Regulatory Toxicology

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Regulatory Toxicology
Chapter 10
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Safety evaluation Risk Assessment
Chapter 10
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Safety Evaluation
Part 1
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Risk Assessment
Part 2
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Introduction and Definitions
Section 1
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Historical context

• Advance in analytical chemistry forced the
  regulatory agencies to develop tolerance levels
  such as thresholds limit values and acceptable
  daily intakes.
• nondetects are not equivalent to not present.
  There is no absolute safe.

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Historical context

• During 20 years before 1990, only 7 substances
  (vinyl chloride, asbestos, benzene,
  radionuclides, mercury, arsenic, beryllium) had
  been regulated under the basis of no-effect level
  widely agreed as safe at that time.
• Replacement of safety levels with acceptable
  risk levels .

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Historical context

• NRC(1983) Risk Assessment in the Federal
  Government managing the process.
• NAS(1994) Science and Judgment in Risk
  Assessment
• Presidential/Congresssional Commission on Risk
  Assessment and Risk Management (1997)

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Definitions

• Risk The probability of an adverse outcome to
  the human health.
• Hazard Intrinsic toxic properties of
  environmental agents.
• Risk assessment The systematic characterization
  of potential adverse health effects resulting
  from human exposure to hazardous agents or
  situations.

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Definitions

• Risk characterization The combination of
  qualitative and quantitative analysis of risk.
• Risk management The process by which policy
  actions are chosen to control hazards identified
  in risk assessment.
• Risk communication The challenging process of
  making risk assessment and management information
  comprehensible to community groups and
  stakeholders.

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Key steps of risk assessment
Section 2
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Key Steps

• Hazard identification
• Dose-response assessment
• Human exposure assessment
• Risk characterization

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Risk Perception

• Knowledge
• Life experience
• Psychological factors
• Political factors
• Social and economical factors

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Hazard identification

• Assessing toxicity of chemicals
• Structure / activity relationship
• In vitro and short-term tests
• Animal bioassays
• Use of epidemiologic data
• Mechanistic considerations

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Dose-response assessment

• Needs for extrapolations
• Threshold approaches non-carcinogenic chemicals,
  system toxicants
• Nonthreshold approaches carcinogenic chemicals,
  ionizing irradiation
• Models derived from mechanistic assumptions

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Human exposure assessment

• To determine exposure pathways
• To quantify pathway-specific exposure
• To calculate overall exposures
• Point estimation method
• Probabilistic method

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Risk characterization

• Noncancer risk calculation
• NOAEL or LOAEL
• RfD or RfC
• Cancer risk calculation
• Radiation risk factor
• Carcinogenic potency factor

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Noncancer Risk Assessment

• Identify critical effect.
• Identify NOAEL or LOAEL for the critical effect.
• Apply UFs to the NOAEL or LOAEL to derive RfD or
  RfC.

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As Defined by EPA

• RfD or RfC is ...
• an estimate (with uncertainty spanning perhaps an
  order of magnitude) of
• a daily (for RfD) or continuous (for RfC)
  exposure to the human population (including
  sensitive subgroups)
• that is likely to be without an appreciable risk
  of deleterious effects during a lifetime.

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Uncertainty analysis

• factors uncertainty
• 10 individual difference
• 10 or 3 difference between animal and human
• 10 or less extrapolation from sub- to chronic
• 10 or less extrapolation from LOAEL to NOAEL
• 10 or less data quality
• These factors are as used by the U.S. EPA.
  Other health organizations use similar factors.
  In EPA, the maximum UF for any given database is
  3,000. Databases weaker than this are judged too
  uncertain to estimate RfD/RfCs.

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Framework of risk assessment / management
Section 3
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Risk assessment is a challenging area in
toxicology