JAS Toxicity
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Transcript of JAS Toxicity
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Prof. J.A. Swenberg, DVM, PhD
Dept Environmental Sciences and Engineering
Rosenau [email protected]
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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
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Acute Toxicity Studies
Repeated dose studies - rat, mouse (5-
10/sex/dose), dog, monkey (2/sex/dose)
In-life observations
Necropsy
Histopathology
Clinical pathology (optional)
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Acute LD50 Values vs Toxicity
Chemical
______________________________________
LD50 (mg/kg)
_________________
Toxicity
_________________
Sodium chloride 4000 Slightly toxic
DDT 100 Moderately toxic
Picrotoxin
StrychnineNicotine
5
21
Highly toxic
Dioxin
Botulinum toxin
0.001
0.00001
Super toxic
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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
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Subchronic Toxicity
13 week study +/- 4 wk recovery (3 dosesand control)
Species - rat (10/sex/dose), dog or monkey(2/sex/dose)
In-life observations (+/- ophthamology)
Clinical pathology Necropsy
Histopathology
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Carcinogenicity Study
2 years (3 doses and control)
Species - rats and mice (50/sex/dose)
In-life observations
Clinical pathology (rats, optional)
Necropsy Histopathology
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Carcinogenicity Study Evaluation
Issues
Survival
Body weight Variability of
endpoints
Pathology Working
Group
MTD
Statistics vs biology Dose-response
Mechanistic factors
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MTD ISSUE
The Maximum Tolerated Dose is defined
as the highest dose of a chemical or drug
that can be administered for the animalslife without causing excessive toxicity or
decreasing survival (except due to tumor
induction).
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MTD Debate I
Normal physiology, homeostasis and
detoxification or repair mechanisms may
be overwhelmed and cancer, whichotherwise might not have occurred, is
induced or promoted.
OSTP, 1985
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MTD Debate II
More than two-thirds of the
carcinogenic effects detected in feeding
studies would have been missed had thehigh dose been reduced from the
estimated MTD to 1/2 the MTD.
Haseman, FAAT, 1985
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MTD Issue
The problem is not testing for
carcinogenic potential at the Maximum
Tolerated Dose, it is how those data areused in risk assessment. The proper
interpretation and use requires an
understanding of the mechanism(s) ofaction.
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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 animportant role in the development of
backup drugs and chemicals.
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Bradford Hill Criteria
for Cancer Causation
Consistency
Strength
Specificity
Temporality
Coherence
Dose Response
Biological
Plausibility
Experimental
Support Analogy
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1986 EPA Cancer Risk Assessment Guidelines
i h i i f h i
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Systematic Characterization of ComprehensiveExposure-Dose-Response Continuum and the Evolutionof Protective to Predictive Dose-Response Estimates
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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 datagaps
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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
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Human
EPI
Data
Where the
Question ofHealth Risk is
Raised
Respo
nse
Log Dose
Paustenbach (1995
Animal
Data
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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 1,000workers being not uncommon
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Hazard Identification
A qualitative risk assessment
Does an agent have the potential to increase
the incidence of cancer under any
conditions
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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
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Exposure Assessment
EPA uses the cumulative dose received over
a lifetime
This is expressed as the average daily
exposure
Occupational exposures are usually basedon exposure during the work week
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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
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Helpful Web Sites
www.epa.gov/ncea/
www.fda.gov/cder/
www.ovpr.uga.edu/qau/