UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
° WASHINGTON D.C. 20460
OFFICE OF THE ADMINISTRATOR
SCIENCE ADVISORY BOARD
February 28, 2007
EPA-SAB-07-003
Honorable Stephen L. Johnson
Administrator
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, N.W.
Washington, DC 20460
Subject: Consultation on Enhancing Risk Assessment Practices and Updating EPA's
Exposure Guidelines
Dear Administrator Johnson:
The EPA Office of Science Advisor requested that the Science Advisory Board
(SAB) conduct a consultation to provide input on ways to advance the Agency's human
health risk assessment practices. Additionally, the Risk Assessment Forum requested that
the SAB provide advice on updating the 1992 Exposure Guidelines. On September 6 and 7,
2006, representatives of the Office of Research and Development (ORD) and several other
EPA offices provided informative presentations to the members of the SAB Environmental
Health (EHC) and Integrated Human Exposure (IHEC) Committees and several board
members of the SAB. The focus of the presentations by EPA representatives for this
consultation was on advancements made in human health risk assessment and exposure
assessment. On behalf of the committee members, we would like to express our sincerest
gratitude to the presenters for their expertise, perspectives and insights. Their contributions
greatly increased our understanding of the Agency's current policies, methods, practices and
future directions.
The SAB was asked to comment on the relevance and priority of initiatives by the
Agency to advance human health risk assessment practices and the Agency's approach for
updating the exposure guidelines. They were also asked to suggest other areas and
improvements that should be considered and which would be most important. Committee
members addressed five major topics that emerged as the focus of both efforts during these
consultations; 1) Addressing Aggregate Exposure and Cumulative Risk Assessment, 2)
Addressing Populations, Groups, or Life Stages of Potential Concern, 3) Evaluating Uncertainty
and Variability, Including Probabilistic Analyses, 4) Involving Communities and
Communicating Results, and 5) Use of Data (Mechanistic, Models, Genomics, CompTox, etc.)
versus defaults. Feedback on the charge questions was provided by committee members and
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summarized according to each of the five topics. A compilation of these comments is appended
to the minutes for this meeting. Highlighted in this letter are several key messages that emerged
among the Committee members as a result of the Agency presentations and discussions.
The SAB agreed that the Agency has obviously put great effort into advancing human
health risk assessment practices in many areas. The Agency has utilized sound principles and
science, used external peer review, and is developing guidelines that should result in more
transparent assessments. The Agency presented a comprehensive conceptual framework for
human health risk assessment. Although this framework identified many scientific and
practical needs, it did not provide an assessment of priorities or a plan for meeting those
needs. The SAB is providing a number of overarching recommendations to address both
advancing human health risk assessment and updating the exposure guidelines because the
Agency has focused on many of the same concerns with regard to both efforts. The SAB
recommends that the Agency:
• Develop a plan to assess and prioritize the scientific and practical needs for
improving human health risk assessment.
Topic 1
• Advance cumulative risk assessment methodologies, in order to reflect real-world
human exposure that includes multiple stressors.
• Integrate work completed to better characterize cumulative exposure and risk across
age groups, and among children and the elderly.
Topic 2
• Consistently address early life susceptibility in assessments, using weightings for
children, prenatal exposure, and lifetime to pregnancy (body burden) exposure.
• Include the elderly subpopulation and existing health, medication, and nutrition status
when conducting risk assessments.
• Determine the status of populations in terms of background exposures and disease
factors.
Topic 3
• Characterize variability and uncertainty more fully, including extending where
scientifically feasible related quantitative analyses to the dose response and hazard
identification parts of the Agency's cancer and noncancer risk assessments, and
thereby identify ways to minimize uncertainty.
• More systematically, clarify the underlying assumptions used to build probability
distributions for the processes and the observations on those processes.
• Incrementally replace the current system of single-point uncertainty factors with a set
of distributions using probabilistic methods. (Some of the potential benefits of
probabilistic analyses are included in Attachment 1.)
• Continue to develop mechanisms to evaluate both exposure and effects predictions of
current and new human health risk assessment models.
• Conduct evaluations to determine whether risk assessment predictions match reality.
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Topic 4
• Convene workshops at periodic intervals (2-3 years) to gather new information,
including new data, new techniques and new tools.
• Assess, and probably increase, its program of training for both assessors and
managers to appropriately interpret, communicate, and effectively utilize probabilistic
information in decision-making.
Topic 5
• Whenever possible, use data derived from humans rather than from animals.
• Continue to develop greater understanding of modes and mechanisms of action,
including mechanisms of genotoxicity, to improve understanding of the relevance of
data from animal models to humans.
Finally, the SAB recognizes that the design and implementation of new methods will
require specialized expertise and sustained support. We urge the Agency to provide the
necessary resources and support to ensure that continued improvements are made. We look
forward to working with the Agency to enhance approaches for exposure and human health
risk assessment.
Sincerely,
/Signed/ /Signed/
Rebecca T. Parkin, PhD, MPH Granger Morgan, PhD
Chair, Integrated Human Exposure Chair, Science Advisory Board
Committee and Environmental
Health Committee
Enclosure (Attachment 1)
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ATTACHMENT 1
Some Potential Benefits of Probabilistic Analyses include the following:
• In contrast to the current definition of the Reference Dose (RfD)1, RfDs designed to meet a
probabilistic goal would allow the technical vs. policy considerations to be made explicit in
quantitative terms—making clear how much confidence the analysts should be able to achieve
that risks are below some specified incidence.
• Assessment of uncertainties quantitatively could facilitate "value of information" type analyses
to help set research priorities toward the largest and most easily reducible sources of uncertainty.
• A probabilistic RfD system could help reduce the potentially inaccurate implication of zero risk
below the RfD. The likelihood of finite risks for some non-cancer effects at low doses is
highlighted by the recent example of apparently substantial mortality to vulnerable portions of
the population from ambient levels of small airborne particles.
• A probabilistic RfD system would provide a capability to quantify risk below or above the RfD.
This would allow EPA to quantify benefits of exposure control measures for OMB-mandated
juxtapositions of economic and health consequences of different policy options. Without this
capability, reductions in air toxics and non-cancer effects from other exposures are effectively
not counted in analyses of benefits in regulatory impact analyses. This may lead to
underweighting of efforts to abate such effects in the policy formulation process.
• A probabilistic RfD would remove the apparent contrast in the best current assessments that are
highly sophisticated probabilistic exposure assessments joined to simple-appearing single-point
representations of information from the field of toxicology.
• A probabilistic RfD system would encourage the generation of better information because it
would create a clear regulatory market for such a system. As pointed out in our discussions, this
would improve on the World Health Organization International Programme on Chemical
Safety's (WHO IPCS) data derived uncertainty factor procedures, that are not rigorously
founded in terms of allocation of variances between pharmacokinetic and pharmacodynamic
components, or over-constrained by the requirement that default kinetic and dynamic
components must multiply to the traditional factor of 10.
• An innovative probabilistic system is more likely to attract the efforts of innovative researchers
interested in producing improved technical information and seeing policy responses to that
information. Currently researchers in this area have a difficult struggle to achieve acceptance in
place of the heritage of prior "case law" choices made from the 1954 Lehman and Fitzhugh "100
fold safety factor" paper to the present.
1 Reference Dose (RfD): An estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure to the human
population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. It can be
derived from a NOAEL, LOAEL, or benchmark dose, with uncertainty factors generally applied to reflect limitations of the data used.
Generally used in EPA's noncancer health assessments, as defined in the glossary attached to EPA's IRIS database
(http://www.epa.gov/iris/gloss8.htm. accessed 1/23/07)
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• Examples of the richness of information that could be made available to decision-makers by
implementation of probabilistic methods substituting distributions based on empirical data based
on observations of other chemicals/drugs instead of the single-point uncertainty factors that are
traditionally used) are illustrated in Hattis and Lynch (2007).2
2 Hattis, D. and Lynch, M. K. "Empirically Observed Distributions of Pharmacokinetic and Pharmacodynamic
Variability in Humans—Implications for the Derivation of Single Point Component Uncertainty Factors
Providing Equivalent Protection as Existing RfDs." In Toxicokinetics in Risk Assessment. J. C. Lipscomb and
E. V. Ohanian, eds., Informa Healthcare USA, Inc., 2007, pp. 69-93.
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