Pilot Study On
International Information Exchange
On Dioxins and Related
Compounds
International Toxicity Equivalency Factor (l-TEF)
Method of Risk Assessment for Complex Mixtures
of Dioxins and Related Compounds
Report Number 176
August 1988
North Atlantic Treaty Organization
ommittee on the Challenges of Modern Society
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ACKNOWLEDGEMENTS
This report of the NATO/CCMS Pilot Study on International Information
Exchange on Dioxins and Related Compounds was prepared by the U.S. Envi-
ronmental Protection Agency (EPA), Office of Research and Development,
and Versar Inc., under Contract No. 68-02-4254. Mr. Erich W. Bretthauer,
from the United States Environmental Protection Agency, was the Study
Director for the Exposure and Hazard Assessment Working Group. Dr. Donald
G. Barnes of the U.S. EPA was the chairman of the TEF Subgroup and editor
of this report. Contributing authors and members of the TEF Subgroup are
presented on the following page. Dr. Frederick W. Kutz of the U.S. EPA
Office of Research and Development served as program manager for the prep-
aration of this document. Ms. Judy Bel 1 in of the U.S. EPA Office of
Research and Development was instrumental in the preparation of this
report. Ms. Wendy Grieder of the U.S. EPA Office of International Activi-
ties contributed to the development of this document.
Versar personnel involved in the preparation of this document
included: Mr. David Bottimore, technical reviewer; Ms. Patricia Wood,
task manager; Ms. Juliet Crumrine, technical editor; the Versar
secretarial staff, Ms. Kammi Johannsen and Ms. Lynn Maxfield; and Graphic
Department, including Ms. Kathy Bowles and Mr. Andre Price.
1
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NATO/CCMS Pilot Study on International Information Exchange
on Dioxins and Related Compounds
Membership of the TEF Subgroup
CANADA
Dr. Brendan Birmingham
Ontario Ministry of the Environment
Toronto
Dr. Donald L. Grant - contributing author
Health and Welfare Canada
Ottawa
FEDERAL REPUBLIC OF GERMANY
Prof. Dr. H. Greim - contributing author
GSF Muenchen Institut fur Toxikologie
Neuherberg
ITALY
Dr. Alessandro di Domenico
Istituto Superiore di Sanita
Roma
THE NETHERLANDS
Dr. C.A. van der Heijden
National Institute of Public Health and Environmental Hygiene
Bilthoven
UNITED KINGDOM
Dr. G.K. Matthew
Department of Health and Social Security
London
UNITED STATES
Dr. Donald G. Barnes - Chair and editor
U.S. Environmental Protection Agency
Washington, DC
Dr. James Wilson - contributing author
Monsanto Chemical Co.
St. Louis
Dr. Ellen Silbergeld
Environmental Defense Fund
Washington, DC
i 1
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TABLE OF CONTENTS
Page No.
Executive Summary iv
1. INTRODUCTION 1
2. BACKGROUND 4
2.1 The Need 4
2.1.1 Toxicity Considerations 4
2.1.2 Interpretation of Analytical Results 5
2.2 Efforts to Date 5
2.3 Consensus and Accuracy 8
3. INTERNATIONAL TEF SCHEME 9
3.1 The Scheme 9
3.2 Application of the I-TEF Scheme to Different Data Sets . 13
4. DIRECTIONS FOR THE FUTURE 18
4.1 The Problems 18
4.2 Addressing the Problems 19
5. CONCLUSIONS 21
6. REFERENCES 22
LIST OF TABLES
Table 1. Some Approaches to Estimating Relative Toxicities of
PCDDs and PCDFs 7
Table 2. Relative 2,3,7,8-TCDD Equivalents 11
Table 3. International Toxicity Equivalency Factors (I-TEFs) and
Contribution Within a Homologous Group 12
Table 4. Calculation of Toxicity Equivalents (TEQs) from Isomer-
Specific Data 14
LIST OF FIGURES
Figure 1. Toxic Equivalents in Emissions From a Municipal Waste
Incinerator 10
Figure 2a. Medium-Resolution GC/MS Analysis of TCDDs 16
Figure 2b. High-Resolution GC/MS Analysis of TCDDs 16
i l i
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Executive Summary
The NATO/CCMS Pilot Study on International Information Exchange on
Dioxins and Related Chemicals was initiated to apply the cooperative
efforts of the participating nations to address the dioxin problem.
Information targeted for exchange ranged from exposure and hazard
assessment to technology assessment and management of accidents. In
addition to the major information exchange objective, secondary goals
included the identification of knowledge voids and research program
duplication. The Exposure and Hazard Assessment Working Group carried
out activities for exchanging information on such diverse issues as
research activities, regulations and statutes, analytical laboratories,
and methods of exposure and risk assessment. One of the specific tasks
was to address risk assessment methodologies related to exposures to
complex mixtures of dioxins and furans.
At its meeting in Las Vegas, Nevada, in September 1986, the partici-
pants of the pilot study established a subgroup to explore a series of
issues associated with "toxicity equivalency factors" (TEFs) for use in
assessing the risks related to exposures to polychlorinated dibenzo-£-
dioxins (PCDDs) and dibenzofurans (PCDFs). The objective was to resolve
the discrepancies among the existing TEF schemes used throughout the
participating nations and to develop an updated TEF scheme that would
provide a consistent basis for risk assessment and regulation. The orig-
inal charge to the TEF Subgroup was broken down into separate tasks and
assigned to the Subgroup members identified as "contributing authors" on
the membership list in this report. Additional insight was gained at a
meeting of available Subgroup members at Dioxin '87, held in October 1987,
in Las Vegas, Nevada. These contributions were synthesized and edited by
the Chair into a draft report, which was distributed to all Subgroup mem-
bers for review and comment in February 1988. This final report reflects
the comments received as a result of that review as well as the discussion
during the concluding plenary meeting of the pilot study in Berlin, on
April 27-28, 1988.
iv
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This report presents an interim procedure for assessing the potential
hazard resulting from exposure to mixtures of PCDDs and PCDFs that should
be of practical assistance in addressing a number of questions associated
with PCDDs and PCDFs. The participants of the study do not suggest that
these TEFs have been definitively derived. The are based on an evaluation
of toxicity data for PCDD and PCDF congeners in a variety of j_n vitro and
in vivo tests, and on current TEF practices of several countries. The
report endorses the TEF concept as an interim measure of prudent science
policy and recommends specific TEF values (the "International-TEFs"
(I-TEFs)) to facilitate communication and consistency among the member
nations. At the same time, the subgroup recommends additional research to
test, refine, and eventually replace the I-TEFs. A background document
that presents the scientific basis for the development of TEFs, as well
as the literature sources and methodology used to determine the specific
I-TEFs, is published as CCMS Report Number 178.
v
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INTERNATIONAL TOXICITY EQUIVALENCY FACTOR METHOD
OF RISK ASSESSMENT FOR COMPLEX MIXTURES
OF DIOXINS AND RELATED COMPOUNDS
1. INTRODUCTION
For the past three years, this Pilot Study on International Informa-
tion Exchange on Dioxins and Related Compounds coordinated an internation-
al effort to address issues associated with polychlorinated dibenzo-£-
dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds. The pro-
ject was conducted under the auspices of the Committee on the Challenges
of Modern Society (CCMS) of the North Atlantic Treaty Organization (NATO).
Participating nations included Canada, Denmark, Federal Republic of
Germany, Italy, Netherlands, Norway, United Kingdom, and United States.
Numerous information exchange activities were undertaken to promote coop-
erative efforts and to identify duplicative efforts and knowledge voids.
When the project was initiated in 1985, it was divided into three areas of
study: exposure and hazard assessment, technology assessment, and manage-
ment of accidents.
The Exposure and Hazard Assessment Working Group, chaired by the
United States, was charged with several tasks concerning research and risk
assessment. Some of these activities included the compilation, analysis,
and distribution of information on research projects, regulations and
statutes, and laboratories with analytical capabilities for dioxins and
related compounds in the participating nations. In addition, the working
group desired to develop an international consensus on the toxicological
significance of complex mixtures of dioxins and furans. In September
1986, the participants of the pilot study established the TEF Subgroup to
address issues involved with the use of "toxicity equivalency factor"
(TEF) approaches to assess the risks posed by mixtures of various isomers
of PCDDs/PCDFs.
Interest in this topic stemmed from the fact that during the late
1970s and early 1980s, analytical chemists achieved the capability of
quantifying, in environmental samples, the presence of PCDDs and PCDFs,
1
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other than the long-studied 2,3,7,8-tetrachlorodibenzo-j>-dioxin (2,3,7,8-
TCDD). The toxicological significance of long-term exposures to these
other congeners was, and is, relatively unknown; therefore, it has been
difficult to ascribe rigorously a particular level of concern to these
compounds. In addition, simply summarizing and succinctly presenting
analytical data on the scores of individual PCDD and PCDF congeners in
some meaningful manner has also been difficult. For these reasons, dif-
ferent schemes have been proposed for estimating the toxicological signif-
icance of complex mixtures of PCDDs and PCDFs in terms of equivalent
amounts of 2,3,7,8-TCDD.
The existence of a variety of TEF schemes has complicated communica-
tion among scientists and regulators from different countries. Since the
advent of the TEF approach, at least 10 different schemes have been used.
Building upon the experience gained in the application of TEF approaches
in a number of different countries and jurisdictions, the TEF Subgroup
examined four central questions:
• Is there a scientific/regulatory consensus on the appropriateness
of the use of the TEF approach?
• Is there a consensus on a particular TEF approach?
• How can a TEF approach be applied to different types of analytical
data sets; e.g., homologue-specific vs. congener-specific?
• What additional research and data are needed to test, refine, or
replace the current I-TEF approach?
To address these issues, individual members of the TEF Subgroup
drafted answers to specific questions. The drafts were circulated within
the Subgroup for review and comment. Several members of the Subgroup met
at The Seventh International Symposium on Chlorinated Dioxins and Related
Compounds (Dioxin '87), held in Las Vegas, Nevada (USA), in October 1987,
and discussed a TEF scheme appropriate for common international use. The
results of these efforts and comments received at the plenary meeting in
Berlin on April 27-28, 1988 have been synthesized in this report. In
addition, an expanded background document to support this report presents
the data and methodology used to determine these "International TEFs"
(I-TEFs) is published as CCMS Report Number 178.
2
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Section 2 of this report discusses the need for the development and
use of TEFs. It includes a brief description of some of the TEF
approaches developed by different countries.
Section 3 presents the "International-TEF" scheme developed by consen-
sus within the participating nations m the Pilot Study on International
Information Exchange on Dioxins and Related Compounds. Representatives
of the member nations participating in the pilot study adopted this
scheme during the concluding plenary meeting of the project in Berlin on
April 27-28, 1988. The section closes with a discussion of how the scheme
can be applied to different data sets.
Section 4 discusses some of the research (data and method development)
activities which would strengthen the current I-TEF approach or enable
its replacement with a more rigorously scientific approach. Section 5
presents the overall conclusions regarding the I-TEF approach.
3
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2. BACKGROUND
2.1 The Need
2.1.1 Toxicity Considerations
In the early 1970s, the term "dioxin" was synonymous with 2,3,7,8-
TCDD, a compound that was widely thought to be present only as an impurity
in a limited number of chemical products. Extensive physicochemical and
toxicologic research has been conducted on the 2,3,7,8-TCDD. From such
studies it has been learned that the compound exhibits a broad range of
toxic effects in laboratory animals. These effects include carcinogenici-
ty, teratogenicity, immunotoxicity, and reproductive effects. They are
observed at exceptionally low doses; in some cases, on the order of
submicrograms per kilogram of body weight per day (ug/kg-d). It is these
striking toxicological properties exhibited at unprecedented low doses
that have attracted the attention and concern of the scientific and regu-
latory communities. While much remains to be learned, sufficient informa-
tion has been developed to support crude assessments of the risks posed by
exposure to 2,3,7,8-TCOD (e.g., NRCC 1981, OME 1984, Kimbrough 1984, USEPA
1985; 1988, FRG 1985).
In the late 1970s and continuing into the 1980s, additional environ-
mental sources of 2,3,7,8-TCDD were identified. Most of these sources
contain PCDDs and PCDFs in addition to 2,3,7,8-TCDD. These findings are
testimony to the innovation, diligence, and skill of analytical chemists
in different countries. The findings also pose a challenge to toxicolo-
gists and regulators who are asked to interpret and act upon the signifi-
cance of the analytical data.
Since there is a relative dearth of information on the toxicity of
PCDDs and PCDFs, other than 2,3,7,8-TCDD, the traditional approaches to
assess the significance of exposure to these additional compounds are
generally not applicable. That is, long-term toxicity data in animals do
exist for few mixtures of PCDDs and PCDFs or for individual components.
Therefore, in order to interpret this growing body of data, a new,
interim approach is needed until more definitive methods can be developed.
4
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2.1.2 Interpretation of Analytical Results
The very wealth of information gathered by analytical chemists on the
more than 200 congeners of PCDDs and PCDFs present in some environmental
samples seems to defy comprehension when the results are displayed as
chromatograms or lists of numbers in tables. While this detailed informa-
tion is of inestimable value in some instances, for other purposes requir-
ing succinct communication, a more concise, comprehensible form of presen-
tation is preferred.
2.2 Efforts to Date
A review of the literature reveals that congeners of PCDDs and PCDFs
are not equally toxic. Also, it is clear that the scientific effort spent
on determining the toxicity of 2,3,7,8-TCDD cannot be reasonably dupli-
cated for each of the other congeners (AOWG 1987, NATO/CCMS 1987). Long-
term cancer studies have only been conducted on 2,3,7,8-TCDD and a mixture
of HxCDDs. Teratogenicity and reproductive effects studies have been con-
ducted on a somewhat greater number of PCDDs and PCDFs. Although limited,
this information from whole animal studies, coupled with data that demon-
strate a strong structure/activity relationship among the members of the
PCDD and PCDF congeners, leads one to devise a means by which the relative
toxicities of these compounds can be assessed for crude, but practical,
purposes.
A hypothesis first developed by Poland and co-workers (Poland et al.
1979) highlighted the importance, with respect to biochemical activity,
of chlorine atoms on the carbons at the 2, 3, 7, and 8 positions on the
dibenzo-£-dioxin nucleus. This hypothesis provided the initial indication
that the PCDDs and PCDFs could be assessed on a comparative basis. The
hypothesis envisioned the binding of these molecules to a cytosolic recep-
tor as the first step in inducing a pleiotropic response in the organism.
One of the responses most frequently observed is an increase in the level
of the enzyme aryl hydrocarbon hydroxylase (AHH) (hence the designation
"Ah receptor"). The affinity of the PCDD or PCDF congeners for the Ah
receptor is related to the magnitude of the enzymic induction. Subsequent
5
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investigations have demonstrated relationships between the ability of the
PCDD and PCDF congeners to bind to the receptor and to induce AHH (and
other microsonial enzymes) and manifestation of toxicity such as thymic
atrophy and body weight loss (Bandiera et al. 1984, Safe et al. 1985),
LDjjq, carcinogenicity, reproductive/teratogenic effects, cell transfor-
mation, and dysfunction of the immune system (Schwetz et al. 1973, Poland
et al. 1976, Bradlaw et al. 1979, Moore et al. 1979, Murray et al. 1979,
Poland et al. 1979, Bradlaw et al. 1980, Knutson and Poland 1980, McKinney
and McConnell 1982, Bandiera et al. 1983, Bandiera et al. 1984, Hassoun
et al. 1984, Weber et al. 1984, Dencker et al. 1985, Gierthy and Crane
1985, Greenlee et al. 1985, Nagayama et al. 1985a,b, USEPA 1985, USEPA
1987, Olson et al. 1988). For detailed discussions, see the background
support document (CCMS Report No. 178).
It should be noted, however, that information questions the validity
of extending the Ah receptor mechanism for TCDD toxicity to species other
than the two strains of mice (C57BL/6J and DBA/2J) in which the correla-
tions are well established. For example, acute lethality (Pohjanvirta et
al. 1988), microsomal enzyme induction (Rozman et al. 1985, Henry and
Gasiewicz 1986), thymic involution (Gorski et al. 1988), induction of
cleft palate (Lamb et al. 1986), induction of hepatic prophyria (Greig et
al. 1984), induction of hyperkeratosis (Puhvel and Sakamoto 1987),
suppression of antibody response to sheep red blood cells (Pazdernik and
Rozman 1985), as a consequence of 2,3,7,8-TCDD administration have been
shown not to correlate with binding affinity to the Ah-high affinity pro-
tein in other strains/species. Also, (Gasiewicz and Rucci 1984) indicate
that the correlation between sensitivity to 2,3,7,8-TCDD toxicity and Ah
receptor binding affinity seen in mice is not necessarily applicable to
other species. Therefore, whenever possible, TEFs are preferentially
based upon whole animal data, rather than solely "Ah-receptor" binding
affinities or enzyme induction.
Both in vivo and/or in vitro data have been used as the basis for the
relative ranking of toxicities of PCDD and PCDF congeners by various
regulatory authorities (see Table 1). Each group proposing such a scheme
6
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Table 1. Some Approaches to Estimating Relative Toxicities
of PCDDs and PCDFs (USEPA 1987)
Basis
Compound
Swiss8
Grantb
Olie c
Commoner
New
York
4 State*
Ontario1
FDA9
o
>
EPA
1981
EPA
Current
Recommend.
(Basis)
Enzyme
LDso
Various
Effects
Various
Effects
Various
Effects
Mono thru di CDDs
0
0
0
0
0
0
0
0
Tri CDDs
0
0
0
1
0
0
0
0
2378-TCDD
1
1
1
1
1
1
1
1
Other TCDDs
0.01
1
0
0.01
0
0
1
0.01
2378-PeCDDs
0.1
0.1
1
1
0
1
0
0.5
Other PeCDD9
0.1
0.1
0
0.01
0
0
0
0.005
2378-HxCDDs
0.1
0.1
0.03
1
0.02
1
0
0.04
Other HxCDDs
0.1
0.1
0
0.01
0.02
0
0
0.0004
2378-HpCDDs
0.01
0.1
0
1
0.005
1
0
0.001
Other HpCDDs
0.01
0.1
0
0.01
0.005
0
0
0.00001
0CDD
0
0
0
0
<0.00001 1
0
0
2378-TCDFs
0.1
0.1
0.33
0.02
0
1
0
0.1
Other TCDFs
0.1
0.1
0
0.0002
0
0
0
0.001
2376-PeCDFs
0.1
0.1
0.33
0.02
0
1
0
0.1
Other PeCDFs
0.1
0.1
0
0.0002
0
0
0
0.001
2378-HxCDFs
0.1
0.1
0.01
0.02
0
1
0
0.01
Other HxCDFs
0.1
0.1
0
0.0002
0
0
0
0.0001
2378-HpCDFs
0.1
0.1
0
0.12
0
1
0
0.001
Other HpCDFs
0
0.1
0
0.0002
0
0
0
0.00001
OCDF
0
0
0
0
0
0
0
0
8 Swiss Government 1982. d Commoner et al. 1984.
b Grant 1977. 8 Eadon et al. 1982.
c Otie et al. 1983. ' Ontario 1982.
3 U.S. DHHS 1983.
h Gravitz et al. 1983.
'U.S. EPA 1981.
7
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has reached the conclusion that these relative rankings--expressed in the
form of "toxicity equivalency factors11 (TEFs)--can be used to express the
appropriate toxicity of a complex mixture of PCDDs and PCDFs as a "toxico-
logical equivalent amount (TEQ)" of 2,3,7,8-TCDD.
In addition to providing a toxicological summary about the mixture
under examination, the TEQ provides a convenient means of summarizing the
often extensive amount of analytical data resulting from a detailed gas
chromatograph/mass spectrometry (GC/MS) investigation from a hazard
assessment point of view. However, in any published report on the
analysis of environmental samples, the individual PCDD and PCDF data
should always be featured, with the TEQ value providing a secondary
summary, calculated from a clearly stated set of TEFs. Analytical results
on all congeners are important, even on those with TEFs presently assumed
as zero; i.e., mono-, di-, tri-, octa- and non-2,7,8-substituted PCDDs
and PCDFs. Such information is valuable for instance in identification
of particular sources (through comparison of homologue profiles and isomer
patterns) and for evaluating environmental transport, transformation, and
fate.
2.3 Consensus and Accuracy
In the opinion of the Pilot Study, there is international consensus
that the TEF approach is an appropriate science policy tool for use in the
absence of more definitive toxicity information. It has been recognized
that the TEFs for some congeners are more soundly supported by data than
others, and those congeners thought to be of greater concern should be
subjected to further investigation.
It should also be noted that the accuracy of an assessment of the
risks associated with exposure to a mixture of PCDDs and PCDFs depends
upon a number of factors, of which the uncertainty in the TEF approach is
only one and perhaps not the largest. The uncertainties relating to
estimated intakes, bioavailability, interspecies extrapolation, safety
factors or mathematical models, possible antagonistic or synergistic
interactions, etc. are likely to carry as much or more uncertainty than
the TEFs.
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3. INTERNATIONAL TEF SCHEME
3.1 The Scheme
The existence of a variety of TEF schemes has complicated communica-
tion among scientists and regulators from different countries when discus-
sing the significance of the analytical results from a particular environ-
mental sample. It is interesting to note, however, that in many cases the
TEQs derived by the different TEF schemes (Table 1) often differ by less
than an order of magnitude when applied to the same environmental mixture
of PCDDs and PCDFs (see Figure 1 and Table 2). For the purpose of illus-
trating the different TEF schemes, the TEQs presented in Figure 1 have not
been rounded off. For practical purposes, however, probably rounding to
order of magnitude accuracy of TEFs/data is warranted. It is commonly
acknowledged that any TEF approach is only an interim procedure to use in
the absence of more definitive data, and that the procedure should be up-
dated to reflect significant changes in the emerging scientific data base.
Given this situation, the members of the this pilot study have devel-
oped a set of TEFs--the "International TEFs" (I-TEFs)--to provide a
uniform approach to summarizing analytical data and their toxicological
significance. The I-TEFs adopted by the pilot study are displayed in
Table 3.
In developing the I-TEFs, the Subgroup was guided by the following
principles:
• The scheme should be as simple as practicable. A complex scheme
suggests greater precision and sophistication than can be scientifi-
cally supported.
• The focus should be on the PCDD and PCDF congeners that are pref-
erentially 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.
• The TEFs should reflect the relative toxicity exhibited by the
various congeners in a variety of toxicological endpoints.
The principal differences between the I-TEF scheme and earlier schemes
are the following:
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FIGURE 1. TOXIC EQUIVALENTS IN EMMISSIONS FROM A MUNICIPAL
WASTE INCINERATOR (BODDINGTON, 1988)
1
PCDFs
9 -
PCDDs
8 -
8 7"
TJ
o> 6 —
5 ~
4 -
EADON
CANADA
CAL
EPA
l-TEF
DATA FOR ABOVE FIGURE Concentrations in ng/dscm 3 @ 7%02)
X. TEF
Homologu^*^
DATA
EADON
CANADA
CAL
EPA
l-TEF
TCDD 2378
0.301
0.301
0.301
0.301
0.301
0.301
TCDD (OTHER)
2.739
0
0.2739
0
0.02739
0
PCDD 12378
0.786
0.786
0.393
0.786
0.393
0.393
PCDD (OTHER)
2.244
0
0.01122
0
0.01122
0
HxCDD 123478
0.158
0.00474
0.0158
0.00474
0.00632
0.0158
HxCDD 123678
0.387
0.01161
0.0387
0.01161
0.01548
0.0387
HxCDD 123789
0.0S87
0.001761
0.00587
0.001761
0.002348
0.00587
HxCDD (OTHER)
3.5563
0
0.003556
0
0.0014225
0
HpCDD 1234678
0
0
0
0
0
0
HpCDD (OTHER)
5.94
0
0.000594
0
0.0000594
0
OCDD
9.53
0
0.000953
0
0
0.00953
TOTAL PCDD
25.7
1.1051
1.045
1.1051
0.7562
0.7639
TCDF 2378
2.31
0.7623
0.231
2.31
0.231
0.231
TCDF (OTHER)
29.69
0
0.02969
0
0.02969
0
PCDF 12378
4.24
1.3992
0.424
4.24
0.424
0.212
PCDF 23478
2.49
0.8217
0.249
2.49
0.249
1.245
PCDF (OTHER)
11.97
0
0.01197
0
0.01197
0
HxCDF 123478
1.57
0.0157
0.0785
0.0471
0.0157
0.157
HxCDF 123678
0
0
0
0
0
0
HxCDF 234678
0.46
0.0046
0.023
0.0138
0.0046
0.046
HxCDF 123789
0.0095
0.000095
0.000475
0.000285
0.000095
0.00095
HxCDF (OTHER)
17.2605
0
0.008630
0
0.0017260
0
HpCDF 1234678
0
0
0
0
0
0
HpCDF 1234789
0
0
0
0
0
0
HpCDF (OTHER)
11.2
0
0.0112
0
0.011312
0
OCDF
0.41
0
0.000041
0
0
0.00041
TOTAL PCDF
81.61
3.0036
1.0675
9.101
0.9791
1.8924
TOTAL
4.109
2.112
10.206
1.737
2.6563
10
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Table 2. Relative 2,3,7,8-TCDD Equivalents8 (USEPA1987)
Source
EPA '85
EPA '81
Swiss
NY
CA
St. Louis (Air Particulates)
1
0.3
1
2
40
PCB Fire Soot (Isomer-Specific)
1
0.03
4
3
30
MSW ESP Dust
1
0.2
3
2
30
Lake Sediment
1
...
2
2
30
Milorganite
1
0.6
2
0.9
30
Oslo MSW Flyash
1
—
1
2
20
Ontario MSW Flyash
1
0.8
1
2
3
Japanese Plant A
1
0.3
1
2
7
Japanese Plant B
1
0.6
0.8
2
3
Albany
1
0.3
0.4
2
5
Wright-Patterson (Best)
1
0.2
2
3
20
Wright-Patterson (Worst)
1
0.4
2
2
20
8 Calculated using the Toxicity Equivalence Factors shown in Table 1.
li
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Table 3. International Toxicity Equivalency Factors (1-TEFs)
and Proportion of Congeners of Concern in a Homologous Group
Congener
of Concern
l-TEF
Congeners of Concern
In a Homologous Group
2,3,7,8-TCDD
1
1 out of 22 (5%)
1,2,3,7,8-PeCDD
0.5
1 out Of 14 (7%)
1.2.3.4.7.8-HxCDD
1.2.3.7.8.9-HxCDD
1,2,3,6,7,8-HxCDD
0.1
3 out of 10 (30%)
1,2,3,4,6,7,8-HpCDD
0.01
1 out of 2 (50%)
OCDD
0.001
1 out of 1 (100%)
2,3,7,8-TCDF
0.1
1 out of 38 (3%)
2,3,4,7,8-PeCDF
1,2,3,7,8-PeCDF
0.5
0.05
1 out of 28 (4%)
1 out Of 28 (4%)
1.2.3.4.7.8-HxCDF
1.2.3.7.8.9-HxCDF
1,2,3,6,7,8-HxCDF
2,3,4,6,7,8-HxCDF
0.1
4 out Of 16 (25%)
1.2.3.4.6.7.8-HpCDF
1.2.3.4.7.8.9-HpCDF
0.01
2 out Of 4 (50%)
OCDF
0.001
1 OUt Of 1 (100%)
12
-------
(1) 2,3,4,7,8-PeCDF is assigned a value of 0.5, while 1,2,3,7,8-PeCDF
is assigned a value of 0.05. This assignment reflects the great-
er potency of 2,3,4,7,8-PeCDF, as demonstrated in a variety of
test systems and the lower potency of 1,2,3,7,8-PeCDF exhibited
in teratogenicity studies (Birnbaum et al. 1987).
(2) OCDD and OCDF are assigned a non-zero value: 0.001. This
reflects recent information that administration of OCDD to
laboratory animals for 14 weeks leads to accumulation of OCDD in
the tissues and the appearance of incipient 2,3,7,8-TCDD-1ike
toxicity (Birnbaum et al. 1987). (Earlier experiments with OCDD
had involved larger exposures to single doses, which were
inefficiently absorbed and therefore elicited essentially no
toxic response.)
(3) The non-2,3,7,8-substituted congeners are effectively assigned a
value of zero. This has been done according to principles
described above.
It should be noted that when applied to complex environmental mixtures
of PCDDs and PCDFs (e.g., emissions from combustion sources), the TEQs
calculated by the I-TEF scheme are quite similar to those generated by
several of the existing TEF schemes {see Figure 1).
3.2 Application of the I-TEF Scheme to Different Data Sets
Increasingly, isomer-specific data are being generated in the analyti-
cal laboratory. In such cases, TEQs are easily generated by summing the
products of the concentrations of each of the 2,3,7,8-substituted congen-
ers by their respective I-TEFs (see Table 4).
In other cases, various factors (e.g., limited analytical funds or
difficult analytical matrices) necessitate the reporting of homologue-
specific data; e.g., the total amount of TCDDs present, without distin-
guishing between the individual isomers. In these cases, some assumptions
about the isomeric composition of each homologue must be made.
As a worst case, one could assume that all of the homologue signal
came from the 2,3,7,8-substituted congeners. However, in most
instances,this would be an overestimate. It is preferable to analyze the
situation more closely and to exercise informed scientific judgment, as
illustrated in the three following examples.
13
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Table 4. Calculation of Toxicity Equivalents (TEQs)
from Isomer-Specific Data
Congener
Isomer-Specific
Analytical Data (ppb)
Contribution
l-TEF to TEQ (ppb)
2,3,7,8-TCDD
2
1 2
1,2,3,7,8-PeCDD
6
0.5 3
1.2.3.4.7.8-HxCDD
1.2.3.7.8.9-KxCDD
1,2,3,6,7,8-HxCDD
20
25
20
0.1 2
0.1 2.5
0.1 2
1,2,3,4,6,7,8-HpCDD
1 5
0.01 0.15
OCDD
1 0
0.001 0.01
TOTAL TEQs 1 2
(1/6 Contributed
by 2,3,7,8-TCDD)
14
-------
First, when confronted with homologue-specific data, the risk assessor
can examine the raw data to determine whether some information can be
gleaned from GC/MS peaks, which may be at least partially resolved. For
example, Figure 2a is a medium-resolution chromatogram of TCDDs. The
shaded portion contains the 2,3,7,8-TCDD peak, along with a variety of
coeluting isomers that, as seen in Figure 2b, are clearly separated from
the 2,3,7,8-TCDD in the high-resolution chromatogram of the same sample.
When confronted with data of the type in Figure 2a, it is prudent to
assume that the entire shaded peak is due to the presence of 2,3,7,8-TCDD.
This approach will not underestimate the amount of 2,3,7,8-TCDD in the
sample. At the same time, the approach will avoid the clear overestimate
resulting from the assumption made in the previous paragraph that all of
the TCDD homologue consists of 2,3,7,8-TCDD.
Second, over the past decade, a considerable body of information has
been compiled regarding the congeneric PCDD/PCDF composition of several
types of sources. For instance, analyses of thermal sources such as
incinerators and automobile exhaust generally show that about 5 percent of
the total amount of TCDDs is attributable to 2,3,7,8-TCDD. Thus, it would
be a reasonable first approximation to assume that 5 percent of the total
TCDDs from any combustion source sample consists of 2,3,7,8-TCDD. Adopt-
ing this assumption would result in an estimated contribution to the TEQs
which is 95 percent lower than the worst case and which is more likely to
reflect the actual situation. A similar procedure could be applied to
other homologue groups, given the appropriate information about probable
isomer distributions associated with particular sources.
It should be noted that for the larger TEFs and lower fractional
contribution to their homologous class of 2,3,7,8-substituted tetra- and
penta-CDDs and -CDFs (see Table 3) combine to place a premium on obtaining
an accurate estimate of the relative contribution of the 2,3,7,8-substi-
tuted congeners to these classes. By contrast, in the case of HpCDD, the
worst case estimate will be no more than twofold higher than an estimate
based upon the percentage of the 2,3,7,8-substituted congener found in
most combustion emission samples; i.e., about 50 percent. Further, the
15
-------
FRH 8362
1ST SC/PG:
SELECTED ION CHROMATOGRAM
BTL = 3
00352
D8352
6 FOOT 1% DEXSIL 300 PACKED GLASS COLUMN
160°C to 300" at 16°C/mlnute
Helium carrier gas 30mL/mlnute
2, 3, 7, 8-
-TCDD
333.0
2, 3, 7, 8-TCDD
321.0
Figure 2a. GC/MS analysis using a 6 foot packed Dexsll column, He eluant,
with a quadrupole mass spectrometer as a detector.
FRH 9536
1ST SC/PG:
** SELECTED ION CHROMATOGRAM
109
IS = 7
2/200 UL
D8352
50 METER SILAR 10C GLASS CAPILLARY COLUMN
100°C for 3 minutes, 20°C/mlnute to 180°C, 2°C/mlnute to 240°C
Helium carrier gas 10 psi head pressure
2, 3, 7, 8-1 3 C •) 2 -TCDD
333.0
2, 3, 7, 8-TCDD
321.0
Figure 2b. GC/MS analysis using a 50 meter Silar 10c capillary column,
He eluant, with a quadrupole mass spectrometer as a detector.
16
-------
I-TEF of 0.01 for 2,3,7,8-HpCOO suggests much less of an impact on the
total TEQ relative to the impact of 2,3,7,8-TCDD, which has an I-TEF of
1.0. Similarly, although 2,3,7,8-TCDD and 2,3,7,8-TCDF constitute a simi-
lar fraction of the tetra-substituted congeners, the ten-fold diffrence
in their TEFs makes an error in the concentration of 2,3,7,8-TCDD more
serious than is the case for 2,3,7,8-TCDF.
Third, in a situation in which there is no information about the spe-
cific congeneric composition of a PCDD/PCDF mixture, one could speculate
on the likely composition on the basis of the chemical reactions that are
thought to have given rise to the mixture. For example, the contamination
of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) with principally 2,3,7,8-
TCDD might have been anticipated from the condensation of 2,4,5-trichloro-
phenol used in its synthesis. Therefore, attribution of the entire amount
of a homologue-specific analyses (total TCDDs) of 2,4,5-T to 2,3,7,8-TCDD
would be appropriate (as has been generally confirmed by high resolution
GC/MS analysis).
17
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4. DIRECTIONS FOR THE FUTURE
4.1 The Problems
The I-TEF approach described in this report is an interim procedure
for assessing the toxicity of PCDDs and PCDFs. For the reasons outlined
below, additional research should be conducted to test, refine, or replace
the procedure in order to generate risk assessments with increasing
confidence.
The I-TEF approach reflects the limited information available on
short-term and long-term in vivo experimentation. While preference is
given to data from whole animal, long-term studies, the majority of the
factors are derived from results of short-term in vitro studies that seem
to correlate well with results of subchronic testing in some animals.
It should be recognized that the exact mechanism by which PCDDs and
PCDFs express their toxicity is not known. While, as noted above, the
receptor binding AHH induction model can rationalize some of the whole
animal data, other toxic effects of these chemicals cannot be explained by
this hypothesis alone. Alternative mechanisms have been offered; e.g.,
interference with the effect of thyroid hormones (Rozman et al. 1984,
1985, McKinney et al. 1985a, 1985b, 1985c), general interference with
cellular mechanisms (Rozman and Greim 1985, Weber et al. 1987), and reduc-
tion in vitamin A storage (Thunberg 1979). Some reports (e.g., Holsapple
et al. 1985) have raised questions about the underlying structure/activity
argument that strongly undergirds most of these hypotheses. In summary,
there is no one proposed mechanism-of-action that can account for all of
the jn vivo experimental observations.
While the correlations cited above provide sufficient evidence for
moving forward with the TEF procedure, these approaches contain inherent
limitations. For example, in vitro studies may not represent the biologi-
cal effect of chemical administered in vivo. Also, that in vitro studies
generally involve single high-level exposures. Such studies
do not mimic the chronic low-level ambient human exposures of concern to
whole animals (including humans) in the environment. Chronic exposure
18
-------
involves an array of pharmacokinetic and metabolic complexities that are
absent in the in vitro situation. Possible interaction resulting from
simultaneous exposure to a combination of PCDDs and PCDFs contributes
additional uncertainties. Teratogenic studies in rats (Birnbaum et al.
1987) suggests additivity of effects from combinations of the 2,3,7,8-
substituted PCDDs and PCDFs. Other studies indicate antagonism between
the 2,3,7,8-substituted and the 2,3,7,8-substituted congeners, as well as
the related polychlorinated biphenyls (PCBs) (Safe 1987).
4.2 Addressing the Problems
From the discussion above, it is clear that in order to test, refine,
or replace the I-TEF approach, a vigorous program of research should be
conducted to address the areas of uncertainty. Such a program should
include the approaches developed along the following lines:
(1) Investigate the models proposed for the mechanism of action of
PCDDs and PCDFs.
(2) Test the structure/activity hypothesis in additional endpoints;
e.g., immunotoxicity.
(3) Further examine the toxicokinetics of the various PCDDs and
PCDFs.
(4) Use the findings in 1 through 3 to test the I-TEFs predictions in
long-term using additional single compounds and complex mixtures
of PCDDs and PCDFs.
(5) Investigate the basis for the wide species variability and the
position of humans on this spectrum.
(6) Conduct any feasible epidemiological studies that have the power
to critically test the risk estimates made on the basis of animal
testing.
(7) Widen the area of similar research to include efforts with bromo-
and mixed chlorobromodibenzo-j)-dioxins and dibenzofurans.
It is clear that the pursuit of this line of research will be com-
plicated, time consuming, and costly. Competing, legitimate priorities
limit what any one country can accomplish in this area. Therefore, it is
important that the international community continue to freely exchange
19
-------
information on research-in-progress and research-in-planning, as has been
the case with this NATO/CCMS Pilot Study on International Information
Exchange on Dioxins and Related Compounds.
20
-------
5. CONCLUSIONS
Considerable progress has been made in dealing with the issues associ-
ated with the presence of PCDDs and PCDFs in the environment. Scientific
research has made us aware of the problems posed by these substances and
has indicated some ways to resolve those problems. At the same time,
research to date has not answered all of our questions or addressed all of
our concerns. Unanswered questions include fundamental questions ("How
toxic are PCDDs and PCDFs to humans and other environmental species?"),
more subtle questions ("How are these PCDDs and PCDFs transformed and
transported to humans?"), and clearly practical questions ("How can the
presence of PCDDs and PCDFs be minimized in the environment?").
The I-TEF scheme addresses only a portion of this larger complex of
questions. It rests on a rational, but not definitive, base of scientific
fact. Despite all of its limitations, the I-TEF approach provides a prac-
tical, interim vehicle for the scientific and regulatory community to use
in communicating within itself and with the public in estimating the sig-
nificance of PCDDs and PCDFs in the environment.
21
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