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 Chemical Structures Benzene Toluene Trichloroethylene (TCE) Tetrachloroethylene (Perchloroethylene) or Perc 1

2 Solvents 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 Solvent Neurotoxicity Acute CNS depression Euphoria Sensory, cognitive, motor deficits Reversible after exposure Causes accidents or injuries Good animal models Several mechanistic targets Chronic Organic brain disorder Originally observed in Scandinavian painters Sensory, cognitive, motor deficits Years of high level exposure No good animal models Mechanisms unknown 2

Volatile Organic Compounds Widely used in industry and commerce Emission Sources Factories & chemical plants Smaller shops Mobile sources Indoor air sources Consumer products Pesticide inerts

3 Volatile Organic Compounds 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 Upset Emissions Upsets Startup, maintance, shutdown In some cases, upset releases exceeded annual releases several thousand fold 7,533 upset events reported to Texas in 2004 Some facilities report upset events on average every other day Public Citizen,

compounds in small amounts The Washington Post, Aug.

4 Small Gasoline Engines 2-cycle engines burn only about 60% of the fuel The remainder is emitted as a breathable hydrocarbon mist Contains BTEX Benzene, toluene ethylbenzene and xylene Hundreds of other compounds in small amounts The Washington Post, Aug. 14, 2002 Dry Cleaners Perchloroethylene Detected in colocated apartments Especially in NYC Residents may show poor visual function or other problems 4

5 Acute Solvent Actions are a Function of Lipid Solubility Lipophilic nature measured as LogP Octanol/water partition coefficient Increased partitioning into brain and nerve membranes Seen as evidence for membrane fluidity mechanism of action Goodman & Gilman, 1990 How are VOCs Causing Acute Effects? They were once thought to simply dissolve lipid cell membranes New evidence suggests more selection disruption of nerve membrane ion channel proteins But which ones? 5

V I NMDA/gly NMDA/gly NMDA/gly Glutamate The most common CNS excitatory neurotransmitter NMDA

6 Patch-Clamp Electrophysiology V = IR To equipment with lots of wires, knobs, switches, buttons and lights! V I NMDA/gly NMDA/gly NMDA/gly Glutamate The most common CNS excitatory neurotransmitter NMDA receptor One type of glutamate receptor located in the visual system NMDA receptor activity is inhibited by toluene (in vitro studies, Cruz et al., 1998) Taken from Cruz et al.,

7 Solvents & Ion Channel Function Compound Ion Channel Solvents NMDA Receptor nachr GABAA Receptor Glycine Receptor VSCC* Toluene Inhibits Inhibits Potentiates Potentiates Inhibits/Potentiates Trichloroethylene ND ND Potentiates Potentiates Inhibits/Potentiates Perchloroethylene ND Inhibits ND ND Inhibits/Potentiates 1,1,1-Trichloroethane Inhibits ND Potentiates Potentiates Inhibits Ethanol Inhibits Inhibits/Potentiates Potentiates Potentiates Inhibits Halothane Inhibits Inhibits Potentiates Potentiates Inhibits Bushnell et al., 2005 Chronic Solvent Encephalopathy? 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 7

8 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 Toluene Benzoic acid Hippuric acid CH 3 COOH glycine COOGly Toluene & Acute Behavioral Changes e.g. Choice Reaction Time DRAFT. DO NOT CITE. Behavioral Effect (proportion of baseline) REPORTED DATA PREDICTED EFFECT 95% CONFIDENCE LIMITS Blood Toluene (mg/liter) Meta-analysis of 6 studies, Benignus et al., in press 8

Toluene Abuse Neuropathic effects in humans Following repeated solvent abuse Very high dose levels Cerebellar damage Cerebral atrophy Multiple

9 Toluene Abuse 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 at High Doses Causes Outer Haircell Damage in Chochlea Johnson (1993) 9

10 Ethanol (Alcohol) CH 3 CH 2 OH CNS depressant Legal definition of inebriation based on BACs Often 0.1% (100 mg/100 ml) Acute exposure Euphoria Loss of inhibitions / poor judgment Loss of balance & motor coordination Impaired vision & visual/motor function Ataxia, nausea, vomiting Unconsciousness Ethanol Metabolism CH 3 CH 2 OH Ethanol Alcohol dehydrogenase NAD CH 3 CHO Acetaldehyde + NADH < 10% Catalase H 2 O 2 NADPH 10-30% of metabolized ethanol < 20% Microsomal ethanol oxidizing system (MEOS) = CYP2E1 Rate of metabolism is ~ mg%/hr 10

11 CH 3 CH 2 OH Ethanol Ethanol Metabolism Alcohol dehydrogenase (ADH) NAD CH 3 CHO Acetaldehyde + NADH ADH males > females ALDH isozymes inactive variant in %50 Asians NAD Acetaldehyde dehydrogenase (ALDH) CH 3 COO - + NADH Acetic acid Variant form in Native Americans inhibited by Disulfiram 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. 11

12 Fetal Alcohol Syndrome (FAS) Characterized by: Mental retardation Microcephaly Irritability Reduced birth weight Poor muscle coordination Cranio/Facial anomalies Mechanism poorly understood Methanol (Wood Alcohol) CH 3 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 12

13 Methanol Metabolism (Primates) CH 3 OH Methanol Alcohol dehydrogenase NAD CH 2 O Formaldehyde + NADH CO 2 NAD Formaldehyde dehydrogenase Tetrahydrofolate Low HCOO - Formic acid + NADH Methanol Metabolism (Rodents) CH 3 OH Methanol Catalase CH 2 O Formaldehyde CO 2 NAD Formaldehyde dehydrogenase Tetrahydrofolate HIGH HCOO - Formic acid + NADH Folate deficiency increases the sensitivity of methanol in rodents. Intraretinal metabolism may be important. 13

14 Methanol Visual Toxicity Eells et al., PNAS 2003 n-hexane and Methyl n-butyl ketone Neurotoxicity Sensorimotor polyneuropathy Sensory numbness and paresthesia Distal nerves affected first Clinical signs often delayed for months Axonal swelling and secondary demyelination 2,5-hexanedione is common toxic metabolite 14

15 Spencer & Schaumburg, 2000 Peripheral Neuropathy 15

16 Sources & Readings 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 , 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-doseresponse model for organic solvents: overview and progress on in vitro models and dosimetry. Environmental Toxicology and Pharmacology, 19: , 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), , 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 , 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: 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,

o They are usually used in Forensic or Medico-legal practice, Commonly used are Blood Alcohol Concentration (BAC) and Expired Air

o They are usually used in Forensic or Medico-legal practice, Commonly used are Blood Alcohol Concentration (BAC) and Expired Air 1 ETHANOL: UNIVERSITY OF PNG SCHOOL OF MEDICINE AND HEALTH SCIENCES DIVISION OF BASIC MEDICAL SCIENCES DISCIPLINE OF BIOCHEMISTRY AND MOLECULAR BIOLOGY PBL SEMINAR OVERVIEW OF ALCOHOL (ETHANOL & METHANOL)