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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) * * * * * * * * * * * * * aPredicted 50th ... – PowerPoint PPT presentation

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Title: Human Health Risk Assessment: Moving from Policy to Science


1
Human Health Risk Assessment Moving from Policy
to Science
  • Michael Dourson
  • Toxicology Excellence for Risk Assessment (TERA)

2
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.

3
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)
4
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)
5
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.

6
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.

7
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).

8
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
9
New Concepts
  • Benchmark Dose
  • Chemical Specific Adjustment Factors (CSAF)
  • Categorical Regression
  • Mode of Action

10
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.

11
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
12
New ConceptsExample of Default UF Hg Oral RfD
EPA, 2001
13
Observed Range of CNS Effects in Faroe Children
Percent Children With CNS Effects
Methyl Mercury Dose (µg/kg-day)
10
14
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
15
New Concepts Interindividual Variability in
Ingested Hg
a Corresponding to either 1ppm Hg in hair or 1ppb
in blood
NAS, 2001
16
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
17
New Concepts Ingested Hg
NAS, 2001
Predicted mean probability of MeHg intake
corresponding to 11ppm MeHg in hair.
18
New Concepts Compare ingestion rates
(?g/kg/day) of Seychelles studies from either
deterministic approach or Monte Carlo approach
(ICF Kaiser. 1998)
19
New ConceptsRfD Based on a Monte Carlo
1st
2nd 3 UF for database
3rd
20
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).

21
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)
22
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
23
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)
24
Probability of Effects with Aldicarb
25
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26
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27
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.

28
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29
Detailed Graphical Representation of Chloroform
Extrapolations
BMDL
30
EPAs Postulated Mode Of Action
Chloroform
CYP2E1
Metabolism
Oxidative
Phosgene
Sustained Toxicity
Regenerative Cell Proliferation
Key Events
Tumor Development
31
Mutagenicity Conclusions
  • Weight of Evidence
  • Mutagenicity is not a component of chloroform
    induced neoplasia

32
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

33
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

34
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
35
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

36
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.

37
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.

38
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.

39
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.

40
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.

41
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.

42
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

43
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.

44
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

45
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.
  •  

46
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
47
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

48
NLMs Toxnet
49
Extra Slides
50
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.

51
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.

52
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.
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