Post on 05-Jan-2016
description
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)
Dose-Response
Increasing Dose
Increasing Response
0
The J-shaped curve(hormesis)
Increasing Dose
Incr
easi
ng R
espo
nse
Dose-Response
Dose
Increasing Response
0Threshold
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
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
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
Continuous response eg DNA Binding
Quantal response Dichotomous response
• Corresponds to “occupied receptor”
• Examples: Mortality, Tumor incidence
• Assumes normal (Gaussian) distribution
• Maximum 100% affected
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
When [T] = 0, e = 0
When all receptors are occupied:
e = Emax
Dose (mg/kg)
0 1000 2000 3000 4000 5000
% r
esp
on
se
0
20
40
60
80
100 Dose-response - linear
Dose (mg/kg)0.1 1 10 100 1000 10000
% r
espo
nse
0
20
40
60
80
100 Dose-response - log
LD50 Lethal dose
LC50 Lethal concentration
ED50 Effective dose
Dose (mg/kg)
0.1 1 10 100 1000 10000
% r
esp
on
se
0
20
40
60
80
100
Dose (mg/kg)0.1 1 10 100 1000 10000
% r
espo
nse
0
20
40
60
80
100 Dose-response - log
Some Acute Oral LD50 Values
Category Dose Species Chemical(mg/kg body weight)
Practically nontoxic15 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
Species LD50 (ug/kg body wt)
Guinea-pig 0.5-2
Rat 22-100
Mouse 114-284
Rabbit 10-115
Chicken 25-50
Rhesus monkey < 70
Dog >30-100
Hamster 5051
Species differences in the acute toxicity of dioxin*
*Dioxin: 2,3,7,8-tetrachlorobenzdioxin: TCDD
Oral LD50 Values (mg/kg)
Males Females
Mice 127 137
Rats 355 247
Hamsters 230 249
Rabbits 246 224
Test Compound: Caffeine
Other toxic effects
• Acute / chronic
• Reversible / irreversible
• Immediate / delayed
• Idiosyncratic - hypersensitivity
• Local / systemic
• Target organs