1. 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)

3. Dose-Response Increasing Dose Increasing Response 0

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

5. Dose-Response Dose Increasing Response 0 Threshold

6. 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

7. 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

8. 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

9. Continuous response eg DNA Binding

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

11. e = E max * [T] / (K T + [T]) Where e = response or effect e E max = maximum response [T] = concentration of toxicant K T = the dissociation constant of the toxicant/receptor complex

12. When [T] = 0, e = 0 When all receptors are occupied: e = E max

16. LD 50 Lethal dose LC 50 Lethal concentration ED 50 Effective dose

19. Some Acute Oral LD 50 Values CategoryDoseSpeciesChemical (mg/kg body weight) Practically nontoxic 15 000 Slightly toxic10 000MouseEthanol 5 000 Moderately toxic 4 900RatGlyphosate 750RatAtropine 500 Highly toxic 250RatCarbaryl 50 Extremely toxic 13RatParathion 5 Supertoxic 3RatWarfarin 0.4DuckAflatoxin B 1

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

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

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