Pesticides and Parkinson's Disease

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Winter 2002
Pesticides and Parkinson's Disease
teins that contain ubiquitin, ubiquitin C-terminal hydro-
Parkinson's disease (PD) is the second most prevalent lase, and alpha-synuclein [4]. Animal studies investi-
neuro-degenerative disorder after Alzheimer's disease, gating possible mechanisms for PD use these neuro-
and its incidence increases with age [1]. The etiology logical features to draw similarities between observed
of PD remains elusive and is likely diverse. Recent effects in rodents and Parkinson's disease.
studies have focused on environmental factors and
gene-environment interactions as potential causes.
Epidemiological Studies
The association between pesticide exposure and
Even basic epidemiological information remains uncer- Parkinson's disease has been investigated in numer-
tain. Prevalence and incidence values are difficult to ous epidemiological studies. A meta-analysis of 19
obtain since PD is not a notifiable disease, but it is studies published from 1989 to 1999 found a positive
believed that 1 in every 300 people in Canada and the association between pesticide exposure and
United States has Parkinson's disease [2]. While Parkinson's disease [5]. The majority of the studies
genetic susceptibility is believed to play a large role in reported an elevated risk of PD, and the combined
early-onset PD, most cases of PD seen in North odds ratio was calculated to be 1.94 with 95% confi-
America develop after age 50, suggesting that the dence intervals of 1.49-2.53. A review of more recent
majority of PD is caused by a factor other than genet- studies shows odds ratios consistent with results from
ics [3].
the meta-analysis [6]. Although risk increased with
longer exposure durations, no other indication of a
Clues to potential environmental risk factors for dose-response relation was observed.
Parkinson's disease were first discovered in the early
1980s. An increased risk of severe Parkinson's was A weakness found in most epidemiological studies is
observed in heroin addicts and determined to be trig- that exposure is assessed for broad categories like
gered by a chemical found in synthetic heroin (1- "pesticide" or "pesticide and herbicide" [6]. Even when
methyl-4-phenyl-1,2,36-tetrahydropyridine or MPTP). subgroups were used, they often provided no useful
Later, it was observed that this compound's structure information. In a population-based case-control study
was similar to certain herbicides and pesticides. Since investigating the risk of PD with pesticide exposure,
then, various epidemiological studies and laboratory farming, well water, and rural living, the subgroups her-
experiments suggests an association between pesti- bicides and insecticides could not be evaluated inde-
cides and Parkinson's disease. We summarize here pendently because 90% of the herbicide-exposed sub-
recent studies in the search for environmental toxins jects were also exposed to insecticides [7]. Another
that may contribute to the etiology of Parkinson's dis- limitation is that subjects seldomly recall the specific
class of pesticides used (e.g., carbamates,
organophosphates). For those that are able to remem-
ber, it is nearly impossible to validate actual pesticide
use. While epidemiological studies are suggestive of
Parkinson's disease is marked pathologically by the an association between pesticides and PD, these limi-
selective degeneration of dopaminergic neurons, tations further emphasize the need for complementary
nerve cells that use and produce dopamine as a neu- laboratory research.
rotransmitter substance. These neurons are found in
a large cell mass in the base of the brain known as the
substantia nigra. Dopamine is released in response to Mechanisms of Pesticide Toxicity
an impulse in the nerve axon and diffuses into the Although pesticide use has been linked to Parkinson's
synapse between the nerve ending and the dopamin- disease in various epidemiological studies, the exact
ergic neuron where it interacts with a receptor. As the mechanism of pesticide toxicity still eludes
death of the neurons progresses and dopamine levels researchers. While several explanations have been
drop, signs of the disease (tremors, rigidity, and loss of proposed, recent advances have been made in three
voluntary movement) become more severe.
specific areas.
Another pathological feature characteristic of Gene-Environment Interactions
Parkinson's disease is the formation of Lewy bodies. One explanation is that there may be a genetic sus-
Found within the neuron structure, Lewy bodies are ceptibility to Parkinson's disease resulting from poly-
deposits of abnormally aggregated neurofilament pro- morphisms of specific enzymes involved in the metab-

Pesticides and Parkinson's Disease - Page 2 of 3
olism of pesticides. These enzymes include exist in the environment.
cytochrome P 450 (CYP), CYP2D6, and glutathione
Questions exist concerning the relevance of this work
to humans. The rats in the study by Betarbet et al.
In a case-control study in Australia [8], pesticide expo- were administered rotenone intravenously over a short
sure was a significant risk factor after adjusting for age, period of time. A more realistic application would be to
sex, and family history of PD (odds ratio of 2.3 [95% CI extend these studies to primates and examine low-
1.2-4.4]). Subjects were classified as exposed if they dose long term exposures [13]. Furthermore, the lack
used pesticides more than once-weekly for more than of a detectable change in the complex I system of
six months before onset of disease. Blood samples many individuals with Parkinson's disease suggests
were also taken to identify any polymorphisms of glu- that this may not be the predominant mechanism.
tathione transferases (GSTs). These enzymes are In response, Betarbet et al. acknowledged that while
subject to a variety of polymorphisms, with each affect- not all cases of PD are caused by complex I defects,
ing a different process in the detoxification and metab- the fact that they are undetectable does not necessar-
olism of pesticides. When the authors restricted their ily imply they do not exist [14]. Minimal inhibition of
analysis to only the participants who reported pesticide complex I might be undetectable with conventional
exposure, significantly more patients with Parkinson's assays, but still produce neurological damage.
disease had GSTP1 gene variants. The authors con- Despite the inherent uncertainties, the US EPA is cur-
clude that the polymorphisms influence the ability of rently reviewing rotenone and the implications of this
the GSTs to detoxify pesticides with neurotoxic effects. work [15].
In a study by Hubble et al. [9], researchers investigat- Multiple Exposures
ed the association between PD with dementia and the The effect of multiple exposures to chemicals in the
interaction of environmental and genetic variables. environment has been an important area of interest for
Although none of the genetic markers or environmen- various health outcomes. Because a variety of chemi-
tal factors were independently predictive of PD with cals can be applied to a single crop or farm, it is impor-
dementia, the interaction of cytochrome P 450 and tant to understand the effects of pesticide mixtures.
pesticide exposure produced a statistically significant
odds ratio of 3.17 (95% CI: 1.11-9.05).
Paraquat is an herbicide that has long been considered
a potential risk factor for Parkinson's disease due to its
The results of these studies are limited by the small structural similarity to MPP+, the active metabolite of
population size and recall bias inherent in case-control MPTP. When injected directly into the brain, paraquat
studies. Also, pesticides consist of a wide range of reduces the level of dopamine and alters behavior.
chemical structures and mechanisms of toxicity and However, systemic administration of this herbicide to
may not all contribute to the development of PD. rodents shows little evidence of neurotoxicity. While
Despite these weaknesses, the studies suggest genet- much of the focus has been on paraquat, other class-
ics may affect susceptibility to Parkinson's disease es of pesticides are also known to impair dopaminergic
among the subgroup of people with pesticide expo- activity. Exposure to maneb, a dithiocarbamate fungi-
cide, has been linked to neurological impairments in
agricultural workers.
Mitochondrial Inhibition
Another possible mechanism is the inhibition of mito- A study by Thiuchelvam et al. [16] revealed that
chondrial respiration at complex I of the electron trans- Parkinson's disease may be linked to the combination
port chain, one of the five enzyme complexes of the of these two pesticides. Paraquat and maneb admin-
inner mitochondrial membrane involved in oxidative istered individually to mice caused no neurological
phosphorylation [10]. When it was discovered that damage, but when administered as a mixture, pro-
MPTP's metabolite, 1-methyl-4-pyridinium (MPP+), duced traits characteristic of PD. Paraquat (5 mg/kg or
caused mitochondrial dysfunction, a similar mecha- 10 mg/kg) and maneb (15 mg/kg or 30 mg/kg) were
nism of action was soon reported for Parkinson's dis- injected into mice once a week for 4 weeks. These lev-
els are considered low and are well below the reported
values of LD50, the dose at which 50% of the animals
In a study by Betarbet, et al. [11], the common pesti- tested are killed. Results of administering the
cide rotenone was shown to reproduce neurological paraquat/maneb mixture showed altered dopamine
features of Parkinson's disease. Rotenone is extreme- levels in the substantia nigra, the same area of the
ly toxic to fish, but poses little risk to humans when brain targeted in Parkinson's disease. Moreover,
used properly [12]. The authors were able to show that motor skills in the mice were significantly reduced com-
rotenone produced systemic partial inhibition of com- pared to controls only when combinations of paraquat
plex I in laboratory rats, which resulted in the progres- and maneb were administered together. The authors
sive degeneration of dopaminergic neurons and did not provide a biological mechanism to explain the
deficits in motor skills. These results provide a biolog- interactive effects of paraquat and maneb. However,
ically plausible mechanism for the development of their results suggest the potential for pesticide mixtures
Parkinson's disease after exposure to pesticides. The to act as etiologic agents for Parkinson's disease and
study also emphasizes the need for further research of emphasize the need for further investigation of multiple
complex I inhibitors other than pesticides that may chemical effects.

Pesticides and Parkinson's Disease - Page 3 of 3
10. Giasson BI and VMY Lee. 2000. A new link between
Exposure to pesticides has been frequently identified
pesticides and Parkinson's disease. Nature
Neuroscience 3: 1227-8.
as a potential risk factor for Parkinson's disease in epi-
demiological studies. In addition, recent laboratory 11. Betarbet R, Sherer TB, MacKenzie G et al. 2000.
experiments have provided evidence for neurological
Chronic systemic pesticide exposure reproduces fea-
effects and biologically plausible mechanisms that link
tures of Parkinson's disease. Nature Neuroscience 3:
pesticides to PD.
12. Rotenone ExtoxNet Fact Sheet, Pesticide Information
In response to the many advances made in the field of
environmental risk factors, the National Institute of
Environmental Health Sciences (NIEHS) announced in
August 2002 a $20 million initiative on Parkinson's dis- 13. Jenner P. 2001. Parkinson's disease, pesticides and
mitochondrial disfuntion. Trends in Neuroscience 24:
ease [17]. The funding will allow three major research
centers to collaborate and investigate the environmen-
tal and genetic origins of PD. The Parkinson's Institute 14. Greenamyre JT, Betarbet R, Sherer T, and A Panov.
will investigate the mechanisms of dopamine cell death
2001. Trends in Neuroscience 24: 247.
and the risks associated with metals and pesticides. 15. Rotenone Fact Sheet, US Environmental Protection
The Emory Collaborative Center for PD Environmental
Agency, oppsrrd1/REDs/fact-
Research at Emory University in Atlanta Georgia will
examine the interaction between pesticides and the
proteins involved in maintaining the dopamine within 16. Thiruchelvan M, Brockel BJ, Richfield RB et al. 2000.
nerve cells. The Center for Gene-Environment Studies
Potentiated and preferential effects of combined
paraquat and maneb on nigrostriatal dopamine sys-
in Parkinson's Disease at the University of California,
tems: environmental risk factors for Parkinson's dis-
Los Angeles (UCLA) will study how alterations in the
ease? Brain Research 873: 225-234.
genes that regulate dopamine affect the risk of
Parkinson's disease associated with pesticides. The 17. The Parkinson's Institute News and Press Releases,
NIEHS is already currently supporting studies at the
Director of NIEHS announces $20 million initiative on
parkinson's disease, 6 September 2002.
University of Rochester, the University of Georgia, and
www.parkinsonsinstitute/org/ news
the University of Washington [1]. Recent progress in
this field suggests that with further research, the etiol-
ogy of Parkinson's disease may one day be under-
References Cited:
1. Parkinson's Disease Research at NIEHS, National
Institute of Environmental Science Fact Sheet,
Prepared by the Department of Environmental Health, factsheets/parkinson.htm,
Boston Univeristy School of Public Health under the
24 July 2002.
direction of the International Joint Commission’s Health
Professionals Task Force. The Health Effects Review
2. Parkinson Disease FAQs, Parkinson Society Canada,
is a quarterly publication that summarizes the latest
scientific literature on human health effects and envi-
ronmental pollutants. This does not represent the offi-
cial position of the International Joint Commission.
3. Tanner CM, Ottman R, Goldman SM et al. 1999.
Parkinson disease in twins: an etiologic study. JAMA
Review Coordinator: Verónica Maria Vieira, M.S.
281: 341-346.
Senior Science Advisor: Dr. David M. Ozonoff
4. Lewy Bodies in Parkinson's,
For further information please contact Jim Houston,
Secretary, Health Professionals Task Force
E-mail: [email protected]
5. Priyadarshi A, Khuder SA, Schaub EA et al. 2000. A
meta-analysis of Parkinson's disease and exposure to
pesticides. Neurotoxicology 21: 435-440.
6. Lai BCL, Marion, SA, Teschke K, Tsui JKC. 2002.
Occupaional and environmental risk factors for
Parkinson's disease. Parkinsonism and Related
Disorders 8: 297-309.
7. Gorell JM, Johnson CC, Rybicki BA, et al. 1998. The
risk of Parkinson's disease with exposure to pesticides,
farming, well water, and rural living. Neurology 50:
8. Menegon A, Board PG, Blackburn AC et al. 1998.
Parkinson's disease, pesticides, and gluthathione trans-
ferase polymorphisms. The Lancet 352: 1344-1346.
9. Hubble JP, Kurth JH, Glatt SL et al. 1998. Gene-toxin
interaction as a putative risk factor for Parkinson's dis-
ease with dementia. Neuroepidemiology 17: 96-104.