Michael H. Dong

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Toxicology and Risk Assessment (3rd of 10
Lectures onToxicologic Epidemiology)
? readings

• Michael H. Dong
• MPH, DrPA, PhD

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Taken in the early 90s, when desktop computers
were still a luxury.
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Learning Objectives

• Learn the close linkages among health risk
  perception, regulatory statutes, toxicity
  studies, and related research developments.
• Learn how the above four (4) elements anchor the
  intimate interrelationship between toxicology and
  health risk assessment.

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Performance Objectives

• Able to list the factors of risk and health
  perceptions which have a great impact on health
  statues.
• To describe the spectrum of toxicity studies for
  health risk assessment.
• To appreciate the need for research developments
  related to toxicity data and assessment
  techniques.

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Health Risk Perception
Health Statutes Regulations
Toxicity Studies/Data
Research Developments
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Risk Perception
high
uncontrollable, not observable
Risk Perceived
controllable, not observable
uncontrollable, observable
controllable, observable
low
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Health Perception (I)

• Fundamental to risk perception.
• Based on a broad spectrum of toxic reactions.
• Definitions of adverse health effects not
  uniformly accepted.

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Health Perception (II)

• Problems with interpretation of adverse health
  effects.
• Effects on health risk assessment and toxicity
  studies.
• Different terminology for safe human dose.

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Impacts of Health Risk Perception

• Ways in which NOAEL and uncertainty/safety
  factors used.
• Technology-based vs. risk-based health standards.
• Risks assessment priority.

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Impacts of Health Statutes Regulations

• Mitigation feasibility with demonstration of
  risk.
• Zero tolerance for carcinogens (de minimus risk
  of cancer).
• Balance of risk and benefit.
• Aggregate and cumulative exposure/risk assessment.

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Effects on Health Statutes Regulations

• Effects of advances in assessment methodologies
  and other sciences.
• Toxicity assessment as key step in health risk
  assessment.
• Toward more realistic health policy agenda and
  programs.

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Effects on Toxicity Assessment

• On hazard identification and dose-response
  evaluation.
• Especially on carcinogenic, neurotoxic,
  developmental, and reproductive effects.
• Demanding valid biologic models and high quality
  toxicity data.

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Effects on/of Toxicokinetics Data

• Related to cumulative exposure and risk
  assessment.
• To interspecies extrapolation for equivalent
  dose.
• To strength-of-evidence and weight-of-evidence
  analysis.
• To understanding the toxic agent.

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Effects on/of Exposure Assessment

• On aggregate exposure with probabilistic
  analysis.
• On biomonitoring to measure total internal dose.
• Limitations of biomonitoring.
• Using PB-PK modeling as an aid in biomonitoring.

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Effects on/of Low-Dose Extrapolation Models

• Mechanistic models (one-hit, multi-hit,
  multistage).
• Statistical models (Probit, Logit, Weibull).
• Built on biological considerations.
• Aided with biologic models and pharmacokinetics
  data.

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Physiological-Based Pharmacokinetic (PB-PK)
Modeling (I)

• A set of complex mass-balance differential
  equations offering a time course of a chemicals
  disposition.
• Chemicals disposition is followed in accord with
  PK rate laws.
• Requiring intensive iterations with a computer
  for simulation.

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Physiological-Based Pharmacokinetic (PB-PK)
Modeling (II)

• Powerful tools for interpretation of biomarker
  data.
• For better use of spot sample results where
  complete urine (or other type of sample)
  collection not practical.
• For estimation of internal dose and of timed
  tissue concentrations.

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Toxicity Testing (I) Irritation, Sensitization,
Immunotoxicity

• Guidance on protocols for testing.
• Skin and eye irritation in rabbits.
• Skin sensitization test in guinea pigs.
• Tests on the immune system.

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Toxicity Testing (II) Mutagenicity,
Developmental, Reproductive, Others

• Gene mutation genome mutation Ames test
  transgenic mice.
• General fertility reproductive performance
  teratogenic potential multigeneration studies.
• Toxicity on other organs.

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Toxicity Testing (III) Acute, Subchronic,
Chronic, Carcinogenicity

• Acute lethality acute toxicity.
• Subchronic exposure in two species for 90 days
  or less.
• Chronic exposure typically in rats or mice may
  extend to lifetime for carcinogenicity.

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Regulatory Guidance for Toxicity Testing

• U.S. FDAs Redbook.
• U.S. EPAs testing guidelines.
• OECDs testing guidelines.
• Japans MAFF testing guidelines.

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U.S. Regulatory Actions on Risk Assessment

• FQPA on aggregate/cumulative risk assessments.
• Delaney clause on carcinogen risk assessment.
• The Benzene Decision.

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World Actions on Risk Assessment

• WHOs efforts and influences.
• International comparison.
• WTOs harmonization of risk assessment.
• USA/OECDs good laboratory practices.

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Health Risk Perception
Health Statutes Regulations
Toxicity Studies/Data
Research Developments
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Overview of Next Lecture Epidemiology and Risk
Assessment

• Epidemiologic advances in health risk assessment.
• Epidemiologic approaches to exposure assessment.
• Biomarkers used in epidemiology.