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Dose-Response

Dose-Response. ENVR430 Nov 09, 2009. Casarett and Doull, Chapter 2, pp. 18-27(6 th Edn) Chapter 2, pp. 19-26 (7 th Edn) Timbrell Chapter 2, pp. 7-25 (3 rd Edn). Dose-Response. Increasing Response. 0. Increasing Dose. The J-shaped curve (hormesis). Increasing Response.

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Dose-Response

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  1. Dose-Response ENVR430 Nov 09, 2009 Casarett and Doull, Chapter 2, pp. 18-27(6th Edn) Chapter 2, pp. 19-26 (7th Edn) Timbrell Chapter 2, pp. 7-25 (3rd Edn)

  2. Dose-Response Increasing Response 0 Increasing Dose

  3. The J-shaped curve(hormesis) Increasing Response Increasing Dose

  4. Dose-Response Increasing Response 0 Dose Threshold

  5. Threshold Dose • No effect level • Response at low dose is so low as to be insignificant – A SAFE DOSE • NEL, No Effects Level • NOEL, No Observed Effects Level • NOAEL, No Observed Adverse Effects Level Some Acronyms The basis for regulation

  6. Food Safety, Environmental • ADI, Acceptable Daily Intake • AWI, AMI etc • TDI, Tolerable Daily Intake • MCL, Maximum Contaminant Level (SDWA) • SF, UF, MF: safety, uncertainty, modifying factors • TLV, Threshold Limit Value • TLV-C, ceiling level • STEL, Short-term exposure limit • TWA, Time-Weighted Average (8h day, 40 h week) Occupational exposure limits

  7. Above the threshold • Dose-response is linear ? y = ax + b • Dose-response is not linear Defining the shape of the dose-response curve Theoretical treatment: Assume Quantal or dichotomous response

  8. Continuous response eg DNA Binding

  9. Quantal response Dichotomous response • Corresponds to “occupied receptor” • Examples: Mortality, Tumor incidence • Assumes normal (Gaussian) distribution • Maximum 100% affected

  10. e = Emax * [T] / (KT + [T]) Where e = response or effect e Emax = maximum response [T] = concentration of toxicant KT = the dissociation constant of the toxicant/receptor complex

  11. When [T] = 0, e = 0 When all receptors are occupied: e = Emax

  12. LD50 Lethal dose LC50 Lethal concentration ED50 Effective dose

  13. Some Acute Oral LD50 Values • Category Dose Species Chemical (mg/kg body weight) • Practically nontoxic • 15 000 • Slightly toxic 10 000 Mouse Ethanol • 5 000 • Moderately toxic 4 900 Rat Glyphosate • 750 Rat Atropine • 500 • Highly toxic 250 Rat Carbaryl • 50 • Extremely toxic 13 Rat Parathion • 5 • Supertoxic 3 Rat Warfarin • 0.4 Duck Aflatoxin B1

  14. Species differences in the acute toxicity of dioxin* *Dioxin: 2,3,7,8-tetrachlorobenzdioxin: TCDD

  15. Oral LD50 Values (mg/kg) Test Compound: Caffeine

  16. Other toxic effects • Acute / chronic • Reversible / irreversible • Immediate / delayed • Idiosyncratic - hypersensitivity • Local / systemic • Target organs

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