Risk Assessment Dec 7, 2009 Timbrell 3rd Edn pp 16-21 Casarett & Doull 7th Edn Chapter 7 (pp 107-128)

The Risk Assessment Paradigm National Research Council's 1983 report Risk Assessment in the Federal Government: Managing the Process, called the "Red Book" Hazard Evaluation Dose-Response Evaluation Exposure Assessment Risk Characterization Risk = Probability (of adverse outcome) Hazard ≠ Risk

US EPA

Dr. Costa

Carcinogens Dose-response 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 Increasing Response Slope = Potency Dose No Threshold

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

Incidence of lung tumors Methylene Chloride CH2Cl2 Human 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 Animal data: Concentration in air Incidence of lung tumors 3/45 2000 16/46 4000 41/46

Carcinogens No safe dose Acceptable dose: dose that causes 1 in 106 lifetime risk of cancer Does this apply to all carcinogens ? Flash-back to Dr. Rusyn’s material

Peroxisome Proliferators A wide range of classes of chemicals: lipid lowering drugs, plasticizers, food flavors, industrial solvents, herbicides Cause marked increases in size and number of peroxisomes Potent rodent liver carcinogens Human exposure is from therapeutic, environmental, industrial and other sources No clear epidemiological evidence for or against carcinogenicity in humans

So, we have a chemical that is a non-genotoxic RODENT carcinogen! If we would regulate this chemical, would it help to improve the quality of HUMAN life?

For effects other than cancer: Is there a “safe” dose ?

Dose-Response Increasing Response Dose Threshold

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-species Animal-to-human Intra-species Particularly variability 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 Inter-individual variation in Exposure Metabolism Repair capacity Sensitivity … Uncertainty: Factors that we do not know or understand fully (yet) True magnitude of Exposure Metabolism Repair capacity Sensitivity How to extrapolate from test animals to humans, high to low doses… How to combine risks

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.

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

The Risk Cup Food Quality Protection Act (1996) Amendment to Food Drugs and Cosmetics Act (1906, 1938) “Assess the risk of the pesticide chemical residue [to infants and children] based on…available information concerning the cumulative effects on 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

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 Effecttotal >> PotencyA* DoseA where PotencyB = 0 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