mcdougal

Systemic Toxicity from Skin Exposures

(or what may happen with a failure to decontaminate)

James N. McDougal, Ph.D.Pharmacology and ToxicologyBoonshoft School of MedicineWright State UniversityDayton OH

ACS Advances in Decontamination 2006

Purpose

Summarize and evaluate information available on

systemic toxicity of specific chemicals and chemical

categories


Overview

• Characteristics of cutaneous exposures• How systemic toxicity is assessed• Case reports of chemicals causing

lethality• Chemicals recognized to cause illness


ExternalDose

(skin surface)

SurfaceContamination

Transfer

LiquidSplash

Vaporor

Aerosol

Exposure Scenarios


Cutaneous Toxicity

Two independent factors are responsible:

• Penetration through the skin• Toxic potency


Penetration Through Skin

ExternalExposure

InternalDoseKp

Flux


Toxic Potency

• Mechanism dependent:• Receptors• DNA• Enzymes • Membranes

• Lethal Dose (LD50)• Lowest observable effect level (LOEL)• No observable effect level (NOEL)


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


Human Experience

• Epidemiology studies• “Realistic” exposures• Exposure parameters usually very uncertain• Require large numbers of individuals

• Case Reports• Often accidents or unusual occurrences


Chemical Mixtures

• Very few dermal exposures to “pure” chemicals in the workplace


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


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


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


Route-to-route Extrapolations

• Oral or inhalation toxicity• Requires known permeability• Assumes no route of entry effects


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

Specific ChemicalsCausingMortality


Pesticides


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


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%


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)


Salicylic acid

• Treatment for psoriasis and other skin problems as a 3 or 6% ointment

• 13 deaths recorded• Also causes nausea, confusion and

hallucinations


Dichlorophenol

• Feedstock chemical• 5 deaths in chemical industry (18 yr)• Mechanism – uncouples oxidative

phosphorylation• Inhalation a component


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


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


Chemical Warfare Agents

• Nerve agents• Sarin• Tabun• Soman• VX

• All lethal through the skin


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


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


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


Hexachlorophene

• pHisoHex soap contains 3% hexachlorophene

• 248 children autopsied at U of Washington

• Encephalopathy in 17 neonates related to undiluted bathing in pHisoHex

ChemicalsCausing

Morbidity


Petroleum & Petroleum Products

• CNS depression• Kidney and other cancers• Liver lesions• Skin irritation


Solvents

• CNS depression• Liver and kidney cancers• Leukemia• DNA damage• Cardiac arrhythmias


Inorganic Chemicals

• Variety of cancers• CNS effects• Cholinesterase inhibition• Metabolic effects


Systemic Morbidity

• Selenium sulfide • Nitroglycerin• Glycol ether• Inorganic mercury• Alkyl lead• Boric acid

• DEET• Alcohols• Benzocaine• Lindane• Other topical drugs• TCDD


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


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


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

mcdougal

Business

pesticides acs advances

methods acs advances

workplace acs advances

hallucinationsacs advances

karen wetterhahn acs

cause illnessacs advances

skin problems

skin penetration studies