Regulatory Toxicology
James Swenberg, D.V.M., Ph.D.
Acute Toxicity Studies
• Single dose - rat, mouse (5/sex/dose), dog,
monkey (1/sex/dose)
• 14 day observation
• In-life observations (body wt., food
consumption, clinical observations)
• Necropsy
Acute LD50 Values vs Toxicity
Chemical
______________________________________
LD50 (mg/kg)
Toxicity
_________________ _________________
Sodium chloride
4000
Slightly toxic
DDT
100
Moderately toxic
Picrotoxin
Strychnine
Nicotine
5
2
1
Highly toxic
Dioxin
Botulinum toxin
0.001
0.00001
Super toxic
Acute Toxicity Studies
• Repeated dose studies (usually 14 days) rat, mouse (5-10/sex/dose), dog, monkey
(2/sex/dose)
• In-life observations
• Necropsy
• Histopathology
• Clinical pathology (optional)
Subacute Toxicity
• 28 day study (3 doses and control)
• Species - rat (10/sex/dose), dog or monkey
(2/sex/dose)
• In-life observations
• Clinical pathology
• Necropsy
• Histopathology
Subchronic Toxicity
• 13 week study +/- 4 wk recovery (3 doses and
control)
• Species - rat (10/sex/dose), dog or monkey
(2/sex/dose)
• In-life observations (+/- ophthamology)
• Clinical pathology
• Necropsy
• Histopathology
• Used to set doses for carcinogenicity studies
Chronic Toxicity
• 1 year study +/- 4-13 wk recovery (3 doses
and control)
• Species - rat (10-15/sex/dose), dog or
monkey (2-3 /sex/dose)
• In-life observations including
ophthalmology
• Necropsy
• Histopathology
Carcinogenicity Study
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2 years (3 doses and control)
Species - rats and mice (50/sex/dose)
In-life observations
Toxicokinetic studies
Clinical pathology (rats, optional)
Necropsy
Histopathology
Carcinogenicity Study Evaluation
Issues
• Survival
• Body weight
• Variability of
endpoints
• Pathology Working
Group
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MTD
Statistics vs biology
Dose-response
Mechanistic factors
MTD ISSUE
The Maximum Tolerated Dose is defined
as the highest dose of a chemical or drug
that can be administered for the animal’s
life without causing excessive toxicity or
decreasing survival (except due to tumor
induction).
Current MTD Debate
“Normal physiology, homeostasis and
detoxification or repair mechanisms may
be overwhelmed and cancer, which
otherwise might not have occurred, is
induced or promoted.”
OSTP, 1985
Current Debate
“More than two-thirds of the
carcinogenic effects detected in feeding
studies would have been missed had the
high dose been reduced from the
estimated MTD to 1/2 the MTD.”
Haseman, FAAT, 1985
MTD Issue
The problem is not testing for
carcinogenic potential at the Maximum
Tolerated Dose, it is how those data are
used in risk assessment. The proper
interpretation and use requires an
understanding of the mechanism(s) of
action.
Overview
The integration of metabolism, toxicity,
pathology and mechanism is playing a
much greater role today than ever before.
A better understanding of these areas is
essential for proper regulation of
chemicals and drugs. It can also play an
important role in the development of
backup drugs and chemicals.
General Approaches To Risk Assessment
• Qualitative approach using scientific judgment
• Quantitative approach using safety factors
• Quantitative approach using mathematical models
• Quantitative approach using linear extrapolation
• Biologically-based quantitative risk assessment
Response
Where the
Question of
Health Risk is
Raised
Human
EPI
Data
Animal
Data
Log Dose
Paustenbach (1995)
Cancer Risk Assessment
• Population risks for environmental
carcinogens are usually set at one additional
cancer per 100,000 or 1,000,000 individuals
• Occupational risks are frequently much
higher, with one additional cancer per 1,000
workers being not uncommon
Hazard Identification
• A qualitative risk assessment
• Does an agent have the potential to increase
the incidence of cancer under any
conditions
• Hazard Characterization takes into
consideration the conditions under which
the cancer was induced
Dose-Response Assessment
• The relationship between dose and response
(cancer incidence)
• Two sets of data are usually available
– Data in the observable range
– Extrapolation to responses below the
observable range
Exposure Assessment
• EPA uses the cumulative dose received
over a lifetime
• This is expressed as the average daily
exposure
• Occupational exposures are usually based
on exposure during the work week
Risk Characterization
• Provides an overall conclusion and confidence of
risk for the risk manager
• Gives the assumptions made
• Explains the uncertainties
• Outlines the data gaps
1986 EPA Cancer Risk Assessment Guidelines
Bradford Hill Criteria
for Cancer Causation
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Consistency
Strength
Specificity
Temporality
Coherence
• Dose Response
• Biological
Plausibility
• Experimental
Support
• Analogy
IPCS/EPA Framework for
Evaluating Mechanistic Data
• Introduction
• Postulated mode of
action
• Key events
• Dose-response
relationship
• Temporal association
• Strength, consistency
and specificity of
association with key
events
• Biological plausibility
and coherence
• Other modes of action
• Assessment of mode of
action
• Uncertainties,
inconsistencies and data
gaps
Systematic Characterization of Comprehensive
Exposure-Dose-Response Continuum and the Evolution
of Protective to Predictive Dose-Response Estimates
Helpful Web Sites
• http://cfpub.epa.gov/ncea/
• www.fda.gov/cder/
• www.ovpr.uga.edu/qau/index.html
Risk Assessment Assignments
• Review the Guidelines for Cancer Risk Assessment,
March 2005 at http://cfpub.epa.gov/ncea/
• We will compare these guidelines with the 1986 Cancer
Risk Assessment Guidelines on Friday.
• We will also discuss the Draft Supplemental Guidance
for Assessing Cancer Susceptibility from Early-Life
Exposure to Carcinogens on Monday.
• We will DISCUSS the issues in the next two class
periods. It will NOT be lectures.
Risk Assessment Assignments
Friday & Monday
• Hazard Identification vs Hazard Characterization
• Extrapolation: Linearized multistage vs Biologically-based vs
Linear vs Non-linear
• Framework analysis of Mode of Action
• Dose-response assessment: Extrapolation within and below the
observable data
• Susceptible populations
• Use of defaults
• Why not use safety factor?
• Uncertainties
Risk Assessment Assignments
Monday
• Factors that affect early-life susceptibility
• Evidence for increased early-life susceptibility
• Mode of action vs default in early-life susceptibility
• Quantitative effects of early-life exposure on risk
assessment
• Uncertainties associated with the supplemental
guidance
• Science vs science policy