Mcdougal

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Mcdougal

  1. 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. 2. Purpose Summarize and evaluate information available on systemic toxicity of specific chemicals and chemical categories ACS Advances in Decontamination 2006
  3. 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. 4. Exposure Scenarios Vapor or Aerosol External Liquid Dose Splash (skin surface) Transfer Surface Contamination ACS Advances in Decontamination 2006
  5. 5. Cutaneous Toxicity Two independent factors are responsible: • Penetration through the skin • Toxic potency ACS Advances in Decontamination 2006
  6. 6. Penetration Through Skin External Internal Exposure Kp Dose Flux ACS Advances in Decontamination 2006
  7. 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. 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. 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. 10. Chemical Mixtures • Very few dermal exposures to “pure” chemicals in the workplace ACS Advances in Decontamination 2006
  11. 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. 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. 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. 14. Route-to-route Extrapolations • Oral or inhalation toxicity • Requires known permeability • Assumes no route of entry effects ACS Advances in Decontamination 2006
  15. 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. 16. Specific Chemicals Causing Mortality
  17. 17. Pesticides ACS Advances in Decontamination 2006
  18. 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. 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. 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. 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. 22. Dichlorophenol • Feedstock chemical • 5 deaths in chemical industry (18 yr) • Mechanism – uncouples oxidative phosphorylation • Inhalation a component ACS Advances in Decontamination 2006
  23. 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. 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. 25. Chemical Warfare Agents • Nerve agents • Sarin • Tabun • Soman • VX • All lethal through the skin ACS Advances in Decontamination 2006
  26. 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. 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. 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. 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. 30. Chemicals Causing Morbidity
  31. 31. Petroleum & Petroleum Products • CNS depression • Kidney and other cancers • Liver lesions • Skin irritation ACS Advances in Decontamination 2006
  32. 32. Solvents • CNS depression • Liver and kidney cancers • Leukemia • DNA damage • Cardiac arrhythmias ACS Advances in Decontamination 2006
  33. 33. Inorganic Chemicals • Variety of cancers • CNS effects • Cholinesterase inhibition • Metabolic effects ACS Advances in Decontamination 2006
  34. 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. 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. 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. 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. 42. ACS Advances in Decontamination 2006

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