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Mcdougal

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  • 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 ACS Advances in Decontamination 2006
  • 4. Exposure Scenarios Vapor or Aerosol External Liquid Dose Splash (skin surface) Transfer Surface Contamination ACS Advances in Decontamination 2006
  • 5. Cutaneous Toxicity Two independent factors are responsible: • Penetration through the skin • Toxic potency ACS Advances in Decontamination 2006
  • 6. Penetration Through Skin External Internal Exposure Kp Dose Flux ACS Advances in Decontamination 2006
  • 7. Toxic Potency • Mechanism dependent: • Receptors • DNA • Enzymes • Membranes • Lethal Dose (LD50) • Lowest observable effect level (LOEL) • No observable effect level (NOEL) ACS Advances in 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 ACS Advances in 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 ACS Advances in Decontamination 2006
  • 10. Chemical Mixtures • Very few dermal exposures to “pure” chemicals in the workplace ACS Advances in 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 ACS Advances in 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 ACS Advances in 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 ACS Advances in Decontamination 2006
  • 14. Route-to-route Extrapolations • Oral or inhalation toxicity • Requires known permeability • Assumes no route of entry effects ACS Advances in 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 ACS Advances in Decontamination 2006
  • 16. Specific Chemicals Causing Mortality
  • 17. Pesticides ACS Advances in 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 ACS Advances in 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% ACS Advances in 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) ACS Advances in 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 ACS Advances in Decontamination 2006
  • 22. Dichlorophenol • Feedstock chemical • 5 deaths in chemical industry (18 yr) • Mechanism – uncouples oxidative phosphorylation • Inhalation a component ACS Advances in 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 ACS Advances in 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 ACS Advances in Decontamination 2006
  • 25. Chemical Warfare Agents • Nerve agents • Sarin • Tabun • Soman • VX • All lethal through the skin ACS Advances in 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 ACS Advances in 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 ACS Advances in 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 ACS Advances in Decontamination 2006
  • 29. Hexachlorophene • pHisoHex soap contains 3% hexachlorophene • 248 children autopsied at U of Washington • Encephalopathy in 17 neonates related to undiluted bathing in pHisoHex ACS Advances in Decontamination 2006
  • 30. Chemicals Causing Morbidity
  • 31. Petroleum & Petroleum Products • CNS depression • Kidney and other cancers • Liver lesions • Skin irritation ACS Advances in Decontamination 2006
  • 32. Solvents • CNS depression • Liver and kidney cancers • Leukemia • DNA damage • Cardiac arrhythmias ACS Advances in Decontamination 2006
  • 33. Inorganic Chemicals • Variety of cancers • CNS effects • Cholinesterase inhibition • Metabolic effects ACS Advances in Decontamination 2006
  • 34. Systemic Morbidity • Selenium sulfide • DEET • Nitroglycerin • Alcohols • Glycol ether • Benzocaine • Inorganic mercury • Lindane • Alkyl lead • Other topical drugs • Boric acid • TCDD ACS Advances in 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 ACS Advances in 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 ACS Advances in 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
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  • 42. ACS Advances in Decontamination 2006

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