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Neurotoxic Effects of Solvents

Neurotoxic Effects of Solvents. William Boyes Neurotoxicology Division National Health and Environmental Effects Research Laboratory Office of Research and Development, EPA boyes.william@epa.gov. Chemical Structures. Benzene. Toluene. Tetrachloroethylene (Perchloroethylene) or “Perc”.

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Neurotoxic Effects of Solvents

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  1. Neurotoxic Effects of Solvents William Boyes Neurotoxicology Division National Health and Environmental Effects Research Laboratory Office of Research and Development, EPA boyes.william@epa.gov

  2. Chemical Structures Benzene Toluene Tetrachloroethylene (Perchloroethylene) or “Perc” Trichloroethylene (TCE)

  3. Lipophilic Organic chemical composition Distribute to body lipid-rich tissues Easily cross lipid membranes & barriers Volatility Inhalation is a significant route of exposure Delivery to tissues depends upon the blood:tissue partition coefficient Solvents

  4. CNS depression Euphoria Sensory, cognitive, motor deficits Reversible after exposure Causes accidents or injuries Good animal models Several mechanistic targets Organic brain disorder Originally observed in Scandinavian painters Sensory, cognitive, motor deficits Years of high level exposure No good animal models Mechanisms unknown Solvent Neurotoxicity Acute Chronic

  5. Widely used in industry and commerce Emission Sources Factories & chemical plants Smaller shops Mobile sources Indoor air sources Consumer products Pesticide “inerts” Drinking water Hazardous waste sites Uses include: Organic solvents Cleaning & degreasing Gasoline Paints & glues Dry cleaning Printing Paint strippers, nail polish remover Microelectronic manufacture Volatile Organic Compounds

  6. Some Current Concerns Fuels Dry Cleaners Upsets The Washington Post, Aug. 14, 2002 Public Citizen, 2005

  7. Mechanism of Action • Two hypotheses: • Membrane fluidity • Membrane proteins Antikowiak, Naturwissenschaften, 88: 201-213, 2001

  8. Voltage Current 50 nA 2 sec Female Xenopus Laevis Frog cDNA Cut with Restriction Enzymes In Vitro Transcription Oocyte Removal Surgery mRNA Linearized DNA Separated Stage VI, V Oocytes Incubate 2-7 days at 18oC OocyteInjections EUREKA Currents!!! ACh Clamp at appropriate test potential Two-Electrode VoltageClamp

  9. 1 mM TOL ACh ACh ACh a7 - human a4b2-human 1 mM TOL 1 mM TOL 100nA 2sec ACh ACh ACh ACh ACh ACh 200 nA 20sec 40nA 5sec a4b2-rat a7-rat 1 mM TOL ACh ACh ACh 50 nA 20 sec Toluene Reversibly Inhibits nAChRs Bale et al.,2005

  10. 10 -2 10 -3 10 -4 a7- human a7- rat -2 10 10 -3 -4 10 nAChR Inhibition by Toluene: Concentration-Dependentand Species-Independent 100 100 75 75 % Inhibition % Inhibition 50 50 a4b2-human 25 a4b2-rat 25 0 0 [Toluene] M [Toluene] M Modifiedfrom Bale et al., 2005

  11. Solvents & Ion Channel Function Bushnell et al., 2005

  12. Scandinavian painters and other workers Chronic exposure a variety of impairments of mood and intellectual function leading eventually to dementia Early studies confounded Poorly matched controls Poor documentation of exposure history More recent studies show Increased reaction times Poor visual function Impaired auditory thresholds Impaired motor skills Impaired performance of cognitive and memory tasks Chronic Solvent Encephalopathy?

  13. Chronic Toxic Encephalopathy in a Painter Exposed to Mixed Solvents (Feldman et al., Environmental Health Perspectives 107) 1999 • However: • Limitations in design and strength of association make it impossible to draw reliable conclusions regarding nervous system damage from organic solvents. (Ridgeway et al., 2003)

  14. Neurobehavioral Deficits in Solvent-Exposed Painters Grosch et al., Am J Indust Med, 30:623-632 (1996) Long-term chronic or acute high dose exposure can produce cognitive and behavioral changes (White and Proctor, 1997)

  15. Weight of EvidenceToluene Human Neurotoxicity

  16. CH3 COOH COOGly Toluene • Present in paints, glues, gasoline and many other products • Subject of over 40 EPA Maximum Achievable Control Technology (MACT) / residual risk assessments • The substance of choice for glue sniffers Benzoic acid Toluene Hippuric acid glycine

  17. Toluene and Momentary Brain Concentration Bushnell et al., 2007

  18. Neuropathic effects in humans Following repeated solvent abuse Very high dose levels Cerebellar damage Cerebral atrophy Multiple symptoms of dementia Confounded by hypoxia and other exposures Toluene Abuse

  19. Toluene at High Doses Causes Outer Haircell Damage in Chochlea Johnson (1993)

  20. Ethanol (Alcohol) CH3—CH2—OH • CNS depressant • Legal definition of inebriation based on BACs • Often 0.1% (100 mg/100 ml) (0.08 % in NC) • Acute exposure • Euphoria • Loss of inhibitions / poor judgment • Loss of balance & motor coordination • Impaired vision & visual/motor function • Ataxia, nausea, vomiting • Unconsciousness

  21. Ethanol Metabolism Alcohol dehydrogenase CH3—CH2—OH + NADH CH3—CHO NAD Ethanol Acetaldehyde < 10% Catalase H2O2 10-30% of metabolized ethanol NADPH Rate of metabolism is ~ 15-20 mg%/hr < 20% Microsomal ethanol oxidizing system (MEOS) = CYP2E1

  22. Ethanol Metabolism Alcohol dehydrogenase (ADH) CH3—CH2—OH + NADH CH3—CHO NAD Ethanol Acetaldehyde NAD Acetaldehyde dehydrogenase (ALDH) • ADH • males > females • ALDH isozymes • inactive variant in %50 Asians • Variant form in Native Americans • inhibited by Disulfiram + NADH CH3—COO- Acetic acid

  23. Chronic Ethanol Toxicity • Alcoholism • High % of calories from alcohol • Thiamine deficient • Wernicke's encephalopathy • Damage to multiple brain areas • Impaired cognition, motor function • Korsakoff's psychosis • Acute & Chronic • 100,000 premature deaths / year in U.S.

  24. Fetal Alcohol Syndrome (FAS) • Characterized by: • Mental retardation • Microcephaly • Irritability • Reduced birth weight • Poor muscle coordination • Cranio/Facial anomalies • Mechanism poorly understood • FAS: 0.2 to 1.5 per 1,000 live births in US (CDC) • Other FASDs approximately three times as often as FAS • Drinking and heavier drinking remain at high levels among women of child-bearing age (Caetano et al., 2006) http://www.nlm.nih.gov/medlineplus/ency/imagepages/19842.htm

  25. Methanol (Wood Alcohol) CH3—OH • Clinical signs (people) • Multiphasic syndrome • Early – like ethanol (Central nervous system depression, weakness, headache, vomiting) • Mid- asymptomatic period (12-24 hr) • Late - Severe metabolic acidosis, optic disc edema, and bilateral necrosis of the putamen • Other adverse effects of methanol in humans include minor skin and eye irritation • Formic acid is the toxic metabolite of methanol. • Accounts for the metabolic acidosis and blindness seen in people following methanol poisoning

  26. Methanol Metabolism (Primates) Alcohol dehydrogenase CH3—OH CH2O + NADH NAD Methanol Formaldehyde NAD Formaldehyde dehydrogenase Tetrahydrofolate CO2 HCOO- + NADH Low Formic acid

  27. Methanol Metabolism (Rodents) Catalase CH3—OH CH2O Methanol Formaldehyde NAD Formaldehyde dehydrogenase Tetrahydrofolate CO2 HCOO- + NADH HIGH Formic acid Folate deficiency increases the sensitivity of methanol in rodents. Intraretinal metabolism may be important.

  28. Methanol Visual Toxicity Eells et al., PNAS 2003

  29. n-Hexane and Methyl n-butyl ketone • Neurotoxicity • Sensorimotor polyneuropathy • Sensory numbness and paresthesia • Distal nerves affected first • Clinical signs often delayed for 6-12+ months • Axonal swelling and secondary demyelination • 2,5-hexanedione is common toxic metabolite

  30. Spencer & Schaumburg, 2000

  31. Peripheral Neuropathy

  32. Anthony, DC., Montine, T.J., Valentine W.M., and Graham, D.G. Toxic responses of the nervous system. In Casarett and Doull’s Toxicology: the Basic Science of Poisons, Sixth Edition. McGraw-Hill Medical Publishing Division, New York, pp 535-563, 2001 Bushnell, P.J., Shafer, T.J., Bale, A.S., Boyes, W.K., Simmons, J.E., Eklund, C. and Jackson, T.L. Developing an exposure-dose-response model for organic solvents: overview and progress on in vitro models and dosimetry. Environmental Toxicology and Pharmacology,19: 607–614, 2005. Benignus, V.A., Bushnell, P.J. and Boyes, W. K. Toward cost-benefit analysis of acute behavioral effects of toluene in humans. Risk Analysis, 25 (2), 447-456, 2005. Bruckner, J.V. and Warren, D.A., W.K. Toxic effects of solvents and vapors. In Casarett and Doull’s Toxicology: the Basic Science of Poisons, Sixth Edition. McGraw-Hill Medical Publishing Division, New York, pp 869-916, 2001 Schreiber, J S; Hudnell, H K; Geller, A M; House, D E; Aldous, K M; Force, M E; Langguth, K W; Prohonic, E J; Parker, J C (2002) Apartment residents’ and day care workers’ exposures to tetrachloroethylene and deficits in visual contrast sensitivity. Environ Health Perspect 110:655–664. Arlien-Søborg, P. (1992). Solvent Neurotoxicity. CRC Press, Boca Raton FL. Spencer PS., and Schaumburg H.H. Experimental and Clinical Neurotoxicology, 2nd Edition, Oxford University Press, 2000. Sources & Readings

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