Human Health Risk Assessment: Moving from Policy to Science

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Human Health Risk Assessment Moving from Policy
to Science

• Michael Dourson
• Toxicology Excellence for Risk Assessment (TERA)

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Toxicology Excellence for Risk Assessment (TERA)

• Toxicology Excellence for Risk Assessment (TERA)
  is a non-profit, 501(c)(3) corporation organized
  for scientific and educational purposes. 
• The mission of TERA is to support the protection
  of public health by
• developing, reviewing and communicating risk
  assessment values and analyses,
• improving risk assessment methods through
  research,
• and educating risk assessors and managers and the
  public on risk assessment issues.

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Risk Assessment/Management
BEST AVAILABLE TECHNOLOGY
DOSE RESPONSE ASSESSMENT
PUBLIC RESPONSE
RISK CHARACTERIZ- ATION
HAZARD IDENTIFICATION
KIDS
COST
POLITICAL CONSIDERATIONS
EXPOSURE ASSESSMENT
ENGINEERING OPTIONS
(National Academy of Sciences, 1983)
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Risk Assessment/Management
BEST AVAILABLE TECHNOLOGY
DOSE RESPONSE ASSESSMENT
MOS
HI
PUBLIC RESPONSE
RISK CHARACTERIZATION
COST
HAZARD IDENTIFICATION
MOE
KISS
MCLG
NSRL
POLITICAL CONSIDERATIONS
Peer Review
EXPOSURE ASSESSMENT
ENGINEERING OPTIONS
(National Academy of Sciences, 1983)
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As Defined by EPA an Reference Dose (RfD) or
Reference Concentration (RfC) Is

• an estimate (with uncertainty spanning perhaps an
  order of magnitude) of
• 
  
• a daily oral (for RfD) or continuous inhalation
  (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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HOW ACCURATE ARE THESE ESTIMATES?

• RfDs and RfCs are considered to be accurate
  estimates of doses below a toxicity threshold,
  because they are based on a review of all
  toxicity data and individual uncertainty factors
  are considered to be somewhat protective.
• ....If you play golf, accurate drives are
  generally those that land in the fairway,
  although they may be scattered over a wide area.

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How Precise Are These Estimates?

• Not very! Each uncertainty factor varies with
  ranges up to about 10-fold. Several factors are
  generally multiplied to estimate a subthreshold
  dose and some factors overlap, thereby increasing
  variability and decreasing precision.
• .....If you play golf, precise drives are those
  that consistently land in one area of the
  fairway (or the creek).

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New Concepts

• Over the last several years, scientists have
  begun using more data when extrapolating dose
  response and choosing uncertainty factors
• Methods range from default (presumed
  protective) to those incorporating more
  biological data (biologically-based protective)

Meek et al, 2001
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New Concepts

• Benchmark Dose
• Chemical Specific Adjustment Factors (CSAF)
• Categorical Regression
• Mode of Action

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Benchmark Dose/Concentration

• What is a Benchmark Dose/Concentrations (BMD/C)?
• The dose/concentration producing a predetermined
  level of adverse effect.
• For example, a 10 increase in animals developing
  liver necrosis.
• A BMD/C is calculated by fitting a mathematical
  dose-response model to data.

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Example of Calculation of a BMD for a Given
Incidence or Tumor Response
BMD
BMD Lower Bound
animals responding
NOAEL

BMD
BMDL
150
200
dose
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New ConceptsExample of Default UF Hg Oral RfD
EPA, 2001
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Observed Range of CNS Effects in Faroe Children
Percent Children With CNS Effects
Methyl Mercury Dose (µg/kg-day)
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New Concepts Chemical Specific Adjustment
Factors (CSAFs)

• Renwick (1993) proposed breaking the interspecies
  and intraspecies UFs into toxicokinetic (TK) and
  toxicodynamic (TD) components
• This approach was modified by World Health
  Organization- International Programme on Chemical
  Safety as follows

IPCS, 1994 2001
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New Concepts Interindividual Variability in
Ingested Hg
a Corresponding to either 1ppm Hg in hair or 1ppb
in blood
NAS, 2001
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New ConceptsExample of Chemical Specific
Adjustment Factors (CSAF) Categorical Default
for Hg
Total UF 5.8 Methyl Hg RfD 2 E-4 mg/kg-day
Dourson et al., 2001
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New Concepts Ingested Hg
NAS, 2001
Predicted mean probability of MeHg intake
corresponding to 11ppm MeHg in hair.
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New Concepts Compare ingestion rates
(?g/kg/day) of Seychelles studies from either
deterministic approach or Monte Carlo approach
(ICF Kaiser. 1998)
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New ConceptsRfD Based on a Monte Carlo
1st
2nd 3 UF for database
3rd
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Summary of Hg Example

• Limited scientific data supports use of default
  uncertainty factor for intra-species variability
  of 10 (Hg RfD 1 E-4) (EPA, 2001).
• Newer methods on categorical defaults allow
  replacement of defaults with compound specific
  data (Hg RfD 2 E-4) (Dourson et al., 2001).
• Monte Carlo Analysis requires more data but
  allows probabilistic approach to RfD
  determination (1st percentile Hg RfD 3 E-4)
  (ICF Kaiser. 1998).

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Categorical Regression
RfD Definition Regression
model "without appreciable risk" r lt
10-2 "is likely to be" P()
gt 0.95 "deleterious effect"
severity moderate or frank New RfD
Definition P ( r lt 10-2 at doseltRfD ) gt 0.95
where r P (severity gt1)
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Aldicarb Clinical Studies
Frequency of Clinical Signs or Blood Cholinesterase Frequency of Clinical Signs or Blood Cholinesterase Frequency of Clinical Signs or Blood Cholinesterase Frequency of Clinical Signs or Blood Cholinesterase Frequency of Clinical Signs or Blood Cholinesterase
Study Dose (mg/kg-day) Group Size Clinical Signs Blood Cholinesterase Inhibitiona
Haines, 1971 0.025 4 1 Apprehension 4 Whole blood
Haines, 1971 0.05 4 1 Runny nosec 4 Whole blood
Haines, 1971 0.10 4 4 Weakness and sweating, Nausea in 2 individuals 4 Whole blood
Wyld et al., 1992b 0 22 0 0 Plasma 0 RBC
Wyld et al., 1992b 0.010 8 2 Headachesc 0 Plasma 0 RBC
Wyld et al., 1992b 0.025 12 1 Sweating 12 Plasma 11 RBC
Wyld et al., 1992b 0.050 12 1 Sweating 1 Plasma 1 RBC
Wyld et al., 1992b 0.06 1 1 Sweating 1 Plasma 1 RBC
Wyld et al., 1992b 0.075 3 1 Lightheadedness 3 Plasma 3 RBC
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Effect Categories of Aldicarb Exposure in Humans
Frequency of Categories of Effect Associated with Aldicarb Exposure in Humans Frequency of Categories of Effect Associated with Aldicarb Exposure in Humans Frequency of Categories of Effect Associated with Aldicarb Exposure in Humans Frequency of Categories of Effect Associated with Aldicarb Exposure in Humans Frequency of Categories of Effect Associated with Aldicarb Exposure in Humans Frequency of Categories of Effect Associated with Aldicarb Exposure in Humans Frequency of Categories of Effect Associated with Aldicarb Exposure in Humans
Study Dose (mg/kg/day) Group Size Frequency of Responders within Categories of Frequency of Responders within Categories of Frequency of Responders within Categories of Frequency of Responders within Categories of
Study Dose (mg/kg/day) Group Size NO Effects Non-adverse Effects Adverse Effects Frank Effects
Wyld 0.0 22 22 (22) 0 (0) 0 (0) 0 (0)
Wyld 0.010 8 8 (0) 0 (0) 0 (0) 0 (0)
Wyld 0.025 12 0 (0) 8 (11) 4 (1) 0 (0)
Wyld 0.025 4 0 (0) 0 (3) 4 (1) 0 (0)
Wyld 0.50 12 0 (0) 1 (11) 11 (1) 0 (0)
Wyld 0.50 4 0 (0) 0 (4) 4 (0) 0 (0)
Wyld 0.075 4 0 (0) 0 (2) 4 (2) 0 (0)
Haines 0.10 4 0 (0) 0 (0) 2 (2) 2 (2)
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Probability of Effects with Aldicarb
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Under the EPA (2005) Guidelines for Carcinogen
Risk Assessment

• Chloroform is likely to be carcinogenic to humans
  by all routes of exposure under high-exposure
  conditions that lead to cytotoxicity and
  regenerative hyperplasia in susceptible tissues.
• Chloroform is not likely to be carcinogenic to
  humans by any route of exposure under exposure
  conditions that do not cause cytotoxicity and
  cell regeneration.
• EPA has determined that the RfD can be considered
  protective against increased risk of cancer.

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Detailed Graphical Representation of Chloroform
Extrapolations
BMDL
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EPAs Postulated Mode Of Action
Chloroform
CYP2E1
Metabolism
Oxidative
Phosgene
Sustained Toxicity
Regenerative Cell Proliferation
Key Events
Tumor Development
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Mutagenicity Conclusions

• Weight of Evidence
• Mutagenicity is not a component of chloroform
  induced neoplasia

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Metabolism Conclusions

• Predominate pathway
• P450 (CYP2E1)-mediated oxidative pathway
• Phosgene key reactive metabolite

• The following play little, if any role in
  chloroform induced tumors--
• Reductive P450 metabolism free radical
  production
• GST catalyzed conjugation

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Toxicity-Regenerative Proliferation
Conclusions

• Strong association of doses that cause sustained
  toxicity-proliferation tumors
• No persistent toxicity-proliferation in organs
  that do not show tumors
• Tumors are preceded by toxicity-proliferation

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Mode of Action Human Relevance

• Key steps are basic biochemical and cellular
  events in common to rodents humans

Oxidative CYP2E1 Metabolism Cell Injury
Death Regenerative Proliferation
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MOA Conclusions for Chloroform

• Postulated MOA Well Supported
• Other MOAs NOT Well Supported
• Human Relevance Presumed
• Applies to Children (but not more susceptible)
• Consistent with Nonlinear Dose Response
• Risk Approach Based on Protection Against
  Sustained Toxicity/Proliferation

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Summary of Traditional Approach New Methods

• Estimates of safe doses/concentrations are...
• accurate but imprecise
• believed to be without risk, but cannot
  estimate risk
• Benchmark Dose, Chemical Specific Adjustment
  Factors (CSAF) Categorical Regression Mode of
  Action analysis
• ask different questions of the data
• are not alternatives to each other
• nor are they alternatives to the current Safe
  dose
• Methods of combining two or more of these
  approaches are being used.

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What is Peer Review?

• Involves review of a draft product for quality by
  specialists who were not involved in its
  preparation.
• Evaluation of assumptions, alternate
  interpretations, methodologies, and conclusions.
  
• Reviewers have training experience to
  authors.
• Peer reviewers should be independent of authors
  and sponsoring organizations.
• Review serves to ensure that quality meets the
  standards of the scientific community.
• Peer Review is not the same as public comment.

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For a Peer Review to be Credible, it Must be
Independent

• Authors/sponsors should not participate in
  selection of peer reviewers.
• Candidates should be carefully screened for
  conflict of interest and biases.
• Panels should include reviewers with diverse
  perspectives and backgrounds.
• List of questions (charge) for reviewers should
  cover key issues and be objective.
• Reviewers must be provided with necessary
  documentation.
• Process should be public and transparent.
• Sponsors and authors should have limited
  interaction with the reviewers.

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Conflict of Interest (COI)

• National Academy of Sciences (NAS) procedures for
  panel selection
• NAS defines a conflict of interest as any
  financial or other interest which conflicts with
  the service of the individual because it
• could significantly impair the individuals
  objectivity
• could create an unfair competitive advantage for
  any person or organization.
• The term conflict of interest means something
  more than individual bias. There must be an
  interest, ordinarily financial, that could be
  directly affected by the work of the committee.

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Bias

• NAS procedures for panel selection on bias
• Questions of lack of objectivity and bias
  ordinarily relate to views stated or positions
  taken that are largely intellectually motivated
  or that arise from the close identification or
  association of an individual with a particular
  point of view or the positions or perspectives of
  a particular group.
• Biases are not necessarily disqualifying, but a
  balance of potentially biasing backgrounds or
  professional or organization perspectives is
  needed.
• Some potential sources of bias may be so
  substantial that they would prevent an individual
  from considering others perspectives or relevant
  evidence contrary to their strongly held
  position.

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Panel Selection Procedures

• Identification of scientific expertise necessary
  to address key issues.
• Search for appropriate candidates, evaluate
  credentials.
• Contact most promising candidates for interest
  and availability. Query them on conflicts of
  interest and biases. Avoid candidates with
  conflicts and substantial biases.
• Select a panel of independent experts, that is
  balanced with regard to necessary disciplines,
  biases, and has a diversity of perspectives.

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Some Independent Peer ReviewsOrganized by TERA

• Captan carcinogenicity classification.
• Resorcinol safe dose for Pennsylvania clean up.
• World Trade Center Residential Clean up Levels.
• Voluntary Childrens Chemical Evaluation Program.
  
• Texas CEQ review of methods for estimating values
• See http//www.tera.org/peer for meeting reports

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World Trade Center Residential Assessment 

• Meeting held in NYC, October 2002.
• Document prepared by federal, state and city
  agencies U.S. EPA, NYC, ATSDR.
• TERA selected panel and organized meeting.
• Public invited to nominate experts, attend
  meeting to observe, submit oral and written
  comments.
• Final report summarized discussions, and
  conclusions. Included copies of public comments.

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Texas Commission on Environmental Quality (TCEQ)

• A panel of expert scientists conducted a Peer
  Review of a technical guidance document prepared
  by the (TCEQ), State of Texas.
• Technical guidance describes the process used by
  staff of the Toxicology Section to develop
  Effects Screening Levels, Inhalation Reference
  Values, and Unit Risk Factors.
• Panel made numerous recommendations for
  improvements.
• TCEQ revised its methods.
• http//www.tceq.state.tx.us/implementation/tox/esl
  /peer_rev/PRmain.html

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Alliance for Risk Assessment (ARA)

• Partnership with the National Library of Medicine
• Serves as shared resource to facilitate
  collaborative risk issue resolution among
  stakeholders.  
• Designed with input from colleagues from over 30
  States, federal agencies, tribes, and NGOs, who
  need a more timely constructive way to resolve
  issues. 
• Example uncertainty in determining appropriate
  risk values to use for chemicals like TCE has
  spurred interest from state and local risk
  assessment colleagues.
•  

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Alliance for Risk Assessment (ARA)
Alliance Menu Options
Stakeholder Process
States, Fed. Agencies, Public Interests,
Industry
Steering Committee
Risk Document Development
Initiation of Risk Issue
Training and Certification
Non-profit Collaborators
Risk Information Exchange (RiskIE)
Risk Communication
Document Draft
Risk Research And Tools
Peer Reviews
Peer Consult
Peer Review
Release to Public
ITER
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International Toxicity Estimates for Risk (ITER)
Database

• Part of the National Library of Medicine.
• Free web-based data.
• Contains peer-reviewed risk values for more than
  600 chemicals from 5 agencies, plus independent
  groups. Agencies include ATSDR, EPA IRIS,
  Health Canada, RIVM (the Netherlands), NSF Int.
• Used by over 500 risk assessors daily.
• Provides a central source for peer-reviewed risk
  values to foster data sharing.
• http//www.tera.org/iter

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NLMs Toxnet
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Extra Slides
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Pennsylvania-Resorcinol

• A reference dose (RfD) for resorcinol was
  prepared by AMEC Earth and Environmental, Inc for
  Beazer East, Inc.
• RfD (safe dose) developed to inform risk-based
  clean up decisions under Pennsylvania Department
  of Environmental Protection (DEP) regulations.
• Authors revised assessment with peer review panel
  recommendations.
• Panels recommendations accepted by the Science
  Advisory Board of PA DEP.

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Captan Tumor Mode of Action

• EPAs cancer assessment for Captan was based on
  EPAs 1986 Cancer Guidelines.
• EPA OPP indicated they were not planning a
  re-evaluation, but would consider an
  independently reviewed reassessment.
• The Captan Task Force sponsored an updated
  analysis, which supported a non-linear mode of
  action.
• TERA convened an independent peer review panel.
  The panel agreed with the nonlinear mode of
  action, and gave recommendations.
• EPA OPP accepted the conclusions of the
  independent peer review.
• NRDC challenged OPP EPA acknowledged the
  challenge, but held to its acceptance.

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Voluntary Childrens Chemical Evaluation Program

• VCCEP is part of the U.S. EPAs Chemical
  Right-to-Know Initiative. The goal of the VCCEP
  pilot is to enable the public to better
  understand potential health risk to children from
  chemical exposures.
• EPA asked companies to sponsor 23 chemical
  evaluations in a pilot program. This required
  collection or development of health effects and
  exposure information and integration into a risk
  assessment and a data needs assessment.
• TERA organizes peer consultations with panels
  of experts for each of the submitted assessments.
  
• Reviewer recommendations regarding data needs are
  summarized in a meeting report.
• EPA makes decisions regarding the need for more
  testing.