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Dose-Response

Dose-Response. ENVR430 Oct 13, 2008. 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 Oct 13, 2008 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. Quantal response Dichotomous response • Corresponds to “occupied receptor” • Examples: Mortality, Tumor incidence • Assumes normal (Gaussian) distribution • Maximum 100% affected

  9. Basic assumptions • (a) The response is causally related to the compound administered • (b) The response is a function of the concentration at the site of action • (c) The concentration at the site of action is related to the external dose • (d) An interaction at the site of action initiates a proportional response • (e) The crucial interaction involves reversible formation of a receptor-toxin complex

  10. Receptors • Usually proteins • Located on outside of cell wall, or inside cell • Interact with ligands

  11. Receptors important in Pharmacology • Agonists and antagonists of neurotransmitters: cholinergic receptors: acetylcholine; nicotinic receptors: skeletal muscle, autonomic ganglia; muscarinic receptors: smooth muscle, heart, exocrine glands • Adrenergic receptors: dopamine, endorphins, enkephalins, histamine • Hormone receptors: Insulin, cortisone (glucocorticoids), estrogen, progesterone, testosterone, prostaglandins • Drug receptors: Benzodiazepines

  12. Receptors important in Toxicology • Ah (TCDD) receptor • CAR, PPARα • Steroid receptors

  13. Reversible formation of a receptor-toxin complex k1 R + T R-T k-1 R = receptor T = toxic compound R-T = receptor-compound complex k1 and k-1 are rate constants for formation and dissociation (respectively) of the complex R-T

  14. k1 * [R] * [T] = k-1 * [R-T] KT is the dissociation constant of the complex, = k-1/k1 = [R] * [T] / [R-T] Total concentration of receptors [Rt] = [R] + [R-T], or [R] = [Rt] - [R-T] KT = ([Rt] - [R-T])*[T] / [R-T] = ([Rt]*[T] - [R-T]*[T])/[R-T] Proportion of total receptors that are occupied = [R-T]/[Rt] [R-T] = ([Rt] - [R-T])* [T] / KT = [Rt]*[T]/KT - [R-T] * [T]/KT [R-T] + [R-T]*[T]/KT = [Rt] * [T] /KT = [R-T] * (1 + [T]/KT) [R-T] = ([Rt] * [T]/KT) / (1 + [T]/KT) [R-T]/[Rt] = [T] / KT * (1 + [T]/KT) = [T] / (KT + KT*[T]/KT) [R-T]/[Rt] = [T] / (KT + [T]

  15. Response or effect e is proportional to [R-T] • Maximum response Emax occurs when all the receptors are occupied • e / Emax = [R-T] / [Rt] • [R-T]/[Rt] = [T] / (KT + [T]) • then e / Emax = [T] / (KT + [T]) • and e = Emax * [T] / (KT + [T])

  16. When T = 0, e = 0 When all receptors are occupied: [R-T] = [Rt] e = Emax

  17. Other Considerations • Duration of exposure • Interaction may not be reversible • Repair or removal of complex R-T may be important • Response may be multi-step, binding of T to R may not be the rate-limiting step • Uniform population - no significant inter-individual differences in response

  18. LD50 Lethal dose LC50 Lethal concentration ED50 Effective dose

  19. 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

  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

  23. WHERE DO WE MEASURE THE DOSE ? • External dose • Internal dose • Dose at target tissue • Dose of active species at molecular target of action

  24. Do we have to measure the internal dose ? Mathematical Models Kinetics

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