1. Systemic Toxicity from Skin
Exposures
(or what may happen with
a failure to decontaminate)
James N. McDougal, Ph.D.
Pharmacology and Toxicology
Boonshoft School of Medicine
Wright State University
Dayton OH
2. Purpose
Summarize and evaluate
information available on
systemic toxicity of specific
chemicals and chemical
categories
ACS Advances in
Decontamination 2006
3. Overview
• Characteristics of cutaneous exposures
• How systemic toxicity is assessed
• Case reports of chemicals causing
lethality
• Chemicals recognized to cause illness
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Decontamination 2006
4. Exposure Scenarios
Vapor
or
Aerosol
External
Liquid Dose
Splash (skin surface)
Transfer
Surface
Contamination
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Decontamination 2006
5. Cutaneous Toxicity
Two independent factors are
responsible:
• Penetration through the skin
• Toxic potency
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6. Penetration Through Skin
External Internal
Exposure Kp Dose
Flux
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Decontamination 2006
8. How do we Evaluate
Cutaneous Toxicity?
• Human experience
• Studies in animals (dermal LD50, etc.)
• ACGIH skin notation
• Calculations:
• Based on permeability
• Route-to-route extrapolations
• Structure-activity
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Decontamination 2006
9. Human Experience
• Epidemiology studies
• “Realistic” exposures
• Exposure parameters usually very uncertain
• Require large numbers of individuals
• Case Reports
• Often accidents or unusual occurrences
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Decontamination 2006
10. Chemical Mixtures
• Very few dermal exposures to “pure”
chemicals in the workplace
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Decontamination 2006
11. Mixed Exposures
• Function of lung– maximize absorption
• Function of skin – minimize absorption
• Most dermal exposures have inhalation
component
• Vapor
• Dust or aerosol
• Whole body vapor exposure – less than
10% of the body burden from skin
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Decontamination 2006
12. Skin Notation
• American Congress of Governmental Industrial
Hygienists (ACGIH)
• “potential significant contribution to overall
exposures by cutaneous route.”
• 24% of the chemicals with threshold limit values
(TLVs) also have a skin notation
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Decontamination 2006
13. Animal Studies
• Dermal toxicity studies (i.e. LD50)
• High exposure levels
• Hard to control exposure
• May not extrapolate to humans very well
• Skin penetration studies
• In vitro with human or animal skin
• Variable results depending on methods
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Decontamination 2006
14. Route-to-route
Extrapolations
• Oral or inhalation toxicity
• Requires known permeability
• Assumes no route of entry effects
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Decontamination 2006
15. Structure-Activity
Correlation approach (Potts-Guy)
• Predicts permeability (Kp) based on
octanol/water partition coefficient and
molecular weight
• Only for penetration from aqueous solution
• Frequently differs from experimental
measurements by an order of magnitude
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Decontamination 2006
17. Pesticides
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Decontamination 2006
18. Pesticides
• Widely used, hundreds of compounds
designed to be toxic to insects
• Worldwide
• 3 million cases of poisoning/yr
• About 220,000 deaths worldwide (1990)
• Developing countries
• 13-fold incidence of poisoning
• 85% of pesticide use
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Decontamination 2006
19. Pesticides
California Pesticide Illness Surveillance
Program (PISP) summarizes illness/injury
in 2000 by type of exposure
• Direct contact with pesticides 40%
• Spray, mist or fumes 40%
• Residue 20%
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Decontamination 2006
20. Acids
• Hydrofluoric acid
• OSHA investigated 4 (skin alone) and 11
mixed exposure deaths in 11 years
• >2.5% BSA may be lethal (hypocalcemia)
• Inhalation can contribute
• Monochloroacetic acid
• ECETOC reports at least 26 fatalities (18yrs)
• >10% BSA may be lethal (lactic acidosis)
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Decontamination 2006
21. Salicylic acid
• Treatment for psoriasis and other
skin problems as a 3 or 6% ointment
• 13 deaths recorded
• Also causes nausea, confusion and
hallucinations
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Decontamination 2006
22. Dichlorophenol
• Feedstock chemical
• 5 deaths in chemical industry (18 yr)
• Mechanism – uncouples oxidative
phosphorylation
• Inhalation a component
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Decontamination 2006
23. Dimethyl Mercury
• Use rare – only 100 labs worldwide
as a NMR standard
• Lethality rare – only 4 known cases
• Penetrates latex and PVC gloves
• Binds to S-containing amino acids
and kills nerve cells
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Decontamination 2006
24. Dimethyl Mercury
• Aug 96 - Dartmouth
Chemistry Professor spilled
“several drops” on glove
• Jan 97 – tingly, slurred
speech & balance problems
• 3 weeks later lapsed into
coma and died in Jun 97
Dr. Karen Wetterhahn
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Decontamination 2006
25. Chemical Warfare Agents
• Nerve agents
• Sarin
• Tabun
• Soman
• VX
• All lethal through
the skin
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Decontamination 2006
26. Cancer-causing Chemicals
• Very few documented cases of systemic
cancer from skin exposures
• Benzidine – bladder tumors
• Arsenic – hemangiosarcoma of liver
• Many chemicals cause systemic cancers
and are absorbed through the skin
• We don’t know if enough can penetrate
the skin to cause cancer
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Decontamination 2006
27. Phenol
• Was used as antiseptic
• May cause death by
protein denaturation
• 64 sq in. (2% BSA)
exposure was lethal
• Volatile enough to have
inhalation component
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Decontamination 2006
28. Hexachlorophene
• Hexachlorophene (6.3%) added to
“baby powder” in France due to
manufacturing error
• Caused encephalopathy and
ulcerative skin lesions
• 36 of 204 exposed children died
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29. Hexachlorophene
• pHisoHex soap contains
3% hexachlorophene
• 248 children autopsied at
U of Washington
• Encephalopathy in 17
neonates related to
undiluted bathing in
pHisoHex
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Decontamination 2006
35. Green Tobacco Sickness
• Caused by working in
wet tobacco fields
• Migrant workers
exposed 8-12 weeks
per year
• Break off flowers at top
of 4-6 ft high plants
• Harvest leaves by hand
picking from bottom
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Decontamination 2006
36. Green Tobacco Sickness
• Headache, nausea and
dizziness
• Illness reported in 9% of
workers
• Hospital treatment in 1%
of workers
• Nicotine poisoning from
dermal contact
• Smoking may be
protective
• Tolerance may occur
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Decontamination 2006
37. Summary
• The skin DOES provide good protection
from absorption compared to other routes
• There are chemicals that can and do
cause systemic toxicity (lethality and
morbidity) from skin exposures
• We do not know if the vast majority of
toxic chemicals cause toxicity from skin
exposures
ACS Advances in
Decontamination 2006
