Pesticides
and Parkinsonism:
Is There a Link Between Environmental Toxins and Neurodegenerative
Disorders? Alan H. Lockwood, MD Abstract Multiple,
converging lines of evidence from epidemiological, twin, and individual patient
studies, as well as studies in animals, suggest that there may be a link between
exposure to pesticides and the eventual development of Parkinson’s disease
(PD). Since PD is common and shares some features with other neurodegenerative
disorders, there is a concern that long-term exposure to environmental factors,
particularly pesticides, may play a role in the development of this class of disorders.
Since these diseases usually develop late in life, and since the number of old
people is increasing, the number of people affected by PD and the other neurodegenerative
disorders is increasing and will continue to increase into the foreseeable future.
As the case for an etiological link between pesticides and PD gets stronger, the
need to invoke the “precautionary principle” will become more apparent.
Physicians have a special responsibility to educate and provide guidance to colleagues,
the public, and policy makers charged with regulating the chemicals in our environment.
[M&GS 2000;6:86-90]
The publication of
Rachel Carson’s Silent Spring marked the beginning of an era [1].
This landmark book introduced many to the idea that there are unintended consequences
associated with the use of pesticides. While most of us are familiar with the
arguments calling for regulations to ban or limit lead, dioxins, DDT, and other
compounds that have well-described consequences, there is a lingering concern
that there may be other serious, unknown, consequences associated with the use
of pesticides. These concerns are heightened by several recent studies that have
strengthened the hypothesis that Parkinson’s disease (PD) or, more properly,
parkinsonism, may be caused by environmental toxins [2,3].
Parkinson’s
disease was described by James Parkinson in 1817. The disease that bears his
name is characterized by tremor, bradykinesia (slowness), rigidity, and a loss
of postural reflexes. PD is but one of a number of conditions that are all typified
by akinesia and rigidity [4]. These conditions, which include
progressive supranuclear palsy, diffuse Lewy body disease, cortico-striatonigral
degeneration, cortical-basal ganglionic degeneration, and many others, are referred
to as forms of parkinsonism because of their resemblance to idiopathic PD [4].
Because of the similarities in the clinical manifestations of these disorders
and an absence of clearly defined pathophysiological mechanisms that separate
them into distinct nosological entities, many patients are diagnosed as having
parkinsonism, or PD, until the emergence of distinguishing characteristics. This
may take years. For some, a correct diagnosis may never be made or may be made
only at autopsy. Nature and Scope
of Parksinson’s Parkinson’s disease affects more than 500,000
Americans and costs the economy more than $20 billion per year [5].
It is second only to Alzheimer’s disease among the neurodegenerative diseases.
Parkinson’s disease usually begins after age 50, and the incidence increases
exponentially with increasing age. Between 1.5% and 2.5% of all Americans who
reach the age of 70 have Parkinson’s disease. As the population of the nation
ages, the number of people with PD is certain to increase. Since some patients
with PD have signs and symptoms that are seen in other neurodegenerative diseases
such as Alzheimer’s disease, amyotrophic lateral sclerosis, and others, there
is some concern that they may share common pathogenetic mechanisms. The
cause of PD is unknown. After the 1916-27 influenza pandemic, large numbers of
patients developed post-encephalitic parkinsonism. Typically, the signs and symptoms
of this condition began less than 5 years after the acute illness, with 85% of
all patients developing the syndrome within 10 years.
Speculations about environmental factors and the etiology of PD began almost two
decades ago when several patients were identified who developed what appeared
to be typical PD at an extraordinarily young age [6]. Epidemiological
studies of these patients revealed that they were drug abusers who used so-called
designer drugs--drugs usually manufactured in illicit laboratories designed to
have structural characteristics similar to opiates. In the attempt to synthesize
a meperidine-like drug, it was found that an unintended chemical reaction produced
the compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Further research
showed that MPTP is a toxin that kills the dopaminergic neurons in the brain,
producing a syndrome that is almost identical to typical PD [7,8].
It was not long before others noted that the structure of MPTP was similar to
paraquat, a widely used herbicide registered by the US Environmental Protection
Agency (EPA) used to treat crops, such as cotton, soybeans, sugarcane, and sunflowers.
Risk Factors The structural similarity between MPTP
and other pesticides triggered epidemiological studies designed to evaluate risk
factors for the development of PD. These studies received additional impetus from
the discovery that an extract from the plant cycas circinalis L. was linked to
the development of a neurodegenerative disorder referred to as Parkinson-amyotrophic
lateral sclerosis-dementia complex found in people from Guam [9].
The affected individuals appear to have eaten the seeds of the cycad, a traditional
source of food and medicine among the Chamorro people. With westernization and
changes in eating habits, this condition has died out.
A number of epidemiological studies have sought to define risk factors for the
development of PD. Oddly, cigarette smoking reduces the risk of developing Parkinson’s
disease [10]. Since PD was not described until the early
part of the 19th century, many have suggested that PD is related in some way to
the industrial age. This hypothesis is supported by several studies. In a 1989
case-control study in the People’s Republic of China, Tanner et al. found
that occupational exposure to industrial chemicals, printing plants, or quarries
was associated with an increased risk of PD (relative risk range 2.39-4.5), whereas
raising pigs, growing wheat, and village residence were associated with a reduced
risk of PD (relative risk range .17- .57) [11]. Since chemical
use was not characteristic of the Chinese agricultural system at that time, the
authors linked industrial processes to the development of PD. A similar conclusion
was drawn by Schoenberg et al. who found an age-adjusted prevalence ratio for
PD of 341/100,000 among black residents of Copiah County, Mississippi, which was
compared to an age-adjusted prevalence ratio of 67/100,00 in Igbo-Ora, Nigeria
[12]. These studies attributed the difference to the degree
of industrialization of the two sites. Pesticides
and PD A number of studies have focused on pesticides and have linked exposure
to an increased risk for the development of PD. In a case-controlled study involving
120 Taiwanese patients with PD and 240 hospitalized controls, the risk for developing
PD was increased by 2.04 for living in a rural environment, by 1.81 for farming,
by 3.22 for use of paraquat, and by 2.89 for other herbicide-pesticide use [13].
In an Israeli study, the incidence of PD was increased five-fold among the residents
of three adjacent kibbutzim in the Negev desert who all drew on a common aquifer,
and who were all exposed to similar agricultural chemicals [14].
Clustering of these cases suggested strongly that an environmental factor was
responsible, such as drinking well water and/or exposure to agricultural chemicals.
Additional support for the link between pesticides and PD came from the study
of Semchuk et al., who performed a case-control study of 130 residents of Calgary,
Alberta, Canada with neurologist-confirmed PD, and 260 age- and sex-matched controls
[15]. Prior occupational herbicide use was the only consistent
predictor for the development of PD. Hubble et al. formed similar conclusions,
using different methods, in a study of rural and urban residents of Kansas [16].
They did a principle components analysis of data regarding residency, occupation,
medical history, social history, and diet. In a further analysis, significant
predictors for the development of PD, in order of strength, were pesticide use,
family history of neurologic disease, and depression, with a 92% predicted probability
for PD if all three were positive (odds ratio = 12.0). Doubts have been
raised in some minds due to differences in methodology, differences in the populations
studied, and differences in the criteria used to make or confirm the diagnosis
of PD. Nevertheless, the weight of the evidence gathered a decade ago suggests
strongly that exposure to industrial chemicals, particularly pesticides, is a
significant risk factor for the development of PD. The role of the environment
as a factor in the development of PD was given new focus by a recent twin study
reported by Tanner and her associates [2], who evaluated almost 20,000 twin pairs
and identified 193 twins with PD, employing the techniques of molecular biology
to establish zygosity and comprehensive neurological evaluations by specialists
in the diagnosis of PD. These data were used to calculate concordance rates for
monozygous and dizygous pairs, stratified by age. Among twins with PD diagnosed
after age 50 years, the pairwise concordance was 0.106 in the monozygous pairs
and virtually identical at 0.104 among the dizygous pairs. Among twins diagnosed
with PD before age 51 years, the concordance rates were 1.00 in monozygous pairs
and 0.167 among the dizygous pairs. The relative risk for concordance for those
diagnosed when younger than age 50 years was 6.0 and 1.02 for those diagnosed
at age 50 or greater. Thus, among twins with one member affected by PD before
the age 50, the second twin was 6 times more likely to develop PD if they were
a monozygous pair rather than a dizygous pair. Zygosity had no effect on the risk
of developing PD in the second twin if the disease developed after age 50. This
near-identity for risk after age 50 showed clearly that PD that develops after
the age of 50 is not likely to be due to genetic factors. These data suggest strongly
that non-genetic, i.e., environmental factors, determine the risk of developing
PD after age 50, the most common time for this condition to appear [3].
Another recent publication described five patients who had developed reversible
parkinsonism after exposure to organophosphates [17]. These
patients did not have the classical form of the disease, in that they did not
improve after the administration of anti-parkinsonian drugs (typically, PD improves
after pharmacological treatment, whereas other indistinguishable akinetic-rigid
syndromes, such as striatonigral degeneration may not respond). Three of these
patients came from the same family, suggesting a genetically determined susceptibility
to these compounds. At a recent symposium on Parkinson’s disease, researchers
from Atlanta reported on the development of an animal model of Parkinson’s
disease using rotenone [18]. Systemic administration of this
pesticide caused degeneration of the neural pathways implicated in the development
of PD. Common Toxic Factor These data demonstrate
that there is increasing, credible evidence that exposure to environmental toxins,
particularly pesticides, may lead to the development of PD. Because of similarities
among neurodegenerative diseases as a group, and particularly because of the data
implicating a common toxic factor causing the PD-demential-amyotrophic sclerosis
complex in Guam, the relationship between pesticides and the etiology of PD may
be an indication of a more widespread problem. We
are awash in a sea of chemicals. According to the EPA, 4.5 billion pounds of pesticides
are used in the US each year. We use 77 million pounds of organophosphates: 60
million pounds are used in agriculture and 17 million pounds are used in homes,
on lawns and golf courses, and for other non-agricultural purposes. According
to the Foundation for Advancements in Science and Education, the US exported more
than 338 million pounds of pesticides during 1995 and 1996. This total included
at least 21 million pounds of pesticides whose use is forbidden in the US. Most
of these shipments were directed to the developing world. In the 1980s more than
200,000 deaths were attributed to organophosphate poisonings in developing countries,
largely among agricultural workers [19]. Whether exposed
workers will develop additional health problems, including PD, remains to be seen.
In the landmark publication Pesticides in the Diets of Infants and Children,
experts from the National Academy
of Sciences showed clearly that organophosphate residues are present in easily
detectible amounts in our water supply [20]. Because children
consume more water per unit body weight than adults, they are particularly vulnerable.
The report found that children were frequently exposed to pesticide residues in
excess of a reference dose and that, for some, these exposures were high enough
to cause symptoms of acute organophosphate poisoning. Implications
for Policy At the time of that report, pesticide tolerances were defined
largely by the industry that manufactures them. These tolerances were based on
agricultural practices and were not related to worker or consumer health. This
is changing. As a part of the Federal
Insecticide Fungicide and Rodenticide Act (FIFRA), the EPA is reviewing pesticide
use to make more appropriate decisions concerning the use of these compounds.
The 1996
Food Quality Protection Act further requires that uses must be “safe,”
in that EPA must conclude “with reasonable certainty that no harm will come
from aggregate exposure” to these compounds. By aggregate exposure, the act
intends that all exposures, including those in food, water, and residential sources
must be considered. Cumulative effects from multiple pesticides must be considered.
Exposures must account for the special sensitivity of children and infants. In
another important departure from prior regulatory standards, multiple end-points
must be considered, including possible endocrine effects. It will no longer be
sufficient to conclude that a pesticide is safe as long as it does not cause cancer.
As a consequence of these findings, the National Institutes of Health has issued
a special request for applications (RFA
ES-00-002, The role of the environment in Parkinson’s disease), directed
at the neuroscience community, for research studies that focus on the role of
the environment and Parkinson’s disease. This call will be answered, but
proving that there is an unequivocal link between the use of pesticides and the
development of Parkinson’s disease is likely to be difficult, if not impossible.
It is more likely that the weight of the evidence will increase slowly. Since
pesticide exposure begins early in life, a lifelong avoidance of these ubiquitous
compounds may be required. What is the responsibility of physicians? Since
society as a whole derives benefits from pesticides, the debates concerning their
use are likely to intensify. The best answers will not come easily. There is,
as yet, no smoking gun linking pesticides and neurodegenerative disorders. Yet
the evidence forging that link is getting stronger. At the present time, there
are no known cures for any of the neurodegenerative disorders. The effective therapies,
directed at the symptoms of PD, all have side effects and limitations. The ability
to prevent PD would be welcome. On entering into the practice of medicine,
physicians subscribe to the Hippocratic Oath and its fundamental tenet “first
do no harm.” This principle is gaining acceptance in environmental law and
practice in the form of the “precautionary principle.” Briefly stated,
the precautionary principle asserts that scientific proof of a causal link between
human activity and its effects is not required before preventive actions should
be taken. Physicians have a commitment to their patients and are obligated to
collect and evaluate data that can help define the etiology of PD and other diseases
linked to environmental exposures. Converting these data into educational programs
and policies that inform and benefit all is a daunting, but essential, task. Opposition
to the precautionary principle from those with a vested economic interest in the
chemicals it would limit should not stop us from combining good science and responsible
actions. References 1.
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15. Semchuk KM,
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text]
16. Hubble JP, Kurth JH, Glatt SL, Kurth MC,
Schellenberg GD, Hassanein RE, et al. Gene- toxin interaction as a putative risk
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17. Bhatt MH, Elias
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18. Greenamyre JT, MacKenzie G, Garcia-Osuna
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19. Jeyaratnam J. Acute pesticide poisoning:
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20. Committee
on Pesticide Residues in the Diets of Infants and Children. Pesticides in the
diets of infants and children. Washington, DC: National Academy Press. 1993. [Return
to text] AHL is a physician with the Departments
of Neurology and Nuclear Medicine, VA Western New York Healthcare System and University
of Buffalo, Buffalo, NY USA. Address correspondence to: Alan H. Lockwood, MD,
Center for PET (115P), VA Western NY Healthcare System, 3495 Bailey Avenue, Buffalo,
NY 14215 USA; e-mail: alan@petnet.buffalo.edu.
Copyright © 2000 Medicine & Global Survival, Inc.
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