Environmental Factors and Parkinson’s Disease

Alan H. Lockwood, M.D.Alan H. Lockwood, M.D.

Professor of Neurology and Nuclear Medicine, Professor of Neurology and Nuclear Medicine, University at Buffalo, University at Buffalo,

VA Western NY Healthcare System, VA Western NY Healthcare System, Buffalo, NYBuffalo, NY

Past President and Chairman, Past President and Chairman, Environment and Health CommitteeEnvironment and Health CommitteePhysicians for Social ResponsibilityPhysicians for Social Responsibility

James Parkinson1755-1824

1817 original description of 1817 original description of the disease that now the disease that now bears his name.bears his name. TremorTremor RigidityRigidity BradykinesiaBradykinesia Loss of postural reflexesLoss of postural reflexes

Parkinson’s Disease PD is one of many akinetic-rigid PD is one of many akinetic-rigid

syndromes: differential dx difficultsyndromes: differential dx difficult Second most common neurodegenerative Second most common neurodegenerative

disease (trails Alzheimer’s Disease).disease (trails Alzheimer’s Disease). Usually begins after age 50.Usually begins after age 50. Incidence increases exponentially after age Incidence increases exponentially after age

50: by age 70, 1.5 - 2.5% are affected.50: by age 70, 1.5 - 2.5% are affected. As population ages, total number affected As population ages, total number affected

is certain to increase.is certain to increase. Cost is about $20 billion per year.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 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 AgencyU.S. Environmental Protection Agency

Pesticide UseAccording to EPA, 4.63 billion pounds of According to EPA, 4.63 billion pounds of

pesticides are used in the U.S.in 1997.pesticides are used in the U.S.in 1997. Organophosphates – 77 million poundsOrganophosphates – 77 million pounds

60 million lbs. used by agriculture60 million lbs. used by agriculture

17 million lbs. non-agricultural use17 million lbs. non-agricultural use

Foundation for Advancements in Science Foundation for Advancements in Science and Education: and Education:

U.S. exported 338 million lbs pesticides U.S. exported 338 million lbs pesticides 1995-6, 21 million pounds of these are 1995-6, 21 million pounds of these are banned for use in the U.S.banned for use in the U.S.

Paraquat, Pesticides, and Parkinsonism: Barbeau’s data Paraquat depletes dopamine from Paraquat depletes dopamine from

brains of frogs.brains of frogs.Barbeau et al., Life Sci. 1985:16:1529.Barbeau et al., Life Sci. 1985:16:1529.

Parkinsonism varies among Parkinsonism varies among hydrographic regions of Quebec, with hydrographic regions of Quebec, with highest prevalence in rural areas of high highest prevalence in rural areas of high pesticide use. Three methods used to pesticide use. Three methods used to define Parkinsonism.define Parkinsonism.

Barbeau et al., Adv. Neurol. 1986;45:299.Barbeau et al., Adv. Neurol. 1986;45:299.

Parkinsonism in Quebec

Barbeau et al., Adv. Neurol. 1986;45:299.Barbeau et al., Adv. Neurol. 1986;45:299.

Parkinsonism and Rural LifePeople’s Republic of ChinaPeople’s Republic of China

Industrial exposure (chemicals, printing Industrial exposure (chemicals, printing plants, quarries) had higher risk of PD plants, quarries) had higher risk of PD relative risk range: 2.39 - 4.5relative risk range: 2.39 - 4.5

Village life in pre-chemical era (raising Village life in pre-chemical era (raising pigs, growing wheat) relative risk .17 - .57 pigs, growing wheat) relative risk .17 - .57

Tanner et al., Neurology 1989;39:660-664Tanner et al., Neurology 1989;39:660-664..

Parkinsonism among BlacksParkinsonism among Blacks 341/100,000 in Copiah County MS341/100,000 in Copiah County MS 67/100,000 in Igbo-Ora, Nigeria67/100,000 in Igbo-Ora, Nigeria

Schoenberg et al. Neurology 1988;38:645-646..

Pesticides and Parkinsonism Case control study of 120 Taiwanese with Case control study of 120 Taiwanese with

PD and 240 controls: risk for developing PD PD and 240 controls: risk for developing PD = 2.04 for rural life, 1.81 for farming, 3.22 for = 2.04 for rural life, 1.81 for farming, 3.22 for use of paraquat, 2.89 for other herbicide-use of paraquat, 2.89 for other herbicide-pesticide use.pesticide use.

Liou et al., Neurology 1997;48:1583-1588.Liou et al., Neurology 1997;48:1583-1588.

Israeli study, incidence of PD increased 5-Israeli study, incidence of PD increased 5-fold in 3 adjacent kibbutzim with common fold in 3 adjacent kibbutzim with common water supply.water supply.

Goldsmith et al., Arch Environmental Health 1990;45:88-94Goldsmith et al., Arch Environmental Health 1990;45:88-94..

Pesticides and Parkinsonism

Case-control study, Alberta, 130 Case-control study, Alberta, 130 patients with neurologist-confirmed PD, patients with neurologist-confirmed PD, 260 age-sex matched controls – prior 260 age-sex matched controls – prior occupational herbicide use only occupational herbicide use only consistent predictor of PD.consistent predictor of PD.

Semchuck et al., Neurology 1992;42:1328-1335.Semchuck et al., Neurology 1992;42:1328-1335...

In Kansas, among rural and urban In Kansas, among rural and urban residents, significant predictors of PD residents, significant predictors of PD were: pesticide use, family Hx were: pesticide use, family Hx neurological disease, and depression.neurological disease, and depression.

Hubble et al., Neuroepidemiology 1998;17:96-104.Hubble et al., Neuroepidemiology 1998;17:96-104.

Parkinsonism after Organophosphate Exposure

5 patients developed reversible 5 patients developed reversible parkinsonism after exposure to parkinsonism after exposure to organophosphates.organophosphates.

Three patients all from the same family.Three patients all from the same family. Did not have classical form of the Did not have classical form of the

disease in that antiparkinsonian drugs disease in that antiparkinsonian drugs were ineffective.were ineffective.

Bhatt et al., Neurology 1999;52:1467-1471.Bhatt et al., Neurology 1999;52:1467-1471.

Parkinson Disease in Twins

An Etiologic StudyTanner, et al. JAMA, 1999;281:341-346Tanner, et al. JAMA, 1999;281:341-346

Design:Design: Twin study comparing concordance Twin study comparing concordance rates of PD in MZ and DZ twin pairs. rates of PD in MZ and DZ twin pairs.

Results:Results: In 71 MZ and 90 DZ pairs with In 71 MZ and 90 DZ pairs with complete diagnoses, pairwise concordance complete diagnoses, pairwise concordance was similar (0.129 overall, 0.155 MZ, 0.111 was similar (0.129 overall, 0.155 MZ, 0.111 DZ; relative risk, 1.39; 95% confidence DZ; relative risk, 1.39; 95% confidence interval, 0.63-3.1). interval, 0.63-3.1).

Tanner, et al., continued

Results, cont:Results, cont: In 16 pairs with diagnosis at or before In 16 pairs with diagnosis at or before age 50 years in at least 1 twin, MZ concordance age 50 years in at least 1 twin, MZ concordance was 1.0 (4 pairs), and DZ was 0.167 (relative risk, was 1.0 (4 pairs), and DZ was 0.167 (relative risk, 6.0; 95% confidence interval, 1.69-21.26).6.0; 95% confidence interval, 1.69-21.26).

Conclusions:Conclusions: The similarity in overall concordance The similarity in overall concordance suggests strongly that suggests strongly that genetic factors do not play genetic factors do not play a major role in causing typical PDa major role in causing typical PD. No genetic . No genetic component is evident when the disease begins component is evident when the disease begins after age 50 years.after age 50 years.

Editorial:Editorial: Understanding Parkinson’s Disease Understanding Parkinson’s DiseaseCummings JAMA 1999;281:376-378.Cummings JAMA 1999;281:376-378.

Animal Models

Rotenone: Rotenone: naturally occurring compound: insecticide naturally occurring compound: insecticide

and piscicide, inhibitor of complex I, and piscicide, inhibitor of complex I, crosses cell membranes easily, does not crosses cell membranes easily, does not depend on dopamine transporter (unlike depend on dopamine transporter (unlike MPTP).MPTP).

Paraquat:Paraquat: free-radical generator, oxidative stressorfree-radical generator, oxidative stressor

Maneb:Maneb: fungicide, inhibits glutamate transport, fungicide, inhibits glutamate transport,

disrupts dopamine uptake and releasedisrupts dopamine uptake and release

Rotenone Effects

C: cytoplasmic inclusions in C: cytoplasmic inclusions in S. nigra contain ubiquitin S. nigra contain ubiquitin immunoreactivity.immunoreactivity.

F: EM shows dense core with F: EM shows dense core with fibrillar elements – core fibrillar elements – core contains contains -synuclein -synuclein immunoreactivity.immunoreactivity.

Betarbet, et al., Nature Neuroscience 2000;3:1301Betarbet, 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

ToleranceTolerance = permissible residue level in food = permissible residue level in food Tolerance = NOAEL ÷ Uncertainty FactorsTolerance = NOAEL ÷ Uncertainty Factors Interspecies extrapolationInterspecies extrapolation = 10x= 10x Intraspecies variation Intraspecies variation = 10x= 10x FQPA children’s safety factor = 1-10xFQPA children’s safety factor = 1-10xTotal UF appliedTotal UF applied general populationgeneral population 100100 childrenchildren 100-1000100-1000 women of childbearing agewomen of childbearing age 100-1000100-1000

Organophosphate Exposure in U.S. infants, 1-2 years old

Source: U.S. EPA, Revised OP Cumulative Risk Assessment, 2002

MOE = PODindex compound ÷ Exposures summed for all routes

Manipulation of MOE Reduce Apparent Risk – No Change in Exposure

Manipulate FQPA safety factorManipulate FQPA safety factor FQPA allows EPA to set safety factor for FQPA allows EPA to set safety factor for

children and fetuses between 1-10children and fetuses between 1-10 R-OPCRA sets factor at 1 - 3R-OPCRA sets factor at 1 - 3

Manipulate interspecies safety factor Manipulate interspecies safety factor currently set at 10currently set at 10 pesticide industry conducting human pesticide industry conducting human

experiments to eliminate this factorexperiments to eliminate this factor

Chlorpyrifos Metabolites in Urine

3,5,6-Trichloro-2-pyridinolPositive test for everyone at or above 25Positive test for everyone at or above 25 thth percentile percentile

Geometric mean at At 95Geometric mean at At 95tthtth % ( % (g/g creatinine, 95% CI)g/g creatinine, 95% CI)

Total, age 6 - 59Total, age 6 - 59 8.42 (6.27 – 11.6)8.42 (6.27 – 11.6)6 – 11 years6 – 11 years 14.0 (8.74 – 21.7)14.0 (8.74 – 21.7)20 – 59 years20 – 59 years 6.42 (4.98 – 10.7)6.42 (4.98 – 10.7)Mexican-AmericanMexican-American 5.79 ( 4.35 – 9.04)5.79 ( 4.35 – 9.04)Non-Hisp. BlackNon-Hisp. Black 8.93 (5.91 – 13.7)8.93 (5.91 – 13.7)Non-Hisp. WhiteNon-Hisp. White 8.44 (6.14 – 12.5)8.44 (6.14 – 12.5)

Source: CDC Exposure Report, January, 2003Source: CDC Exposure Report, January, 2003

2,4-D Metabolites in Urine2,4-Dichlorophenol

Positive test for all at or above 50Positive test for all at or above 50 thth percentile percentileGeometric mean at At 95Geometric mean at At 95tthtth % ( % (g/g creatinine, 95% CI)g/g creatinine, 95% CI)

Total, age 6 - 59Total, age 6 - 59 13.9 (10.3 – 23.0)13.9 (10.3 – 23.0)6 – 11 years6 – 11 years 25.3 (12.5 – 76.9)25.3 (12.5 – 76.9)20 – 59 years20 – 59 years 11.6 (8.70 – 21.8)11.6 (8.70 – 21.8)Mexican-AmericanMexican-American 48.7 (26.7 – 65.9)48.7 (26.7 – 65.9)Non-Hisp. BlackNon-Hisp. Black 28.9 (8.47 – 161)28.9 (8.47 – 161)Non-Hisp. WhiteNon-Hisp. White 10.7 (6.43 – 19.2)10.7 (6.43 – 19.2)

Source: CDC Exposure Report, January, 2003Source: CDC Exposure Report, January, 2003

DDT Metabolites in Bloodp,p’-DDE, banned since 1973

Positive test for everyone at or above 10Positive test for everyone at or above 10thth percentile percentileGeometric mean at At 95Geometric mean at At 95tthtth % (ng/g lipid, 95% CI) % (ng/g lipid, 95% CI)

Total, age 12 and olderTotal, age 12 and older1780 (1520 – 2230)1780 (1520 – 2230)12 - 19 years12 - 19 years** 528 (364 – 644)528 (364 – 644)20 and older20 and older 1990 (1570 – 2510)1990 (1570 – 2510)Mexican-AmericanMexican-American 4940 (3280 – 7810)4940 (3280 – 7810)Non-Hisp. BlackNon-Hisp. Black 2160 (1470 – 4010)2160 (1470 – 4010)Non-Hisp. WhiteNon-Hisp. White 1220 ( 1040 – 1410)1220 ( 1040 – 1410)** Note: subjects were born Note: subjects were born afterafter 1973 EPA ban 1973 EPA ban

Source: CDC Exposure Report, January, 2003Source: CDC Exposure Report, January, 2003

Costs and Benefits of Environmental Regulations – in millions of dollars

AgencyAgency CostCost BenefitBenefit

EPAEPA 23.4-26.623.4-26.6 120.8 - 193.2120.8 - 193.2

HHSHHS 3.2 - 3.33.2 - 3.3 9.1 - 11.79.1 - 11.7

TransportationTransportation 4.2 - 6.74.2 - 6.7 6.1 - 9.56.1 - 9.5

AgricultureAgriculture 1.6 - 1.71.6 - 1.7 3.1 - 6.23.1 - 6.2

EnergyEnergy 2.52.5 4.7 - 4.84.7 - 4.8

Source: White House Office of Management and Budget, 2003

To Minimize Pesticide Exposure Don’t use “Pest Strips” or crack and Don’t use “Pest Strips” or crack and

crevice fillers containing DDVPcrevice fillers containing DDVP Consume certified organic productsConsume certified organic products Treat drinking water with activated Treat drinking water with activated

charcoal filter charcoal filter Adopt integrated pest management Adopt integrated pest management

policies in your homepolicies in your home Close windows and stay off lawns when Close windows and stay off lawns when

others sprayothers spray

If you use pesticides Practice and support Integrated Pest Practice and support Integrated Pest

Management (IPM) strategiesManagement (IPM) strategies Home, schools, workplace (hospitals too!)Home, schools, workplace (hospitals too!)

Follow instructions on labelFollow instructions on label Wear protective clothing and filter air when Wear protective clothing and filter air when

applying, close windows to reduce driftapplying, close windows to reduce drift Keep pesticides away from kidsKeep pesticides away from kids

Store pesticides in safe placeStore pesticides in safe place Keep kids and pets off of lawns, etc. after useKeep kids and pets off of lawns, etc. after use Support neighbor notification lawsSupport neighbor notification laws

Support the Precautionary Principle

Asserts, briefly, that scientific proof of a Asserts, briefly, that scientific proof of a causal link between human activity and its causal link between human activity and its effects is not required before taking effects is not required before taking preventive action. preventive action.

This principle is gaining strength in This principle is gaining strength in international law and practice.international law and practice.

Familiar to physicans as: Familiar to physicans as: “First do no harm.”“First do no harm.”

For More Information

http:// www.psr.orghttp:// www.psr.org Follow links to Environment, Emerging Follow links to Environment, Emerging

LinksLinks http://www.epa.govhttp://www.epa.gov

Follow links to pesticidesFollow links to pesticides http://www.envirohealthaction.orghttp://www.envirohealthaction.org

On-line environmental action center, On-line environmental action center, contact governmental officialscontact governmental officials