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

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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)

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Dose (mg/kg)0.1 1 10 100 1000 10000

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LD50 Lethal dose

LC50 Lethal concentration

ED50 Effective dose

Dose (mg/kg)

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Dose (mg/kg)0.1 1 10 100 1000 10000

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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