Presentation is loading. Please wait.

Presentation is loading. Please wait.

Neurotoxic Effects of Solvents

Similar presentations

Presentation on theme: "Neurotoxic Effects of Solvents"— 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 Benzene Toluene
Tetrachloroethylene (Perchloroethylene) or “Perc” Trichloroethylene (TCE)

3 Solvents Lipophilic Volatility 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

4 Solvent Neurotoxicity
Acute Chronic 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

5 Volatile Organic Compounds
Uses include: Organic solvents Cleaning & degreasing Gasoline Paints & glues Dry cleaning Printing Paint strippers, nail polish remover Microelectronic manufacture 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

6 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, 2005

7 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

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

9 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

10 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?

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

15 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 CH3 COOH COOGly 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
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
CH3—CH2—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

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

21 Alcohol dehydrogenase (ADH)
Ethanol Metabolism Alcohol dehydrogenase (ADH) CH3—CH2—OH CH3—CHO + NADH 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 CH3—COO- + NADH Acetic acid

22 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.

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

24 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

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

26 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.

27 Methanol Visual Toxicity
Eells et al., PNAS 2003

28 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

29 Spencer & Schaumburg, 2000

30 Peripheral Neuropathy


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, 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 , 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.

Download ppt "Neurotoxic Effects of Solvents"

Similar presentations

Ads by Google