Environmental Factors and
Parkinson’s Disease
Alan H. Lockwood, M.D.
Professor of Neurology and Nuclear Medicine,
University at Buffalo,
VA Western NY Healthcare System,
Buffalo, NY
Past President and Chairman,
Environment and Health Committee
Physicians for Social Responsibility
James
Parkinson
1755-1824
1817 original description of
the disease that now
bears his name.
 Tremor
 Rigidity
 Bradykinesia
 Loss
of postural reflexes
Parkinson’s Disease
PD is one of many akinetic-rigid
syndromes: differential dx difficult
 Second most common neurodegenerative
disease (trails Alzheimer’s Disease).
 Usually begins after age 50.
 Incidence increases exponentially after age
50: by age 70, 1.5 - 2.5% are affected.
 As population ages, total number affected
is certain to increase.
 Cost is about $20 billion per year.

Clues to Etiology of Parkinsonism
Etiology is unknown.
 After 1916-27 influenza pandemic, many
affected - most within 5 years, 85% within
10 years of acute illness.
 Links to environmental factors:

 After
use of designer drugs.
 Many epidemiological studies.

Twin study rules out major genetic factors.
MPTP and Parkinsonism

MPTP

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Byproduct of sloppy chemistry in designer
drug labs attempting to make meperidine
analog.
 Selective toxin kills dopaminergic neurons.
 Exposed individuals develop syndrome
virtually identical to idiopathic PD.
Langston et al., Science 1983;219:979-980.
Ballard et al., Neurology 1985;35:949-956.
Pesticides: “substances
used to prevent, destroy,
repel or mitigate any pest
ranging from insects,
animals and weeds to
microorganisms ...”
U.S. Environmental Protection Agency
Pesticide Use
According to EPA, 4.63 billion pounds of
pesticides are used in the U.S.in 1997.
– 77 million pounds
60 million lbs. used by agriculture
17 million lbs. non-agricultural use
 Organophosphates
Foundation for Advancements in Science
and Education:
 U.S.
exported 338 million lbs pesticides
1995-6, 21 million pounds of these are
banned for use in the U.S.
Paraquat, Pesticides, and
Parkinsonism: Barbeau’s data

Paraquat depletes dopamine from
brains of frogs.
Barbeau et al., Life Sci. 1985:16:1529.

Parkinsonism varies among
hydrographic regions of Quebec, with
highest prevalence in rural areas of high
pesticide use. Three methods used to
define Parkinsonism.
Barbeau et al., Adv. Neurol. 1986;45:299.
Parkinsonism in Quebec
Barbeau et al., Adv. Neurol. 1986;45:299.
Parkinsonism and Rural Life
People’s Republic of China
 Industrial
exposure (chemicals, printing
plants, quarries) had higher risk of PD
relative risk range: 2.39 - 4.5
 Village life in pre-chemical era (raising
pigs, growing wheat) relative risk .17 - .57
Tanner et al., Neurology 1989;39:660-664.
Parkinsonism among Blacks
 341/100,000
in Copiah County MS
 67/100,000 in Igbo-Ora, Nigeria
Schoenberg et al. Neurology 1988;38:645-646.
Pesticides and Parkinsonism

Case control study of 120 Taiwanese with
PD and 240 controls: risk for developing PD
= 2.04 for rural life, 1.81 for farming, 3.22 for
use of paraquat, 2.89 for other herbicidepesticide use.
Liou et al., Neurology 1997;48:1583-1588.

Israeli study, incidence of PD increased 5fold in 3 adjacent kibbutzim with common
water supply.
Goldsmith et al., Arch Environmental Health 1990;45:88-94.
Pesticides and Parkinsonism

Case-control study, Alberta, 130
patients with neurologist-confirmed PD,
260 age-sex matched controls – prior
occupational herbicide use only
consistent predictor of PD.
Semchuck et al., Neurology 1992;42:1328-1335..

In Kansas, among rural and urban
residents, significant predictors of PD
were: pesticide use, family Hx
neurological disease, and depression.
Hubble et al., Neuroepidemiology 1998;17:96-104.
Parkinsonism after
Organophosphate Exposure
5 patients developed reversible
parkinsonism after exposure to
organophosphates.
 Three patients all from the same family.
 Did not have classical form of the
disease in that antiparkinsonian drugs
were ineffective.

Bhatt et al., Neurology 1999;52:1467-1471.
Parkinson Disease in Twins
An Etiologic Study
Tanner, et al. JAMA, 1999;281:341-346
Design: Twin study comparing concordance
rates of PD in MZ and DZ twin pairs.
Results: In 71 MZ and 90 DZ pairs with
complete diagnoses, pairwise concordance
was similar (0.129 overall, 0.155 MZ, 0.111
DZ; relative risk, 1.39; 95% confidence
interval, 0.63-3.1).
Tanner, et al., continued
Results, cont: In 16 pairs with diagnosis at or before
age 50 years in at least 1 twin, MZ concordance
was 1.0 (4 pairs), and DZ was 0.167 (relative risk,
6.0; 95% confidence interval, 1.69-21.26).
Conclusions: The similarity in overall concordance
suggests strongly that genetic factors do not play
a major role in causing typical PD. No genetic
component is evident when the disease begins
after age 50 years.
Editorial: Understanding Parkinson’s Disease
Cummings JAMA 1999;281:376-378.
Animal Models
Rotenone:
 naturally
occurring compound: insecticide
and piscicide, inhibitor of complex I,
crosses cell membranes easily, does not
depend on dopamine transporter (unlike
MPTP).
Paraquat:
 free-radical
generator, oxidative stressor
Maneb:
 fungicide,
inhibits glutamate transport,
disrupts dopamine uptake and release
Rotenone Effects
C: cytoplasmic inclusions in
S. nigra contain ubiquitin
immunoreactivity.
F: EM shows dense core with
fibrillar elements – core
contains -synuclein
immunoreactivity.
Betarbet, et al., Nature Neuroscience 2000;3:1301
Synergistic Effects of
Maneb and Paraquat
Source: Thiruchelvam, et al., J. Neurosci. 2000;20(24:9207-14
Maneb and Paraquat
Exposure During Development
Thiruchelvam et al., NeuroToxicology 2002;23:621-633
Linking PD and Pesticides
Glasson and Lee, News, Nature Neuroscience 2000;3:1227
Tolerance and Uncertainty Factors
Tolerance = permissible residue level in food
 Tolerance = NOAEL ÷ Uncertainty Factors
 Interspecies extrapolation
= 10x
 Intraspecies variation
= 10x
 FQPA children’s safety factor
= 1-10x
Total UF applied
 general population
100
 children
100-1000
 women of childbearing age
100-1000
Organophosphate Exposure in
U.S. infants, 1-2 years old
MOE = PODindex compound ÷ Exposures summed for all routes
Source: U.S. EPA, Revised OP Cumulative Risk Assessment, 2002
Manipulation of MOE
Reduce Apparent Risk – No Change in Exposure

Manipulate FQPA safety factor
 FQPA allows
EPA to set safety factor for
children and fetuses between 1-10
 R-OPCRA sets factor at 1 - 3

Manipulate interspecies safety factor
 currently
set at 10
 pesticide industry conducting human
experiments to eliminate this factor
Chlorpyrifos Metabolites in
Urine
3,5,6-Trichloro-2-pyridinol
Positive test for everyone at or above 25th percentile
Geometric mean at At 95tth % (mg/g creatinine, 95% CI)
Total, age 6 - 59
6 – 11 years
20 – 59 years
Mexican-American
Non-Hisp. Black
Non-Hisp. White
8.42 (6.27 – 11.6)
14.0 (8.74 – 21.7)
6.42 (4.98 – 10.7)
5.79 ( 4.35 – 9.04)
8.93 (5.91 – 13.7)
8.44 (6.14 – 12.5)
Source: CDC Exposure Report, January, 2003
2,4-D Metabolites in Urine
2,4-Dichlorophenol
Positive test for all at or above 50th percentile
Geometric mean at At 95tth % (mg/g creatinine, 95% CI)
Total, age 6 - 59
6 – 11 years
20 – 59 years
Mexican-American
Non-Hisp. Black
Non-Hisp. White
13.9 (10.3 – 23.0)
25.3 (12.5 – 76.9)
11.6 (8.70 – 21.8)
48.7 (26.7 – 65.9)
28.9 (8.47 – 161)
10.7 (6.43 – 19.2)
Source: CDC Exposure Report, January, 2003
DDT Metabolites in Blood
p,p’-DDE, banned since 1973
Positive test for everyone at or above 10th percentile
Geometric mean at At 95tth % (ng/g lipid, 95% CI)
Total, age 12 and older
1780 (1520 – 2230)
12 - 19 years*
528 (364 – 644)
20 and older
1990 (1570 – 2510)
Mexican-American
4940 (3280 – 7810)
Non-Hisp. Black
2160 (1470 – 4010)
Non-Hisp. White
1220 ( 1040 – 1410)
* Note: subjects were born after 1973 EPA ban
Source: CDC Exposure Report, January, 2003
Costs and Benefits of Environmental
Regulations – in millions of dollars
Agency
Cost
Benefit
EPA
23.4-26.6
120.8 - 193.2
HHS
3.2 - 3.3
9.1 - 11.7
Transportation
4.2 - 6.7
6.1 - 9.5
Agriculture
1.6 - 1.7
3.1 - 6.2
2.5
4.7 - 4.8
Energy
Source: White House Office of Management and Budget, 2003
To Minimize Pesticide Exposure
Don’t use “Pest Strips” or crack and
crevice fillers containing DDVP
 Consume certified organic products
 Treat drinking water with activated
charcoal filter
 Adopt integrated pest management
policies in your home
 Close windows and stay off lawns when
others spray

If you use pesticides

Practice and support Integrated Pest
Management (IPM) strategies
 Home,



schools, workplace (hospitals too!)
Follow instructions on label
Wear protective clothing and filter air when
applying, close windows to reduce drift
Keep pesticides away from kids
 Store
pesticides in safe place
 Keep kids and pets off of lawns, etc. after use
 Support neighbor notification laws
Support the Precautionary Principle
Asserts, briefly, that scientific proof of a
causal link between human activity and its
effects is not required before taking
preventive action.
 This principle is gaining strength in
international law and practice.
 Familiar to physicans as: “First do no harm.”

For More Information
http:// www.psr.org
 Follow links to Environment, Emerging
Links
 http://www.epa.gov

 Follow

links to pesticides
http://www.envirohealthaction.org
 On-line
environmental action center,
contact governmental officials