Medicine and Global Survival  [Printer-friendly version]
June 1, 2000


[Rachel's introduction: "As the case for an etiological [cause-and-
effect] link between pesticides and Parkinson's Disease 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."]

Alan H. Lockwood, MD**


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

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

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

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.


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** Alan H. Lockwood 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:

Copyright 2000 Medicine & Global Survival, Inc.