies (Kamel et al, 2002 and Tanner et al., 2011) focused on pesticides, and in particular, paraquat as a cause of Parkinson's disease. Both studies are derived primarily from the US Agricultural Health Study (AHS). The review concluded that these and other epidemiological studies which they also reviewed were inadequately designed and often underpowered with very few exposed individuals. The studies were not population-based, failed to distinguish incident from prevalent cases (Tanner et al., 2011), relied on multiple comparisons, and may have reported results selectively. They also noted that the results across the studies are inconsistent. In summary, a conclusion regarding these relationships cannot be reached based on the current literature and further research with higher methodological standards is needed to reach a definitive conclusion.
Reference: Mandel JS, Adami HO, Cole P (2012). Paraquat and Parkinson's disease: an overview of the epidemiology and a review of two recent studies. Regul Toxicol Pharmacol. 2012 Mar;62(2):385-92. doi: 10.1016/j.yrtph.2011.10.004. Epub 2011 Oct 15.
Assessments have shown that there is no evidence of an increased incidence of Parkinson's disease, relative to that expected in the local and national population, either as the underlying cause of death or as a mentioned cause of death among workers involved in the manufacture of paraquat. Assessments have also shown there is no evidence of parkinsonism among survivors who ingested paraquat for the purpose of self-harm. Specifically:
- A cohort epidemiological assessment of workers involved in the manufacture of paraquat between 1961 and 1995 has evaluated whether there is any evidence, from analysis of death certificates, of increased incidence of Parkinson's disease as the underlying cause of death or as a mentioned cause of death among those with long-term exposure to paraquat.
- This work concluded that there was no evidence of an increased incidence of Parkinson's disease among paraquat production workers based on mentions of Parkinson's disease on the death certificates of workers who had died. A strength of this study is the likely higher exposure of workers engaged in paraquat production than many of the subjects in case-control studies classified as exposed to paraquat.
Reference: Tomenson J.A., Campbell C (2011). Mortality from Parkinson’s disease and other causes among a workforce manufacturing paraquat: a retrospective cohort study. BMJ Open 2011;2:e000283. doi:10. 1136/bmjopen-2011-000283.
- A medical toxicologist has conducted a health outcome assessment of survivors who intentionally ingested paraquat for the purpose of self-harm to evaluate whether there is any evidence of increased incidence of Parkinson's disease-like symptoms (i.e. parkinsonism) among those with acute, high dose exposure to paraquat.
- This analysis found no connection between confirmed high-dose paraquat exposure in humans and the development of parkinsonism.
Reference: Brent J., Schaeffer T.H (2011). Systematic Review of Parkinsonian Syndromes in Short- and Long-Term Survivors of Paraquat Poisoning. Journal of Occupational and Environmental Medicine, 53 (11): 1332-1336.
According to current scientific knowledge, Parkinson's disease does not develop naturally in any animals except humans. Rats and mice are widely used for modeling Parkinson's disease. Traditionally, animal models of Parkinson's disease rely on the use of specific toxins (most often MPTP), which selectively accumulate in the dopaminergic neurons, causing cellular dysfunction and death. A specific strain of mouse (C57BL/6), treated intraperitoneally with paraquat, has been used to model the cellular losses from the brain region (substantia nigra) seen in Parkinson's disease. The reliance on this model as evidence of the human condition is controversial and has been challenged in the scientific literature.
Several manuscripts have shown that paraquat, when administered systemically to C57BL/6 mice, can induce dopaminergic cell loss in the substantia nigra. However, the dose level at which this occurs is unclear and paradoxically does not appear to be accompanied by cell loss as evidenced by validated corresponding pathology markers.
A 2013 publication reported a series of studies in which paraquat was administered by intraperitoneal injection to C57BL/6J mice. Only 0.3% of the dose entered the brain and it was then slowly eliminated. In this study series paraquat did not cause pathological or neurochemical changes in the brain when given in doses up to and including 3 x 25 mg paraquat dichloride/kg. These studies did not consistently detect a significant dopaminergic cell loss, as reported by others, neither was there any evidence of neuronal cell death in the relevant region of the brain (SNpc), nor any effect on neurotransmitter levels in the striatum. Additional studies are required to resolve the differences between these results and those reported by others, including the in vivo studies by Peng et al. (2004).
Reference: Breckenridge C B et al., 2013 Pharmacokinetic, neurochemical, stereological and neuropathological studies on the potential effects of paraquat in the substantia nigra pars compacta and striatum of male C57BL/6J mice. NeuroToxicology, 37, 1–14
The results of this study have subsequently been confirmed in a comprehensive inter-laboratory investigation in which paraquat administered at maximum tolerated doses did not result in any neuropathology (Smeyne et al., 2016). This research employed three distinct methods of assessment, performed by three groups of investigators who were all ‘blinded’ to treatment, for a series of neuropathological indices evaluated in two ages and two sub-strains of male C57BL/6 mice, housed under different conditions in two laboratories. Paraquat, administered either once or twice weekly to 9- or 16-week old mice from two suppliers, had no effect on the number of dopaminergic neurons in the SNpc, as assessed by two groups, each blinded to treatment, using different stereological methods. In addition, blinded assessments conducted independently by a neuropathologist and a stereologist did not find any evidence of neuronal cell death (neuropathology) or neuroinflammation (neuropathology and stereology). Based on the scope and comprehensiveness of this study, the authors concluded that “… it is implausible that DA neurons could have died without detection in PQ-treated mice”.
Reference: Smeyne, R.J., Breckenridge, C.B., Beck, M., Jiao, Y, Butt, M., Wolf, J.C, Zadory, D., Minnema, D, Sturgess, N.C., Cook, A.R., and Botham, P., (2016). Assessment of the effects of MPTP and paraquat on dopaminergic neurons and microglia in the substantia nigra pars compacta based upon 2-D and 3-D stereological methods. PLOS ONE, DOI:10.1371/journal.pone.o164094, 2016 October 27
- In the Neurotoxicity supplement for paraquat, the Australian Agricultural and Veterinary Chemical Assessment Team Office of Chemical Safety, APVMA (2016) concluded that “the overwhelming weight-of-evidence, taking into consideration the available database of studies on experimental animals, human epidemiology studies and poisoning cases, is that paraquat does not induce neurotoxicity via the oral, dermal or intranasal routes; routes that are of relevance to human exposure to this pesticide. The OCS is therefore satisfied that exposure to paraquat, when used as a herbicide, does not pose a risk of neurotoxicity in humans and that lung damage remains the most sensitive and critical toxicological endpoint of concern in establishing health-based guidance values.”