Risk AssessmentNov 7, 2008

Timbrell 3rd Edn pp 16-21

Casarett & Doull 7th Edn Chapter 7 (pp 107-128)

The Risk Assessment Paradigm

• Hazard Evaluation

• Dose-Response Evaluation

• Exposure Assessment

• Risk Characterization

Risk = Probability (of adverse outcome)

Hazard ≠ Risk

National Research Council's 1983 report Risk Assessment in the Federal Government: Managing the Process, called the "Red Book"

US EPA

Dr. Costa

1938 Food, Drug and Cosmetic Act• Requires that “safe tolerances” be set for

“unavoidable poisonous substances”.

Miller Amendment (1954) Chemical pesticides and other residues tolerated at levels at which evidence can show that they “do not cause any deleterious effects”

Food Additives Amendment (1958)• GRAS List Generally

RegardedAsSafe

• Delaney Clause

The Delaney Clause

No Food Additive Shall be Deemed to be Safe if it is Found to Induce Cancer when Ingested by Man or

Animals, or if it is Found, After Tests which Are Appropriate for the

Evaluation of the Safety of Food Additives, to Induce Cancer in Man

or Animals

Carcinogens

• No safe dose

• Single molecule Cancer

• Acceptable dose: dose that causes 1 in 106 lifetime risk of cancer

• Need to define Potency

Dose-response

Dose-Response

Dose

Increasing Response

0

No Threshold

Slope = Potency

Modeling the dose-response• One hit

– linear model

• Multi-hit– Logit, Probit, Weibull, Gamma– Armitage-Doll Multistage Model (biologically-based)– Linearized Multistage (LMS) Model

P(D) = 1 – exp(-q0 - q1D - q2D2 - …- qnDn)

P(D) = q0 - q1D

q1 = q* = potency, units (dose) -1

e.g. (mg/kg/day) -1

Methylene Chloride CH2Cl2Human cancer risk derived from bioassay with

B6C3F1 female mice (Reitz et al., 1989) Model Cancer risk for 1 μg/m3

Probit < 10 -15

Logit 2.1 x 10-13

Weibull 9.8 x 10 -8

LMS 4.1 x 10 -6

Concentration in air Incidence of lung tumors

0 3/45

2000 16/46

4000 41/46

Animal data:

Carcinogens

• No safe dose

• Acceptable dose: dose that causes 1 in 106 lifetime risk of cancer

• All carcinogens ?

Flash-back to Dr. Rusyn’s material Flash-back to Dr. Rusyn’s material

Peroxisome ProliferatorsPeroxisome Proliferators

A wide range of classes of chemicals: A wide range of classes of chemicals: lipid lipid lowering drugs, plasticizers, lowering drugs, plasticizers,

food flavors, industrial solvents, herbicides food flavors, industrial solvents, herbicides Cause marked increases in size and number of Cause marked increases in size and number of

peroxisomes peroxisomes Potent rodent liver carcinogensPotent rodent liver carcinogens Human exposure is from therapeutic, Human exposure is from therapeutic,

environmental, industrial and other sourcesenvironmental, industrial and other sources No clear epidemiological evidence for or against No clear epidemiological evidence for or against

carcinogenicity in humans carcinogenicity in humans

So, we have a chemical that So, we have a chemical that is a non-genotoxic RODENT is a non-genotoxic RODENT

carcinogen!carcinogen!

If we would regulate this chemical, If we would regulate this chemical,

would it help to improve the quality would it help to improve the quality

of HUMAN life?of HUMAN life?

Is there a “safe” dose ?

For effects other than cancer:

Dose-Response

Dose

Increasing Response

0Threshold

Non-carcinogens

No

Observed

Adverse

Effects

Level

NOAEL

ACCEPTABLE DAILY INTAKE (ADI) or TOLERABLE DAILY INTAKE (TDI)

The amount of a substance that can be ingested over a lifetime without significant health risk

ADI = NOAEL Safety Factor(s)

Poor quality of data

Safety Factor = 10 x 10 [x 10] [x 10]Inter-speciesAnimal-to-human Intra-species Particularlyvariability inter-individual severe effect

variability

Units: mg/kg/day

Based on most sensitive species and most sensitive end-point

Extrapolations• From short-term studies to lifetime

exposure

• From high doses in animal studies to low doses in environmental exposure

• From animals to humans

Scale from animal to human

• Scale according to body weight (BW)

• Scale according to surface area – (BW)2/3

• Scale according to relative metabolic rates – (BW)3/4

• Biological modeling – physiologically-based (PBPK)

Variability - Uncertainty

Factors in determining acceptable dose

• Species differences, gender, age, body weight

• Approach has been chemical by chemical.

• Multiple chemical exposure - combined risk assessment approach. Multiple sources of exposure need to be accounted for.

1996 Food Quality Protection Act

• Amendment to FDCA, removes application of Delaney Clause to pesticides and pesticide residues

• The “Risk Cup”

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”

Interactions

• Additivity

• Synergism

• Potentiation

• Antagonism

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

Combinations

• Binary mixtures

• Ternary mixtures

• Four- , five-component mixtures

• Six, seven, eight….

• ...

• Complex mixtures

Additivity

• Chemicals A, B, C…N are all toxic

• Potency of mixture = Sum of potencies * concentrations of constituents

• Effecttotal = PotencyA * DoseA + PotencyB * DoseB + PotencyC * DoseC +…..+PotencyN * DoseN

Synergism

• The whole is greater than the sum of the individual constituents

Effecttotal >> PotencyA* DoseA + PotencyB* DoseB… +… + PotencyN* DoseN

Potentiation

• One constituent A is toxic, the other B is not.

• Effect of the combination A + B is greater than the effect of the active constituent

Effecttotal >> PotencyA* DoseA

where PotencyB = 0

Antagonism

• Effect of the whole is less than the sum of the effects of the individual components

Effecttotal << PotencyA* DoseA + PotencyB* DoseB… +… + PotencyN* DoseN