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Risk Assessment. Dec 3 - 5, 2007. 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" .

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Risk assessment l.jpg

Risk Assessment

Dec 3 - 5, 2007

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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

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Food and Drug Administration(FDA)

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

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“Anyone who says saccharin is injurious to health is an idiot”

Theodore Roosevelt

(26th President of the USA, 1901-1909)

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1938 Food, Drug and Cosmetic Act idiot”

  • 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

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Miller Amendment idiot” (1954)

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

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1958 Food Additives Amendment idiot”





  • GRAS List

  • Delaney Clause

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The Delaney Clause idiot”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

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Carcinogens idiot”

  • No safe dose

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

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Dose-Response idiot”

Increasing Response



No Threshold

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For effects other than cancer: idiot”

Is there a “safe” dose ?

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Dose-Response idiot”

Increasing Response




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Non-carcinogens idiot”







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The amount of a substance that can be ingested over a

lifetime without significant health risk


Safety Factor(s)

Poor quality of data

Safety Factor = 10 x 10 [x 10] [x 10]


Animal-to-human Intra-species Particularly

variability inter-individual severe effect


Units: mg/kg/day

Based on most sensitive species and most sensitive end-point

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Extrapolations idiot”

  • From short-term studies to lifetime exposure

  • From animals to humans

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Scale from animal to human idiot”

  • 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)

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Factors in determining acceptable dose idiot”

  • 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.

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1996 Food Quality Protection Act idiot”

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

  • The “Risk Cup”

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The Risk Cup idiot”

  • 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”

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Interactions idiot”

  • Additivity

  • Synergism

  • Potentiation

  • Antagonism

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Interactions can be expected between chemicals that idiot”

  • Act by binding to the same receptor

  • Act through the same mechanism

  • Require the same enzyme for activation/detoxication

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Combinations idiot”

  • Binary mixtures

  • Ternary mixtures

  • Four- , five-component mixtures

  • Six, seven, eight….

  • ...

  • Complex mixtures

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Additivity idiot”

  • 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

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Synergism idiot”

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

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

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Potentiation idiot”

  • 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

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Antagonism idiot”

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

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

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Drinking water disinfectant by-products

↔ infectious diseases

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“Acceptable” risks idiot”

  • Carcinogens: 1 in 106 over lifetime

  • Occupational exposures: 1 in 103 – 1 in 104 over working lifetime

  • Enteric diseases: 1 in 104 per year

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Comparison of Risks idiot”