April 27, 1995
EPA-SAB-EHC-COM-95-002
Honorable Carol M. Browner
Administrator
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Subject: Science Advisory Board's Commentary on the EPA's use of the Benchmark
Dose calculation method.
Dear Ms. Browner:
At the April 6, 1994 meeting of the SAB's Environmental Health Committee (EHC), the
Committee was briefed by staff from the Office of Research and Development (ORD) on the
Agency's progress in analyzing the "Benchmark Dose" method as an alternative to the current
"NOAEL/LOAEL (No Observed Adverse Effects Level/Lowest Observed Adverse Effects
Level) approach for calculating reference dose (RfD) levels. The Committee has long advocated
the study of this methodology, and has stated its view of the advantages of the Benchmark
approach in several previous advisory documents.1
During the briefing, Staff informed the Committee that a "White Paper" on the Bench-
mark approach was being prepared and would be available for SAB for review in the future. In
its subsequent discussions, the EHC identified some key issues which it believes are critical to
developing both a full understanding of the benchmark methodology and its eventual
1 Environmental Health Committee, U.S. EPA Science Advisory Board, 1990. Use of Uncertainty
and Modifying Factors in Establishing Reference Dose Levels. EPA-SAB-EHC-90-005; Environmental
Health Committee, U.S. EPA Science Advisory Board, 1993. Review of the Office of Solid Waste and
Emergency Response's Draft Risk Assessment Guidance for the Superfund Human Health Evaluation
Manual EPA-SAB-EHC-93-007.
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implementation, and which should be addressed in any future Agency statements on this topic.
Specifically, the EHC recommends that the Agency:
a) Examine and assess the comparability of the Benchmark and current
NOAEL/LOAEL calculation for many data sets, involving different types of
toxicity and routes of exposure. This work should extend the recent efforts
sponsored by the Agency on developmental toxicity2 and should compare NOAEL
and benchmark calculations obtained both from individual data sets and data set(s)
used to define the "critical effect." The Committee would also be interested in
seeing comparisons between the benchmark and NOAEL calculations and results
obtained using threshold and non-threshold extrapolation models.
b) Comment on the effects of the underlying experimental design on the results of the
benchmark dose calculation, as well as on the range of doses needed to character-
ize the dose response curve.
c) Address methodology for dealing with situations where dose-response data may
not be monotonic in form. The Committee is aware that dealing with non-mono-
tonic data is (in this context, and with the NOAEL/LOAEL approach as well) very
difficult, and that in fact, no good methodology may yet be available. Nonethe-
less, we believe that the White Paper should at least deal with the issue and
perhaps suggest some possible approaches.
d) Comment on the differential impacts on the benchmark dose calculation of using
various types of data sets. Specifically, dose-response data sets underlying a
benchmark dose calculation may be of a continuous or quantal type, and require
differing approaches for their use.
Developing a full understanding of the Benchmark dose and the data requirements for
valid use of this methodology would contribute to the EPA's goal of providing credible science in
2 Faustman, E., Allen, B., Kavlock, R., and Kimmel, C. 1994. Dose-response assessment for
developmental toxicity—characterization of database. Fund. andApp, Tox., 23, 478-486; Allen, B. Kavlock,
R., Kimmel, C., and Faustman, E. 1994. Dose-response assessment for developmental toxicity
—comparison of generic benchmark dose estimates with NOAELS. Fund. andApp. Tox. 23:487-495; Allen,
B. Kavlock, R., Kimmel, C., and Faustman, E. 1994. Dose-response assessment for developmental toxicity-
statistical models. Fund. andApp. Tox. 23:496-509
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support of the risk assessment process. Consequently, we again wish to encourage the Agency to
proceed vigorously in its review and development of this approach. We look forward to your
response to these recommendations.
Sincerely,
Dr. Genevieve Matanoski, Chair
Science Advisory Board
Dr. Frederica Perera, Chair
Environmental Health Committee
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