-------
United States
Environmental Protection
Agency
EPA/625/3-89/016
March 1989
Interim
Procedures for
Estimating Risks
Associated with
Exposures to
Mixtures of
Chlorinated Dibenzo
p-Dioxins and
-Dibenzofurans
(CDDs and CDFs)
and
1989 Update
RISK A^ESSMENT FORUM
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Notice
The toxieity equivalency factor (TEF) method is an interim procedure for
assessing the risks associated with exposures to complex mixtures of
chlorinated dibenzop-dioxins and dibenzofurans (CDDs and CDFs). The
method relates the toxieity of the 210 structurally related chemical pollutants
and is based on a limited data base of in vivo and in vitro toxieity testing. By
relating the toxieity of the 209 CDDs and CDFs to the highly studied 2,37 8-
tetrachlorodibenzo-p-dioxin (2,3.7,8-TCDD), the approach simplifies the
assessment of risks involving exposures to mixtures of CDDs and CDFs.
such as incinerator fly ash, hazardous wastes, contaminated soils, and bio-
logical media. During the late 1970s and early 1980s, various regulatory
agencies in the United States, Canada, and Europe, developed their own
TEF schemes. As a result, numerous and slightly different TEF methods
existed which complicated communication among scientists and agencies in
addressing the toxicological significance of complex mixtures of CDDs and
CDFs.
Parti
In 1987, the EPA formally adopted an interim TEF procedure (EPA-
TEF/87), which has been used by EPA regulatory programs and Regions in
addressing a variety of situations of environmental contamination involving
CDDs and CDFs. The EPA-TEF/87 method, published as "Interim
Procedures for Estimating Risks Associated with Exposures to Mixtures of
Chlorinated Dibenzo-p-dioxms and -Dibenzofurans (CDDs and CDFs)".
(EPA/625/3-87/012) is republished (with minor editorial corrections) in this
updated report. In the 1987 report, the Agency emphasized that the method
was interim in nature and committed itself to periodically update the TEFs as
additional toxieity data were generated.
Part II
Since the time that the 1987 report was published, the Agency was active
in an international project aimed at adopting a common set of TEFs. the
International TEFs/89 (t»TEFs/89), to promote consistency in addressing
contamination involving CDDs and CDFs. This first update report. "1989
Update to the Interim Procedures for Estimating Risks Associated with
Exposures to Mixtures of Chlorinated Dibenzo-p-Oioxtns and -Dibenzofurans
(CDDs and CDFs)," identifies EPA's adoption of the l-TEFs/89 as a revision
to the EPA-TEFs/87 currently in use. In general, the effect of these
modifications is likely to bo modest for many complex mixtures. This report
also presents the rationale, methodology, and toxieity data used to determine
Hie new values and describes the differences between the two schemes. The
l-TEFs/89 represent an improvement in an already useful risk assessment
tool. However, the approach remains interim in nature and should be
continued to be revised as new data are developed. In addition, the complete
replacement of any TEF method by a bioassay method appears to be
feasible within the near future.
in the 1987 report, the term toxieity "equivalence" factor was used, but for
the 1989 update, the term toxieity "equivalency" factor is being used to be
consistent with NATOCCMS.
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Part I
Interim Procedures for Estimating
Risks Associated with Exposures to
Mixtures of Chlorinated Dibenzo-p-
Dioxins and -Dibenzofurans (CDDs
and CDFs)
October 1986
Authors
Judith S. Bellin, Ph.D.
Office of Solid Waste and Emergency Response
Donald G. Barnes, Ph.D.
Office of Pesticides and Toxic Substances
Technical Panel
Co-Chairmen: Donald G. Barnes (OPTS)
Hugh L. Sprtzer (ORD)
Steven Bayard, Ph.D. (ORD) Paul Milvy, Ph.D. (OPPE)
Irwin Baumel, Ph.D. (OPTS) Abe Mrttelman, M.S. (OSWER)
Judith Bellin, Ph.D. (OSWER) Debdas Mukerjee, Ph.D. (ORD)
David Cleverly, M.S. (OAQPS) Chartes Nauman, Ph.D. (ORD)
Frank Gostomski, Ph.D. Jerry Stara, Ph.D., D.V.M.
(ODW/OWRS) (ORD)
Charalingayya Hiremath, Ph.D. (ORD)
Risk Assessment Forum Staff
Dorothy E. Patton, Ph.D., J.D., Executive Director
Risk Assessment Forum
U.S. Environmental Protection Agency
Washington, DC 20460
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Disclaimer
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade
names or commercial products does not constitute endorsement or
recommendation for use.
-------
Contents
Page
Us! of Tables , iv
Peer Review M
Science Advisory Board Review vi
Preface vii
I. Summary 1
II. The Need for a Procedure for Assessing the Risk Associated
with Exposure to Complex Mixtures of CDDs and CDFs 4
III. Approaches to Hazard Assessment for CDD/CDF Mixtures .... 6
A. The Ideal Approach—Long-Term, Whole-Animal Toxicity
Assay of Mixtures 6
B. A Promising Approach—Short-Term, Biological Assay of
Mixtures 6
C. A Reductionist Approach—Additivity of Toxicity of
Components 6
D. An Interim Approach—237B-TCDD Toxicity Equivalence
Factors (TEFs) 7
IV. The 2378-TCDD Toxicity Equivalence Factors (TEFs)
Approach to Assessing the Toxicity of Complex
Mixtures of CODs and CDFs 6
V. Applications to Risk Assessment 14
VI. Comparison of the TEF Approach with Results of Biological
Testing 23
VII. Research Needs 25
References 26
Appendix A: Nomenclature A-l
Appendix B: Comparison of Different Approaches to Calculating
2378-TCDD Equivalents B-1
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Ust of Tables
Number
1. Some Approaches to Estimating Relative Toxicities of PCODs
and PCDFs 2
2. Potencies of Dioxins Relative to 2,3,7,8-TCDD 10
3. COD/CDF Isomers of Most Toxic Concern 12
4. PCDDs/PCDFs in Some Environmental Samples 16
5. Use of the TEF Approach 19
B-1. Relative 237B-TCDD Equivalents B-2
B-2. Calculation of 2378-TCDD Toxictty Equivalents for St. Louis
Air Particutates Using Homologue-Specrfic Data . B-3
B-3. Calculation of 2378-TCDD Toxicrty Equivalents for PCB
Fire Soot Using Isomer-Specific Data B-4
B-4. Calculation of 2378-TCDD Toxicity Equivalents for MSW ESP
Dust Using Homotogue-Specific Data and 2378 TEFs B-6
B-5. Calculation of 2378-TCDD Toxicity Equivalents for Lake
Sediment Using Homoiogue-Specific Data B-7
B-6. Calculation of 2378-TCDD Toxicity Equivalents for
Mitorgantte Using Homologue-Specific Data B-9
6-7. Calculation of 2378-TCDD Toxicrty Equivalents for Oslo
MSW Fly Ash Using Homologue-Specific Data B-10
B-B. Calculation of 2378-TCDD Toxicity Equivalents for Ontario
MSW Fly Ash Using Homotogue-Specrtic Data B-12
B-9. Calculation of 2378-TCDD Toxictty Equivalents for MSW at
Japanese Plant A Using Homoiogue-Specific Data B-13
B-10. Calculation of 2378-TCDD Toxicity Equivalents for MSW at
Japanese Plant B Using Homologue-Specific Data B-15
B-11. Calculation of 2378-TCDD Toxictty Equivalents for MSW at
Albany Using Homologue-Specific Data B-16
B-12. Calculation of 2378-TCDD Toxicity Equivalents for WP Air
Force Base {Best) Using Homologue-Specific Data B-18
B-13. Calculation of 2378-TCDD Toxicity Equivalents for WP Air
Force Base (Worst) Using Homologue-Specific Data B-19
IV
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External Peer Review
The following External Peer Reviewers have reviewed and commented
on an intermediate draft of this report.
Dr. Renate Kimbrough Dr. Ellen K. Silbergeld
Centers (or Disease Control Environmental Defense Fund
Or. John F. Gierthy Or. Brendan Birmingham
New York State Ministry of Environment
Department of Health Toronto, Ontario
Dr. Man Poland Dr. Martin Boddington
McArdte Laboratory for Priorities issues Directorate
Cancer Research Environment Canada
Dr. Richard Kociba Dr. Stephen Safe
Dow Chemical Company Texas A & M University
Dr. Barry Commoner Dr. Linda Bimbaum
CBNS Queens College National Institute of
New York Environmental Health Sciences
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U.S. Environmental Protection Agency
Science Advisory Board Review
The Oioxin Equivalency Subcommittee of the U.S. EPA Science Advisory
Board has reviewed and commented on the (inal draft ol this report.
Dr. Allan Okey
The Hospital (or Sick Children
Toronto. Ontario
Or. Nancy Kim
New York State Bureau of
Toxic Substances Management
Dr. Ellen K. Silbergeld
Environmental Defense Fund
Dr. Stephen Safe
Texas A & M University
Dr. Linda Bimbaum
National Institute of
Environmental Health Sciences
Dr. Robert Huggett
Virginia Institute of Marine Science
College of William and Mary
Terry F. Yosie. Director
U.S. EPA Science Advisory Board
Dr. Tom Qasiewica
University of Rochester
Medical Center
Dr. Richard Griesemer, Director
Oak Ridge National Laboratory
Dr.Robert Near
Chemical Industry
Institute of Toxicology
Dr. Patrick Durkin
Syracuse Research Corporation
'Did not attend the Science Advisory Board Meeting
VI
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Preface
As part of its effort to address risks posed by chlorinated dibenzop-
dioxins and chlorinated dibenzofurans (CDDs and CDFs) in the environment,
the U.S. Environmental Protection Agency (EPA) has adopted an interim
procedure, based on dioxin "toxicity equivalence" factors (TEFs), for
estimating the hazard and dose-response of complex mixtures containing
CDDs and CDFs in addition to 2,3,7.8-TCDD. The TEF procedure, and the
scientific data upon which it is based, are the subject of this report.
This report, which has been extensively reviewed by EPA and external
(non-EPA) experts, was prepared for EPA's Risk Assessment Forum (Forum)
and was approved by the EPA Risk Assessment Council in August 1986. In
September 1986. the report was reviewed by a special Subcommittee of me
Agency's Science Advisory Board (SAB), a congressionally mandated body
of independent scientists.
The SAi Subcommittee concurred with EPA's view that the TEF method
is a reasonable interim approach to assessing the health risks associated
with exposure to mixtures of CDDs and CDFs for risk management purposes.
They noted that the method proposed may lack scientific validity and agreed
with EPA on the importance of efforts to validate the method by selected
experimental testing of hypotheses. The Agency received strong
encouragement to continue research on other approaches to estimating risks
for substances in mixtures. The Subcommittee also indicated that it was
important that the interim approach be re-evaluated systematically by EPA
as lessons are learned from toxicotogtcal research and from application.
Lastly, the group cautioned that the interim TEF method should be largely
reserved for special situations where the components of the mixture are
known, where the composition of the mixture is rot expected to vary much
with time, and where the extrapolations are consistent with existing animal
data. Some aspects of the report have been revised to take the
Subcommittee's comments into account.
These SAB comments reinforce EPA's views on the strengths and
limitations of the TEF approach. Throughout development of the report. EPA
scientists have emphasized that the TEF approach is an interim science
policy to be used pending development of more rigorous and scientifically
robust approaches, some of which are mentioned in the report. The Agency
intends to encourage and to pursue a range of research activities which will
both further test the hypotheses that underlie this interim procedure and lead
to alternative, more direct approaches to determining the toxicity of COD and
CDF mixtures.
Research on CDDs and CDFs continues at a rapid pace, and the Agency
is closely monitoring changes in the data base upon which the TEF approach
has been established. Through an annual updating of the approach, the
Forum will assure thai TEF factors remain current with the existing animal
data.
The TEF procedure will be used generally throughout the Agency for
situations in which the components of the mixture are known (or can be
reasonably anticipated) and where the composition is not expected to vary
greatly with time.
VII
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On other issues the SAB Subcommittee and other peer reviewers
recommended that EPA ansider more explicitly the effects of
pharmacodynamics (the bioavailability, absorption, distribution, metabolism,
and elimination) of relevant environmental mixtures in whole animals when
assigning TEFs to the homologues and isomers of COOs and CDFs. For
example, studies suggest that higher chlorinated CDDs and CDFs are less
likely to be absorbed during acute exposures. Further, some CDDs and
CDFs are more likely to be metabolized and eliminated than are others. The.
Forum will review these issues and recommend changes in some TEFs, as
approporiate.
In summary, the TEF approach provides a useful interim method for
consistently interpreting the significance of CDD and CDF residues in the
environment, until more direct methods are available. Users should be aware
of the uncertainties associated with the procedure. In addition to the
uncertainties inherent in the 2.3.7.B-TCDD quantitative risk assessment,
which the TEF approach implicitly adopts, the approach includes the added
qualitative assumption that the other CDDs and CDFs will demonstrate the
same chronic effects as 2.3.7.&-TCDD. While there are good scientific
reasons to expect this to be the case, Me data to support this assumption are
limited.
The Agency plans to update the TEFs on a regular basis, incorporating
additional information as it becomes available so that the approach will
reflect the best current scientific thinking. The intent is to replace this interim
procedure wrth a more rigorous approach as research results permit.
VIII
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I. Summary
The U.S. Environmental Protection Agency (EPA) is often confronted with
the need to determine the risks associated with exposure to materials such
as soot, incinerator fly ash. industrial wastes, and soils which contain
complex mixtures of chlorinated dibenzo-p-dioxms (CDDs) and chlorinated
dibenzofurans (CDFs).1 Recognizing the-public and toxtcological concern
generated by these chemicals and the significant gaps in our ability to
evaluate the human health potential of these compounds by existing
procedures, the CDD.CDF Technical Panel of the Risk Assessment Forum
(Forum) is recommending an interim method to aid in the assessment of the
human health risks posed by mixtures of CDDs and CDFs until data gaps are
filled.
The Technical Panel has reviewed a spectrum of approaches for making
such assessments, consistent with EPA's Guidelines for the Health Risk
Assessment of Chemical Mixtures, and has concluded that a direct biological
assessment of the toxicity of complex mixtures of CDDs and CDFs is
preferred. However, a validated bioassay that can plausibly be applied to
such mixtures is not now available, although promising research is in
progress in the area. An alternative approach involves explicit analysis and
toxicotogical determination of each of the constituent CDD/CDF congeners.
The data required for such an approach also need to be developed and are
not likely to be generated soon. The Forum therefore concludes that, as an
interim science policy measure, a reasonable estimate of the toxic nsks
associated with a mixture of CDDs and CDFs can be made by taking into
account the distribution of CDD/CDF congeners or homologues and the likely
relative toxicity of these compounds. This document describes the
recommended interim procedure for generating the "2378-TCDD
equivalence" of complex mixtures of CDDs and CDFs, based on congener-
or homologue-specific data, and for using such information in assessing risk.
(The recommendations are summarized in the rightmost column of Table 1.)
The Forum acknowledges that this procedure is not based on a thoroughly
established scientific foundation, instead, the approach represents a
consensus recommendation for interim science policy, subject to change as
additional data are available. The approach is judged to be applicable to
mixtures of CDDs and CDFs. but should not be construed as being
applicable as well to mixtures of other chemicals.
The basis of this approach, i.e.. the assignment of toxicity equivalence
factors (TEFs) is subject to revision as new scientific data become available
in the future. Consequently, risk assessors and risk managers are urged to
use informed discretion, noting specific problems on a case-by-case basis.
when applying the procedure to any particular situation. The Forum urges
the support of research to test further the hypotheses that underlie this
interim procedure and to develop the preferred approaches.
1 See Appendix A lor the nomenclature and conventions used in this paper
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T*b/« I. Some Approach** to fsllmallng Ralatlva Totlclllat of PCOOs and PCOFt
Sas/s/
compound
(Basis)
Mono thru di COOs
Tri COOs
2378- rcoo
00»er rCOOs
2378-PeCDOs
offier PeCODs
237fl-H*C0Ds
Ofl»er HxCDDs
2378-HpCDD$
Other HpCDDs
OCOD
2378-TCDFs
Other TCOFs
2378PeCDFs
othar PeCDFs
Swiss*
Enzyme
0
0
1
0.01
01
0.1
Of
Of
001
0,01
0
01
01
01
0.1
Grant*
Oliec
Commoner*
0
0
1
1
01
01
01
01
01
01
0
01
01
01
01
New
York
, Stale*
10*,
0
0
f
0
1
0
003
0
0
0
0
033
0
0.33
0
Ontario'
Various
effects
0
1
1
001
1
0.01
1
0.01
1
0.01
0
002
00002
0.02
00002
FDA9
Various
effects
0
0
1
0
0
0
002
002
0005
0005
«O.OQ001
0
0
0
0
CA*
0
0
1
0
1
0
1
0
1
0
1
1
0
1
0
ww
1981
0
0
1
1
0
0
0
0
0
0
0
0
0
0
0
£f>A
currant
recommend
Various
effects
0
0
1
001
0.5
OW5
004
0.0004
0.001
000001
0
01
0.001
01
0001
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Table 1. (continued)
8as/s/
compound
(Basis)
2378-H«CDF$
orfter HxCDFs
2370-HpCQFs
other HpCDFs
OCDF
Swiss*
Enzyme
0.1
01
Of
0
0
Grant*
OHe"
Commoner11
Of
or
01
Of
0
.Mew
for*
S»»*
to»
act
0
0
0
0
Ontario'
Various
effects
0.02
00002
0.02
00002
0
FDA9
Various
effects
0
0
0
0
0
CA"
t
0
1
0
0
EPA'
1961
0
0
0
0
0
EPA
current
recommend
Various
effects
0,01
0.000t
0.00 I
0.0000 1
0
•Swist government. 19K.
"Grant, 1977,
cOlie 91 el, 1903
1904,
•Eadorielal. 1902.
'Ontario govommenl.
9U.S. OHMS, 1983.
hGravitz et at, 1983.
•US
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II. The Need for a Procedure for Assessing the Risk
Associated with Exposure to Complex Mixtures of
CDDs and CDFs
During the late 1970s, the Agency was faced with assessing the human
health significance of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin
(2.3.7,8-TCDD). In preparation for the cancellation hearings for the herbicides
2,4,5-tnchtorophenoxyacetic acid (2,4,5-T) and Silvex, the Agency generated
risk assessments for several toxic responses for 2,3,7,8-TCDD, The
quantitative cancer risk assessment developed by the Carcinogen
Assessment Group was later adapted for use in the Water Quality Criteria
(WQC) Document lor 2.3,7,8-TCDD (U.S. EPA. 19B4a). in addition to
carctnogenicity concerns, the WQC document contains an assessment of
systemic toxtcrty based on reproductive effects resulting from exposure to
2.3,7,8-TCDD.
Later, it became clear that exposure situations exist in the country which
involve more than 2.3,7.8-TCDD alone. Data on emissions from combustion
sources (e.g., hazardous waste and municipal waste incinerators) and
contents of waste from certain industrial production processes indicate that
the majority of the 75 CDDs and 135 CDFs can be detected in the
environment.
in recant years, the reporting of at least homotogue-specific data for the
CDDs and CDFs has become commonplace, and the Agency has taken
some steps to address the significance of these findings. For example, the
Health Assessment Document for Polychlorinated Dibenzo-p-Dioxins,
prepared for the Office of Air Quality Planning and Standards (U.S. EPA,
l9B5b). contains a quantitative risk assessment for a mixture of
hexachlorodibenzo-p-dioxins (HxCODs) based on carctnogenicity studies
conducted by the National Cancer institute. These concerns have also led to
regulatory action; e.g., several industrial wastes containing tetra-, penta-. and
hexa-chlorodioxins, and -dibenzofurans were recently designated by the
Agency as EPA hazardous wastes.
Faced with increasing amounts of isomer* and homologue-specific data,
and recognizing the significant potency and structure-activity relationships
exhibited in in two and in vitro studies of CDDs and CDFs, the Technical
Panel perceives a need to address more generally the potential risks posed
by the congeners other than 2,3.7.8-TCDD and the mixture of HxCDDs 2
Detailed consideration of the toxicity of the vast majority of the CDDs and
CDFs is limited by the lade of a complete lexicological data base on most of
the congeners. Further, it is unlikely that many long-term test results will be
available soon. For example, research on 2.3,7.8-TCDD has been under way
for more than two decades at an estimated cost of more than one hundred
million dollars. Although this chemical has been investigated to a much
greater extent than any of the other CDDs and CDFs, unanswered questions
* In tft* Mrty i980t th* Agancy ttmtatma • nwtfxxf tor m mpranmM* MMnmtnt of the
nt*» of ttw •mtmcn of COO* and COFt MMnmn ma» ttm Mgh-MmiMraum mc»wninn
o* PCSs ma combustion o< mmaett WMM (U.S. EPA. 1W1; U.S. EPA, 1M21: SM T»bte
i Th« oreoKiim imMnnd in Mt doeum»ni a a ivNiwnwnt of m*i »ppro«cn A
comMroon at« vwwty ot nwrnoOs i* Mdud*d in App«ndot B
-------
remain. Therefore, the Forum believes that an interim science policy position
should be adopted for use in assessing risks associated with CDD/CDF
mixtures, until more definitive scientific data are available.
-------
III. Approaches to Hazard Assessment for CDD/CDF
Mixtures
A. The ideal Approach--Long-Term, Whole-Animal ToxleKy
Assay of Mixtures
Under ideal conditions, an assessment of the toxicrty of a mixture of
chemicals is best accomplished by direct evaluation of its toxic effects, e.g.,
by determining the effects of chronic exposure in an experimental animal
(U.S. EPA. I985a). Such an assessment is time-consuming and costly and
would theoretically have to be performed for each of the many mixtures of
environmental importance. Therefore, this idealized approach would cause
unacceptable delays in addressing the potential health risks associated with
exposures to CDD'CDF mixtures.
Long-term animal studies might be considered for some categories of
CDD/CDF sources which have characteristic compositions; e.g., emission
from some combustion sources. However, the need for an interim approach
would remain.
B. A Promising Approach—Short-Term, Biological Assay of
Mixtures
An alternative, and perhaps more achievable, approach to hazard
assessment of a mixture is a shon>tetm assay (in wo or in vitro) that
indirectly provides a measure of the mixture's potential toxicrty. in the case
of mixtures containing CDDs and CDFs, short-term assays are under
development that directly determine the 2,3,7,8-TCDO-like response which
could be used as a measure of the tox/c/fy of the mixture as a whole. Such
assays take advantage of the similar toxic end points induced by CDDs and
CDFs. and have been used to assess the potential health hazards of
exposure to CDD/CDF-contammated soot from PCS fires (Eadon et a!.. 1982:
Gierthy and Crane. 1984; Qravitz et al., 19B3), and for predicting the potential
toxicity of incinerator fly ash (Rizzardim et al.. 1983; Sawyer et al., 1983).
Although the development of such "mixture assays" is progressing rapidly
(e.g.. Safe et al.. 1985), additional work is required to more fully validate the
assay findings for specific toxic end points, especially chronic effects, and
aspects of pharmacokinetics need to be considered. The Forum, recognizing
the importance of short-term assays, encourages research in this area.
C. A Reductionist Approach-AddWvtty of Toxicrty of
Components
In the absence of a fully developed "mixture assay," the components in a
mixture of CDDs and CDFs could theoretically be identified and quantified by
analytical chemists. Then the toxicity of the mixture could be estimated by
adding the toxicity contributed by each of its components. In the case of
-------
most environmental mixtures, however, this method would be of limited value
since congener-specific analyses tor the 75 CDOs and 135 CDFs potentially
present m the mixture are seldom available. In addition, there is little
information available on the toxic potency of most of these congeners.
Therefore, this approach is not viable at this time, nor is it likely to be
feasible in the near future.
D. An Interim Approach—2378-TCDD Toxicrty Equivalence
Factors (TEFs)
The Forum recommends a fourth alternative for estimating the risks
associated with exposure to complex mixtures of CDDs and CDFs. in this
approach, as in approach C above, information is obtained on the
concentrations of homologues and/or congeners present .in the mixture.
Then, using the available lexicological data and reasoning on the basis of
structure-activity relations, the significance of the exposure to each of the
components is estimated and expressed as an "equivalent amount of 2378-
TCDD." Combining this information with hazard information on 2,3,7,8-TCDD,
and assuming additivity of effects, the risks associated with the mixture of
CDDs and CDFs can be estimated if exposure is known. Key to the approach
are the 2378-TCDD Toxicity Equivalence Factors (TEFs) which are derived in
Section IV.
The general approach using TEFs as outlined here is not unique; several
organizations have used simitar approaches (see Table 1). At one extreme,
all CDOs and CDFs could be assumed to be as toxic as 2,3,7,8-TCDD (all
TEFs ~ 1). This position is not recommended since the limited long-term
data (2-year cancer bioassays) on 2,3,7,8-TCDD and a mixture of 2378-
HxCCDs (and the greater body of short-term data on many CDDs and CDFs}
indicate that such an assumption is overly conservative. At the other extreme
one could totally ignore the presence of CODs and CDFs other than those for
which adequate long-term data are available (most TEFs = 0). This position
is not recommended in light of the similar toxic properties of several of these
compounds and the structure-activity relationship demonstrated for effects
resulting from less than lifetime exposures.
instead, the Forum recommends that the TEF procedure presented in
Section IV be adopted as a matter of science policy on an interim basis,
subject to revision as hew experimental data become available. Based on the
available scientific information, the Forum believes that this approach
represents an appropriate means of approximating the potential risk ol
exposure to mixtures of CDOs and CDFs for purposes of risk management.
The approach will enable the Agency to deal with many, but not all, of its
problems: e.g., assigning priority to Superfund sites, estimating the extent to
which a hazardous waste site should be cleaned up, guiding decisions on
which manufacturing wastes can be delisted as EPA hazardous wastes, and
estimating risks associated with the emission of CDDs and CDFs from
combustion sources.
The remainder of this document discusses the TEF approach in greater
detail, illustrates its use in risk assessment, and identifies additional
research, the results of which would provide information for adjustments to
this interim approach.
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IV. The 2378-TCDD Toxicity Equivalence Factors
(TEFs) Approach to Assessing the Toxfcity of
Complex Mixtures of CDDs and CDFs
2,3.7,8-TCDD is one of 75 CDDs. Exceptionally low doses of this
compound elicit a wide range of toxic responses in many animals, 0,9,,
adverse reproductive effects, ttiymic atrophy, and a "wasting syndrome"
leading to death. Although the Agency prefers definitive human evidence
when assessing the potential human carcinogenicity of chemicals, such data
are rarely available and are lacking in the case of CDDs and CDFs. However,
EPA's Carcinogen Assessment Group (GAG) has determined that, based on
demonstrated effects in animals, there is sufficient evidence to regard
2.3,7,8-TCDD and a mixture of two 237&-HxCDDs as probable human
carcinogens. The GAG quantitative assessment indicates that these
chemicals are among the most potent animal carcinogens evaluated by the
Agency to date. Limited data suggest that some of the other CDDs may have
other toxic effects similar to those of 2.3,7,8-TCDD, again at very low doses.
Moreover, these toxicity concerns are not restricted to CDDs. Limited
experimental data, supplemented by structure/actwrty relationships in in vitro
tests that are correlated with in wvo toxic effects of CDFs, indicate that some
of these compounds exhibit "2.3,7,8-TCDD-Tike" toxicity (Bandiera et a!.,
1984; Okey et a!.. 1984: Safe et a!, 1985).
The biochemical mechanisms leading to the toxic response resulting from
exposure to CDDs and CDFs are not known in detail. However, experimental
data have accumulated which suggest that an important role in the
development of systemic toxicity resulting from exposure to these chemicals
is played by an intracellular protein, the Ah receptor, the putative product of
a gene locus designated Ah. This receptor binds hatogenated polycyciic
aromatic molecules, including CDDs and CDFs. It has been postulated that
the Ah locus controls several pMotropic responses: a limited, but widely
expressed gene complex that includes the structural genes for aryl
hydrocarbon hydroxylase
-------
bind 2,3,7.8-TCDD and AHH induction (Denison and Wilkinson. 1985;
Gasiewicz and Ruca, 1984; Neat, 1985); and in the mouse the development
of TCDD-induced liver toxicity cannot be ascribed solely to the presence o<
the Ah receptor (Greig et al.. 1984).
A recent review concludes that although there are inconsistencies across
species in the Ah receptor being the sole mechanism of toxicity of CDDs and
COFs, the data suggest that the binding of these compounds to the receptor
is in some way related to some of the biological effects seen in experimental
animals (Neat, 1985).
Table 2 summarizes information on a variety of end points elicited by
CDDs and CDFs: acute toxicity, carcinogemcity, reproductive effects,
receptor, binding, enzyme induction, and in vitro cell transformation. For
ease of comparison, the data are normalized to unity for 2,3,7.8-TCDD. For
example, 2378-HxCDDs have about 5% the Ah receptor binding strength of
2,3,7.8-TCDD. Their reproductive toxicity and carcinogenic potency are,
respectively, about 1% and 4% that of 2.3.7,8-TCDD. Kociba and Cabey
(1985) recently presented similar data.
The structure/activity generalizations based on the data in Table 2 support
the generalizations in the literature concerning the congeners that are most
likely to be of toxic concern (Poland and Knutson, 1982; Gasiewicz and
Rued. 1984; Bandiera et al., 1984). That is, congeners that are substituted in
the lateral 2.3,7, and 8 positions are likely to exhibit toxic effects at lower
doses than other congeners. This includes the 15 tetra-. penta-. hexa- and
heptachlorinated CDDs and CDFs listed in Table 3. 3
The "2378-TCDD equivalence factors" (TEFs) listed in Tables 1 and 3
were assigned using several criteria.
1. Definitive data on human carcinogenicity.
2. In the absence of definitive data on human carcinogenicity, information
on carcinogenic potency is based on long-term animal studies which
takes precedence over any other data.
3. When carcinogenic activity has not been demonstrated, data on repro-
, ductive effects become determinative because of the significance of this
' end point in humans. In addition, the estimated exposure levels poten-
tially resulting in reproductive and carcinogenic effects are similar.
•"The Technical Panel a •were that tome nveengators (eg. Qnnt, 1877; Oto et •(.. 1983;
Common* el ml, 1984; end Onimno government. 1982. 1984) have broadly defined congeners
gf concern to include those lit- to hapta- eonganeis which ere subsmutad with at leest three
entwines m me tour liter*) (2, 3. 7. end 8) position* The maty data (Table 2) eta not strongly
support this extended range of concern Further, the increased level ot eompiewty invoked by
including these eddrttanai congeners suggest* • ereeter level of •ecuracy end reeoliition then
ihe Technical Panel bslievei is presently warranted by the itr* .amyoacn.'
The Technicel Penet« etso aware thai reoemor binding dele suggest • relatively high potential
tonctty for 1.2.4.6.7-P*X)F EnrmnMon of stereocaemicel model* ehom thai the 4 and 6
positions o> COFs etfMM partial overlap with the were! chlorine groups of Z.3.7.B-TGOO
(Bendwm et el.. 19841 I'towevet. ttm inciesjea reeepior bndng ectrvity is net reflected in en
increased potency ot i.2.4.6.7-PeCOF Men enzyme mducer (fee Table t), en end point irhicti
hes been shown to mneute with subctironc lonoty (Sift et el.. IBtS). Therefore, the Techmeel
P»n*l ts tieeung 1,2,4,8,7-PeCOF m a "non-2378-conoenef" et Ms time; however, edrjitionet
del* could leed to e chenoje «th» oosiion.
li3.6.7- end 2.3.4.8.7-PeCOf ere e«mcM es potent es 2378-PeCDF in the induction o< AHH
ectiMty m human tymphorjfetstoid cmitt in WBO (see TeWe 2). However, because this eseey seems
to yieid relative gotenciet thet do not egwe with other short*tenn leeu. end because dose-
tesponse deta are not eveMeble for this essay, these data are not included n the overall
evaluation at the present urn*.
-------
Tablt 2. J*0ftflc tmmuno-
Cell cell toticity
kerattn. assay in vitro
001* - 0005"
f" f» |< IO.P
- <0.00f-0.0l« -
05*
— . — — —
0005*
_ _ _ _
— — ' _ _
— — — —
- - _ _
QOOf
O.f»> 0.05* 0.1' O.r°, »"
-------
Fable 2. (continued)
Enzyme Induction
Cji£lf JfQ0
pig
Chemical LDSO
JCOFs
2378-PeCDF
12467 PeCOF
PeCDFs
2378HxCDFs 0017*
HxCDFs
2378 HpCDFs -
HpCDFs
R0fW"OC» I/C ttvGt
Carcino- teratogenic Receptor
genictty effects binding
- - 0.00 1 -0.05**
0 13*;0.7»;Q6"
- - 0 IS*1
- - 0001-0 I**
- - 004-0.5**
0.00 >••"
_ — _
- - <0.00th
AHH
Animal
Cells
*000t«;
004»>
«0 3<< 04-"
0.002h
<0001 2d."«>
005-0.2*""
0 001 ">. 0002"
0004s
<000»'
Human
cells
0.4m
08m
~~
06m
09™
-
_
—
EROO
Cell
keratin.
*0.005d
0 l
-------
Title 3. COOlCDF Isomtn ot Most Toxic Concern*
Oioxin Oibvnzofuran
isomer TEF*> /somer TEF*
2,3,7,8-TCDD ' 2,3,7,8-TCDF 0.1
zjf.4.r,t'f»caF 0.1
0.04 1,2.3.4,7,8'HxCDF 0.01
T.2,3.7.B.9-HfCOO Q°* t,2.3,7,8,9-H*COF 0.01
°'°* 1.2.3,fi.7,8-«*COF 'J-g{
0.001 I.2.3.4.«,?.B-«DCOF 0.00!
0.001
• in osc/i homologous group, me re/auwe rtuoc/ry tecror for me isomers not ftsrecf
aaove /s J/TOO of me va/ue //steo" above.
"TEF = Towcyfy Equwaience f acrar a re/abve loxicity as»gri8d
4. When neither carcinogenic nor reproductive effects have been
demonstrated, the weight of the evidence of the ift vitro test data is
estimated. To simplify the approach and to acknowledge the
approximate nature of the approach, these estimates are rounded off to
the nearest order of magnitude. Somewhat more weight is placed on
data from receptor binding interaction and oxidative enzyme induction,
due to the correlations between these in vitro end points and certain in
MVO systemic efforts; e.g., thymic atrophy and body weight loss.
The above criteria were applied as described below.
1. Since the primary concern is with chronic effects, the relative
carcmogenicrty responses (Table 2) for 2,3,7,B-TCDD and the mixture of
two 2378-HxCDDs^ were used to generate the TEF for 237B-PeCDD.
The TEF for 2378-PeCDD (0.5) is the arithmetic mean of the
carcinogenic potency values for 2.3.7.B-TCDD (1) and 2378-HxCDDs
(0.04). Data on receptor binding, enzyme induction, and cell
keratmization generally support this value.
2. 2,3,7,8-TCDF is assigned a TEF of 0.1 primarily because it is 1 to 2
orders of magnitude (OMs) less potent than 2,3,7,8-TCDD in
reproductive toxicity tests. Also, it is about one OM less potent than
2.3,7,8-TCDD in the in vitro tests.
3. The 2378-PeCDF congeners are assigned a TEF of 0.1 due to the
responses seen in m vitro tests. Greater reliance was placed on me
animal enzyme induction studies due to the more significant correlations
observed between this end point and subchronic responses than have
been observed with the receptor binding end point. The human cell data
were accorded less weight because these experiments were conducted
at only one exposure concentration.
4. Because in vitro data in general show HxCDFs to be about one tenth as
potent as PeCDFs, their TEF is assigned a value of 0.01 (0.1/10).
Further, the date generally suggest that CDFs are somewhat less toxic
than the analogous CDDs. Therefore, the TEF for 2378-HxCDFs should
be less than that of the 2378-HxCDDs (0.04).
4SM Aop*nd« A, iwn 0, fw MDUraMn ol notation.
12
-------
5. The 2378-HpCDDs and 2378-HpCDFs are assigned TEFs 3 OM less
than that for 2,3.7,8-TCDD because the enzyme induction potencies of
these congeners differ from that of 2.3,7.8-TCDD by about this factor.
6. Based on the data m Table 2. the non-2378-substituted isomers are 1 to
2 OMs less potent than the 2378-substituted isomers. Since these data
are limited to in vrtro systems, a factor of 0.01 is applied to the non-
2378-substituted. as compared to the 2378-substituted congeners.
With the exception of 2.3.7.8-TCDD, the 2378-HxCDDs. and 2378-TCDF.
the TEFs are not based on the results of major animal (reproductive.
carcinogenic) studies. Generally. TEFs are based on estimates of the relative
toxicity in in vitro tests whose relationship to the chronic effects of concern is
largely presumptive. However, as discussed above, studies on systemic
effects continue to reinforce the view that the short-term assays provide
important fundamental information on the toxicity of the CDDs and CDFs.
In summary, the Forum concludes that there is a sufficiently plausible
basis for the TEF approach of estimating risks associated with exposures to
CDDs and CDFs and recommends that the Agency adopt the approach, on
an interim basis, as a maner of science policy. The TEFs should be revised
as additional scientific information is developed. It should be noted that this
general approach to estimating such CDD/CDF risks has been taken by other
regulatory groups (see Table 1 and Appendix B).
13
-------
V. Applications to Risk Assessment
. In general, as assessment o< the human health risk of a mixture of CDDs
and CDFs, using the TEF approach, involves the following steps:
1. Analytical determination of the CDDs and COFs in the sample.
2. Multiplication of congener concentrations in the sample by the TEFs m
Table 1 to express the concentration in terms of 2378-TCDD equiva-
lents,
3, Summation of the products in step 2 to obtain the total 2378-TCDD
equivalents in the sample.
4. Determination of human exposure to the mixture in question, expressed
in terms of 2378-TCDD equivalents
5. Combination ol exposure from step 4 with toxicity information on 2,3.7,8-
TCDD (usually carcinogenicity and/or reproductive effects) to estimate
risks associated with the mixture.
In cases in which the concentrations of the 15 congeners are known:
2378-TCDD Equivalents = S (TEF of each 2378-CDO/CDF congener
x the concentration of the respective congener)
+ £ (TEF of each non-2378-GDDCDF congener
x the concentration of the respective congener)
Samples of this calculation for several environmental mixtures are provided
in Table 4.
In cases where only the concentration o< homologous groups is known, i.e.,
no isomer-specific data are available, different approaches are possible. For
example, the assumption that the 2378-congeners of concern constitute all of
the CDDs and COFs present in the mixture is likely to provide an upper-
bound, most conservative estimate ot the toxicity. Alternatively, one could
assume that the occurrence of each of the congeners in the mixture has
equal probability (Olie et al.. 1983: Commoner et al.. 1984). For instance
2,3.7,8-TCDD is one of 22 possible TCDDs and would constitute about 4% of
a mixture of isomers occurring with equal probability In other situations
particular knowledge of chemical reaction parameters, process conditions.
and results from related studies (e.g.. congener distributions in emissions
form combustion sources) might enable one to estimate the relative
occurrence of 2378-congeners. However, one must be careful to explicitly
explain and justify whatever assumptions are made. Table 5 illustrates the
results obtained using different methods to estimate the proportion of 2378 to
non-2378 isomers in the absence of analytical data for individual isomers.
The calculated 2378-TCDD equivalents can then be used to assess the
health risk of a mixture. As an explicit example, consider a municipal solid
waste (MSW) combustor whose paniculate emissions, the CDD/COF mixture
m question, are the same as the electrostatic precipitator (ESP) catch cited in
columns 5 and 6 of Table 4, The sample is estimated to contain 32 ppb
2378-TCDD equivalents: i.e.. 32 picograms of 2378-TCDD equivalents per
milligram of mixture. Suppose t*--t an exposure analysis indicates that a
person living downwind from tne cinerator receives an average daily dose
of 1 ng of the mixture-kg body weight resulting from inhalation (i.e., without
-------
consideration of other possible routes of exposure). This exposure estimate
is combined with the upper-bound carcinogenic potency of 2,3,7,8-TCDD
(1.6 x io5 per mg«kg*day {U.S. EPA, i984b]) to generate the upper 95%
limit of the excess risk of developing cancer (from inhalation exposure alone)
for a person living downwind from the facility emitting the mixture under
consideration, assuming lifetime exposure:
upper 95% limit of excess cancer risk resulting from inhalation exposure
= [potency] x {exposure]
= (1.6 x 105 per mg 2,3.7.8-TCDD-kg-day]
x (32 pg TCDD'mg mixture x 1Q-9 mg 2.3,7,8-TCDD.'pg
x 1 ng mixture/kg-day x 1(H mg mixture-ng mixture}.
15
-------
Table 4. PCDDs/PCDFf in Some environmental Samples
MSW ffy ash'
o>
f»f panics.
Sr. LOUIS*
Isomer
rcoos
PoCODs
HxCDDs
HpCDDs
OCDO
TCDFs
PeCOFs
HxCDFs
HpCOFs
OCDF
JEF
1
05
004
0001
0
or
01
00»
OOOt
0
COD.F
cone.
(ppt
02
r
1.2
25
»70
-
—
—
-
-
rcoo
eqls
»
02
05
0048
0025
0
_
_
_
-
-
maw
CSPdusi*
COD/F
cone.
fppb)
S
fO
160
120
260
40
80
280
160
40
rcoo
eqts
S
5
6.4
012
0
4
a
2.0
0.16
0
(.HUB
COO/F
cone
(PP
0
O.I
OJ4
OS
1.3
013
0,14
0-38
1.13
0.14
rcoo
e
-------
Table 4. (continued)
Thermal degradation prods.
from dielectric fluids' Japanese MSW*
Isomer
rcoos
2378
other
PeCDDs
2378
other
HxCDDs
2370
other
HpCDDs
2378
other
OCDD
TEF
1
0.01
05
0.002
004
00004
0001
000001
0
Run Run
813-40 83061ASKL PI A T£F
CDD.'F TCDD CDD,F TCDD CDDiF JCDD
cone. eqls. cone. eqls. cone. eqts
PI B TEF
CDDIF TCDD
cone. eqts.
(ng) (iig) llblMMBTU(x10*)l
'
0 0 0 0 0.1 01
0000 0.07 0.035
0000 004 0.002
0 0 330 0.33 0.02 < 0.001
0 0 37 0 001 0
058 058
0.47 0.24
0.36 0.014
0.08 < 0.001
0.04 0
Soot from
Commercial CPs PCB fires
246TCPC PCP*
CDDIF TCDD CDDIF TCDD CDDIF
cone. eqts. cone. eqts. cone.
TCDD
eqts.
fppm) (ppm) (ppm)
<0i - <0.i - 0.6
06
<0 1 - <0.1 - 2.5
25
<1 - 25 0.1 11
36
<1 - 175 0.18 3
4
<1 0 500 0 2
06
0.01
1 25
001
004
—
—
—
0
-------
Table 4. (continued)
Isomer
TCDDs
2378
other
PeCDOs
2378
other
HxCDDs
2378
ofher
HpCDDs
2378
other
OCDD
Total TCDD
eqls.
Thermal degradation prods.
horn dielectric fluids* Japanese MSW*>
Run Run
81340 8306IASKL ft A 7EF Pi B
COO.F TCDD CDDlf TCDD CDDIf TCDD CDD.'f
cone. eqls. cone. eqts. cone, eqls cone
TEF (ng) fag} llb/MMBTUfxto^tl
01 690 69 1400 140 131 0 131 125
0001
01 43 43 6400 640 038 0.030 046
0001
001 7 007 9(0 91 0,06 0006 0.06
OOOflr
OOOJ 0 0 29 0029 0.01 (ppm)
1.5 015 <0 I
175 » 75
-------
Table s. • Use of Me If F Approach
MSW fly ash*
tsomer
Total TCDDs
2378-TCDDs
other TCDDs
Total PeCDDs
2378 PeCDDs
other PeCDDs
Total HxCDDs
2378-HxCDDs
other HxCDDs
Total HpCDDs
2378-HpCDDs
other HpCDDs
Total TCDFs
2378-TCDFs
Other TCDFs
TEF
f
r
001
0,5
OS
0005
004
004
0.0004
0001
0001
000001
01
0.1
0001
Ptopft.
factor
t
005
095
1
007
093
,
03
0.7
1
05
05
f
003
097
PCB fire soot*
TCDD eqls
CDDiF (ppm)
(ppm) AC Bc Cc
12 12
12 02 06
1.2 -H
50 2,5
SO 02 13
SO .-
*•' 02
47 0.1
47
7 -
7
7
*• 2.8
28 O.I 1.2
28 -
CDDIF
—— cone.
& (ppb)
85
85
85
213
213
213
354
354
354
Ifl4
184
184
209
209
209
Sample i
TCDD eqts
(pph)
AC flc 0
85
4.3
08
107
70
10
142
43
0.1
02
01
1 —
209
06
02
Sample 2
TCDD eqls
CDDiF (ppb)
~~™" cone. — — *— — — — ^— ^— — —
c (ppb) *= B^ Oc
27 27
27 01
27
6.6 3.3
6.6 0.2
66
116 05
116 01
.ff.6
5.7
57 -
5.7
70 07
70
7.0
-------
Jable S. (continued)
MSW fly as/i"
Isomer
Total PeCDFs
2378P9CDFS
other PeCDFs
Total HxCDFs
2378-HxCDFs
Other HxCDFs
Total HpCDFs
2378-HpCDFs
other HpCDFs
T£F
0.1
01
0001
001
0.01
0.0001
0001
0001
OOOOOI
Propn.
factor
1
0.07
093
1
0.25
0.75
1
050
0.50
CODIF
cone.
(ppm)
670
670
670
965
965
965
460
460
460
PCB
fin soot*
TCDD eqts.
(ppm)
A"
67
97
OS
Be
47
06
24
0.1
02
—
c«= c
350
03
6.7
—
03
—
CDDIF
* (PPb)
549
549
549
1082
1082
1082
499
499
499
Sample i
TCDD eqts.
(ppb)
Ae Bc Dc
54.9
38
05
108
27
01
OS
02
—
Sample 2
rCOO eqts.
CDD/F (ppb)
(ppb) A*
17.8 1.8
178
178
321 03
32.1
32.1
109
109
10.9
B* £K
0.1
—
0.1
—
—
—
—
Total estimated TCDD equivalents (TEF)
Measured TCDD Equivalents
AHH bioassay
EROD bioassay
Receptor binding assay
Acute toxicily bioassay
84
294
58
26
4
5
32
-------
Table S. (continued)
MSW % ash"
Isomet
Tola! JCDDs
2378-TCDDs
other TCDDs
Total PeCDDs
2378-PeCODs
other PeCDDs
Total HxCDDs
2378-HxCDDs
other HxCDDs
Total HpCDDs
2378-HpCDDs
Other HpCDOs
Total TCDFs
2378-TCDFs
other TCDFs
Total PeCDFs
2378-PeCDFs
other PeCOFs
FfF
1
I
001
05
05
0005
004
004
00004
0001
0001
OOOOOf
0 1
Or
0001
0 I
o.r
ooo»
Prop/l.
ractor
1
005
095
t
007
093
t
03
07
1
05
05
r
003
0.97
t
007
093
Sample 3
TCDO eqts
CDDiF (ppb)
(ppb) AC B* 0*
129 12.9
129 06
129 01
375 188
375 13
375 0.2
75 3
75 09
75
419
419
419
82 08
82
82
198 20
198 01
198
CDDiF
(ppb)
24
24
24
79
79
79
97
97
97
91
91
91
44
44
44
210
21 0
21 0
Sample 4
TCDD BQIS.
(ppb)
Ac Bc D0
24
01
—
40
0.3
—
04
0 1
—
-
—
—
04
-
—
21
01
—
-------
Fable 5. (continued)
MSW lly ashh
ro
w
Isomer TEF
Total HxCDFs 001
2378-HxCDFs 001
Other HxCDFs 0.000 1
Total HpCDFs 0001
237$-HpCDFs 0001
other HpCDFs 0.00001
Total estimated TCDD equivalents |TI
Measured TCOD Equivalents
AHH bioassay
EROD bioassay
Receptor binding assay
Acute toxicity bioassay
Propn.
factor
f
025
075
f
0.50
0.50
:F)
Sample 3
FCOO eqls
CDDIF fpftb) CDDIF
(ppbt Ae 8C 0* fppto)
387 04 2t6
38 7 0 t 21 6
387 - 216
206 - '66
206 - »66
20.6 - '66
38 2
4
5
65
_
Sampte 4
TCDD oqts
fppfcj
Ac Bc Dc
02
01
—
. _
—
*»
9 07
2
2
11
—
•Das Hosiers. 1984. assuming only homotogue-specttic concentrations are known (lor isomer-specific analyses: see Tahle 4).
bSa*vye/ ef a/., >983
<:A = estimated assuming 2378-rsomers consWu/e 100% of a homotogous group.
B ~ estimated assuming occurrence of all isomors in a homologous group is equally probable (thus using the proportionality factor in column
three)
C = estimated by utilizing isomer-specific analyses (see Table 4}
D * estimated by direct bmassay.
•'Values rounding off to less ttian 0. i are ormrted
-------
VI. Comparison of the TEF Approach with Results of
Biological Testing
A limited number of in vivo and in vitro approaches have been employed in
assessing the toxicity of complex mixtures of CDDs and CDFs. While the
results from these attempts are not definitive, it is instructive to compare
those results with the results from the TEF approach proposed here.
Eadon et al. (1982) investigated the toxicity of CDD'CDF-contaminated
soot associated with a fire involving PCB-contatning electrical equipment.
Using the results from acute in vivo toxicity (LD50) studies in which the soot
was the test substance, the researchers determined that it had the acute
toxicity expected of material containing about 60 times the amount of 2.3.7.8-
TCDD actually found by GC<'MS analysis.
Table 5 illustrates the results of employing the TEF approach through
three different procedures, each of which depends upon the results of
GC/MS analysis of the soot. In the first instance (A. in Table 5). the analytical
data have been consolidated to totals within a homologous class. These
concentrations are treated as if they consisted completely of 2378-members
of the class and. therefore, are multiplied by the TEF appropriate for the
2378-members of the class. The resulting estimate of 2378-TCDD
equivalents by this procedure is about 80.
In procedure B the assumption is made that the occurrence of each of the
congeners in a homologous class is equally probable; e.g., the concentration
of 2,3,7,8-TCDD is 1/22 (about 5%) of the concentration of the total TCDDs.
This approach leads to an estimate of the total 2378-TCDD equivalents of 8.
A rather unique data base exists in the case of the soot from this fire in
that an extensive isomer-specific analysis of the sample is available (as cited
in Des Rosiers. 1984). Therefore, the full array of TEFs from Table 1 (using
the current EPA recommendations) can be applied. This procedure (C in
Table 5) results in an estimate of roughly 50 for the total 2378-TCDD
equivalents in the sample.
As might be expected, the most conservative of these procedures. A.
leads to the highest estimate. Approach B (using theoretical probability of
occurrence) leads to an estimate that is about 10-fold lower than the isomer-
specific results C, reflecting the fact that the 2378-congeners are present in
somewhat higher than "equal probability" proportions in this particular soot
sample. Given the complexity of the analysis involved, the approximate
nature of the TEF method, and the vagaries of the assay, a major feature of
note in Table 5 regarding the soot samples is that the results of procedures
A. B, and C span a range of only one order of magnitude and bracket the
bioassay estimate, reported by Eadon et al. (1982).
Table 5 also shows the results of the application of approaches A and B to
published results of homologue-specific CDD and CDF concentrations in fly
ash from four municipal solid waste combustors (Sawyer et al.. 1983) In
addition, extracts from the fly ash samples were analyzed by three bioassay
techniques (AHH induction, EROD induction, and receptor binding). Again.
the calculated results span an order of magnitude, with the bioassay results
lying within or close to this range.
These data suggest that the TEF approach is likely to be a useful interim
tool for the rough (order of magnitude) estimation of the toxicity of complex
23
-------
mixtures of CDDs and COFs. The availability ot additional data comparing
the results of analytical and biological assays will enable a conctusion
regarding the preferred method of estimating TEFs (e.g.. method A or B of
Table 5).
24
-------
VII. Research Needs
The Forum recommends that the Agency support research that would
allow actual measurement of mixtures containing CDDs arif C" ither
'than drawing inferences from component toxicity The resultr. • • search
could reduce the need for the TEF approach. In addition, resea -nould be
conducted in order to provide a firmer basis for. and to guiae appropriate
modification of, the TEF approach. Several areas of research are appropriate
for these purposes.
1. Validation and completion of the in vitro test data such as those listed in
Table 2.
2. Investigation of the relationships between short-term in vivo and in vitro
tests and the toxic end points of concern; i.e.. carcmogenicity.
reproductive toxicity. immunotoxicity. and other significant human health
effects resulting from CDD'CDF exposure.
3. Determination of the impact of pharmacodynamics, including
bioavailability. potential for absorption, and toxic potencies of
metabolites of CDDs and CDFs in in vitro tests, relative to the potencies
of the parent compounds. As pointed out by several reviewers, this
would enable refinement of the TEF approach.
4. Investigation of additional short-term assays which can test the
mechanistic hypotheses underlying the TEF approach.
25
-------
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27
-------
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29
-------
Appendix A
Nomenclature
The following terminology and abbreviations are used in this document:
1. The term "congener" refers to any one particular member of the same
chemical family; e.g., there are 75 congeners of chlorinated dibenzo-p-
dioxins
2, The term "homologue" refers to a group of structurally related
chemicals that have the same degree of chlorination. For example, there
are eight homologues of CDDs, monochlorinated through
octochlorinated.
3. The term "isomer" refers to substances that belong to the same
homologous class. For example, there are 22 isomers that constitute the
homotogues of TCDDs.
4. A specific congener is denoted by unique chemical notation. For
example, 2,4.8,9-tetrachlorodibenzofurtn is referred to as 2,4,8,i-TCDF.
5. Notation for homologous classes is as follows:
Dibenzo-p-dioxm D
Dibenzofuran F
No. of halogens Acronym Example
1
2
3
4
5
6
7
8
1 through 8
M
0
Tr
T
Pe
Hx
Hp
O
CDDs and CDFs
2,4-DCDD
t,4,7,8-TCDD
6. Dibenzo-p-dioxms and dibenzofurans that are chlorinated at the 2,3,7,
and 8 positions are denoted as "2378" congeners, except when 2,3,7,8*
TCDD is uniquely referred to: e.g., 1.2,3,7,8-PeCDF and 2,3,4,7,8-
PeCDF are both referred to as "2378-PeCDFs."
A-i
-------
Appendix B
Comparison of Different Approaches to Calculating
2378-TCDD Equivalents
Table 1 in the text lists a number of different approaches for calculating
2378-TCDD toxicity equivalents. Five of the approaches (those that deal with
4-position 2378-substituted congeners, but not 3-position substituted
congeners) were applied to the data in Table 4 in the text.
These approaches were also applied to some of the data included in Table
I of the Report of the Citizens Advisory Committee on Resource Recovery in
Brooklyn (March. 1985). produced by Ketcham and the Mt. Sinai School of
Medicine.
A summary comparison of the relative results is found in Table B-1. with
the supporting tables (Tables B-2 through B-13) attached. (Note that the units
of mass emission are not the same for all of the facilities. Therefore,
comparison of absolute numbers between facilities may be invalid).
These data indicate that, in general, the methods used by the Swiss
government. New York State, and the U.S. EPA (the 1981 approach and the
1985 proposal) all generate results which are within an order of magnitude of
each other. This suggests that, within the range considered, the results are
not particularly sensitive functions of the TEFs selected.
The procedure recommended by the state of California, however, gives
results which are roughly an order of magnitude higher than those generated
by the other approaches. In general, the greater the contribution from the
TCDDs, the greater the similarity in the results of the methods. This is due to
the fact that all methods assign a TEF of 1 for 2.3,7.8-TCDD (and 1 to all
TCDDs, when isomer-specific analyses are not available). Because higher
chlorinated CDDs and CDFs contribute significantly to the total, the disparity
is greater between the state of California results and those produced by the
other methods, since California assumes that all 2378-substituted CDDs and
CDFs are as potent as 2.3.7.8-TCDD. The other methods acknowledge, to
one degree or another, the reduced toxicity of higher chlorinated species:
see Table 2.
B-1
-------
faille fl-J. Rtlatfin 2378-TCDD Equivalents'
Source 1
Si. Louis
air partcuiates
PCS fire soof
(isomer-soecific)
MSW ESP dust
lak» sediment
Miloryanite
Oslo MSW Hy ash
Ontario MSW Hy ash
Japanese plant A
Japanese plant B
Albany
Wright-Patterson (best)
Wrigtn-Paserson (worst)
?PA15
t
•1
7 •
1
I
f
J
I
t
f
, 7
J
EPA «T
0.3
0,03
0.2
_
0.6
-
0.8
0,3
0.6
0.3
0.2
0.4
Swiss
1
4
3
2
2
1
1
f
0.8
0.4
2
2
NY
2
3
2
2
0,9
2
2
2
2
2
3
2
CA
40
30
30
30
30
20
3
7
3
5
20
20
'Calculated using the Toucity £
-------
CO
Table 0-2. Calculation of Z378-TCDD fox/cify Equivalents lor SI. Louis Air Particulars Using Homologue-Specitic Data
EPA 198$ EPA 1981 Switzerland , New York California
Compound
Mono to tn
237BTCDO
TCDDs
2378-PeCDD
PeCDDs
2376-HxCDD
HxCODs
2378 HpCDD
HpCDDs
OCDD
Mono lo Iri
237BTCDF
TCOFs
2378-PeGDF
PeCDFs
2378-HxCDF
HxCDFs
Lftiu/r
cone.
(ppb)
X
02
0
1
0
1.2
0
25
0
170
X
NA
0
NA
0
NA
0
TEFs
0
1
001
05
0005
004
00004
ooor
000001
0
0
01
0001
01
0.001
001
0.0001 .
res
(ppb)
0
02
0
05
0
0048
0
0025
0
0
0
0
0
0
0
0
0
TEFs
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
TEs
(ppb)
0
02
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
TEFs
0
1
001
01
0.1
01
0.1
001
0.01
0
o
0
0.
0
0.
0
0
TEs
(ppb)
0
02
0
01
0
012
0
025
0
0
0
0
0
0
0
0
0
TEFs
0
1
0
1
0
003
0
0
0
0
0
033
0
033
0
001
0
TEs
tPPb)
0
02
0
1
0
0038
0
0
0
0
0
0
0
0
0
0
0
TEFs
0
1
0
1
0
1
0
1
0
0
0
1
0
1
0
1
0
TEs
(PPb)
0
02
0
1
0
12
0
25
0
0
0
0
0
0
0
0
0
-------
Table B-2. (continued)
Compound
2378-HpCDF
HpCDFs
OCOF
cone.
NA
0
NA
Total 2378- TCOD equivalents
EPA 1985 EPA
TCs
TEFs fppb) TEFs
0.001 0 0
000001 0 0
000
0.7
1981
TEs
(PPb)
0
0
0
02
Table B-3. Calculation of 2378-rCDD Toxlcltf equivalents tor PCB Fir* Soot
Compound
Mono to in
2378-TCOD
TCDDs
2378-PeCDD
PeCDOs
cone
(ppm)
X
06
06
25
2.5
EPA 1985 EPA
Ti$
TEFs (ppm) TEFs
0 0 0
I 06 i
001 0006 1
05 125 0
0005 00125 0
1981
TEs
(ppm)
0
06
06
0
0
Switzerland
TEs
fiFs (ppb)
0.1 0
0 0
0 0
07
Using Isomer-Speclllc
Switzerland
New
TEFs
0
0
0
Data
New
TEs
TEFs (ppm) TEFs
0 0
1 06
0.01 0006
0 1 025
0 1 025
0
1
0
t
0
Yoik
TEs
(ppb)
0
0
0
12
Vort
TEs
(ppm)
0
06
0
2.5
0
California
TEs
TEFs (ppb)
1 0
0 0
0 0
27 4
California
TEs
TEFs (ppm)
0 0
1 06
0 0
1 25
0 0
-------
Table B-3. (continued)
Compound
237B-HxCDD
HxCDDs
2378-HpCOD
HpCOOs
OCOO
Mono to tri
2378-TCDF
TCDFs
2378-PeCDF
PeCDFs
2378-HxCDF
HxCDFs
2378-HpCDF
HpCDFs
OCDF
CDD/F
cone.
(ppm)
11
36
3
4
2
X
12
16
358
3f2
670
295
285
»72
40
EPA
TEFs
004
00004
0.001
0.00001
0
0
01
0001
01
0.001
001
0.0001
0001
000001
0
Total 2378-TCDD equivalents
1985
TEs
(ppm)
0044
000144
0003
000004
0
0
12
0.016
358
0312
67
00295
0285
000172
0
46
EPA
TEFs
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1981
TEs
(ppm)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1.2
Switzerland
TEFs
0.1
01
0.01
001
0
0
0
0
0
0.
0
0
01
0
0
TEs
(ppm)
Oil
036
003
004
0
0
1 2
16
358
31.2
67
295
285
0
0
f96
New
TEFs
003
0
0
0
0
0
033
0
033
0
001
0
0
0
0
York
TEs
(ppm)
0033
0
0
0
0
0
396
0
IIB 14
0
67
0
0
0
0
132
California
TEFs
1
0
1
0
0
0
1
0
1
0
1
0
1
0
0
TEs
1 1
0
3
0
0
0
12
0
358
0
670
0
285
0
0
f332
-------
Table 8-4. Calculation ol 2378-TCDD Toxiclty Equivalents lor MSW ESP Ousf Using Homologue-SpecHIc Data and 2378 TtFs
EPA 1985 EPA 1981 Switzerland New York California
Compound
Mono to tri
2378 TCDD
TCDDs
2378PeCDO
PeCDDs
2378-HxCDD
HxCDDs
2378-HpCDD
HpCDDs
OCDD
Mono to tri
2378 -TCDF
TCOFs
2378-PeCDF
PeCDFs
2378 HxCDF
HxCDFs
OULT/r
cone.
(PPb)
K
5
0
10
0
160
0
120
0
260
X
40
0
80
0
280
0
TEFs
0
1
001
05
0005
004
00004
0001
0.00001
0
0
01
OOOI
01
0.001
001 .
00001
TEs
(PPb)
0
5
0
5
0
64
0
0 12
0
0
0
4
0
a
0
2.8
0
TEFs
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
TEs
(PPb)
0
5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
TEFs
0
1
001
01
01
01
01
001
001
0
0
0.
0.
0
0.
0
0
TEs
(PPb)
0
5
0
1
0
16
0
12
0
0
0
4
0
8
0
28
0
TEFs
0
1
0
1
0
003
0
0
0
0
0
033
0
033
0
001
0
TEs
(PPb)
0
5
0
10
0
48
0
0
0
0
0
13.2
0
264
0
28
0
TEFs
0
1
0
1
0 .
1
0
1
0
0
0
1
0
1
0
1
0
TEs
(PPb)
0
5
0
10
0
160
0
120
0
0
0
40
0
80
0
280
0
-------
Table 0--» (continued)
EPA 1985
EPA 1981
Swifter/and
Wew Korfc
California
Compound
2378 HpCDF
HpCOFs
OCDF
Total 237B-TCDD
cone
(ppb)
160
0
40
equivalents
Table B-5 Calculation ot 2378-
Compound
Mono to lit
2378-TCDD
TCDDs
2378-PeCDD
PeCOOs
2378HxCOD
HxCDDs
CDO/F -
cone.
(ppb)
t
0
0
01
0
0.34
0
TEFs
0001
000001
0
rfs
(ppb)
0/6
0
0
31
TEFs
0
0
0
TEs
(ppb)
0
0
0
5
TCDO fOKfc/fy Equivalents for take Sediment
EPA
TEFs
0
1
O.OI
05
0005
004
00004
1985
TEs
0
0
0
005
0
00136
0
EPA
TEFs
0
1
1
0
0
0
0
1981
TEs
(ppb)
0
0
0
0
0
0
0
TEFs
01
0
0
Using
TEs
(ppb)
16
0
0
79
Homologue
Switzeilanci
TEFs
0
1
001
0.1
01
01
O.I
TEs
0
0
0
001
0
0034
0
TEFs
0
0
0
•Specific
TEs
(ppb)
0
0
0
62
Data
New York
TEFs
0
I
0
1
0
003
0
TEs
(ppb)
0
0
0
01
0
00102
0
TEs
TEFs (ppb)
1 160
0 0
0 0
855
California
TEs
TEFs (ppb)
0 0
1 0
0 0
t O.I
0 0
1 034
0 0
-------
Table B-5. (continued)
EPA 190S
EPA 1981
Switzerland
New York
California
to
Compound
2378-HpCDD
HpCDDs
OCDD
Mono to tri
2378- JCDF
TCOFs
2378-PeCDF
PeCDFs
2378-HxCOF
HxCDFs
2378-HpCDF
HpCDFs
OCDF
IsWIl — — — — .___.__ — "•- -'• I" ____— ^^— — _________
cone, TEs TEs TEs TEs TEs
(ppb) TEFs (ppb) TEFs (ppb) TEFs (ppb) TEFs (ppb) TSFs (ppb)
OS 0001 00005 0 0 001 OOOS 00 1 OS
0 000001 0 00 001 0 00 0 0
130 0 00 0
x 0 000 0
013 01 0013 0 00
0 0001 0 000
0 14 01 0014 00 0
0 0001 0 000
038 001 00038 00 0
0 00001 0 000
113 0001 000113 0 0 01
0 000001 000 0
0.14 0 0 0 0 0
Total 2378- TCDD equivalents 01 0
0 O'O 0 0
000 00
0013 033 00429 1 0.13
000 00
0014 033 00462 1 014
0 00 0 0
0038 001 00038 1 038
0 00 0 0
0113 0 0 1 113
000 00
000 00
12 0.2 27
-------
Table B-6. Calculation ol 2378-TCDD Totlclty Equivalents for Mllorganlte Using Homologue-Spectllc Data
EPA 1985 EPA 1961 Switzerland New York
California
2Compound
Mono to tri
237B-TCDD
TCDDs
2378-PeCDD
PeCDDs
237B-HxCDD
HxCDDs
2378HpCDD
?> HpCDDs
to
OCDD
Mono to tri
2378-TCDF
TCDFs
2378-PeCDF
PeCDFs
237B-HxCDF
HxCDFs
OL/L//r
cone.
(ppn
X
206
0
0
0
2768
0
7600
0
60000
X
NA
0
NA
0
NA
0
TEFs
0
1
001
05
0005
004
00004
0001
000001
0
0
01
0001
01
0001
001
0.0001
TEs
(ppn
0
206
0
0
0
11072
0
76
0
0
0
0
0
0
0
0
0
TEFs
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
TEs
(ppn
0
206
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
TEFs
0
1
001
01
01
01
01
001
001
0
0
01
01
0 1
01
01
0.1
TEs
(ppn
0
206
0
0
0
2768
0
76
0
0
0
0
0
0
0
0
0
TEFs
0
r
0
J
0
003
0
0
0
0
0
0.33
0
033
0
001
0
TEs
(ppn
0
206
0
0
0
8304
0
0
0
0
0
0
0
0
0
0
0
TEFs
0
1
0
1
0
1
0
1
0
0
0
1
0
1
0
1
0
TEs
(PPD
0
206
0
0
0
2768
0
7600
0
0
0
0
0
0
0
0
0
-------
Fable 8-6. (continued)
EPA 1985
EPA 1981
Switzerland
New York
California
Compound
237iHpCDF
HpCDFs
OCDF
Total 2378-TCDD
isLHS/r
cone.
tppn
NA
0
NA
equivalents
TEFs
0001
000001
0
TEs
(PPt)
0
0
0
324
T£Fs
0
0
0
03 Table B-7. Calculation of 2378-TCDD Toxlclty Equivalents tor
o
Compound
Motto to tri
2378-TCDD
TCDDs
237B-PeCOD
PeCDDs
2378-HxCDD
HxCDDs
rnn/c '
cone.
(PPI)
n
NA
0
it
0
51
0
EPA
TEFs
0
1
oot
05
0005
004
00004
1985
TEs
(PPD
0
0
0
55
0
204
0
res
IPPO
0
0
0
206
TEFs
Oi
0
0
Of lo MSIT Fly Ash Using
EPA 1981
TEFs
0
1
1
0
0
0
0
TEs
(PPi)
0
0
0
0
0
0
0
TEs
(wn
0
0
0
SS9
Homologut
Switzerland
TEFs
0
I
001
0 t
01
01
0 1
TEs
(PPt)
0
0
0
t t
0
S t
0
TEFs
0
0
0
•Specific
TEs
(PPt)
0
0
0
289
Data
New York -
TEFs
0
1
0
1
0
003
0
TEs
(PPt)
0
0
0
11
0
1 53
0
TEs
TEFs (ppt)
1 0
0 0
0 0
f0600
California
TEs
TEFs (ppl)
0 0
f 0
0 0
t ft
0 0
1 51
0 0
-------
fable 0-7, (continued)
Compound
2373-HpCOO
HpCDDs
OCOD
Mono to tri
2378-TCDF
TCDFs
2378-PeCDF
PeCDFs
2378H*CDF
HaCDFs
2378HpCOF
HpCDFs
OCDF
cone
(ppti
119
0
IBS
X
NA
0
NA
0
NA
0
NA
0
NA
EPA
TEFs
0001
000001
0
0
01
0001
01
0001
001
00001
0001
000001
0
Total 23 78 - TCDD equivalents
1985
TEs
0 119
0
0
0
0
0
0
0
0
0
0
0
0
77
EPA
TEFs
0
0
0
0
0
0
0
0
0
0
0
0
0
I90>
TEs
(PPD
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Switzerland
TEFs
001
001
0
0
0 1
01
0.1
01
01
01
0 1
0
0
TEs
1 19
0
0
0
0
0
0
0
0
0
0
0
0
7,4
New
TEFs
0
0
0
0
033
0
033
0
001
0
0
0
0
Vorh
TEs
n
0
0
0
0
0
0
0
0
0
0
0
0
0
12,5
California
TEFs
1
0
0
0
1
0
1
0
1
0
1
0
0
TEs
(PPD
119
0
0
0
0
0
0
0
0
0
0
0
0
181
-------
Table B-8. Calculation of 2378-TCDD Toxtctty equivalents lor Ontario MSW Fly Ash Using Homologue-SpecHIc Data
EPA 1985 if A 1981 Switzerland New York California
Compound
Mono to tri
2378 TCDD
rcoDs
2378-PeCDD
PeCDDs
2378-HxCDD
HxCDDs
2373-HpCDD
m HpCDDs
iS OCDD
Mono to Iri
237B-TCDF
TCDFs
2378-PeCDF
PeCDFs
23T8HxCDF
HxCDFs
WL/iwr
cone,
(PP»
X
54 1
0
487
0
59 1
0
434
0
467
g
NA
0
NA
0
NA
0
TEFs
0
1
001
05
0005
0.04
0.0004
0001
000001
0
0
01
0001
01
0001
001
00001
ns
(ppf)
0
541
0
2335
0
2364
0
0434
0
0
0
0
0
0
0
0
0
TEFs
0
1
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
TEs
(PPt)
0
541
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
TEFs
0
1
001
0 1
O.t
01
0 t
001
001
0
0
0.
0
0
0
0
0
TEs
0
541
0
467
0
591
0
4 34
0
0
0
0
0
0
0
0
0
TEFs
0
1
0
1
0
0.03
0
0
0
0
0
033
0
033
0
001
0
TEs
(PPt)
0
541
0
467
0
1773
0
0
0
0
0
0
0
0
0
0
0
TEFs
0
1
0
1
0
I
0
f
0
0
0
f
0
t
0
1
0
TEs
(PPt)
0
641
0
467
0
591
0
43)
0
0
0
0
0
0
0
0
0
-------
Table B-8. (continued)
EPA 1985 EPA I98t Switzerland New York California
Compound
2378-HpCDF
HpCDFs
OCDF
Total 237B-TCDD
i,uuir
cone,
iPPt)
NA
0
NA
equivalents
ro Table 0-9. Calculation ol 2378-
CO
Compound
Mono to tri
2378 TCDD
TCDDs
2378PeCDD
PeCDDs
2378-HxCDD
HxCDDs
CDDIF
conc.»
JC
or
0
00?
0
004
0
TEFs
0001
000001
0
res
(ppi)
0
0
0
799
JEFs
0
0
0
TEs
(PPt)
0
0
0
541
TEFs
01
0
• o
TCDD Toxtcity Equivalents lor MSW at Japanese Plant A
EPA
TEFs
0
1
001
05
0005
004
00004
1985
Tis*
0
Of
0
0035
0
000(6
0
EPA
TEFs
0
t
1
0
0
0
0
1981
TEs»
0
0,1
0
0
0
0
0
TEs
(PPD
0
0
0
65 1
Using
Switzerland
TEFs
0
I
001
01
01
01
01
res*
0
01
0
0007
0
0004
0
TEFs
0
0
0
TEs
(ppt)
0
0
0
1028
Homologue-Speclltc
New
TEFs
0
t
0
1
0
003
0
York
Tfs-
0
0.1
0
007
0
00012
0
TEs
TEFs (ppt)
1 0
0 0
0 0
2033
Data
California
TEFs TEs»
0 0
1 O.I
0 0
1 007
0 0
t 004
0 0
-------
Table 0-9. (continued)
EPA I9B5
EPA 1981
Switzerland
New Yoik
California
o>
Compound
2378HpCDD
HpCDOs
OCOO
Mono to In
2378-TCDF
JCDFs
2378 PeCDF
PeCOFs
2378HxCDF
HxCDFs
2378-HpCDF
HpCDFs
OCDF
<~-uuir — • — — • — •" .
cone * TEFs TCs* TfFs TEs* TEFs TEs* TEFs TEs* TEFs JEs*
002 0001 000002 0 0 001 00002 0 0 1 002
0 000001 0 00 001 000 00
001 00 000
x 0 0 0 00
131 01 0131 0 0 0
0 0001 0 000
0.38 01 0038 0 0 0
0 0001 0 0 0 0
006 001 00006 0 00
0 00001 0 000
001 0001 000001 0 0 O.I
0 000001 0 000
0004 0 00 00
Total 23 78-TCDD equivalents 03 01
0 00 00
0 00 00
0131 033 04323 I 131
0 00 00
0038 033 01254 1 038
0 00 00
0006 OOf 0.0006 1 006
0 00 00
0001 0 0 I 00?
0 00 00
000 00
03 07 20
"lAwrs =tblMMBT,Ul*tO*)
-------
Table 0-10. Calculation ol 2378-TCDD roxfc/fy Equivalents tor MSW at Japanese Plant B Using Homologue-SpecKfc Data
EPA 1985 EPA 1981 Switzerland New York California
Compound
Mono to tri
2378-TCDD
TCODs
237BPBCDD
PeCDDs
2378 HxCDD
HxCDDs
2378 HpCDD
HpCDDs
OCDD
Mono to In
2378-TCDF
TCDFs
2378P8CDF
PeCDFs
2378-HxCDF
HxCDFs
\svuir
cone.*
X
058
0
047
0
036
0
0.08
0
004
X
125
0
046
0
0.06
0
TEFs
0
1
001
05
0005
004
00004
0001
000001
0
0
o r
0001
01
0001
001
00001
ns*
0
058
0
0235
0
00144
0
000008
0
0
0
0 125
0
00*6
0
00006
*0
TEFs
0
1
1
0
0
0
o
0
0
0
0
0
0
0
0
0
0
T£s«
0
058
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
. TEFs
0
1
001
01
or
or
01
001
oor
0
0
01
01
O.I
01
O.I
or
res-
0
058
0
0047
0
0036
0
00008
0
0
0
0 125
0
0046
0
0006
0
TEFs
0
0
f
0
003
0
0
O
0
0
033
0
033
0
o.o r
0
r&«
0
056
0
047
0
00108
0
0
0
0
0
04»25
0
0 1518
0
00006
0
TEFs
0
t
0
1
0
1
0
1
0
0
0
1
0
t
0
t
0
TEs*
0
058
0
047
0
036
0
008
0
0
0
1 25
0
046
0
006
0
-------
Table 0-JO (continued)
EPA 1985
EPA I9B1
Switzerland
New York
California
Compound
237a-HpCDF
HpCOFs
OCDF
isuutr
cone."
0,02
0
0,01
TEFs
0-00 1
0,00001
0
Total 2378 TCDD equivalents
• re$*
00000?
0
0
to
re*
0
o
0
res*
0
0
0
06
TfFs
01
0
0
TEs*
0002
0
0
00
TEFs
0
0
0
res*
0
0
0
IB
refs res*
r 002
0 0
0 0
33
•Units = lt>/MM BTU{xlO*)
Table B-11. Calculation ol 2378-
m
m
Compound
Mono io Iri
2378-TCDD
TCDDs
237S-PeCQO
PeCDDs
2378-HxCDD
HrCODs
CDDIF -
cone
(ngim3)
*
045
14
97
0
S3
0
FCOO Toiictty Equivalents lor MSW 81 Albany
EPA
TEFs
0
I
001
05
0005
004
00004
>9flS
res
fngim3)
0
045
0 14
49 S
0
3.12
0
EPA
JiFs
0
t
r
0
0
0
0
(901
res
(ngim3)
0
045
14
0
0
0
0
Using Homologue
Switzerland
TEFs
0
t
001
0 t
or
or
o, r
res
(ngim3)
0
045
0 14
9 7
0
S3
0
•Specific
New
TEFs
0
i
0
I
0
003
0
Data
York
res
(ngsitt*)
0
0*5
0
97
0
159
0
California
res
TEFs (ng
-------
Table B-11. (continued)
03
Compound
2378-HpCOD
HpCDDs
OCDD
Mono to tri
2379-TCDF
ICDFs
237t-PeCDF
P0CDFS
2378-HxCDF
HxCDFs
HpCDFs
OCDF
cone.
(nglm*)
71
0
10
i
2,1
33
2t
0
4
0
1
0
2
EPA
TEFs
0.001
000001
0
0
O.I
0.001
01
0001
0.01
00001
0 001
000001
0
Total 2378-fCDO equivalents
1985
res
0.071
0
0
0
021
0033
2.1
0
0.04
0
0001
0.
0
54
£PA
TEFs
O
0
0
0
0
0
0
0
0
0
0
0
0
1981
res
(nglmi)
0
0
0
0
0
0
0
0
0
0
0
0
0
14
SwittetlantJ
TEFs
001
001
0
0
0
0
0
0
0
0.
O.I
0
0
res
(nglm*)
0.71
0
0
0
021
33
21
0
04
0
0.1
0
0
22
New York
TEFs
0
0
0
0
033
0
033
0
001
0
0
0 .
0
res
(ngtm*)
0
0
0
0
0693
0
G93
0
004
0
0
0
0
107
California
TEFs
1
0
0
0
1
0
I
0
I
0
1
0
0
TEs
(nglm3)
71
0
0
0
21
0
21
0
4
O
1
0
Q
250
-------
Table B-12. Cilcutition ol 2378-TCDD Toitclty EtfuJvatonti lorWP AFB (Best) Using Homologue-Specltlc Oat*
EPA 1985 EPA 1981 Switzerland New York
California
m
m
Compound
Mono to tri
2378-TCDD
TCDDs
2378PaCDD
PeCDDs
2378HxCDD
HxCDDs
23/8-MpCOO
HpCODs
OCDO
Mono to M
2378-TCDF
TCDFs
2378P0CDF
PeCDFs
2378-HxGDF
HxCDFs
tfi/uir
cone.
X
0.4
0
0.4
0
1
0
3
0
3
*
8
0
3
0
4
0
m*
0
t
001
.05
0005
004
00004
0001
OOOOOf
0
0
0 1
ooor
Of
0.001
oor
o.ooor
res
inglm*}
0
04
0
02
0
004
0
O003
0
0
0
08
0
03
0
0.04
• o
TEFs
0
1
f
0
0
0
0
0
0
0
0
0
0
0
0
0
0
fngfm1)
0
04
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
rffs
0
i
001
0 r
0 f
o r
O.I
oor
oor
0
0
0
0.
0.
0
0.
0
res
(ngirn3!
0
04
. 0
004
0
0 I
0
003
0
0
0
08
0
0.3
0
0,4
0
TEFs
0
1
0
1
0
003
0
0
0
0
0
033
0
033
0
oor
0
TEs
(nglm3)
0
04
0
04
0
003
0
0
0
0
0
264
0
om
0
004
0
JEFs
0
1
0
t
0
1
0
I
0
0
0
r
0
i
0
r
0
res
(nglm3)
0
04
0
04
0
1
0
3
0
0
0
8
0
3
0
4
0
-------
Table B-12. (continued)
EPA 1985
EPA 1981
Switzerland
New York
California
Compound
2378-HpCDF
HpCDFs
OCDF
UL/L"r
cone
9
0
2
TEFs
0.001
000001
0
Total 237B-TCDD equivalents
o, Table B-13. Calculation of 2378-
)
0
0
0
45
Data
York
TEs
(nglm3)
0
4
0
3
0
018
0
TEs
TEFs (ng/m3)
1 9
0 0
0 0
288
California
TEs
TEFs (ng/m3)
0 0
1 4
0 0
1 3
0 0
1 6
0 0
-------
Table B-13. (continued)
8
Compound
2378HpCDD
HpCDDs
OCDD
Mono to tri
2378-TCDF
TCDFs
237BPeCDF
PeCDFs
2378-HxCDF
HxCDFs
237BHpCDF
HpCDFs
OCDF
cone.
32
0
16
X
31
0
15
0
23
0
93
0
B
EPA
TEFs
0001
000001
0
0
01
0001
01
0001
001
00001
0001
000001
0
Total 2378-TCDD equivalents
19B5
TEs
(nglm3)
0032
0
0
0
31
0
15
0
023
0
0093
0
0
110
EPA I9BI
TEFs
0
0
0
0
0
0
0
0
0
0
0
0
0
TEs
0
0
0
0
0
0
0
0
0
0
0
0
0
4
Switzerland
TEFs
001
001
0
0
0
0
0.
0
0
0
01
0
0
TEs
(ngim*)
032
0
0
0
31
0
15
0
23
0
93
0
0
21 4
New York
TEFs
0
0
0
0
033
0
033
0
001
0
0
0
0
TES
(ngim3)
0
0
0
0
1023
0
495
0
023
0
0
0
0
226
California
TEFs
1
0
0
0
1
0
1
0
1
0
1
0
0
TEs
(nglm*)
32
0
0
0
31
0
15
0
23
0
93
0
0
207
-------
Part II
1989 Update to the Interim
Procedures for Estimating Risks
Associated with Exposures to
Mixtures of Chlorinated Dibenzop-
Dioxins and -Dibenzofurans
(CDDs and CDFs)
March 1389
Authors
Donald G. Barnes. Ph.D.
Staff Director, Science Advisory Board
Frederick W. Kutz, Ph.D.
Office of Research and Development
David P. Bottimore, B.S.. B.A.
Versar, Inc.
Technical Panel
Donald G. Barnes. Ph.D., Co-chair
Frederick W. Kutz, Ph.D.. Co-chair
David W. Cleverly, M.S.
Contractor support to the Technical Panel
was provided by David P. Bottimore. Versar, Inc.,
under Contract No. 68-02-4254
Risk Assessment Forum Staff
Dorothy E. Patton, Ph.D., J.D., Executive Director
William P. Wood, Ph.D., Science Coordinator
Linda Tuxen, B.S.. Technical Liaison
Risk Assessment Forum
U.S. Environmental Protection Agency
Washington, DC 20460
-------
Disclaimer
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved tor publication. Mention of trade
names or commercial products does not constitute endorsement or
recommendation for use.
-------
Contents
Page
USt of Tables , iv
List ol Figures iv
Acknowledgments v
EPA Review viii
List of Acronyms x
Overview 1
Background 3
A. The TEF Concept 3
B. Development ol the EPA-TEFs/87 6
C. Subsequent Developments on the International Front 6
D. Status of the TEF Concept 8
III. Update of EPA-TEFs/87. Adopting the l-TEF/89 Scheme 13
A. Similarities Between l-TEFs'89 and EPA-TEFs/87 13
B. Differences Between l-TEFs/89 and EPA-TEFs/87 14
1. Increased Simplicity 14
2. l-TEFs/8i for all Non-2378 Congeners are Zero 14
3. Distinguishing Between 1.2.3.7,8- and
2,3,4,7,8-PeCDF , 15
4. Increasing the TEFs for the 2378-HxCDDs'Fs and
-HpCDDs/Fs 18
5. Assigning Non-Zero TEF Values to OCDD and
OCDF 20
IV. Summary 21
References 22
Appendix 25
-------
Ust of Tables
Number Page
1. Number of Congeners by Homologue and
Substitution Type ("2378" vs. "non-2378") 3
2, Toxicity Equivalency Factors 13
3. International Toxicity Equivalency Factors/89 (l-TEFs/89):
Comparison of Relative Potency Data for trie 2378-Substituted
CDDs and CDFs 16
Ust of Figures
Number Page
1. Examples of 2378 and non-2378-Substituted Oioxins
and Furans 4
2. Toxicity Equivalents in Emissions from a Municipal
Waste Incinerator 9
3. Toxicity Equivalents in Human Milk Sample 11
4. Toxicity Equivalents in a Pentachlprophenol Wood Treatment
Site Soil Sample 12
5, 2378-Substituted Pentachlorodibenzoturans 18
IV
-------
Acknowledgments
This report was prepared for EPA use and is based on two documents
published by the NATO/CCMS Pilot Study on International Information
Exchange on Dioxins and Related Compounds. This EPA report summarizes
the methodology/rationale used to develop the updated international Toxicity
Equivalency Factor/Si (l-TEF/89) method. This EPA report also highlights the
changes made from the previous EPA-TEF/8? scheme and the toxicologies!
data supporting those changes.
The contributors to the two NATO/CCMS documents are acknowledged
below and represent members of a special "TEF Subgroup" established by
the Pilot Study to develop international consensus on a TEF scheme. In
addition to the authors and members of the NATO/CCMS Pilot Study, other
reviewers of the two NATO/CCMS documents are acknowledged for their
contributions to the development of the l-TEF/89 method and the documents
describing it.
NATO/CCMS Report 176-
Authors
•International Toxicity Equivalency Factor
(I-TEF) Method of Risk Assessment for Complex
Mixtures of Dioxins and Related Compounds
Dr. Donald G. Barnes
TEF Subgroup Chair and Editor
U.S. Environmental Protection Agency
United States
Dr. Donald L. Grant
Contributing Author
Health aid Welfare Canada
Canada
Dr. Frederick W. Kutz
Contributing Author
U.S. Environmental Protection Agency
United States
Reviewers
Mr. David P. Bottimore
Contributing Author
Versar Inc.
United States
Prof. Dr. med Helmut Greim
Contributing Author
GSF Muenchen Institut
fur Toxikologie
Federal Republic of Germany
Dr. James Wilson
Contributing Author
Monsanto Chemical Company
United States
Dr. Judith S. Bellm
U.S. Environmental Protection Agency
United States
Dr. Brendan Birmingham
Ontario Ministry of the
Environment
Canada
-------
Dr. E.A. Cox
Inspectorate of Pollution
Department o< the Environment
United Kingdom
Dr. Arne Grove
Kemiteknik. Teknologisk Institut
Denmark
Ms. Frances Pollitt
Department of Health and Social
Security
United Kingdom
Dr. C.A. van der Heijden
National Institute of Public Health
Monsanto Chemical Company
and Environmental Hygiene
The Netherlands
Dr. Alessandro di Domenico
Istituto Superiore di Sanita
Italy
Dr. G.K. Matthew
Department of Health and
Social Security
United Kingdom
Dr. Ellen Silbergeld
Environmental Defense Fund
United States
Dr. Job A. van Zorge
Ministry of Housing,
Physical Planning and
Environment
The Netherlands
NATO/CCMS Report 178—Scientific Basis for the Development of the
International Toxicity Equivalency Factor (I-TEF)
Method of Risk Assessment for Complex
Mixtures of Dioxins and Related Compounds
Authors
Dr. Stephen H. Safe
Principal Author
Texas A&M University
United States
Dr. Frederick W. Kutz
Contributing Author
U.S. Environmental Protection Agency
United States
Reviewers
Mr. David P. Bottimore
Contributing Author
Versar Inc.
United States
Dr. Donald G. Barnes
U.S. Environmental Protection Agency
United States
Dr. Linda S. Bimbaum
National Institute of Environmental
Health Sciences
United States
Dr. Brendan Birmingham
Ontario Ministry of the
Environment
Canada
Mrs. Sigrid Louise Bjornstad
State Pollution Control
Authority
Norway
-------
Or. Martin J. Boddington
Environment Canada
Canada
Or. Alessandro di Domenico
Istituto Supenore di Samta
Italy
Prof. Dr. med. Helmut Greim
GSF Muenchen Institute fur
Toxikologie
Federal Republic of Germany
Dr. G.K. Matthew
Department of Health and Social
Security
United Kingdom
Dr. James R. Olson
State University of New York -
Buffalo
United States
Dr. E. A. Cox
Inspectorate of Pollution.
Department of the Environment
United Kingdom
Dr. Donald L. Grant
Health and Welfare Canada
Canada
Dr. Ame Grove
Kemtteknik, Teknologisk Institut
Denmark
Ms. Christa Morawa
Umweltbundesamt
Federal Republic of Germany
Ms. Frances Pollitt
Department of Health and
Social Security
United Kingdom
Dr. Ellen Silbergeld
Environmental Defense Fund
United States
Dr. C.A. van der Hiejden
National Institute of Public Health
and Environmental Hygiene
The Netherlands
Dr. Job A. van Zorge
Ministry of Housing,
Physical Planning and Environment
The Netherlands
Dr. James Wilson
Monsanto Chemical Company
United States
VII
-------
EPA Review
Drafts of this report were reviewed by EPA's Risk Assessment Forum
and other EPA staff members, and EPA's Risk Assessment Council
concurred with the final report.
EPA Risk Assessment Forum (1988-1989)
Forum Members
Michael A. Catlahan, Office of Research and Development
Michael Dourson, Office of Research and Development
Penny Fenner-Crisp, Office of Pesticides and Toxic Substances
Richard N. Hill. Office of Pesticides and Toxic Substances
Peter W. Preuss. Office of Research and Development
Donald G. Barnes. Office of the Administrator
Elizabeth Bryan, Office of Pesticides and Toxic Substances
Ha Cote, Office of Air and Radiation
Lee Mulkey, Office of Research and Development
Robert Dyer, Office of Research and Development
William Fariand, Office of Research and Development
Edward Ohanian, Office of Water
Roy Smith, Region III
Dorothy E. Patton, Chair
Designated Representatives
Timothy Barry, Office of Policy. Planning, and Evaluation
Patricia Roberts. Office of General Counsel
Reva Rubenstem. Office of Solid Waste and Emergency Response
Marian Olson, Region II
Elmer Akin, Region IV
Milton Clark. Region V
Jaci Schlachter. Region VII
Suzanne Wuerthele. Region Vlil
Arnold Den. Region IX
Dana Davoli, Region X
EPA Risk Assessment Council (1988-89)
Donald G. Barnes. Office of the Administrator
Erich W. Bretthauer, Office of Research and Development
Don Clay, Office of Air and Radiation
Michael B. Cook. Office of Water
VIII
-------
Michael B. Cook, Office of Water
Renate Kimbrough, Office of the Administrator
Victor Kimm, Office of Pesticides and Toxic Substances
Sylvia Lowrance. Office of Solid Waste and Emergency Response
John A. Moore, Office of Pesticides and Toxic Substances, Chairman
William J Muszynski, Region II
Peter W. Preuss, Office of Research and Development
Rosemane C. Russo, Office of Research and Development
Ken Sexton, Office of Research and Development
Stephen R. Wassersug, Region lit
Other EPA Reviewers
Other EPA staff members were asked to review drafts of this report.
David A. Bennett, Office of Solid Waste and Emergency Response
William Burnam. Office of Pesticides and Toxic Substances
David G. Oolan, Region V
Fred S. Hauchman, Office of Air and Radiation
Stephen Kroner, Office of Water
C.C. Lee, Office of Pesticides and Toxic Substances
Alexander McBride. Office of Solid Waste and Emergency Response
Debdas Mukerjee, Office of Research and Development
IX
-------
Ust of Acronyms
AHH aryl hydrocarbon hydroxylase
CDDs/CDFs chlorinated dibenzo-p-dioxms and -dibenzofurans
COWG Chlorinated Dioxins Work Group
CEC Commission of the European Communities
EPA U.S. Environmental Protection Agency
EPA-TEFs/87 toxicity equivalency factors adopted by EPA in 1987 and
published ("purple book") as U.S. EPA, 1987
EPA-TEQs/87 toxicity equivalents (based on EPA-TEFs/87)
HxCDO hexachlortnated dibenzo-p-dioxin
HxCDF hexachlonnated dibenzofuran
HpCOO heptachlorinated dibenzo-p-dioxin
HpCDP heptachlonnated dibenzofuran
l-TEFs/89 International Toxicity Equivalency Factors adopted by the
North Atlantic Treaty Organization - Committee on the
Challenges of Modern Society, Pilot Study on
International Information Exchange on Oioxins and
Related Compounds
t-TEQs/89 International Toxicity Equivalents (based on t-TEFs/89)
MWC municipal waste combustor
NATO/CCMS North Atlantic Treaty Organization/Committee on the
Challenges of Modern Society, Pilot Study on
International information Exchange on Oioxins and
Related Compounds
OCDD octachlorodibenzo-p-dioxm
OCDF octachlorodibenzofuran
OECO Organization for Economic Cooperation and Development
PeCOO pentachlorinated dibenzop-dioxm
PeCDF pentachlonnated dibenzofuran
PCP pentachloropnenol
RfD reference dose
SAB EPA's Science Advisory Board
SAR structure-activity relationship
2,3,7,8-TCDD 2,3.7,8-tetrachlorodibenzo-p-dioxin
TEF toxicity equivalency factor
TEQ toxicity equivalents
UNEP United Nations Environmental Programme
WHO World Health Organization
-------
1. Overview
In the spring of 1987 the U.S. Environmental Protection Agency (EPA)
formally adopted an interim procedure for estimating risks associated with
exposures to mixtures of the 210 chlorinated dibenzo-p-dioxm and
chlorinated dibenzofuran (CDD/CDF) congeners, .including 2,3,7,8-
tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) (U.S. EPA, 1987). The procedure,
based upon data available through 1985, uses a set of derived toxicity
equivalency factors (TEFs) to convert the concentration of any CDD/CDF
congener into an equivalent concentration of 2.3,7,8-TCDD. The approach
simplifies the assessment of both carcinogenic and noncarcinogenic risks
involving exposures to mixtures of CDDs/CDFs.
In the 1987 report, the Agency committed itself to periodically update the
TEFs, hereafter referred to as "EPA-TEFs/87," Since 1985, additional data
have become available that suggest that modifications in some of the factors
are appropriate at this time. In addition, the Agency was active in an
international effort aimed at adopting a common set of TEFs ("International
TEFs/89" or "I-TEFs/89"), so that information can be exchanged more
readily and greater harmony can be achieved in reacting to environmental
contamination by CDDs/CDFs, The international project was conducted
under the auspices of the North Atlantic Treaty Organization's Committee on
Challenges of Modern Society (NATO/CCMS) and benefited from
participation by U.S. scientists from both industry and environmental groups.
as well as from the EPA.
This first updating report describes the I-TEFs/89. which replace the EPA-
TEFs/87 currently in use. This revision is based on an examination of the
relevant scientific evidence and a recognition of the value of international
consistency in trie field.
Section II reviews the development of the original EPA-TEFs/87, the more
recent scientific data, and the international activities that have led to the
current modifications recommended in the report. Section III focuses on the
differences between the EPA-TEFs/87 and I-TEFs/89 and identifies areas
where further changes might occur as more data are collected. Section IV
provides a concluding summary.
The i-TEFs/89 represent an improvement in an already useful risk
assessment tool. However, the approach remains "interim" in character and
should be replaced as soon as practicable with a bioassay method, as
mentioned in the initial report. Promising progress is being made in this area.
Further, regulatory authorities are encouraged to collect congener-specific
data on all CDD/CDF-containmg environmental samples and to summarize
the estimated combined effect of these chemicals in terms of "International
Toxiaty Equivalents/89 (l-TEQs/89)." The l-TEQs/89 are obtained by
applying the l-TEFs to the congener-specific data and summing the results.
Each statement of l-TEQs/89 in a sample should be accompanied by an
indication of the percent of those l-TEQs/89 that are contributed by 2,3.7,8-
TCDD itself. The congener-specific data will be indispensable in evaluating
data in terms of any modified TEF schemes that might appear in the future.
In addition, such data might prove helpful in identifying the possible
source(s) of CDD/CDF contamination by applying pattern-recognition
-------
techniques to "fingerprints" of congener distributions found in environmental
and source samples.
This report is not intended to be a full exposition of the TEF concept and
status. Rattier, it serves as an update to EPA's initial report
-------
II. Background
A. The TEF Concept
Chlorinated dibenzo-p-dioxins and dibenzofurans (CDDs/CDFs) constitute
a family of 210 structurally related chemical compounds (Table 1 and Figure
1). During the late 1970s and early 1980s. EPA encountered a number of
incidents of environmental pollution in which the toxic potential of CDDs and
CDFs figured prominently, e.g.. emissions from combustion sources. Initially.
concern was focused solely on 2.3,7,8-TCDD, which was produced as a low
level by-product during the manufacture of certain herbicides.
rao/e 1. Number of Congeners by Homologue (number of chlorines) and
Substitution Type ("2378" vs. "non-2378")
Type/Homoiogue rCI 2C1 3CI 4CI SCI 6CI 7C1 SCI Total
2378-CDDs
non-2378-CDDs
0
2
0
70
0 7
14 21
7
73
3
7
J
I
7
0
Subtotal
2378-CDFs
non-2378 -CDFs
0
4
0
76
0 7
28 37
2
2S
4
72
2
2
7
0
Subtotal
7
68
75
70
725
735
Total 2378-CDDs/Fs = 17
Total non-2378-CDDsfFs = 193
Reference. NATQ/CCMS. 7988O.
During the past 20 years, many studies have been conducted to elucidate
the toxic effects of 2,3.7,8-TCDD. The data obtained from these studies are
summarized in a number of reviews (WHO. 1988: NRCC. 1981; Exner. 1987;
U.S. EPA. 1985; U.S. EPA. 1988). While these data have not answered all of
the questions, the data do show that 2,3,7,8-TCDD can produce a variety of
toxic effects, including cancer and reproductive effects, in laboratory animals
at very low doses. While some reports in the literature suggest that the
chemical can produce similar effects in humans, more definitive information
should be forthcoming from epidemiological studies currently in progress
(Fingerhut et at.. 1989: AOWG, 1987).
For risk assessment purposes. EPA classifies 2,3,7,8-TCDD as a "B2"
carcinogen with a potency of 1.6 x 10s (mg/kg-d)-1. by far the most potent
carcinogen yet evaluated by the Agency (U.S. EPA. 1985). The chemical is
also the most potent reproductive toxin yet evaluated by the Agency, with a
Reference Dose (RfD) of 1 pg/kg-d (U.S. EPA. 1985).
More recently, the Agency has confronted a wide variety of cases in which
the concentrations of some of the other 209 CDDs/CDFs greatly exceed that
of 2,3,7,8-TCDD, e.g., exposure to CDD/CDF impurities in technical
pentachlorophenol and CDD/CDF emissions from certain combustion
-------
MM*M. p-MMto
On *> It ICOOi: 14.,
It • M*M» tCDD
II * »T»-HiCOD
er ""f ^o" "*]•" a
ci ci
1 J,l.*.f .7-lMM«MWMtMtU*>*-«IMI«
Figure t. Examples of 2378 and non-2376—sutactitutad aioxins and furans.
-------
sources. Much less is known about the toxicity of these other congeners;
however, available information shows cause for some concern. Of the limited
number of CDDs/CDFs tested thus far, only a mixture of 1,2,3.6,7,8- and
1,2,3,7,8,9-hexachlorodibenzo*p*dioxin (HxCDD) has been shown to be
carcinogenic in laboratory animals when administered at low doses for a
lifetime.
While data available from long-term in vivo studies are limited for the
majority of CDDs/CDFs, a much larger body of data is available on short-
term in vivo studies and a variety of in vitro studies. These experiments
cover a wide variety of end points; e.g., developmental toxicity, cell
transformation, and enzyme induction (aryl hydrocarbon hydroxylase [AHH])
(U.S. EPA 1987). While the doses necessary to elicit the toxic response
differ in each case, the relative potency of the different compounds
(compared to 2,3,7,8-TCDD) is generally consistent from one end point to
another. This general consistency of relative potency for the same
compounds across several end points gives added credence to the TEF
concept as it is applied to CDDs/CDFs.
This information, developed by researchers in several labs around the
world, reveals a strong structure-activity relationship (SAR) between the
chemical structure of a particular CDD/CDF congener and its ability to elicit a
biological/toxic response in various in vivo and in vitro test systems
(Bandiera et at., 1984; Olson et at., 1989; U.S. EPA 1987; NATO/CCMS,
I988a.b). Research has also revealed a mechanistic basis for these
observations. That is, a necessary (but not sufficient) condition for expression
of much of the toxicity of a given CDD/CDF congener is its ability to bind
with great specificity to a particular protein receptor located in the cytoplasm
of the cell. This congener receptor complex then migrates to the nucleus of
the cell, where it initiates reactions leading to expression of toxicity (Poland
and Knutson, 1982).
The structure-activity relationship can be summarized as follows:
congeners in which the 2. 3, 7, and 8 lateral positions are occupied with
chlorines (the so-called "2378-substituted congeners") are much more active
than are the other congeners (the so-called "non-2378-substituted
congeners") (Figure 1 and Table 1). In addition, when researchers compared
the results from a wide variety of studies (both in mo and in vitro} for
different responses, the relative responses between that of different
CDDs/CDFs and that of 2.3.7,8-TCDD were remarkably consistent (Bellm and
Barnes, 1983. U.S. EPA 1987).
These observations suggested two important possibilities:
1. The relatively abundant short-term in vitro toxicity studies for
CDDs/CDFs could be used to supplement (with appropriate caveats) the
comparative lack of long-term in wvo results for these compounds.
2. An estimate of the long-term in vivo toxicrties of many of the CDDs/CDFs
could be expressed in terms of an equivalent amount of 2.3.7,8-TCDD or
"toxicity equivalents" (TEQs). The TEQs could be generated by using a
factor (the "toxicity equivalency factor* {TEF]), derived from an
examination of the available toxicity data, to convert the concentration of
a given CDD/CDF into an equivalent concentration of 2,3,7,8-TCDD.
-------
B. Development of the EPA-TEFs/87
The TEF approach, first suggested in 1977 (Grant, 1977), was pursued by
several scientists and jurisdictions during the early- and mid-1980s (e.g.,
Ontario Government. 1982: Eadon et al., 1986: Swiss Government, 1982;
Commoner et al.. 1984; California Air Resources Board, 1986). In the early
1980s the Agency's Chlorinated Dioxms Work Group (CDWG) began the
development of a TEF scheme to address some of the CDD/CDF problems
being encountered by the Work Group. In 1985 the CDWG's parent group.
the Oioxin Management Task Force, formally asked the Agency's Risk
Assessment Forum (Forum) to review the proposal. During the same time
period, the approach was presented at the Fifth International Symposium on
Chlorinated Dioxms and Related Compounds and it subsequently appeared
in a peer-reviewed journal (Barnes et al.. 1986).
The Forum modified the document, principally by making more explicit the
process by which the EPA-TEFs/87 were selected. In 1986. the Forum
transmitted the document to the Risk Assessment Council (Council) for its
review and examination for policy implications. The Council approved the
use of the procedure and. in a transmittal memorandum to the Administrator.
identified the program areas that were most likely to be impacted by the
adoption of the approach. In addition, the Agency's Science Advisory Board
(SAB) reviewed the document and. with certain caveats, approved the
approach. In January 1987, upon completion of these reviews, the
Administrator formally made the EPA-TEF/87 procedure a part of official
Agency policy. The interim procedure subsequently appeared as a Forum
monograph in March 1987 (U.S. EPA 1987).
Throughout the review process, it was continually emphasized that the
TEF approach constituted an interim procedure. First, the document
explicitly stated that additional research should be conducted to replace the
EPA-TEF/87 procedure with a preferred approach; i.e., one that directly
measures the bioiogical/toxicological response of the mixture of CDDs/CDFs
in question. Second, an explicit commitment was made to update the EPA-
TEFs/87 themselves as new scientific information dictated.
C. Subsequent Developments on the International Front
During the early 1980s the issue of CDDs/CDFs attracted growing interest
in many countries around the world. In fact, several areas of concern about
CDDs/CDFs were first noted outside the United States; e.g.. the widespread
environmental release of 2.3.7,8-TCDD in Seveso. Italy, in 1976 and the
European discoveries of the formation of CDDs/CDFs in certain combustion
processes in the mid-1970s. During that time, regulatory agencies in the
United States (California and New York), Canada, and Europe developed
their own TEF schemes. As a result, numerous environmental regulations
and statutes were developed which set limits for CDDs and CDFs based on
these TEF schemes (NATO/CCMS, 1988C). While the legitimacy of the TEF
approach was thereby acknowledged, the existence of so many slightly
different TEF schemes complicated communication among scientists and
agencies in discussing the toxicological significance of environmental
mixtures of CDDs and CDFs. This situation also reflected a lack of any
coordinated attempt to reach a scientific consensus on a specific set of
TEFs.
In an attempt to provide a forum in which the scientific aspects of these
issues could be collegially discussed, the EPA, in conjunction with authorities
in the Federal Republic of Germany and in Italy, formed a special "Dioxin
Information Exchange" committee under the NATO/CCMS mechanism. The
-------
Pilot Study on International Information Exchange on Dioxins and Related
Compounds was initiated in 1985 and focused its attention on the exchange
of information on research, exposure/risk assessment, regulation, technology
assessment, and management of accidents involving dioxins and related
compounds. Other participating nations included Canada, Denmark, the
Netherlands. Norway, and the United Kingdom, with Sweden and Austria
involved as observer nations. International organizations that were involved
included the World Health Organization (WHO), the Commission of the
European Communities (CEC), the Organization for Economic Cooperation
and Development (OECD). and the United Nations Environmental
Programme (UNEP).
In September 1986. in Las Vegas, Nevada, the NATO/CCMS committee
formed a subgroup to examine the issues associated with the TEF approach.
Specifically, the TEF Subgroup was given the responsibility of developing a
position paper on the subject, including:
1. A consensus statement on the appropriateness of the TEF approach; its
level of accuracy; its application to both congener-specific and
homotogue-specific data; and additional research needed to support and
even replace the TEF approach.
2. The possibility of reaching an international consensus on a specific set
(or range) of TEFs to be applied to CDD/CDF-contaminated
environmental samples.
3. The development of consistency within the broad scientific community.
The complete text of the charge to the subgroup can .be found in the
Appendix.
After one year the TEF Subgroup had made sufficient progress that it was
encouraged to seek consensus on a single set of TEFs that could serve the
entire international community. Use of a single set of TEFs would increase
consistency in data reporting and provide some measure of comparability in
risk assessments undertaken around the world. Using previous schemes as a
starting point, including a recent one adopted by the Nordic countries (Van
Zorge. 1988), the Subgroup developed a specific set of TEFs. dubbed the
"International TEFs/89" (l-TEFs/89). for consideration by the parent group.
The Subgroup selected the specific TEFs based on available data (U.S. EPA
1987; Olson et al.. 1989; NATO/CCMS I988b) and were guided by the
following principles:
1. The scheme should be as simple as practicable. A complex scheme
suggests greater precision and sophistication than can be scientifically
supported.
2. The focus should be on the CDD and CDF congeners that are
preferentially accumulated in mammalian tissue. These are principally
the congeners that are substituted at the 2.3,7. and 8 positions and which
are the more toxic forms.
3. The TEFs should reflect the relative toxicity exhibited by the various
congeners in a variety of lexicological end points.
A draft document describing the l-TEFs/89 was examined and discussed
by the participants of the NATO/CCMS Dioxin Information Exchange
Committee at its meeting in Berlin in April 1988. After considerable
discussion the l-TEFs/89 were approved in principle. The l-TEFs/89 were
subsequently published in August 1988 (NATO/CCMS. 1988a) and presented
at the Eighth International Symposium on Chlorinated Dioxins and Related
Compounds in Umea. Sweden, in August 1988.
-------
The TEF Subgroup was charged with developing a more detailed technical
support document, which has now been completed (NATO/CCMS, 1988b)
The Dioxin information Exchange Committee asked the representatives of
the member countries to seek formal adoption of the l-TEF/89 scheme by
their respective regulatory authorities. This request to seek adoption of the
l-TEF/89 scheme comes at a time when the Agency is fulfilling its
commitment to periodically update the EPA-TEFs/87, based upon the
generation of new information. Several other regulatory agencies in the
Nordic countries, the Netherlands, Canada, the United Kingdom, New York
State, and Ontario (Canada) have adopted the l-TEF/89 scheme as the
preferred interim approach.
0. Status of the TEF Concept
Events since 198? clearly indicate that the TEF concept has been widely
accepted and used by the scientific and regulatory communities in many
parts of the world. Austria. Canada, Denmark, the Federal Republic of
Germany, Finland, Italy, the Netherlands, Norway, Sweden, Switzerland, and,
the United Kingdom have all moved forward in this area. Japan is
considering the approach as well.
Several of these groups have been forthright in citing shortcomings in
the science base supporting the TEF concept. Both the NATO report
(NATO/CCMS. I988a) and the World Health Organization report (WHO,
1988) identified limitations to the TEF approach; e.g.. the extrapolation from
short-term to long-term effects and the possible differences in metabolic
effects among species. For example, many of the short-term results seen in
munne systems are not observed in rat systems. Also, the connection
between the enzyme induction response, which supports several of the TEF
values, and several of the toxic end points manifested by CDDs/CDFs, is
unclear. Other mechanisms of action, e.g.. effect on vitamin A synthesis and
estrogen-like activity, have been suggested as playing an important role in
the toxicity of CDDs/COFs.
These continuing elements of uncertainty in the TEF approach highlight
the need to treat the approach as "interim," that is, one tfiat needs to be
further buttressed by experimental data and eventually replaced with a more
direct biological assay. In spite of these acknowledged limitations, all of the
groups listed above have endorsed the TEF approach as a feasible
procedure for addressing a difficult environmental health problem at this
time. Within EPA, the EPA-TEFs/87 have been used effectively by most of
the regulatory program offices and many of the Regions. It has been useful
to both risk assessors and risk managers in summarizing and communicating
the significance of analytical findings of CDDs/COFs detected in various
environmental samples.
During the past two years, however, new lexicological data have been
generated that call into question some of the EPA-TEF/87 values assigned to
certain of the CDD'CDF congeners (see Section III). (These changes are
independent of any recommended changes in the estimated carcinogenic
potency of 2.3.7,8-TCDD [U.S. EPA, 19B8J.) This paper recommends mod-
ifications to some of the EPA-TlFs>87 in light of these new data. The effect
of these modifications is likely to be modest for many complex mixtures of
CDDs and CDFs found in environmental samples, as illustrated by the
marginal difference in TEQs calculated by applying the EPA-TEFs/87 and
the l-TEFs/89 to data on CDDs/CDFs in emissions from a municipal waste
combustor (Figure 2). For mixtures in which 2,3,7,8-substituted congeners
-------
11 •
e"* 1e"
* t-
* «
I "
I i-
|
i
^
EADON
CANADA CALIFOIINIA EP*-TEO«(I7 I-TtOi'19
Data tor Abov* Figure (Conctntr«lion» In ng(d»cm3@ ?% 0?)
•Mem
1JTI.TCDD
reoet foiMtm
iHTt-Meoo
'•COD* (OTMtH)
111471-HlGDD
ItMM-MlCtW
ItaWI-NlCDO
MlCDOl lOTNtH)
1**4ttt-MtCl>0
MtCDOl (OfMEN)
OCOD
TOTAL COO.
ilTt-TCDF
TCOFl lOTMtH)
IWTt-MCDF
JM7*-'
-------
predominate (e.g., biological specimens), the l-TEQs/89 will be greater
(Figure 3).
In cases in which 2,3,4,7,8-PeCDF,. HpCDDs/Fs, and/or OCDD/F predom-
inate, however, the l-TEQs/89 can differ markedly from the EPA-TEFs/87.
For example. Figure 4 presents data from soil samples taken from around a
pentachlorophenol (POP) wood treatment site in Region III. The
preponderance of hepta- and octa- congeners results in more than an order
of magnitude increase in the TEEQs estimated by the l-TEF/89 approach
compared to the EPA-TEF/87 approach. This is a reflection of the increased
weight given to 2378-HpCDDs/Fs and OCDO/F in the t-TEF/89 scheme.
The reader should note, however, that these estimates ignore the issue of
relative bioavailability of the COD/CDF congeners, which have not been
thoroughly investigated. Lower relative bioavailability of the hepta* and octa-
forms compared to the tetra- forms would generally reduce the concern for
TEQ estimates for samples such as those which are dominated by the hepta-
and octa- forms. Research in this area is needed to resolve this point.
In samples taken from biological organisms exposed to PCP-contaminated
soils in Region IX, the TEQs were within a factor of two of each other, when
calculated by the l-TEF/89 method or the EPA-TEF/87 method. Although the
data are limited, they appear to suggest that the differences in TEQs
observed in the PCP-contaminated soil samples are not observed in tissues
of organisms exposed to this soil.
The need for additional research remains. This report reiterates the strong
recommendation, stated in the 1967 EPA report, that research should
continue and primarily focus on developing test methods which can
determine more directly and more accurately (and probably less
expensively) the biological/toxicological response of complex environmental
mixtures of CDDs and CDFs, thereby obviating the need for any TEF
scheme. Considerable progress has been made in this area during the past
two years (NATO/CCMS. I988b) and replacement of the TEF approach
within the next five years appears to be an achievable goal.
Further, regulatory authorities are encouraged to collect congener-specific
data on all CDD/CDF-containing environmental samples and to summarize
the estimated combined effect of these chemicals in terms of l-TEQs/89.
The l-TEQs/89 are obtained by applying the l-TEFs/89 to the congener-
specific data and summing the results. Each statement of l-TEQs/89 in a
sample should be accompanied by an indication of the percent of those
l-TEQs/89 that are contributed by 2.3.7.8-TCDD itself. The congener-specific
data will be indispensable in evaluating data in terms of any modified TEF
schemes that might appear in the future. Further, such data might prove
helpful in identifying the possible sources(s) of CDD/CDF contamination by
applying pattern-recognition techniques to "fingerprints" of congener
distributions found in environmental and source samples.
Additional research that would bolster our understanding of this area
includes:
1. Exploration of the details of the CDD/CDF-receptor-mediated mechanism
of toxictty; e.g., the role of different species/tissue concentrations of the
receptor, the intranuclear events leading to enzyme induction, and the
marked differences in the responses of different species. Such
information may prove useful in understanding other receptor-mediated
responses induced by other compounds.
2. Investigation of the link between short-term toxicity (e.g., enzyme
induction and subchronic effects) and carcinogemcity and other long-
term effects.
10
-------
0.8-
a 0.6-
0.4-
u
e o 2_
«*.* —
0.3
I
EPA-TEQs/87
0.6
I
l-TEO»/89
Data for Above Figure:
CONGENER
2378 • TCDD
12378 • PeCDD
123478 • HlCDD
123678 • HlCDD
123789 • HlCDD
1234678 • HpCDD
OCDD
TOTAL CDDs
2378 • TCDF
12378 • PeCDF
23478 - P«CDF
123478 'HlCDF
123678 • HlCDF
234678 • HlCDF
1234678 • HpCDF
OCDF
TOTAL CDF*
TOTAL TEO»
fiOURCP
DATA (ppt)
0.11
0.18
0.08
0.73
0.15
1.3
5.7
0.12
0.022
0.51
0.097
0.078
0.04
0.19
0.082
TEF SCHEME
EPA.-TEF/87
0.11
0.09
0.0032
0.029
0.006
0.0013
0
0.24
0.012
0.0022
0.051
0.00097
0.00078
0.0004
0.00019
0
0.066
EPA-TEOs/67>0.3
37%
Contributed by
2,3,7.8 - TCDD
l-TEF/89
0.11
0.09
0.008
0.073
0.015
0.013
O.OOS7
0.31
0.012
0.0011
0.26
0.0097
0.0078
0.004
0.0019
0.000052
0.30
I-TEO*/89»0.6
18%
Contributed by
2,3,7,8 - TCDD
ftoforanc*: Llndstrom and Rapp«, 1t88.
Figure 3. Toxlcfty equivalents in human milk sample.
11
-------
1.6'
1.4 —
S- 1.2 —
a.
e 1.0-q
4
o
o
o.s —
0.4.
0.2-
0
O.OS
1.4
Ef»A>TEQ»/S?
I •
-TEQi/88
Date for Abov* Flgur*:
SPECIES
2371 ' TCOO
OtfMr TCDO«
2371 • P«COD
Ottwr P*CDD«
2371 • HiCOD*
OOMT HcCOO*
237t - HpCDD
OttMr HpCOO*
OCDD
TOTAL COD«
tvn • Tcor
OHMT TCOr*
12l?t -PtCDF
23471 . PtCDF
OttMT P*CPP*
airs . HICDP*
OHMr HtCOF*
t37t . HpCOF«
Qtt*t MpCOF*
OCDF
TOTAL CDfm
TOTAL TEQ«
SOURCE
DATA (ppt)
Jt
««.4
313
•7t
3.7
3.3
11
41.S
TEF SCHEME
EPA>TEF/I7
0.01
0.0««
0.0030
0
O.OTt
0.00037
0.0033
O.OOOU
0
0.003
EPA-TEO«/I7>O.OI
I'TEF/I»
0
0.«6
0
O.It
1.34
e
0.033
0
0.042
o.ot
l-TEQa/lt-1.4
R*f*r*ne«: Smith, 1MB.
Figure 4. Toxtctty equrvatantx In • p»ntachtoroph«no( wood trutmant site
•oUsampi*.
12
-------
III. Update Of EPA-TEFs/87:
Adopting the l-TEF/89 Scheme
A. Similarities Between l-TEFs/89 and EPA-TEFs/87
Table 2 displays the l-TEFs/89 and the EPA-TEFs/87.
The two sets of TEFs have several concepts in common. They share the
conceptual framework of the TEF approach. That is. the structure-activity
relationship is assumed to be sufficiently strong that estimates of the long-
term toxicity of minimally tested congeners of CDDs/CDFs can be
reasonably inferred on the basis of available information.
Table 2. raticfty CQuiva/encr Factors
Compound
Mono-. Or-, and TriCDDs
2.3.7.8-TCDD
Other TCOOs ,
2,3.7.8-^BCOO
Other PeCOOs
2378-HxCDDs
Other HxCODs
2.3.7.8-HpCDD
Other HpCOOs
OCOO
Mono-. DI-. and TriCDFs
2.3.7.8-TCDF
Other TCDFs
l.2.3.7.8-PeCDF
2.3.4.7,8-PeCDF
Other PeCDFs
2378-HxCDFs
Other HxCDFs
2379-HpCDFs
Other HpCDFs
EPA-TEFs/87
0
J
0.07
0.5
0.005
0.04
0.0004
0.007
0.00007
0
0
O.J
0.00 »
O.J
O.J
0.007
0.07
0.0007
0.007
0.00007
l-TEFs/89
0
7
0
0.5
0
O.J
0
0.0 J
0
0.007
0
O.J
0
0.05
0.5
0
O.J
0
0.07
0
OCDF 0 0.007
Reference: Adapted from NATO/CCMS. J988a.
In assigning TEFs, priority is generally given to the results from long-term.
whote-animai studies followed by the results from short-term, whole-animal
studies. Among the remaining short-term in vivo and in vitro data, priority is
generally given to the results of enzyme induction studies This is due to the
13
-------
tact that a good correlation has been generally observed between enzyme
induction activity and short-term, whole-animal results; i.e.. tnymic atrophy
(r * 0.91), body weight loss (r - 0.84) m rats, and inhibition of body weight
gain in guinea pigs
-------
For example, fly ash from municipal waste combustors (MWCs) generally
contains detectable amounts of CDDs/CDFs. In most instances, the amount
of non-2378-substituted congeners vastly outweighs the amount of 2378-
substituted congeners in such samples. However, when mice or fish are
exposed to MWC fly ash and their tissues are subsequently analyzed for the
presence of CDDs/CDFs, essentially only the 2378-substituted congeners are
detected (Kuehl et al., 1986; Van den Berg et al., 1985). Similarly, the
"background levels" of CDDs/CDFs routinely found in human tissues (fat.
blood, and milk) contain almost exclusively 2378-substituted congeners
(Rappeetal.. 1987).
The environmental concern of the Agency rests primarily with long-term
exposures. It is the 2378-substituted congeners that seem to pose the
greatest long-term potential, since the non-2378-substituted congeners
appear to be either not absorbed or quickly eliminated by biological systems.
Therefore, in the interest of keeping the TEF system as simple as possible.
attention is focused exclusively on 2378-substituted congeners in the
l-TEF/89 scheme.
3. Distinguishing Between 1,2,3,7,8- and 2,3,4,7,8-PeCDF
For the homologous class of 2378-substituted PeCDFs, the l-TEF/89
scheme introduces an additional complexity that was not a part of the EPA-
TEF/87 scheme. In the EPA-TEF/87 scheme, both isomers were assigned a
value of 0.1. In the l-TEF/89 scheme, the 2,3,4,7,8-PeCDF is assigned a
value of 0.5. while the 1,2.3,7.8-PeCDF is assigned a value of 0.05. This is
the only instance in which the l-TEFs/89 depart from the guiding principle of
"simplicity" in which TEFs are expressed as rounded orders of magnitude.
This departure is prompted by a growing body of data that indicate that
2,3.4.7,8-PeCDF is notably more active than originally thought.
Rationale:
Based upon the data in Table 3. it can be seen that:
(a) The 0.5 value for 2.3,4,7,8-PeCDF gains support from the in vivo
thymic atrophy data (0.43) and the mouse immunotoxicity data (0.8).
(b) The 0.05 value for 1,2.3.7,8-PeCDF gains support from the in vivo
investigations of thymic atrophy data (0.05) and the in wvo and in
vitro investigations of enzyme induction data (0.003-0.06).
(c) The higher value for 2.3.4,7,8-PeCDF over 1,2.3,7.8-PeCDF is also
supported by mouse teratogenicity data. Note that there is one
outlier m the eight data points reported for 1,2.3.7,8-PeCDF in Table
3. Specifically, there is a 0.95 value recorded for reduction in body
weight gain seen in guinea pigs. This one experiment in one
laboratory should be investigated further to determine its possible
significance. At the present time, however, the weight of the
evidence argues for the lower TEF.
The fact that the two 2378-substituted congeners can elicit such different
biological responses can be rationalized by examining the stereochemistry of
the two chemicals (Bandiera et al.. 1984). When superimposed on the
molecular structure of 2,3.7,8-TCDD, the C-4 of the "bent" PeCDF is more
stereochemically a "lateral position" (i.e., closer to C-3 on the 2,3,7,8-TCDD
skeleton), white the C-1 is even less stereochemically a "lateral position"
(i.e., farther away from C-2) (see Figure 5). Therefore, the 2.3,4.7,8-PeCDF
would theoretically be expected to be more active than the 1.2.3.7.8-PeCDF
since it has more chlorine substituents in the lateral positions.
15
-------
Table 3. International Tonlcltf equivalency Factors/8* (l-JfFs/89). Comparison of Relative Potency Oaf* for the 2378-Substltuted CODs
and COFs
Observed f£F flanges
Congener
2,3.7.fl-rcoo
1.2,3.7.8 PeCOD
1.2.3,4,7,8-HxCDD
55 1,2.3,7,8.9'HnCDD
1,2,3,6.7.8-HxCDD
1,2.3.4.6.7.8-HpCDD
OCDD
i-reFsm
i
OS
0.1
0-1
01
001
0001
Range
Dam *
Range
Data *
Range
Data =
Range
Data -
fin vivo taxicittes)
1
* 0053 059
{059*1. 0«St 0081'. 0053')
* 0018-024
(0.24**. 0084'. 00189', 0 13')
* 0016-0,14
(00169*. 0.14<"t)
- 0015-0 16
(0.1 6"', 0.01 i^>
_
Aryf hydrocarbon
hytlroxylase induction
(in vivo} (in vilro)
1 »
0.13 Range * 00065-0011
(013" Oala * (00 II, '00065")
013 Range = 0034-0046
fO >3'/ Data ~ (003410046")
0008
fOOOfl"?)
00f2
0003
f0.003"B>
0 0002C 0 0006
(0.0006"°)
Relevant
section in
text
-
HIB-4
IIIB4
III 84
IIIB4
III 84
-------
Tattle 3, (continued)
Observed TEF ranges
Aryt hydrocarbon
hytlroxylase induction
Congener
2,3,7,t-TCDF
2,3,4.7.8 PeCDF
t,2,3.7,8-PeCDF
1,2,3,4.7,8-HxCDF
1. 2.3.6. 7.0-HxCDF
1,2,3.7,a,9-HxCDF
2.3.4,6,7,8-HxCDF
l,2,3,4,&JM-HpCDF
t.2,3.4,7.8,9-HpCDF
OCDF
I-T&S/89
01
05
005
Of
Of
Of
Of
OOf
OOf
0001
(in vivo toxicities)
Range - o rfi-0. (7
Data «• (00179', 0,f7»>', COS1"', 0.025', O.Otff)
Range - 0.048-080
Data = (081"1. 0.479. 0,43'. 0.t3
0.012
(0.012')
0015
(OOI5'>
-
(in vilro)
flange - 0018-009
Data = (00*0/0.09";
Range = 028 t.4t
Data = (028-141")
Range = 0.028-0.06
Data - (Q.OSIQ.O28")
Range = 0.20-050
Data = (0.2010 $&>)
Range = 0.049-0. 153
Data = (0.04910 I53n)
Range = 0 1 1-0 33
Data = (0.1H0.33h)
-
Relevant
• secffon m
text
-
MB 3
IIIB3
IIIB4
HIM 4
IIIB4
IIIB4
I1IB4
W.B.4
IttBS
oguinea pig and 'rat data
Q'guinea pig and ""'moose lethalities
<=Cou!ure etal,, 1988
mlmouse leralogentcity and "'mouse immunotoxicity
"rat hepatoma data (AAHifROD)
"Bral hepatoma data (AAH)
Reference Dewed from TaUes 3, 4, 5. 7, and 8 from NATOICCMS, I988b.
-------
Cl
Ci
c
ci
1, 2, 3, 7, 8 - PeCDF on 2, 3, 7, 8 - TCDD
CI
CI
2,3,4,7,6- PeCDF on 2, 3, 7, 8 - TCDD
Figure $. 237l—Sub*tttut*
-------
Rationale:
Different lines of argument support these changes:
2378-HxCDDs
(a) Following the principle of simplicity, a whole order of magnitude
number (0.1) is more appropriate than a fractional order of
magnitude number (0.04).
(b) As seen in Table 3, the 0.1 value is supported by short-term in vivo
thymic atrophy (0.084) and aryl hydrocarbon hydroxylase (AHH)
induction (0.13) results for 1,2.3,7.8-HxCDD. The in vitro enzyme
induction results are generally an order of magnitude lower.
(C) Since the presence of non-2378-substituted congeners is effectively
ignored in the l-TEF/89 scheme, somewhat higher TEFs for the
237B-congeners tend to'compensate for the small toxic contribution
of any non-2378 congeners that were explicitly included in the EPA-
TEF/87 scheme.
The EPA-TEFs/87 assigned a value of 0.04 to the 2378-HxCODs, based
upon the results of a study by the National Toxicology Program in which a
mixture of 2378-HxCDDs was fed to rodents during their lifetimes. It was
argued that such in vivo data should take precedence over shorter-term
and/or in vitro data, since the former are generally more relevant to the
exposures of concern to humans. In this document, however, the arguments
of simplicity and the value of international consensus carry more weight.
especially in light of the approximate nature of the results of a single animal
study.
2378-HxCDFs
(a) The 0.1 value is supported by short-term in vivo thymic atrophy
data, i.e.. 0.18 and 0.097 for 1,2.3.4,7,8-HxCDF and 1,2.3,6.7,8-
HxCDF, respectively. The inhibition of weight gain results are about
an order ot magnitude lower. The in vitro enzyme induction results
range from 0.05 to 0.2; however, they are given less weight since
they are not whole animal studies.
(b) Since the presence of non-2378-substituted congeners is effectively
ignored in the l-TEF/89 scheme, somewhat higher TEFs for the
2378-substituted congeners tend to compensate for the small toxic
contribution of any non-2378-substituted congeners that were
specifically included in the EPA-TEF/87 scheme.
2378-HpCDDs/Fs
(a) The data base is very slim for these compounds. Only short-term in
vitro data exist. On the surface, these data would argue for a 0.001
value. However, recent whole animal data suggest that the
perchlorinated CDDs/CDFs slowly bioaccumulate in exposed
organisms (Couture et at.. 1988). Highly chlorinated species such as
HpCOOs/HpCDFs are likely to behave in a similar fashion.
Therefore, an extra measure of prudence is advisable; hence, an
l-TEF/89 of 0.01 was chosen.
(b) Since the presence of non-2378-substituted congeners is effectively
ignored in the l-TEF/89 scheme, somewhat higher TEFs for the
2378-substituted congeners tend to compensate for the small toxic
contribution of any non-2378-substituted congeners that were
specifically included in the EPA-TEF/87 scheme.
19
-------
5, Assigning Non-Zero TEF Values to OCOD and OCDF
The l-TEF/89 scheme assigns a value of 0.001 to OCDD and OCDF. The
EPA-TEF/8? approach assigned these congeners a value of zero.
Rationale:
In the EPA-TEF/87 scheme, OCDD and OCDF were assigned values of
zero on the basis of results of limited short-term in vivo and in vitro data. In a
recently published study (Couture et al., 1988), however, male rats were
exposed to low levels of OCDD for 13 weeks. At the end of the experiment,
the animals were beginning to show signs of toxicity that were reminiscent of
"dioxin toxicity." Detectable levels of OCDD had accumulated in the
organism. These data suggest that OCDD exhibits minimal toxicity in short-
term studies simply because so little of the compound is absorbed in a short
time. Exposed for longer periods, however, the animals appear to absorb and
accumulate sufficient amounts of the compound in their systems to manifest
"dioxin-like" effects.
Based on these new data (summarized in Table 3), a TEF value of 0.001
has been assigned to both OCDD and OCDF in the l-TEF/89 scheme, it
should be noted, however, that this value reflects the results of a single
experiment.
20
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IV. Summary
Table 2 shows the EPA-TEFs/87 and the l-TEFs/89. The changes reflect
an international consensus reached by a working group of the NATO/CCMS
and adopted in principle in April 1988. Adoption of this consensus position
by the international scientific and regulatory communities will facilitate
communication about and discussion of environmental contamination
involving CODs/CDFs.
The values should continue to be viewed as rough approximations that are
"interim" in nature, requiring periodic updating. In addition, there should be a
continuation of research into the development of a biologically based
analysis that can quickly and accurately measure the lexicological potential
of complex mixtures of CDDs and CDFs. Such research holds the promise of
removing the need for any TEF scheme. This is particularly important in light
of the emerging data showing that some of the CDDs/CDFs and related
compounds can exhibit antagonistic effects (Safe. 1987), a possibility that is
ignored in current TEF approaches.
There is only a marginal difference between the EPA-TEF/87 and l-TEF/89
schemes when the different factors are applied to the same complex mixture
of CODs/COFs. such as those found in MWC fly ash or biological samples
(Figures 2 and 3). Consequently, small changes away from the international
consensus l-TEFs/89 should be discouraged. That is. any arguable increase
in accuracy is likely to be small and will be purchased at the cost of a
decrease in effective communication and an increase in conflict/confusion
among scientists, agencies, and affected members of the public.
The authors would like to strongly reiterate that analytical chemists are
encouraged to analyze mixtures on a congener-specific basis, to the extent
possible. Such information may prove to be invaluable in identifying sources
of and transformation processes for CDDs/CDFs in the environment. In
addition, such detailed information will permit recalculation of estimated
toxicities for these samples if l-TEF/89 values are changed in the future in
light of new scientific data. In any event, summary results should be
expressed in l-TEQs/89 with the contribution from 2,3,7,8-TCDD clearly
noted (see Figures 2 and 3).
Several matters should receive close scrutiny prior to any future updating
of the l-TEF/89 values. For example, a case could be made that the I-TEF/B9
for 1.2.3,7,8-PeCDF is too low. However, this suggestion is based upon one
experiment whose results are not consistent with the results of several other
tests. Additional work should be conducted on this compound to resolve the
apparent ambiguity. Also, investigations should be conducted to determine
whether compounds in which only three of the four critical lateral positions
are occupied merit non-zero values. Finally, more work needs to be done to
clarify the toxicity associated with long-term exposures to low levels of highly
chlorinated CDDs/CDFs.
21
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24
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Appendix
Proposal on the Toxicity Equivalency Factor (TEF)
Concept to Assessing Risks of CDDs/CDFs
September 1986
Given the growing concern about the broad range of CDDs/COFs reported
in a large number of environmental media, various groups have developed
toxicity equivalency factors (TEFs) for converting levels of CDDs/CDFs into
"equivalent" amounts of 2.3,7.8-TCDD. While these approaches are not
defensible on indisputable scientific grounds, there is a generally
acknowledged underlying scientific rationale for such a policy position.
As various groups have developed related but somewhat different
schemes for TEFs, there has emerged a need for a broad-based international
consensus statement on the concept of the TEF approach so that risk
managers and the public can properly appreciate these schemes. Therefore.
Working Group A on exposure and hazard assessment is forming a
subcommittee to address TEFs at two levels:
A. Proposal
1. Leve/f
(a) Develop a consensus statement on the appropriateness of the TEF
concept.
(b) Develop a consensus statement on the level of accuracy that should
be attributed to the TEF concept and any of its specific approaches.
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the chairmanship of the United States. The names of the designated
members are due to Mr. Bretthauer, Group A Chair, by October 25,
1986.
(b) During the next 10 months, the subcommittee will interact to
accomplish the tasks in Level 1 and make as much progress as
possible on the items in Level 2.
(c) As part of their efforts, and as a platform for airing the issues, trie
subcommittee will organize a special session on TEF and related
topics at Dioxtn 1987 meeting in Las Vegas.
(d) The subcommittee will present its results and recommendations at
the CCMS meeting next fail for consideration by the full CCMS
Committee on Dioxin information Exchange.
26
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