1. Dose-Response ENVR430 Oct 08, 2007
Casarett and Doull, Chapter 2, pp
Timbrell Chapter 2 (pp. 7-25)

3. Dose-Response
Increasing Response
Increasing Dose

4. Dose-Response
Increasing Response
Dose
Threshold

5. Dose threshold No effect level
Response at low dose is so low as to be insignificant

6. Some Acronyms NEL, No Effects Level NOEL, No Observed Effects Level
NOAEL, No Observed Adverse Effects Level

7. More Acronyms ADI, Acceptable Daily Intake TDI, Tolerable Daily Intake
AWI, AMI etc
TDI, Tolerable Daily Intake
MCL, Maximum Contaminant Level (SDWA)
SF, UF, MF: safety, uncertainty, modifying factors

8. Defining the shape of the dose-response curve
Continuous response
Quantal or dichotomous response

9. Continuous response e.g. tumor multiplicity, tumor size
enzyme levels (ALT, AST)
Maximum value limited by the magnitude of the possible measurements

12. Quantal response Dichotomous response
Corresponds to “occupied receptor”
Maximum 100% affected
Tumor incidence
Mortality
Gaussian distribution

13. 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

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

16. 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

17. Receptors important in Toxicology
Ah (TCDD) receptor
Steroid receptors

18. 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

19. 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]

20. 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])

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

26. LD50
LC50
ED50

27. 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

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

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

30. Other Factors 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

31. Other factors II Assumes normal (Gaussian) distribution
Uniform population - no significant inter-individual differences in response
Dichotomous (quantal) response e.g. tumor incidence

32. Other factors II Assumes normal (Gaussian) distribution
Assumes uniform population - no significant inter-individual differences in response – shape of curve can give clues
Timing of exposure may be important
Exposure to multiple agents

33. Environmental Exposures
Food
Nutrients
Additives
Residues
Combustion products
Occupational exposures
Etc

34. Interactions
Additivity
Synergism
Potentiation
Antagonism

35. The Risk Cup Food Quality Protection Act (1996)
“Assess the risk of the pesticide chemical residue [to infants and children] based on…available information concerning the cumulative effects of infants and children of such residues and other substances that have a common mechanism of toxicity”

36. Interactions can be expected between chemicals that
Act by binding to the same receptor
Act through the same mechanism
Require the same enzyme for activation/detoxication

37. Combinations Binary mixtures Ternary mixtures
Four- , five-component mixtures
Six, seven, eight….
...
Complex mixtures

38. Additivity Chemicals A, B, C…N are all toxic
Potency of mixture = Sum of potencies of constituents
Effecttotal = PotencyA * DoseA + PotencyB * DoseB + PotencyC * DoseC +…..+PotencyN * DoseN

39. Synergism
Potency of the whole is greater than the sum of the potencies of the individual constituents
Effecttotal >> PotencyA* DoseA + PotencyB* DoseB… +… PotencyN* DoseN

40. Potentiation Effecttotal >> PotencyA* DoseA where PotencyB = 0
One constituent is toxic, the other is not.
Potency of the combination is greater than the potency of the active constituent
Effecttotal >> PotencyA* DoseA
where PotencyB = 0

41. Antagonism
Potency of the whole is less than the sum of the potencies of the individual components
Effecttotal << PotencyA* DoseA + PotencyB* DoseB… +… PotencyN* DoseN

42. Systemic toxicology Dermal - Dr. Nylander-French
Nervous, reproductive, renal, hematopoietic systems - Prof. Swenberg
Liver - Dr. Simmons
Lung - Dr. Costa