UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D c. 20460
Novanber 4, 1986 SHB-EC-87-QQ8
Honorable Lee M. Thomas D ,= ,=,<; EOF
Administrator • r»ft *Q«,N,STPATQ,,
U. S. Environmental
Protection Agency
401 M Street, S. W. - ' "
Washington, D. C. 20460
Dear Mr. Thomas:
The Science Advisory Board's (SAB) Dioxin Toxic Equivalency
Methodology Subcommittee met in public session on September 8 to review a
draft document prepared by the Agency's Risk Assessment Forum and entitled
"Interim Procedures for Estimating Risk Associated with Exposures to
Mixtures of Chlorinated Dibenzo-p_-Dioxins and Dibenzofurans (CDDs and
CDFs}." The document sets forth an approach for assessing the hazard of
CDD and CDF mixtures relative to the toxicity of- the 2,3,7,8-tetrachloro-
dibenzo-p_-dioxin (TCOD) isomer*
The request for SAB review of this Toxic Equivalency Factor (TEF)
methodology originated on February 27, 1986 from Assistant Administrator
for Air, Craig Potter, who recommended SAB review in relation to his
office's ongoing interest in assessing dioxin risks associated with municipal
waste conbustion. The SAB Executive Committee accepted this request and
formed the Dioxin Toxic Equivalency Methodology Subcommittee to carry out
the review. The Subccnroittee approached its task with the assumption
that it was reviewing a generic methodology as opposed to one that was
limited solely to the issue of municipal waste conbustion.
The Subcommittee's report consists of two sections: 1) its consensus
statement on the draft document in its current form, and 2) comments on
individual steps that EPA should initiate to improve the document or the
scientific data base for toxic equivalency evaluation. The Subcommittee has
already forwarded the comments of its individual members to the Agency's staff,
The Subcommittee generally concludes that the draft document represents
a successful interim attempt to articulate a scientific rationale and
procedures for developing risk management decisions for mixtures which
contain CDDs and CDFs related in structure and activity to TCDD. The
Subcormittee's major recommendations include: placing greater emphasis on
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toxicokinetics, including metabolism; assigning priority to using human
data, when available? validating the TSF methodology by selected testing
o£ hypotheses; articulating clearly the decision steps, assomptions and
rrethods of calculation; restating and re-emphasizing the interim nature
of the methodology,* and addressing the possibility of chemical and
toxieological interactions with other types of compounds in complex
environmental mixtures.
We appreciate the opportunity to review the TEF methodology and to
present our technical evaluation. We request that the Agency formally
respond to the scientific advice provided in the attached report.
Sincerely,
Richard Griesener, Chaiman
Dioxin Toxic Equivalency
Methodology Subcommittee
Norton Nelson, Chairman
Executive Committee
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Report of the Science Advisory Board's Dioxin Toxic jjjguivalency
Methodology Subcommittee FollcftfingjEts Evaluation
of EPA's Toxic Equivalency Factor Methodology for CDte and CDFs
A, Major Subcomittee Conclusions
EPA has proposed interim procedures for estimating health risks for
CDDs and CDFs based on the premises that? (a) toxicity equivalence factors
can be assigned to untested (or incompletely tested) ccnpounds on the basis of
structure/activity relationships? and (b) the toxicity of mixtures of these
compounds can be approximated for policy purposes by the suras of their TEF
times concentrations. Btpirically, the present proposal falls generally
between the positions adopted by certain European countries, which rank
2,3,7,8 TCDD far above any other congener in toxicity, and that initially
proposed by the state of California, which equates all the dioxin congeners.
All have used similar scientific assunptions in developing policy*
The Subcoirpdttee agrees that the congeners of CDDs and CDFs constitute
a class of chemical substances that share similar structural relationships
and qualitatively similar toxic effects and, therefore, can reasonably be
considered together. From the limited toxicologic data available it seems
reasonable, too, to consider those tetra-to hexa-chlorinated cenpounds with
chlorine substitutions at the lateral 2,3,7,8 positions as a closely related
subclass in terms of biological activity and environmental fate.
The Subcotimittee also concurs that the problems in assessing the health
risks of dibenzo-jD-dioxins and dibenzofurans are two-fold. They include:
limited information from human or experimental studies about the hazards from
exposure to these compounds (few of the 75 CDDs and 135 CDFs have been tested
at all) and even more limited information about their possible interactions-'
in mixtures. Indications of interactions, mostly additive, are found in
certain experimental model systems (e.g. binary combinations). Not addressed
in the draft document, however, is the possibility of chemical and toxicologic
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interactions with other types of compounds in complex environmental mixtures,
especially solvents that might affect uptake and retention by the body.
EPA should address the latter subject in the TEF document/, perhaps with
more specific reference to its recently published Risk Assessment Guidelines
and to three National Academy of Sciences1 reviews on toxicological interactions,
the last of wj^ich is currently being prepared for EPA and the National
Institute of Environmental Health Sciences. The Subcommittee- also questions
the basis for including or excluding other chemicals with effects similar
to CDDs and CDFs, such as chlorinated biphenylenes.
Based upon its review of the draft document, the Subcommittee concludes
that the method proposed by EPA is a reasonable Interim approach to assessing
the health risks associated with exposure to mixtures of CDDs and CDFs for
risk management purposes. It is necessary, howeveri as lessons are learned
fron toxicologic research and fron application, the approach should be
re-evaluated systematically by EPA. Moreover, attempts should be made to
validate the method by selected experimental testing of hypotheses. For
example, more data are needed on in vivo potencies of additional PCDDs and
PCDFs to compare with in vitro test results. The assumption of additivity
can be evaluated by comparing observed activities with predicted activities
in selected tests.
The Subcommittee recommends that EPA place more emphasis on the jjiteriro
nature of the method in the document. The Subcommittee anticipates that,
over time, the method will be modified and eventually superseded as more
precise data become available. Meanwhile, the general method proposed
appears to have utility for this and for other classes of closely related
compounds where toxicologic data are incomplete. Application of structure
activity relationships is an old and established practice of demonstrated
usefulness in pharmacology and toxicology.
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However, EPA should not abandon its exploration of other approaches to
estimating risks for substances in mixtures. For example, where variability
in the composition of environmental samples is not wide, a reference standard
approach might be used (similar to those used in toxicology for selecting a
reference cigarette or a representative blend of gasolines). As another
example, the incorporation of a small amount of radiolabeled test compound
into a representative and defined mixture might be one useful way of determining
in vivo whether the uptake and metabolism of one congener is greatly modified
by the presence of other substances in a mixture.
Some additional technical comments that the Subcommittee wishes to draw
to the Agency's attention include; 1) perceptions by many Subcwramittee
members of an over-reliance upon the postulated mechanisms of the Ah
reeeptor/AHH enzyme induction upon which to gauge relative and absolute
toxicity; 2) the need to discuss the work of iMatsumura, Rozman, Greenlee,
Poellinger and others on additional toxicologically significant effects of
the dioxins other than those associated with receptor binding or with
eytochrcroe P-450 induction; 3) observations of a disassociation between AHH
induction and cytotoxicity in studies on the gonado toxicity of TCDDj and
4) examination of the extent to which the longer biological half-life of
higher chlorinated dioxin isomers, as compared to 2,3,7,8-TCDD, counter-
balances their lesser _in vivo potency*
B. Major Subcommittee Recommendations
The Subcommittee has several recommendations for improving the report.
First, the draft report narrative is relatively brief and may not be
readily understood by those not familiar with dioxins. For example, four
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possible approaches are introduced and one (TEF) selected, but the document
does not clarify what the other three aproaches are and the reasons for
their rejection." The first approach, long-term animal testing, might be
appropriate for municipal incinerator fly ash, where analytic data suggest
there is a characteristic pattern of composition. The second approach
(short-term assays) is not clearly described (not even whether they are
in vivo or in vitro). The third approach, additivity of the toxicity of
components, is at first rejected in the narrative but then forms the
basis for handling the equivalents to 2,3,7,8-TCDD in mixtures.
Because the draft document presents a procedure, it is essential
that the decision steps be clearly articulated, the assumptions made
explicit, and the mechanics of calculating be illustrated in a stepwise
fashion. To approach the subject from the viewpoint of studying the
whole class of pollutants and to avoid bias by selecting data, the Subcom-
mittee recommends that the tabular data be enlarged to include all compounds
with zero to eight substituted chlorines. Biological.activity has been •
reported for di- and tri-CDDs, and carcinogenicity studies exist for DD
and 2,7 DCDD, as examples. Moreover, the activity of brominated and
other substituted compounds should also be indicated and a specific
effort encouraged to collect data on non-chlorine substituted compounds.
In contrast with the document's first priority on carcinogenic and
then on teratologic effects in animals, the Subccnniittee recommends that
the TEF methodology assign first priority to human data when it exists, in
evaluating experimental data, EPA should continue to follow the current
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toxicologic practice of evaluating all endpoints, and selecting the ones
most reliable, -sensitive, and important for risk assessment. Tfius, columns
should be added to the tables in the docunent for other important toxic
endpoints including irarnunotoxicity, thymic atrcphy, body weight, and enzyme
induction in vivo. The limited data points from tfhich TEFs are currently
derived (e.g. carcinogenicity of 2,3,7,8-TCDD, 2,3,7,8-Hx CDlas and repro-
ductive effects of those compounds plus 2,3,7,8-TCDF) should be critically
re-examined and the range of experimental data and estimated potencies frcm
all studies tabulated. Itie Subcommittee also recommends that EPA consider
assigning higher relative TEFs to CDPs in general, and 2,3,4,7,8-PeCDF in
particular.
The Subcommittee strongly believes that EPA should assign greater
priority to obtaining and using data on toxicokinetics, including metabolism.
The rates of uptake and distribution of compounds alone and in mixtures
are important measures of bioavailability and dosirnetry. The kinetics of
metabolism and excretion, along with those of receptor kinetics and
affinities, should be especially useful for interspecies ecxRparisons and
for estimating risks for this particular class of eempounds.
The Subcommittee wishes to emphasize that the method proposed may lack
scientific validity. The associated errors have not been quantified, it
is important, therefore, that the Agency make every effort to validate
the method. The Subcommittee recorroends periodic review and analysis as
better data are obtained, and that EPA make systematic efforts to obtain '
critically important data, including that from in vivo tests on compounds
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with representative positional substitutions. Efforts should continue to
develop methods for assaying the biologic activity of important mixtures
(e.g. fly ash) in in vitrp systems, using other cells in addition to
hepatocytes and' other endpoints in addition to AHH activity. Until the
uncertainties are reduced, the interim TEF method should be largely
reserved for specific situations where the components of the mixture are
known, where the composition of the mixture is not expected to vary much
with time, and where the extrapolations are consistent with existing
animal data.
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0. S, ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
DIOXIN TOXIC EQUIVALENCY SUBCOMMITTEE
ROSTER
Dr. Richard Griesemer
Director, Biology Division
Box Y
Oak Ridge National Laboratory
Oak Ridge, Tennessee 37830
Dr. Linda Birnbaum
National institute of Environmental
Health Sciences
Post Office Box 12233
Research Triangle Park, NC 27709
Dr. Patrick Durkin
Syracuse Research Corporation
Merrill Lane
Syracuse, New York 13210
Dr. Robert Huggett
Chairman, Department of
Chemical Oceanography
Virginia institute of
Marine Science
College of William and Mary
Gloucester Point, Virginia 23062
Dr. Renate Kimbrcugh *
Center for Environmental Health
Centers for Disease Control
1600 Clifton Road
Atlanta, Georgia 30333
Unable to attend the meeting
Terry P. Yosie, Director
Science Advisory Board
U. St Environmental Protection
Agency ,
401 M Street, S. W.
Washington, D, C. 20460
Dr. John Doull
Professor of Phamacology
and Toxicology
University of Kansas
Medical Center
Kansas City, Kansas 66207
Dr. Ton Gasiewicz
Department of Radiation Biology
and Biophysics
University of Rochester Medical Centej
Associate Professor
Roan 4-6951
575 Elinwood Avenue
Rochester, New York 14642
*
Dr. Nancy Kim
Director,, Bureau of Toxic Substance
Assessment
New York State Department of Health
ESP Corning Tower BMg,, Room 359
Albany, New York 12237
Dr. Robert Neal*
President, Chemical Industry
Institute of Toxicology
Post Office Box 12137
Research Triangle Park, NC 27709
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Dr. Allen Okey
Division of Clinical Pharmacology
Hospital for Sick Children
555 University Avenue
Ibronto, Ontario M5G1X8
Dr. Ellen Silbergeld
Senior Scientist „
Environmental Defense Fund
1616 P Street, N. W.
Washington, D. C.
Dr. Steve Safe
Department of Physiology and
Pharmacology
College of Veterinary Medicine
Texas A&M University
College Station, Texas 77843
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