1. Dose-Response ENVR430 Oct 13, 2008
Casarett and Doull, Chapter 2, pp (6th Edn)
Chapter 2, pp (7th Edn)
Timbrell Chapter 2, pp (3rd Edn)

3. Dose-Response
Increasing Response
Increasing Dose

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

5. Dose-Response
Increasing Response
Dose
Threshold

6. Threshold Dose Some Acronyms The basis for regulation 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. Quantal response Dichotomous response
Corresponds to “occupied receptor”
Examples: Mortality, Tumor incidence
Assumes normal (Gaussian) distribution
Maximum 100% affected

10. 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

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

12. 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

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

14. Reversible formation of a receptor-toxin complexk1
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

15. 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]

16. 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])

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

22. 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

24. LD50 Lethal dose
LC50 Lethal concentration
ED50 Effective dose

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

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

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

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

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

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