VOLUME 113 | NUMBER 9 | September 2005 • Environmental Health Perspectives
Parkinson disease (PD) and Alzheimer disease
(AD) are the two most common neurodegen-
erative diseases of the older American popula-
tion. PD affects more than 500,000 Americans
(National Institute of Neurological Disorders
and Stroke 2004; Siderowf and Stern 2003).
About 50,000 new cases are reported each
year, and in recent years the annual number of
deaths from PD has increased steadily
(Lilienfeld et al. 1990). Internationally, the
incidence rate for PD approximates 17 per
100,000 per year, although this is probably an
underestimate (Twelves et al. 2003). AD has
been diagnosed in an estimated 2.3 million
persons in the United States, and there are
approximately 360,000 newly diagnosed cases
each year (Brookmeyer et al. 1998). It is esti-
mated that by 2050, as the U.S. population
continues to age, as many as 14 million
Americans may have AD (Lewin Group
Causation of both PD and AD is com-
plex. In a minority of cases, particularly in
early onset AD and PD, etiology appears to be
primarily genetic (Tanner et al. 1999). But in
most cases, causation appears to involve inter-
actions among multiple genetic and environ-
mental factors (Foster 2002; Kennedy et al.
2003). We hypothesize that exposure of the
developing brain to still undefined toxic envi-
ronmental agents during windows of vulnera-
bility in early life—in utero and in early
postnatal life—may be an important contribu-
tor to causation.
Here we provide an overview of the
emerging body of evidence on the environ-
mental origins of neurodegenerative disease.
We focus especially on environmental expo-
sures that occur early in life during windows
of developmental vulnerability. We offer rec-
ommendations for future research. This
report and its recommendations are based on
the conference “Early Environmental Origins
of Neurodegenerative Disease in Later Life:
Research and Risk Assessment” sponsored by
the Mount Sinai Center for Children’s
Health and the Environment. The conference
was held in New York City on 16 May 2003.
The Pathology of PD and AD
PD presents clinically as a disorder of motor
function characterized by tremor, slow and
decreased movement (bradykinesia), muscu-
lar rigidity, poor balance, and problems in
gait (Parkinson’s Disease Foundation 2004).
Pathologically, PD patients show loss of
dopaminergic neurons in the substantia nigra
(SN) pars compacta and frequently have
Lewy bodies, eosinophilic intracellular inclu-
sions composed of amyloid-like fibers and
α-synuclein (Dawson and Dawson 2003).
AD is characterized by a deterioration of
cortical neurons, resulting in dementia. The
two typical histopathologic features are
a) plaques, which are clumps of insoluble
β-amyloid protein fragments that accumulate
extracellularly, and b) intracellular neuro-
fibrillary tangles composed of altered tau
protein (Alzheimer’s Association 2003).
Costs of Neurogenerative
A 1997 economic study prepared for the
Parkinson’s Disease Foundation estimated the
annual cost of treatment per patient to be
approximately $24,000 (John C. Robbins
Associates 1997). The estimated total annual
costs of treating PD in the United States range
from $12 to 25 billion. These costs are spread
across families, benefit providers, social secu-
rity, Medicare, and Medicaid. In addition to
the financial costs, there are the human costs
of pain and suffering, sadness and despair, and
reduction in overall quality of life.
Combined Medicare and Medicaid
spending on AD amounted to more than
$50 billion in 2000 and is anticipated to
increase to nearly $83 billion by 2010 (Lewin
Group 2001). Preliminary statistics from
2001—the most recent year for which these
This article is part of the mini-monograph “Early
Environmental Origins of Neurodegenerative Disease
in Later Life: Research and Risk Assessment.”
Address correspondence to P.J. Landrigan, Center
for Children’s Health and the Environment,
Department of Community and Preventive Medicine,
Box 1057, One Gustave L. Levy Pl., Mount Sinai
School of Medicine, New York, New York 10029
USA. Telephone: (212) 241-4804. Fax: (212) 996-
0407. E-mail: firstname.lastname@example.org
We express our sincere thanks to L. Boni of the
Center for Children’s Health and the Environment,
Department of Community and Preventive
Medicine, Mount Sinai School of Medicine, New
York, New York.
The views expressed in this article are the opinions
of the authors and do not represent endorsement or
policy of their affiliated institutions or the U.S.
Environmental Protection Agency.
The conference was co-sponsored by the
U.S. Environmental Protection Agency (U.S. EPA
CR X-83043201-0), the National Institute of
Environmental Health Sciences (NIEHS 273-MH-
310208), the Beldon Fund, the Baumann Family
Foundation and the Bachmann-Strauss Dystonia
and Parkinson Foundation Inc., NIEHS Superfund
grant P42-ES07384, NIEHS Children’s Center
(P01-ES009584), and U.S. EPA Children’s Center
The authors declare they have no competing
Received 1 September 2004; accepted 10 May 2005.
Early Environmental Origins of Neurodegenerative Disease in Later Life
Philip J. Landrigan,1Babasaheb Sonawane,2Robert N. Butler,3Leonardo Trasande,1Richard Callan,1
and Daniel Droller1
1Center for Children’s Health and the Environment, Department of Community and Preventive Medicine, Mount Sinai School
of Medicine, New York, New York, USA; 2National Center for Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Washington, DC, USA; 3International Longevity Center, New York, New York, USA
Parkinson disease (PD) and Alzheimer disease (AD), the two most common neurodegenerative
disorders in American adults, are of purely genetic origin in a minority of cases and appear in most
instances to arise through interactions among genetic and environmental factors. In this article we
hypothesize that environmental exposures in early life may be of particular etiologic importance and
review evidence for the early environmental origins of neurodegeneration. For PD the first recog-
nized environmental cause, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), was identified in
epidemiologic studies of drug abusers. Chemicals experimentally linked to PD include the insecticide
rotenone and the herbicides paraquat and maneb; interaction has been observed between paraquat
and maneb. In epidemiologic studies, manganese has been linked to parkinsonism. In dementia, lead
is associated with increased risk in chronically exposed workers. Exposures of children in early life to
lead, polychlorinated biphenyls, and methylmercury have been followed by persistent decrements in
intelligence that may presage dementia. To discover new environmental causes of AD and PD, and
to characterize relevant gene–environment interactions, we recommend that a large, prospective
genetic and epidemiologic study be undertaken that will follow thousands of children from concep-
tion (or before) to old age. Additional approaches to etiologic discovery include establishing inci-
dence registries for AD and PD, conducting targeted investigations in high-risk populations, and
improving testing of the potential neurologic toxicity of chemicals. Key words: Alzheimer disease,
maneb, manganese, National Children’s Study, neurodegenerative disease, paraquat, Parkinson
disease, pesticides. Environ Health Perspect 113:1230–1233 (2005). doi:10.1289/ehp.7571 available
via http://dx.doi.org/ [Online 26 May 2005]
data are available—from the Centers for
Disease Control and Prevention (CDC) list
AD as the eighth leading cause of death in the
United States, responsible for 62,000 deaths
annually (CDC 2003a).
PD and AD may co-occur and may share
some etiologic or predisposing factors. Elderly
patients who develop rapidly progressive PD
may be at up to 8 times increased risk of
developing AD (Wilson et al. 2003). Although
the risk of developing AD and PD increases
with age, neither of these diseases nor the
symptoms of dementia are part of normal
aging. In the absence of disease, the human
brain can function well into the tenth decade
[National Institute on Aging (NIA) 2000].
The Barker Hypothesis
Through detailed reconstructions of neonatal
and medical histories of birth cohorts in the
United Kingdom, David Barker of the
University of Southampton proposed what is
now termed “the Barker hypothesis” (Osmond
and Barker 2000), the concept that parameters
of fetal, infant, and childhood growth may be
predictors of disease in later life. Barker found
that infants with low birth weight, small head
circumference, and low ponderal index at birth
are at increased risk of developing coronary
heart disease, hypertension, stroke, insulin resis-
tance, and diabetes as adults. He found also that
reduced fetal growth and impaired development
during infancy were associated with increased
mortality from cardiovascular disease (CVD) in
both men and women, independent of social
class and other confounders such as smoking,
alcohol consumption, and obesity (Barker et al.
1993; Osmond et al. 1993). This association is
strong and graded, is observed in various popu-
lations, and is specific to CVD. In Barker’s
studies, low birth weight followed by obesity in
later life led to a particularly high risk of CVD
and insulin resistance. Further analysis indi-
cated that hypertension may begin in utero and
become magnified with age (Law et al. 1993).
Barker hypothesized that fetal undernutri-
tion during critical periods of vulnerability in
early development leads to persistent changes
in hormone levels and in altered tissue sensi-
tivity to these hormones, permanently altering
the metabolism and body structure (Hinchliffe
et al. 1992; Lumbers et al. 2001).
The Expanded Barker
At the 2003 Mount Sinai Conference on
Early Environmental Origins of Neurological
Degeneration, we explored the plausibility of
extending the Barker hypothesis to encompass
brain development and to explore the impacts
of toxic chemicals on brain development.
Conferees generally supported the hypo-
thesis that early exposures to environmental
toxicants could later affect the brain and that
such associations are biologically plausible
(De la Fuente-Fernandez and Calne 2002).
This consensus was based on experimental
studies of associations between early-life expo-
sures to pesticides and PD (Thiruchelvam
et al. 2000a, 2000b), as well as on epidemio-
logic studies of the toxic and apparently irre-
versible effects on the developing brain of
in utero exposures to lead, methylmercury, and
polychlorinated biphenyls (Grandjean et al.
1997; Jacobson et al. 1990; Needleman et al.
1990). A mechanistic hypothesis proposed
(Langston et al. 1999) that early exposures to
neurotoxic chemicals reduce the number of
neurons in critical areas of the brain such as
the SN to levels below those needed to sustain
function in the face of the neuronal attrition
associated with advancing age (Figure 1).
Evidence for the Environmental
Origins of Parkinson Disease
Twin studies. A large-scale study of twins
designed to assess genetic versus environmental
factors in the etiology of PD found a high
degree of concordance within twin pairs for
early-onset PD (onset before age 50) but much
less concordance for disease of late onset
(Tanner et al. 1999). This finding suggests that
early onset PD may be of genetic origin in
most cases (although the etiologic role of a
shared environment can never be completely
excluded), whereas beyond 50 years of age
environmental factors become increasingly
important (Tanner et al. 1999).
MPTP and PD. Several clinical and epi-
demiologic studies have demonstrated that
exposures to certain synthetic chemicals are
associated with increased incidence of PD. The
first of these studies was the description in
1982 of severe Parkinson-like symptoms
among a group of drug users in northern
California who had taken synthetic heroin con-
taminated with MPTP (1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine; Langston et al.
1999). This episode strongly supported the
concept that exogenous chemicals can cause or
contribute to causation of PD (Priyadarshi
et al. 2001). MPTP was subsequently shown to
act selectively—specifically injuring dopamin-
ergic neurons in the nigrostriatal system in
humans as well as in experimental animals
(Langston et al. 1999). Evidence also was
found for ongoing dopaminergic nerve cell loss
without Lewy body formation in these
patients. This suggested a self-perpetuating
process of neurodegeneration. Years later, con-
sistent with that hypothesis, postmortem
examination of persons who had been exposed
to MPTP showed a marked microglial prolifer-
ation in the SN pars compacta (Orr et al.
2002). In some patients, MPTP-induced PD
appeared almost immediately after exposure,
whereas in others, onset became evident only
months or years later, apparently reflecting
progressive injury against a background of
declining physiologic reserve.
Paraquat and PD. An etiologic link has
been suggested between PD and the herbicide
Brooks et al. 1999; McCormack et al. 2002).
Paraquat is structurally similar to MPP+, the
active metabolite of MPTP. Epidemiologic
data suggest a positive dose–response relation-
ship between lifetime cumulative exposure to
paraquat and risk of PD (Liou et al. 1997). In
experimental studies in which paraquat has
been administered to animals, researchers have
observed loss of SN dopaminergic neurons,
depletion of dopamine in the SN, reduced
ambulatory activity, and apoptotic cell death
(Liu et al. 2003).
Maneb and PD. Exposure to the dithio-
carbamate fungicide maneb has been reported
to enhance uptake of MPTP and to amplify its
neurotoxicity; both paraquat and maneb target
brain dopamine. In animal studies, early-life
exposure to a combination of paraquat and
maneb produced destructive effects on the
nigrostriatal dopaminergic system and abnor-
malities in motor response that were more
severe than those produced by either agent
alone. These effects were amplified by aging
(McCormack et al. 2002; Thiruchelvam et al.
Rotenone and PD. The insecticide
rotenone induces clinical and pathologic
features in rats similar to those induced by
PD, including selective degeneration of the
nigrostriatal dopaminergic system and move-
ment disorders (Liu et al. 2003; Sherer et al.
2003). Synergistic effects have been observed
in animals administered a combination of
rotenone and lipopolysacchide, a molecule
that stimulates inflammation (Gao et al.
2003; Thiruchelvam et al. 2000b).
Manganese and PD. Although manganese
is an essential trace element, chronic occupa-
tional exposure to high levels of this metal
causes accumulation in the basal ganglia, result-
ing in manganism, a condition characterized by
tremors, rigidity and psychosis (Mergler and
Early environmental origins of neurodegenerative disease
Environmental Health Perspectives • VOLUME 113 | NUMBER 9 | September 2005
Figure 1. Long-term consequences of early loss of
critical neurons after developmental damage. DA,
dopaminergic. The impact of early developmental
damage is not immediately evident but produces
disease years or decades later as the number of
neurons decreases with advancing age.
Percent of DA neurons remaining
Threshold for onset of PD symptoms
Baldwin 1997). This condition has been
reported in manganese miners. Concern exists
that widespread introduction of the manganese-
containing fuel additive MMT (methyl-
cyclopentadienyl manganese tricarbonyl) to the
U.S. gasoline supply may increase population
exposure to manganese and thus increase risk
of parkinsonism in sensitive populations
(Needleman and Landrigan 1996).
Other chemicals and PD. Exposures to
pesticides and other organic compounds are
widespread in the American population
(CDC 2003b). Levels of organochlorines
have been found to be elevated in the brains
of persons with PD (Fleming et al. 1994). A
study of French elderly individuals found an
association between past occupational expo-
sure to pesticides, low cognitive performance,
and increased risk of developing AD or PD
(Baldi et al. 2003). Other reported links
between environmental factors and PD
include increased risks from drinking well
water, rural living, farming, and exposure to
agricultural chemicals (Liou et al. 1997;
Priyadarshi et al. 2001).
Epidemiologic studies have shown
inverse, apparently protective relationships
between cigarette smoking, coffee consump-
tion, and PD (Hernan et al. 2002).
Inflammation and PD. Inflammation of
the brain in early life caused by exposure to
infectious agents, toxicants, or environmental
factors has been suggested as a possible cause
or contributor to the later development of PD
(Liu et al. 2003). The inflammatory process in
such cases may involve activation of brain
immune cells (microglia and astrocytes),
which release inflammatory and neurotoxic
factors that in turn produce neurodegenera-
tion (Liu and Hong 2003). This concept first
arose in the suggestion that infection with
influenza virus in the pandemic of 1918 pro-
duced an increased risk of PD. More recently,
infection with certain microorganisms such as
the soil bacterium Nocardia asteroides has been
proposed as a risk factor for PD (Kohbata and
Beaman 1991). In animal experiments, expo-
sure to bacterial endotoxin lipopolysaccharide
in utero induced dopaminergic neurodegenera-
tion (Gao et al. 2002; Liu et al. 2000, 2003).
Isolated populations of high risk for PD.
PD incidence and mortality rates differ among
ethnic groups and exhibit strong regional varia-
tion, thus providing additional evidence
that environmental factors may be involved in
causation (Ben-Shlomo 1997; Foster 2002).
For example, the Chamorros population
of Guam and Rota in the western Pacific have
an unusually high prevalence of motor neuron
disease, a syndrome that includes amyotrophic
lateral sclerosis (ALS), parkinsonism, and pro-
gressive dementia. It has been proposed that
this syndrome of parkinsonian dementia is
related to the consumption of flour made
from cycad seeds (Spencer 2003) or to inhala-
tion of pollen from cycad plants (Seawright
et al. 1995). Consumption of cycad flour may
have been especially common on Guam in the
famine years before and during World War II.
The declining incidence and increasing age at
onset of ALS and parkinsonism–dementia
complex among the Chamorros over the past
50 years together with the decreasing preva-
lence of ALS over the same time in high-inci-
dence areas of Japan and Indonesia suggests
the disappearance of an environmental factor
unique to these population groups (Kurland
and Mulder 1954; Plato et al. 2003).
Evidence for the Environmental
Origins of Dementia
Lead and cognitive function. Childhood
exposure to lead, even at relatively low levels
(Canfield et al. 2003), results in a decline of
cognitive function that persists into adult-
hood and that manifests as a persistent lower-
ing of IQ score plus alteration in behavior
(Needleman et al. 1990). Each increase of
10 µg/dL in the lifetime average blood lead
concentration was found to be associated with
a 4.6-point decrease in IQ (Schwartz et al.
2000). There appears to be no minimum
threshold level below which lead does not
cause brain injury (Canfield et al. 2003). In
addition, elevated lead levels in childhood have
been associated with lower class standing in
high school, lower vocabulary and grammatical-
reasoning scores, poorer hand–eye coordina-
tion, and self-reports of minor delinquent
activity (Needleman et al. 1990).
Occupational exposure to lead among
adults is associated with poorer neurobehav-
ioral test scores and with deficits in manual
dexterity, executive ability, verbal intelligence,
and verbal memory (Schwartz et al. 2000).
Recent data suggest that cognitive function can
decline progressively in older lead workers in
relation to cumulative past occupational expo-
sure to lead (Stewart et al. 1999). Susceptibility
to the persistent effect of lead on the central
nervous system may be enhanced in persons
who have at least one apolipoprotein E-4 allele
(Stewart et al. 2002).
The conferees agreed on recommendations
for future research into the environmental eti-
ology of chronic neurodegenerative disease.
Conduct long-term prospective epidemio-
logic and genetic studies of the impact of
environmental factors on the development of
neurodegeneration. Most previous research on
the causation of the neurodegenerative dis-
orders has been either cross-sectional or retro-
spective in design and thus has been extremely
limited in its ability to discern environmental
etiologic factors that may have been encoun-
tered in early life. Most previous studies have
had to reconstruct past exposures from imper-
fect memory, from incomplete records, or from
biologic markers of uncertain half-life. The
conferees offered the suggestion that a large
prospective cohort study would provide a most
powerful tool to explore possible early environ-
mental causes of neurodegenerative disease. If
such a study were to include genetic analyses, it
would provide a unique means for exploring
the gene–environment interactions that likely
are involved in the genesis of PD and AD.
Ideally such a study should enroll subjects at or
even before conception and follow them
through old age and should incorporate numer-
ous biologic makers of exposure as well as
detailed evaluations of behavioral and lifestyle
factors, including information on occupational
exposures and pesticide use. Such a prospective
design would permit the real-time assessment of
exposures as they occur and avoid the need for
retrospective re-creation of past exposures.
These features are now incorporated into the
proposed National Children’s Study.
Four factors that make this a propitious
time to launch a massive prospective epidemi-
ologic study of the impact of the environment
on health and development, such as the
National Children’s Study, are a) the develop-
ment of better skills in conducting and analyz-
ing data from large prospective studies; b) the
refinement of highly sensitive, extremely accu-
rate chemical analyses that permit detection
and quantification of xenobiotics in body flu-
ids even at very low levels; c) advances in
information technology; and d) capacity for
rapid, relatively inexpensive genetic analysis
(Berkowitz et al. 2001).
Establish registries for Parkinson and
Alzheimer patients. Current data sources that
rely principally on mortality statistics likely
undercount the number of persons with
neurodegenerative diseases. It is important to
foster collaborations among agencies and to
create new links across databases in different
regions of the country to better track incidence
rates of these disorders.
Pursue suspected links between environ-
mental exposures and neurobehavioral disor-
ders in unique, high-risk populations. Targeted
studies of persons with unique patterns of dis-
ease such as the residents of Guam (Kurland
and Mulder 1954) or persons with unusual
environmental exposures such as those exposed
to MPTP (Langston et al. 1999) demonstrate
the value of undertaking clinical and epidemio-
logic pursuit of disease clusters.
Improve toxicity test methods to better
assess chronic neurodegeneration (Slotkin
2004). Too few chemicals are tested for
chronic neurotoxicity, and those that are
examined are typically studied under test pro-
tocols in which the chemicals are administered
during adolescence and the animals sacrificed
and studied 12–24 months later. Functional
Landrigan et al.
VOLUME 113 | NUMBER 9 | September 2005 • Environmental Health Perspectives
Early environmental origins of neurodegenerative disease
Environmental Health Perspectives • VOLUME 113 | NUMBER 9 | September 2005
assessment of neurologic function is often not
included. This approach misses the opportu-
nity to study possible late effects of early expo-
sures. To overcome these limitations in design,
conferees recommended that the duration of
toxicity testing protocols should be extended
to incorporate administration of chemicals in
early life ideally in utero or even before con-
ception, coupled with lifelong follow-up. Such
expanded protocols may also incorporate
functional neurobehavioral test batteries as
well as neuropathologic examinations of rele-
vant areas of the brain (Landrigan et al. 2003).
Alzheimer’s Association. 2003. About Alzheimer’s Disease.
[accessed 12 July 2003].
Baldi I, Lebailly P, Mohammed-Brahim B, Letenneur L, Dartigues
JF, Brochard P. 2003. Neurodegenerative diseases and
exposure to pesticides in the elderly. Am J Epidemiol
Barker D, Osmond C, Simmonds S, Wield G. 1993. The relation of
small head circumference and thinness at birth to death from
cardiovascular disease in later life. BMJ 306:422–426.
Ben-Shlomo Y. 1997. The epidemiology of Parkinson’s disease.
Baillieres Clin Neurol 6:55–68.
Berkowitz GS, Wolff MS, Matte T, Susser E, Landrigan PJ. 2001.
The rationale for a national prospective cohort study of envi-
ronmental exposure and childhood development. Environ
Res 85:59–68. Available: http://nationalchildrensstudy.gov
[accessed 14 July 2003].
Brookmeyer R, Gray S, Kawas C. 1998. Projections of Alzheimer’s
disease in the United States and the public health impact of
delaying disease onset. Am J Pub Health 88:1337–1342.
Brooks AI, Chadwick CA, Gelbard HA, Cory-Slechta DA, Federoff
HJ. 1999. Paraquat elicited neurobehavioral syndrome
caused by dopaminergic neuron loss. Brain Res 823:1–10.
Canfield RL, Henderson CR Jr, Cory-Slechta DA, Cox C, Jusko TA,
Lanphear BP. 2003. Intellectual impairment in children with
blood lead concentrations below 10 microg per deciliter.
NEngl J Med 348:1517–1526.
CDC. 2003a. Deaths: Preliminary Data for 2001. National Vital
Statistics Reports, Vol 51, No 5. Rockville, MD:Centers for
Disease Control and Prevention, National Center for Health
CDC. 2003b. Second National Report on Exposure to
Environmental Chemicals. Atlanta, GA:Centers for Disease
Control and Prevention.
Dawson TM, Dawson VL. 2003. Molecular pathways of neurogen-
eration in Parkinson’s Disease. Science 302:819–922.
De la Fuente-Fernandez R, Calne D. 2002. Evidence for environ-
mental causation of Parkinson’s disease. Parkinsonism Relat
Fleming L, Mann JB, Bean J, Briggle T, Sanchez-Ramos JR. 1994.
Parkinson’s disease and brain levels of organochlorine pes-
ticides. Ann Neurol 36:100–103.
Foster H. 2002. Why the preeminent risk factor in sporadic
Alzheimer’s disease cannot be genetic. Med Hypoth 59: 57–61.
Gao HM, Hong JS, Zhang W, Liu B. 2003. Synergistic dopaminer-
gic neurotoxicity of the pesticide rotenone and inflammogen
lipopolysaccharide: relevance to the etiology of Parkinson’s
disease. J Neurosci 23:1228–1236.
Gao HM, Jiang J, Wilson B, Zhang W, Hong JS, Liu B. 2002.
Microglial activation-mediated delayed and progressive
degeneration of rat nigral dopaminergic neurons: relevance
to Parkinson’s disease. J Neurochem 81:1285–1297.
Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K,
et al. 1997. Cognitive deficit in 7-year old children with
pre-natal exposure to methylmercury. Neurotoxicol Teratol
Hernan MA, Takkouche B, Caamano-Isorna F, Gestal-Otero JJ.
2002. A meta-analysis of coffee drinking, cigarette smoking,
and the risk of Parkinson’s disease. Ann Neurol 52:276–284.
Hinchliffe S, Lynch M, Sargent P, Howard C, Van Velzen D. 1992.
The effect of intrauterine growth retardation on the develop-
ment of renal nephrons. Br J Obstet Gynaecol 99:296–301.
Jacobson JL, Jacobson SW, Humphrey HE. 1990. Effects of
in utero exposure to polychlorinated biphenyls and related
contaminants on cognitive functioning in young children.
John C. Robbins Associates. 1997. Study prepared for the
Parkinson’s Disease Foundation, New York City, cited in
press release dated 20 April 1998. New York:John C. Robbins
Kennedy JL, Farrer LA, Andreason NC, Mayeux R, St. George-
Hyslop P. 2003. The genetics of adult-onset neuropsychiatric
disease: complexities and conundra? Science 302:822–826.
Kohbata S, Beaman BL. 1991. L-Dopa-responsive movement dis-
order caused by Nocardia asteroides localized in the brains
of mice. Infect Immunol 59:181–191.
Kurland LT, Mulder DW. 1954. Epidemiologic investigations of
amyotrophic lateral sclerosis. 1: Preliminary report on geo-
graphic distribution, with special reference to the Mariana
Islands, including clinical and pathological observations.
Neurology 4:355–378, 438–448.
Landrigan PJ, Kimmel CA, Correa A, Eskenazi B. 2003. Children’s
health and the environment: public health issues and chal-
lenges for risk assessment. Environ Health Perspect 112:
Langston W, Forno LS, Tetrud J, Reeves AG, Kaplan JA, Karluk D.
1999. Evidence of active nerve cell degeneration in the sub-
stantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine exposure. J Ann Neurol 46:598–605.
Law C, De Swiet M, Osmond C, Fayers P, Barker D, Cruddas A,
et al. 1993. Initiation of hypertension in utero and its amplifi-
cation throughout life. BMJ 306:24–27.
Lewin Group. 2001. Medicare and Medicaid Costs for People with
Alzheimer’s Disease. Alzheimer’s Association. Available:
[accessed 7 January 2004].
Lilienfeld DE, Sekkor D, Simpson S, Perl DP, Ehland J, Marsh G,
et al. 1990. Parkinsonism death rates by race, sex and geo-
graphy: a 1980s update. Neuroepidemiology 9:243–247.
Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, et al.
1997. Environmental risk factors and Parkinson’s disease: a
case-control study in Taiwan. Neurology 48:1583–1588.
Liu B, Du L, Hong JS. 2000. Naloxone protects rat dopaminergic
neurons against inflammatory damage through inhibition of
microglia activation and superoxide generation. J Pharmacol
Exp Ther 293:607–617.
Liu B, Gao H, Hong J. 2003. Parkinson’s disease and exposure to
infectious agents and pesticides and the occurrence of brain
injuries: role of neuroinflammation. Environ Health Perspect
Liu B, Hong JS. 2003. Role of microglia in inflammation-mediated
neurodegenerative diseases: mechanisms and strategies for
therapeutic intervention. J Pharmacol Exp Ther 304:1–7
Lumbers ER, Yu ZY, Gibson KJ. 2001. The selfish brain and the
Barker hypothesis. Clin Exp Pharmacol Physiol 28(11):
McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C,
Langston JW, Cory-Slechta DA, et al. 2002. Environmental
risk factors and Parkinson’s disease: selective degeneration
of nigral dopaminergic neurons caused by the herbicide
paraquat. Neurobiol Dis 10:119–127.
Mergler D, Baldwin M. 1997. Early manifestations of manganese
neurotoxicity in humans: an update. Environ Res 73:92–100.
National Institute of Neurological Disorders and Stroke. 2004.
Parkinson’s Disease Backgrounder. Bethesda, MD:National
Institute of Neurological Disorders and Stroke. Available:
Needleman HL, Landrigan PJ. 1996. Toxins at the pump. New
York Times, Op-Ed. 13 March: 15.
Needleman HL, Schell A, Bellinger D, Leviton A, Allred EN. 1990.
The long-term effects of exposure to low doses of lead in
childhood. An 11-year follow-up report. N Engl J Med 322:
NIA. 2000. Progress Report on Alzheimer’s Disease. Bethesda,
MD:National Institute on Aging. Available: http://www.
alzheimers.org/pubs/prog00.htm [accessed 6January2004].
Orr CF, Rowe DB, Halliday GM. 2002. An inflammatory review of
Parkinson’s disease. Prog Neurobiol 68:325–340.
Osmond C, Barker D. 2000. Fetal, infant, and childhood growth are
predictors of coronary heart disease, diabetes, and hyper-
tension in adult men and women. Environ Health Perspect
Osmond C, Barker D, Winter P, Fall C, Simmonds S. 1993. Early
growth and death from cardiovascular disease in women.
Parkinson’s Disease Foundation. 2004. Symptoms. Available:
Plato C, Garruto R, Galasko D, Craig U, Plato M, Gamst A, et al.
2003. Amyotrophic lateral sclerosis and Parkinsonism-
dementia complex of Guam: changing incidence rates dur-
ing the past 60 years. Am J Epidemiol 157:149–157.
Priyadarshi A, Khuder SA, Schaub EA, Priyadarshi SS. 2001.
Environmental risk factors and Parkinson’s disease: a meta-
analysis. Environ Res 86:122–127.
Schwartz BS, Stewart WF, Bolla KI, Simon PD, Bandeen-Roche
K, Gordon PB, et al. 2000. Past adult lead exposure is associ-
ated with longitudinal decline in cognitive function.
Seawright A, Ng J, Kurland L, Osborne R, de Matteis F. 1995. The
occurrence and possible health significance of toxins in
cycad pollen. In: Proceedings of the Third International
Conference on Cycad Biology (Vorster P, ed). Pretoria, South
Africa:University of Pretoria, 97–107.
Sherer TB, Kim J-H, Betarbet R, Greenamyre JT. 2003.
Subcutaneous rotenone exposure causes highly selective
dopaminergic degeneration and α-synuclein aggregation.
Exp Neurol 179:9–16.
Siderowf A, Stern M. 2003. Update on Parkinson Disease. Ann
Intern Med 138:651–658.
Slotkin TA. 2004. Guidelines for developmental neurotoxicity and
their impact on organophosphate pesticides: a personal view
from an academic perspective. Neurotoxicology 25:631–640.
Spencer PS. 2003. Food toxins, AMPA receptors, and motor neu-
ron diseases. Drug Metab Rev 31:561–587.
Stewart WF, Schwartz BS, Simon D, Bolla KI, Todd AC, Links J.
1999. Neurobehavioral function and tibial and chelatable
lead levels in 543 former organolead workers. Neurology
Stewart WF, Schwartz BS, Simon D, Kelsey K, Todd AC. 2002.
ApoE genotype, past adult lead exposure, and neurobehav-
ioral function. Environ Health Perspect 110:501–505.
Tanner CM, Ottman R, Goldman SM, Ellenberg J, Chan P,
Mayeux R, et al. 1999. Parkinson disease in twins: an etio-
logic study. JAMA 281:341–346.
Thiruchelvam M, Brockel BJ, Richfield EK, Baggs RB, Cory-
Slechta DA. 2000a. Potentiated and preferential effects of
combined paraquat and maneb on nigrostriatal dopamine
systems: environmental risk factors for Parkinson’s disease?
Brain Res 873:225–234.
Thiruchelvam M, Richfield EK, Baggs RB, Tank AW, Cory-Slechta
DA. 2000b. The nigrostriatal dopaminergic system as a pref-
erential target of repeated exposures to combined paraquat
and maneb: implications for Parkinson’s disease. J Neurosci
Twelves D, Perkins K, Counsell C. 2003. Systematic review of inci-
dence studies of Parkinson’s disease. Mov Disord 18:19–31.
Wilson R, Schneider J, Bienias J, Evans D, Bennett D. 2003.
Parkinsonian like signs and risk of incident Alzheimer dis-
ease in older persons. Arch Neurol 60:539–544.