Environmental Factors and Parkinson’s Disease

1. 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

2. James Parkinson1755-1824 1817 original description of the disease that now bears his name. • Tremor • Rigidity • Bradykinesia • Loss of postural reflexes

3. 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.

4. 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.

5. 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.

6. Pesticides: “substances used to prevent, destroy, repel or mitigate any pest ranging from insects, animals and weeds to microorganisms ...” U.S. Environmental Protection Agency

7. Pesticide Use According to EPA, 4.63 billion pounds of pesticides are used in the U.S.in 1997. Organophosphates – 77 million pounds 60 million lbs. used by agriculture 17 million lbs. non-agricultural use 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.

8. 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.

9. Parkinsonism in Quebec Barbeau et al., Adv. Neurol. 1986;45:299.

10. 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.

11. 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 herbicide-pesticide use. Liou et al., Neurology 1997;48:1583-1588. • Israeli study, incidence of PD increased 5-fold in 3 adjacent kibbutzim with common water supply. Goldsmith et al., Arch Environmental Health 1990;45:88-94.

12. 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.

13. 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.

14. Parkinson Disease in TwinsAn 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).

15. 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.

16. 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

17. 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

18. Synergistic Effects of Maneb and Paraquat Source: Thiruchelvam, et al., J. Neurosci. 2000;20(24:9207-14

19. Maneb and Paraquat Exposure During Development Thiruchelvam et al., NeuroToxicology 2002;23:621-633

20. Linking PD and Pesticides Glasson and Lee, News, Nature Neuroscience 2000;3:1227

21. 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

22. 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

23. Manipulation of MOE ReduceApparentRisk– 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

24. Chlorpyrifos Metabolites in Urine3,5,6-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 8.42 (6.27 – 11.6) 6 – 11 years 14.0 (8.74 – 21.7) 20 – 59 years 6.42 (4.98 – 10.7) Mexican-American 5.79 ( 4.35 – 9.04) Non-Hisp. Black 8.93 (5.91 – 13.7) Non-Hisp. White 8.44 (6.14 – 12.5) Source: CDC Exposure Report, January, 2003

25. 2,4-D Metabolites in Urine2,4-Dichlorophenol Positive test for all at or above 50th percentile Geometric mean at At 95tth % (mg/g creatinine, 95% CI) Total, age 6 - 59 13.9 (10.3 – 23.0) 6 – 11 years 25.3 (12.5 – 76.9) 20 – 59 years 11.6 (8.70 – 21.8) Mexican-American 48.7 (26.7 – 65.9) Non-Hisp. Black 28.9 (8.47 – 161) Non-Hisp. White 10.7 (6.43 – 19.2) Source: CDC Exposure Report, January, 2003

26. DDT Metabolites in Bloodp,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

27. Costs and Benefits of Environmental Regulations – in millions of dollars Source: White House Office of Management and Budget, 2003

28. 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

29. 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

30. 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.”

31. 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