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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

Risk Assessment

Dec 3 - 5, 2007

slide2
Toxicology – the dismal science
  • Toxicology + Risk Assessment = the predictive science
the risk assessment paradigm
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 Drug Administration(FDA)
  • Food and Drugs Act (1906) prohibits interstate commerce in misbranded and adulterated foods, drinks and drugs.
slide5

“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
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
slide7
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
1958 Food Additives Amendment

Generally

Regarded

As

Safe

  • GRAS List
  • Delaney Clause
slide9

The Delaney ClauseNo 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
Carcinogens
  • No safe dose
  • Acceptable dose: dose that causes 1 in 106 lifetime risk of cancer
slide11

Dose-Response

Increasing Response

0

Dose

No Threshold

slide13

Dose-Response

Increasing Response

0

Dose

Threshold

slide14

Non-carcinogens

No

Observed

Adverse

Effects

Level

NOAEL

slide15

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
Extrapolations
  • From short-term studies to lifetime exposure
  • From animals to humans
scale from animal to human
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
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
1996 Food Quality Protection Act
  • Amendment to FDCA, removes application of Delaney Clause to pesticides and pesticide residues
  • The “Risk Cup”
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
Interactions
  • Additivity
  • Synergism
  • Potentiation
  • Antagonism
interactions can be expected between chemicals that
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
Combinations
  • Binary mixtures
  • Ternary mixtures
  • Four- , five-component mixtures
  • Six, seven, eight….
  • ...
  • Complex mixtures
additivity
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
Synergism
  • The whole is greater than the sum of the individual constituents

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

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

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

slide29
Competing risks

Drinking water disinfectant by-products

↔ infectious diseases

acceptable risks
“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
Comparison of Risks

Disability

Adjusted

Life

Years

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