Acute Toxicity Studies by thI762H


									      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 Toxicity Studies
• Repeated dose studies - rat, mouse (5-
  10/sex/dose), dog, monkey (2/sex/dose)
• In-life observations
• Necropsy
• Histopathology
• Clinical pathology (optional)
Acute LD50 Values vs Toxicity
Chemical                                 LD50 (mg/kg)      Toxicity
______________________________________   _________________ _________________
Sodium chloride                          4000              Slightly toxic

DDT                                      100               Moderately toxic

Picrotoxin                               5                 Highly toxic
Strychnine                               2
Nicotine                                 1

Dioxin                                   0.001             Super toxic
Botulinum toxin                          0.00001
         Subacute Toxicity
• 28 day study (3 doses and control)
• Species - rat (10/sex/dose), dog or monkey
• 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
• In-life observations (+/- ophthamology)
• Clinical pathology
• Necropsy
• Histopathology
        Carcinogenicity Study
•   2 years (3 doses and control)
•   Species - rats and mice (50/sex/dose)
•   In-life observations
•   Clinical pathology (rats, optional)
•   Necropsy
•   Histopathology
Carcinogenicity Study Evaluation
 • Survival            •   MTD
 • Body weight         •   Statistics vs biology
 • Variability of      •   Dose-response
   endpoints           •   Mechanistic factors
 • Pathology Working
           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 of
decreasing survival (except due to tumor
     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
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.
       Bradford Hill Criteria
       for Cancer Causation
•   Consistency   • Dose Response
•   Strength      • Biological
•   Specificity     Plausibility
•   Temporality   • Experimental
•   Coherence       Support
                  • Analogy
1986 EPA Cancer Risk Assessment Guidelines
Systematic Characterization of Comprehensive
Exposure-Dose-Response Continuum and the Evolution
of Protective to Predictive Dose-Response Estimates
   IPCS/EPA Framework for
  Evaluating Mechanistic Data
• Introduction            • Biological plausibility
• Postulated mode of        and coherence
  action                  • Other modes of action
• Key events              • Assessment of mode of
• Dose-response             action
  relationship            • Uncertainties,
• Temporal association      inconsistencies and data
• Strength, consistency     gaps
  and specificity of
  association with key
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
            Where the
            Question of
           Health Risk is

                       Human      Animal
                        EPI        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
   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
• 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
        Helpful Web Sites

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