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Neurotoxic Effects of Solvents William Boyes Neurotoxicology Division National Health and Environmental Effects Research Laboratory Office of Research.

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Presentation on theme: "Neurotoxic Effects of Solvents William Boyes Neurotoxicology Division National Health and Environmental Effects Research Laboratory Office of Research."— Presentation transcript:

1 Neurotoxic Effects of Solvents William Boyes Neurotoxicology Division National Health and Environmental Effects Research Laboratory Office of Research and Development, EPA

2 Chemical Structures BenzeneToluene Trichloroethylene (TCE) Tetrachloroethylene (Perchloroethylene) or “Perc”

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

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

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

6 Upset Emissions Upsets Upsets Startup, maintance, shutdown Startup, maintance, shutdown In some cases, upset releases exceeded annual releases several thousand fold In some cases, upset releases exceeded annual releases several thousand fold 7,533 upset events reported to Texas in ,533 upset events reported to Texas in 2004 Some facilities report upset events on average every other day Some facilities report upset events on average every other day Public Citizen, 2005

7 Small Gasoline Engines 2-cycle engines burn only about 60% of the fuel 2-cycle engines burn only about 60% of the fuel The remainder is emitted as a breathable hydrocarbon mist The remainder is emitted as a breathable hydrocarbon mist Contains BTEX Contains BTEX Benzene, toluene ethylbenzene and xylene Benzene, toluene ethylbenzene and xylene Hundreds of other compounds in small amounts Hundreds of other compounds in small amounts The Washington Post, Aug. 14, 2002

8 Dry Cleaners Perchloroethylene Perchloroethylene Detected in co- located apartments Detected in co- located apartments Especially in NYC Especially in NYC Residents may show poor visual function or other problems Residents may show poor visual function or other problems

9 Acute Solvent Actions are a Function of Lipid Solubility Lipophilic nature Lipophilic nature measured as LogP measured as LogP Octanol/water partition coefficient Octanol/water partition coefficient Increased partitioning into brain and nerve membranes Increased partitioning into brain and nerve membranes Seen as evidence for membrane fluidity mechanism of action Seen as evidence for membrane fluidity mechanism of action Goodman & Gilman, 1990

10 How are VOCs Causing Acute Effects? They were once thought to simply dissolve lipid cell membranes They were once thought to simply dissolve lipid cell membranes New evidence suggests more selection disruption of nerve membrane ion channel proteins New evidence suggests more selection disruption of nerve membrane ion channel proteins But which ones? But which ones?

11 Patch-Clamp Electrophysiology V = IR To equipment with lots of wires, knobs, switches, buttons and lights ! V I

12 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) NMDA/gly Taken from Cruz et al., 1998

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

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

15 Toluene Present in paints, glues, gasoline and many other products Present in paints, glues, gasoline and many other products Subject of over 40 EPA Maximum Achievable Control Technology (MACT) / residual risk assessments Subject of over 40 EPA Maximum Achievable Control Technology (MACT) / residual risk assessments The substance of choice for glue sniffers The substance of choice for glue sniffers CH 3 Toluene COOH Benzoic acid COOGly Hippuric acid glycine

16 Toluene & Acute Behavioral Changes e.g. Choice Reaction Time Meta-analysis of 6 studies, Benignus et al., in press

17 Toluene Abuse Neuropathic effects in humans 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

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

19 Ethanol (Alcohol) CNS depressant CNS depressant Legal definition of inebriation based on BACs Legal definition of inebriation based on BACs Often 0.1% (100 mg/100 ml) Often 0.1% (100 mg/100 ml) Acute exposure Acute exposure Euphoria Euphoria Loss of inhibitions / poor judgment Loss of inhibitions / poor judgment Loss of balance & motor coordination Loss of balance & motor coordination Impaired vision & visual/motor function Impaired vision & visual/motor function Ataxia, nausea, vomiting Ataxia, nausea, vomiting Unconsciousness Unconsciousness CH 3 —CH 2 —OH

20 Ethanol Metabolism CH 3 —CH 2 —OH Ethanol CH 3 —CHO Acetaldehyde NAD Alcohol dehydrogenase Catalase H 2 O 2 + NADH Microsomal ethanol oxidizing system (MEOS) = CYP2E1 NADPH 10-30% of metabolized ethanol Rate of metabolism is ~ mg%/hr < 10% < 20%

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

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

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

24 Methanol (Wood Alcohol) Clinical signs (people) Clinical signs (people) Multiphasic syndrome Multiphasic syndrome Early – like ethanol (Central nervous system depression, weakness, headache, vomiting) Early – like ethanol (Central nervous system depression, weakness, headache, vomiting) Mid- asymptomatic period (12-24 hr) Mid- asymptomatic period (12-24 hr) Late - Severe metabolic acidosis, optic disc edema, and bilateral necrosis of the putamen 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 Other adverse effects of methanol in humans include minor skin and eye irritation Formic acid is the toxic metabolite of methanol. Formic acid is the toxic metabolite of methanol. Accounts for the metabolic acidosis and blindness seen in people following methanol poisoning Accounts for the metabolic acidosis and blindness seen in people following methanol poisoning CH 3 —OH

25 Methanol Metabolism (Primates) CH 3 —OH Methanol CH 2 O Formaldehyde NAD Alcohol dehydrogenase + NADH HCOO - Formic acid aldehyde Formaldehyde dehydrogenase NAD + NADH CO 2 Tetrahydrofolate Low

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

27 Methanol Visual Toxicity Eells et al., PNAS 2003

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

29 Spencer & Schaumburg, 2000

30 Peripheral Neuropathy

31

32 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-dose- response model for organic solvents: overview and progress on in vitro models and dosimetry. Environmental Toxicology and Pharmacology, 19: 607–614, 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 110:655–664. 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.


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