Use of Data in Assessing Human Health Effects

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Use of Data in Assessing Human Health Effects

• Vanessa T. Vu, Ph.D.
• Endocrine Disruptor Methods
  Validation Subcommittee Meeting
• March 26, 2002
• Washington, D.C.

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Objectives

• Describe ongoing activities addressing human
  relevancy
• Overview of EPAs current approach to human
  health risk assessment
• Focus on data used in Hazard and Dose-Response
  Assessment
• Discuss the need for further work

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EPA Risk Assessment Guidelines

• Provide guidance to the Agency and inform outside
  parties how risk assessments are to be conducted
  to foster sound science, consistency, and
  transparency
• Lay out scientific principles, approaches,
  processes, and procedures for conducting human
  health and ecological hazards and risks
• Guidance for data interpretation, and use of data

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EPA Human Health Risk Assessment Guidelines

• Specific Health Effects
• Carcinogenicity (1986, 1999)
• Neurotoxicity (1998)
• Reproductive toxicity (1996)
• Developmental toxicity (1991)
• Mutagenicity (1986)
• Others
• RfC (1994), Benchmark Dose (2000),
• Chemical Mixtures (1986, 2001)
• Risk Characterization (2000)
• Exposure Assessment (1996)

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Risk Assessment ProcessHuman Health
HAZARDASSESSMENT
DOSE RESPONSE ASSESSMENT
EXPOSURE ASESSMENT
Dose-Response Characterization
Exposure Characterization
Hazard Characterization
Risk Characterization Summary
Integrative Analysis
Risk Characterization Process
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Current Approach

• Emphasize full characterization and integration
• Maximum use of all relevant information
• Expand role of mode of action information
• Harmonized approaches for all toxicities
• Two-step dose response assessment
• Evaluate data in range of observation
• Evaluate in range of human exposure
  (extrapolation)

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Data Used in Hazard and Dose Response Assessment

• Studies of humans
• Data from other species
• Standard screening and toxicity studies
• Toxicokinetic and metabolic studies
• Mode of action information
• Other relevant information, e.g., chemical and
  physical properties, SAR

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Major Default Assumptions

• In the absence of adequate human data
• An agent that produce an adverse effect in
  experimental animal studies is assumed to pose a
  hazard to humans and
• Data from the most appropriate or sensitive
  species should be used
• In the absence of mode of action information
• A linear dose response curve is assumed for
  carcinogenic effects
• A nonlinear dose response (or threshold) is
  assumed for other effects

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Mode of Action

• How does the agent produce its effect?
• Are there data to support a postulated mode of
  action?
• Have other modes of action been considered and
  rejected?

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Mode of Action vs.Mechanism of Action

• Mode of Action
• Key events and processes, starting with the
  interaction of an agent with a cell, through
  functional and anatomical changes, resulting in
  toxicity
• Mechanism of Action
• Detailed molecular description of a key event in
  the induction of toxicity

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Use of Mode of Action Information

• Evaluate relevance of animal models
• Determine relative sensitivity of animal models
  compared to humans
• Identify susceptible subpopulations and estimate
  variability in response
• Refine measures of dose and response

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Use of Mode of Action Information (continued)

• Strengthen inferences regarding the shape of dose
  response curves outside the range of observation
• Provide the basis for an integrated approach for
  all health endpoints
• Extrapolate within chemical classes with common
  mode(s) of action

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Demonstrating a Mode of Action

• To show that a postulated mode of action is
  operative, it is generally necessary to
• Outline the sequence of events leading to effects
• Identify key events that can be measured
• Weigh information to determine whether there is a
  causal relationship between events and toxic
  effects

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Key Event-- Examples

• Metabolism
• Receptor-ligand changes
• DNA or chromosome effects
• Increased cell growth and organ weight
• Hormone or other physiological
  perturbations
• Hyperplasia, cellular proliferation

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Use of Mode-of-Action Information Examples

• Formaldehyde DNA crosslinks
  Cell proliferation
• d-Limonene ?2u-globulin
• Chloroform Cytotoxicity
• Dioxin Receptor-mediated responses
• Perchlorate Altered thyroid homeostasis
• Vinyl acetate Cytotoxicity
  Cell proliferation

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Current ActivitiesCarcinogenicity

• Framework for evaluating mode of action has been
  developed for carcinogenic effect (IPCS, 2000)
• Several activities are underway to provide
  additional guidance for evaluating the relevance
  of the animal mode of action to humans
• EPA-- Finalize EPAs Carcinogen Risk Assessment
  Guidelines
• ILSI-RSI, WHO/IPCS

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Current Activities (continued)

• Review of available data for pharmaceuticals to
  determine similarities and differences between
  animals and humans
• Concordance of toxicity (ILSI-HESI)
• Pharmacokinetics (EPA)

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Endocrine DisruptionEPA Interim Policy

• Based on the current state of science, the
  Agency does not consider endocrine disruption to
  be an adverse endpoint per se, but rather a mode
  or mechanism of action potentially leading to
  other outcomes, for example, carcinogenic,
  reproductive or developmental effects, routinely
  considered in reaching regulatory decisions.
  Evidence of endocrine disruption alone can
  influence priority setting for further testing
  and the assessment of the results of this testing
  could lead to regulatory action if adverse
  effects are shown to occur. This position could
  change as additional data become available on the
  mechanisms and role of endocrine disruptors.
• Special Report on Environmental Endocrine
  Disruption An Effects Assessment and Analysis
  (1997)

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Planned Activities on Endocrine Disruptors

• Case studies demonstrating an integrated approach
  for using all available data to assess effects in
  humans and wildlife species (EPA)
• Framework for Risk Assessment of EDCs (EPA)
• Review of pesticides with common modes of action-
  anti-thyroid, anti-androgen compounds (EPA)

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Future Needs

• Continued research and evaluation of the modes of
  toxic action in animals and human relevancy
• Endocrine disruption modes of action
• Demonstrate the usefulness of a framework to
  evaluate modes of action for non-cancer
  toxicities and human relevancy