Transcript  Toxicology and Risk Assessment Michael H. Dong

Toxicology and
Risk Assessment
(3rd of 10 Lectures on
Toxicologic Epidemiology)
Michael H. Dong

MPH, DrPA, PhD
readings
Taken in the early ’90s, when desktop computers were still a luxury.
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.
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.
Health Statutes
& Regulations
Toxicity
Studies/Data
Research
Developments
low
uncontrollable,
not observable
uncontrollable,
observable
controllable,
not observable
controllable,
observable
Risk Perceived
Risk Perception
high
Health Perception (I)
• Fundamental to risk perception.
• Based on a broad spectrum of
toxic reactions.
• Definitions of adverse health
effects not uniformly accepted.
Health Perception (II)
• Problems with interpretation of
adverse health effects.
• Effects on health risk assessment
and toxicity studies.
• Different terminology for safe
human dose.
Impacts of Health
Risk Perception
• Ways in which NOAEL and
uncertainty/safety factors used.
• Technology-based vs. risk-based
health standards.
• Risks: assessment priority.
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.
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.
Effects on Toxicity
Assessment
• On hazard identification and doseresponse evaluation.
• Especially on carcinogenic,
neurotoxic, developmental, and
reproductive effects.
• Demanding valid biologic models
and high quality toxicity data.
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.
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.
Effects on/of Low-Dose
Extrapolation Models
• Mechanistic models (one-hit, multihit, multistage).
• Statistical models (Probit, Logit,
Weibull).
• Built on biological considerations.
• Aided with biologic models and
pharmacokinetics data.
Physiological-Based
Pharmacokinetic
(PB-PK) Modeling (I)
• A set of complex mass-balance
differential equations offering a time
course of a chemical’s disposition.
• Chemical’s disposition is followed in
accord with PK rate laws.
• Requiring intensive iterations with a
computer for simulation.
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.
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.
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.
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.
Regulatory Guidance
for Toxicity Testing
•U.S. FDA’s Redbook.
•U.S. EPA’s testing guidelines.
•OECD’s testing guidelines.
•Japan’s MAFF testing guidelines.
U.S. Regulatory Actions
on Risk Assessment
•FQPA on aggregate/cumulative
risk assessments.
•Delaney clause on carcinogen
risk assessment.
•The Benzene Decision.
World Actions on
Risk Assessment
•WHO’s efforts and influences.
•International comparison.
•WTO’s harmonization of risk
assessment.
•USA/OECD’s good laboratory
practices.
Health Statutes
& Regulations
Toxicity
Studies/Data
Research
Developments
Overview of Next Lecture
Epidemiology and Risk
Assessment
•Epidemiologic advances in health
risk assessment.
•Epidemiologic approaches to
exposure assessment.
•Biomarkers used in epidemiology.