Risk Assessment Dec 4 -6, 2006

Toxicology – the dismal science Toxicology + Risk Assessment = the predictive science

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

Food and Drug Administration (FDA) Food and Drugs Act (1906) prohibits interstate commerce in misbranded and adulterated foods, drinks and drugs.

“Anyone who says saccharin is injurious to health is an idiot” Theodore Roosevelt (26th President of the USA, 1901-1909)

1938 Food, Drug and Cosmetic Act Requires that “safe tolerances” be set for “unavoidable poisonous substances”. 1940 FDA transferred from USDA to Federal Security Agency, first Commissioner of Food and Drugs appointed 1944 Public Health Service Act 1968 FDA placed in Public Health Service

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

1958 Food Additives Amendment Generally Regarded As Safe GRAS List 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 Acceptable dose: dose that causes 1 in 106 lifetime risk of cancer

Dose-Response Increasing Response Dose No Threshold

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

Dose-Response Increasing Response Dose Threshold

Non-carcinogens No Observed Adverse Effects Level NOAEL

ADI = NOAEL Safety Factor(s) Poor quality of data 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 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)

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 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

Competing risks Drinking water disinfectant by-products ↔ infectious diseases

“Acceptable” risks Carcinogens: 1 in 106 over lifetime Occupational exposures: 1 in 103 – 1 in 104 over working lifetime Enteric diseases: 1 in 104 per year

Comparison of Risks Disability Adjusted Life Years