Presentation on theme: "Neurotoxic Effects of Solvents"— Presentation transcript:
1 Neurotoxic Effects of Solvents William BoyesNeurotoxicology DivisionNational Health and Environmental Effects Research LaboratoryOffice of Research and Development, EPA
2 Chemical Structures Benzene Toluene Tetrachloroethylene (Perchloroethylene) or “Perc”Trichloroethylene (TCE)
3 Solvents Lipophilic Volatility Organic chemical composition Distribute to body lipid-rich tissuesEasily cross lipid membranes & barriersVolatilityInhalation is a significant route of exposureDelivery to tissues depends upon the blood:tissue partition coefficient
4 Solvent Neurotoxicity AcuteChronicCNS depressionEuphoriaSensory, cognitive, motor deficitsReversible after exposureCauses accidents or injuriesGood animal modelsSeveral mechanistic targetsOrganic brain disorderOriginally observed in Scandinavian paintersSensory, cognitive, motor deficitsYears of high level exposureNo good animal modelsMechanisms unknown
5 Volatile Organic Compounds Uses include:Organic solventsCleaning & degreasingGasolinePaints & gluesDry cleaningPrintingPaint strippers, nail polish removerMicroelectronic manufactureWidely used in industry and commerceEmission SourcesFactories & chemical plantsSmaller shopsMobile sourcesIndoor air sourcesConsumer productsPesticide “inerts”Drinking waterHazardous waste sites
6 Upset Emissions Upsets Startup, maintance, shutdownIn some cases, upset releases exceeded annual releases several thousand fold7,533 upset events reported to Texas in 2004Some facilities report upset events on average every other dayPublic Citizen, 2005
7 Small Gasoline Engines 2-cycle engines burn only about 60% of the fuelThe remainder is emitted as a breathable hydrocarbon mistContains BTEXBenzene, toluene ethylbenzene and xyleneHundreds of other compounds in small amountsThe Washington Post, Aug. 14, 2002
8 Dry Cleaners Perchloroethylene Detected in co-located apartments Especially in NYCResidents may show poor visual function or other problems
9 Acute Solvent Actions are a Function of Lipid Solubility Lipophilic naturemeasured as LogPOctanol/water partition coefficientIncreased partitioning into brain and nerve membranesSeen as evidence for membrane fluidity mechanism of actionGoodman & Gilman, 1990
10 How are VOCs Causing Acute Effects? They were once thought to simply dissolve lipid cell membranesNew evidence suggests more selection disruption of nerve membrane ion channel proteinsBut which ones?
11 Patch-Clamp Electrophysiology To equipment with lots of wires, knobs, switches, buttons and lights !V = IRVI
12 Glutamate The most common CNS excitatory neurotransmitter NMDA receptorOne type of glutamate receptorlocated in the visual systemNMDA receptor activity is inhibited by toluene(in vitro studies, Cruz et al., 1998)NMDA/glyNMDA/glyNMDA/glyTaken from Cruz et al., 1998
13 Solvents & Ion Channel Function Bushnell et al., 2005
14 Chronic Solvent Encephalopathy? Scandinavian painters and other workersChronic exposurea variety of impairments of mood and intellectual function leading eventually to dementiaEarly studies confoundedPoorly matched controlsPoor documentation of exposure historyMore recent studies showIncreased reaction timesPoor visual functionImpaired auditory thresholdsImpaired motor skillsImpaired performance of cognitive and memory tasks
15 Toluene Present in paints, glues, gasoline and many other products Subject of over 40 EPA Maximum Achievable Control Technology (MACT) / residual risk assessmentsThe substance of choice for glue sniffersTolueneBenzoic acidHippuric acidCH3COOHCOOGlyglycine
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 Following repeated solvent abuseVery high dose levelsCerebellar damageCerebral atrophyMultiple symptoms of dementiaConfounded by hypoxia and other exposures
18 Toluene at High Doses Causes Outer Haircell Damage in Chochlea Johnson (1993)
19 Ethanol (Alcohol) CNS depressant CH3—CH2—OHCNS depressantLegal definition of inebriation based on BACsOften 0.1% (100 mg/100 ml)Acute exposureEuphoriaLoss of inhibitions / poor judgmentLoss of balance & motor coordinationImpaired vision & visual/motor functionAtaxia, nausea, vomitingUnconsciousness
20 Ethanol Metabolism CH3—CH2—OH CH3—CHO + NADH NAD Ethanol Acetaldehyde Alcohol dehydrogenaseCH3—CH2—OHCH3—CHO+ NADHNADEthanolAcetaldehyde< 10%CatalaseH2O210-30% of metabolized ethanolNADPHRate of metabolism is ~ mg%/hr< 20%Microsomal ethanol oxidizing system (MEOS) = CYP2E1
21 Alcohol dehydrogenase (ADH) Ethanol MetabolismAlcohol dehydrogenase (ADH)CH3—CH2—OHCH3—CHO+ NADHNADEthanolAcetaldehydeNADAcetaldehyde dehydrogenase(ALDH)ADHmales > femalesALDH isozymesinactive variant in %50 AsiansVariant form in Native Americansinhibited by DisulfiramCH3—COO-+ NADHAcetic acid
22 Chronic Ethanol Toxicity AlcoholismHigh % of calories from alcoholThiamine deficientWernicke's encephalopathyDamage to multiple brain areasImpaired cognition, motor functionKorsakoff's psychosisAcute & Chronic100,000 premature deaths / year in U.S.
24 Methanol (Wood Alcohol) CH3—OHClinical signs (people)Multiphasic syndromeEarly – 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 putamenOther adverse effects of methanol in humans include minor skin and eye irritationFormic acid is the toxic metabolite of methanol.Accounts for the metabolic acidosis and blindness seen in people following methanol poisoning
26 Methanol Metabolism (Rodents) CatalaseCH3—OHCH2OMethanolFormaldehydeNADFormaldehyde dehydrogenaseTetrahydrofolateCO2HCOO-+ NADHHIGHFormic acidFolate 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 NeurotoxicitySensorimotor polyneuropathySensory numbness and paresthesiaDistal nerves affected firstClinical signs often delayed for monthsAxonal swelling and secondary demyelination2,5-hexanedione is common toxic metabolite
32 Sources & ReadingsAnthony, 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 , 2001Bushnell, 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), , 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 , 2001Schreiber, 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.