Neurotoxic Effects of Solvents

1
Neurotoxic Effects of Solvents

• William Boyes
• Neurotoxicology Division
• National Health and Environmental Effects
  Research Laboratory
• Office of Research and Development, EPA
• boyes.william_at_epa.gov

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Chemical Structures
Benzene
Toluene
Tetrachloroethylene (Perchloroethylene) or Perc
Trichloroethylene (TCE)
3
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 bloodtissue
  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

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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
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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

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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
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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?

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Patch-Clamp Electrophysiology
To equipment with lots of wires, knobs, switches,
buttons and lights !
V IR
V
I
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• 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
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Solvents Ion Channel Function
Bushnell et al., 2005
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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

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

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Toluene at High Doses Causes Outer Haircell
Damage in Chochlea
Johnson (1993)
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Ethanol (Alcohol)
CH3CH2OH

• 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

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Ethanol Metabolism
Alcohol dehydrogenase
CH3CH2OH
CH3CHO
NADH
NAD
Ethanol
Acetaldehyde
lt 10
Catalase H2O2
10-30 of metabolized ethanol
NADPH
Rate of metabolism is 15-20 mg/hr
lt 20
Microsomal ethanol oxidizing system (MEOS)
CYP2E1
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Ethanol Metabolism
Alcohol dehydrogenase (ADH)
CH3CH2OH
CH3CHO
NADH
NAD
Ethanol
Acetaldehyde
NAD
Acetaldehyde dehydrogenase (ALDH)

• ADH
• males gt females
• ALDH isozymes
• inactive variant in 50 Asians
• Variant form in Native Americans
• inhibited by Disulfiram

CH3COO-
NADH
Acetic acid
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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.

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Fetal Alcohol Syndrome (FAS)

• Characterized by
• Mental retardation
• Microcephaly
• Irritability
• Reduced birth weight
• Poor muscle coordination
• Cranio/Facial anomalies
• Mechanism poorly understood

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Methanol (Wood Alcohol)
CH3OH

• 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

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Methanol Metabolism (Primates)
Alcohol dehydrogenase
CH3OH
CH2O
NADH
NAD
Methanol
Formaldehyde
NAD
Formaldehyde dehydrogenase
Tetrahydrofolate
HCOO-
CO2
NADH
Low
Formic acid
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Methanol Metabolism (Rodents)
Catalase
CH3OH
CH2O
Methanol
Formaldehyde
NAD
Formaldehyde dehydrogenase
Tetrahydrofolate
HCOO-
CO2
NADH
HIGH
Formic acid
Folate deficiency increases the sensitivity of
methanol in rodents. Intraretinal metabolism may
be important.
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Methanol Visual Toxicity
Eells et al., PNAS 2003
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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

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Spencer Schaumburg, 2000
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Peripheral Neuropathy
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(No Transcript)
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Sources Readings

• Anthony, DC., Montine, T.J., Valentine W.M., and
  Graham, D.G. Toxic responses of the nervous
  system. In Casarett and Doulls 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 607614, 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
  Doulls 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
  110655664.
• 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.