United States
Environmental Protection
Agency
Science Advisory
Board (1400)
SABEC95021F
SEPTEMBER 1995
£PA RE-EVALUATING
DIOXIN
>nce Advisory Boai
iew of EPA's Reas
Of Dioxin And Dioxin-Likd Compounds
U.S. Environmental Prote'
Region VII
Information Resource Centdp
901 N. 5th Sty
Kansas City,
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EPA REGION VII IRC
099206
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PAGE i
NOTICE
This report has been written as a part of the activities of the Science Advisory Board,
a public advisory group providing extramural scientific information and advice to the
Administrator and other officials of the Environmental Protection Agency. The Board
is structured to provide balanced, expert assessment of scientific matters relating to
problems facing the Agency. This report has not been reviewed for approval by the
Agency and, therefore, the contents of this report do not necessarily represent the
views and policies of the Environmental Protection Agency, nor of other agencies in
the Executive Branch of the Federal government, nor does mention of trade names or
commercial products constitute a recommendation for use.
COPIES OF THIS REPORT MAY BE ORDERED BY MAIL FROM:
THE SCIENCE ADVISORY BOARD (1400)
U.S. EPA
401 M ST. SW
WASHINGTON DC 20460
OR BY TELEPHONE AT 202-260-8414
REASSESSING DIOXIN
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PA GE II '^^^^^^'^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ii^
ABSTRACT
The Dioxin Reassessment Review Committee (DRRC) met on May 15-16, 1995 to hear
briefings by EPA staff and public comments on EPA's reassessment of dioxin and dioxin-like
compounds. The DDRC addressed 43 health and exposure-related issues.
The Committee commended EPA for doing a very credible and thorough job assembling,
integrating, and analyzing a very large body of data on dioxin emissions, environmental levels,
exposures, and body burdens. The Committee's recommendations largely addresse refine-
ments, not substantive revisions. The Committee agrees that current levels of dioxin-like
compounds in the environment derive primarily from anthropogenic sources and that the
air/plant/animal pathway is probably the primary way in which humans are exposed, and
supports the use of Toxic Equivalencies (TEQ) for exposure analysis.
The Health Assessment draft provides a comprehensive review of the scientific literature
on the biology of dioxin. The Committee is confident that final versions of Chapters One
through Seven will not need further review by the SAB. The Committee agrees with the use of
the TEFs as a basis for developing an overall index of public health risk, but their practical
application depends on the reliability of the TEFs and the availability of representative and
reliable exposure data.
Chapter Eight, on modeling, reflects a great deal of effort, but several Members of the
Committee found the exposition of important points to be unclear. Chapter Eight is also
weakened by its reliance on the standard EPA default assumption of a linear non-threshold
model for carcinogenic risk.
Almost all the Members of the Committee concur with EPA's judgment that dioxin, under
some conditions of exposure, is likely to increase human cancer incidence.
Chapter Nine, on risk assessment, displays both strengths and weaknesses, and needs
to be revised considerably to deal with the weaknesses.
KEYWORDS: dioxin; TCDD; carcinogen; Ah receptor; TEQ; TEF; reassessment; anthropo-
genic; incineration; food
THE SCIENCE ADVISORY BOARD
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: PAGE Hi
U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
DIOXIN REASSESSMENT REVIEW
May 15-16, 1995
HEALTH PANEL
CHAIR
Dr. Morton Lippmann, New York University Medical Center, Institute of Environmental Medicine,
Tuxedo, NY
MEMBERS
Dr. William B. Bunn, Mobil Administrative Services Company, Inc., Princeton, NJ
Dr. Kenny S. Crump, K S Crump Division, Ruston, LA
Dr. Ernest E. McConnell, Raleigh, NC
Dr. Henry C. Pitot, McArdle Laboratory for Cancer Research, Madison, WS
CONSULTANTS
Dr. Richard W. Clapp, Boston University School of Public Health, Boston, MA
Dr. John Doull, University of Kansas, Kansas City, KS
Dr. Ronald W. Estabrook, The University of Texas, Dallas, TX
Dr. John Graham, Harvard Center for Risk Analysis, Boston, MA
Dr. William Greenlee, Purdue University, West Lafayette, IN1
Dr. Norbert Kaminski. Michigan State University, East Lansing, Ml
Dr. Thomas Mack, University of Southern California, Los Angles, CA
Dr. John McLachlan, Tulane University, New Orleans, LA
Dr. David Ozonoff, Boston University School of Public Health, Boston, MA
Dr. Gabriel Plaa, Department of Pharmacology, Montreal, Quebec, Canada
Dr. Donald Reed, Oregon State University, Corvallis, OR
Dr. Knut Ringen, Center to Protect Workers' Rights, Washington, DC
Now at the University of Massachusetts, Worcester, MA.
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PAGE iv ~
Dr. Allen Silverstone, State University of New York Health Science Center,
Syracuse, NY
Dr. Sidney Stohs, Creighton University, Omaha, NE
Dr. Bernard Weiss, University of Rochester. Rochester, NY
Dr. Hanspeter Witschi, University of California, Davis, CA
Dr. Timothy Zacharewski, University of Western Ontario, London, Ontario, Canada
FEDERAL EXPERTS
Dr. Michael Gough, U.S. Congress, Office of Technology Assessment. Washington, DC
Dr. Michael I. Luster, National Institute of Environmental Health Sciences, Research Triangle
Park, NC
Dr. Thomas Umbreit, Food and Drug Administration, Rockville, MD
DESIGNATED FEDERAL OFFICIAL
Mr. Samuel Rondberg, Science Advisory Board (1400F), U.S. Environmental Protection
Agency, Washington, D.C. 20460
EXPOSURE PANEL
CHAIR
Dr. Joan Daisey, Lawrence Berkeley Laboratory, Berkeley, CA
MEMBERS
Dr. Paul Bailey, Mobil Company, Princeton, NJ
Dr. Robert Hazen, Bureau of Risk Assessment, State of New Jersey, Trenton, NJ
Dr. Kai-Shen Liu, California Department of Health Services, Berkeley, CA
Dr. Thomas E. McKone, University of California, Davis, CA
Dr. Maria Morandi, University of Texas Health Science Center at Houston, Houston, TX
Dr. Jonathan M. Samet, Johns Hopkins University, Baltimore, MD
Dr. William Randall Seeker, Energy & Environmental, Research Corp., Irvine, CA
Mr. Ron White, American Lung Association, Washington, DC
CONSULTANTS
Dr. Ronald Hites, Indiana University, Bloomington, IN
THE SCIENCE ADVISORY BOARD
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= PAGE v
Dr. Nancy Kim, New York State Department of Health, Albany, NY
Dr. Dennis Paustenbach, McLaren/Hart/ChemRisk, Alameda, CA
Dr. John Jake Ryan, Bureau of Chemical Safety, Ottawa, Ontario, Canada
Dr. Valerie Thomas, Princeton University, Princeton, NJ
DESIGNATED FEDERAL OFFICIALS
Mr. Samuel Rondberg, Science Advisory Board (1400F) U.S. Environmental Protection Agency,
Washington, DC 20460 ,
Mr. A. Robert Flaak, Science Advisory Board (1400F), U.S. Environmental Protection Agency,
Washington, DC 20460
STAFF SECRETARY
Ms. Mary L Winston, Environmental Protection Agency, Science Advisory Board (HOOF)
Washington, DC 20460
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PAGE vi
TABLE OF CONTENTS
1. EXECUTIVE SUMMARY 1
1.1 Exposure Document 1
1.2 Health Document 3
2. INTRODUCTION 6
2.1 Background 6
2.2 Charge 7
2.2.1 Exposure Document Charge 7
2.2.2 Health Document Charge 10
3. DETAILED FINDINGS-EXPOSURE DOCUMENT 18
3.1 Sources 18
3.1.1 Estimating and Apportioning Sources 18
3.1.2 Source Inventory 19
3.1.3 Dioxin Reservoirs 19
3.1.4 Local/Distant Contributions to Dioxin Levels in Food 20
3.1.5 Uncertainty in Deposition Estimates 21
3.2 Food and Media Levels 21
3.2.1 Problems in Estimating CDD/F Levels 21
3.2.2 Use of U.S. Food Data 22
3.2.3 Air/Plant/Animal Pathway and Other Food Chain Impacts .... 24
3.2.4 Smoking-An Additional Potential Exposure Pathway 25
3.3 Uncertainty in Estimating Human Body Burdens 27
3.4 Estimating Background Exposures via Food/Body Burden Data 28
3.5 Site-Specific Assessment Procedures 28
3.5.1 Steady-State Assumptions and Modeling 28
3.5.2 Mass-Balance Issues 28
3.5.3 Model Validation Issues 29
3.5.4 Photolysis and Atmospheric Transport -..,... 30
3.5.5 Air-to-Plant Transfer 31
3.5.6 Vapor/Particle Partitioning 32
3.5.7 Background Exposures and Site-Specific Evaluation . 33
3.5.8 Evaluation of Multiple Sources 34
3.6 Overall Scientific Foundations of the Reassessment Document 34
4. DETAILED FINDINGS-HEALTH DOCUMENT 37
4.1 Disposition and Pharmacokinetics Issues 37
4.1.1 Strength of the database 37
4.1.2 Disposition and Pharmacokinetics 38
4.1.3 Incremental Exposures and Bioaccumulation 40
4.1.4 Uncertainties in Back Extrapolations of Body Burden 40
4.2 Mechanisms of Dioxin Action 41
4.2.1 Animal-to-Human Extrapolations of Receptor Structure and Function . . 41
THE SCIENCE ADVISORY BOARD
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.. PAGE vii
TABLE OF CONTENTS (CONTINUED)
4.3 Toxic Effects of Dioxin 43
4.3.1 Animal Models for estimating Human Risk 43
4.3.2 Variations in Human Sensitivity 45
4.4 Chloracne as an Indicator of Exposure 46
4.5 Cancer 46
4.5.1 Epidemiological Evidence 46
4.5.2 Carcinogenicity of Dioxin-like Compounds 49
4.5.3 Carcinogenic Activities of Dioxin and Dioxin-Like Compounds 50
4.5.4 Characterization of Dioxin/Dioxin-like Compounds as Human Carcino-
gens 54
4.6 Developmental Toxicity and Animal NOAELs 56
4.7 Human/Animal Databases: Potential for Immunotoxicity 59
4.8 Other Effects 62
4.9 Dose-Response 62
4.9.1 Approaches to Dose-response Determination for Cancer 62
4.9.2 Use of the RfD in Evaluating Incremental Exposures 65
4.9.3 Continuum of Response Postulate 66
4.10 Use of Toxicity Equivalence Factors (TEFs) 67
4.11 Laboratory Animals/ Human Response 69
4.11.1 Animal Data/ Weight-of- Evidence Conclusions for Human Risk 69
4.11.2 Animal vs. Human Data 70
4.12 Overall Scientific Foundations of the Health Reassessment Document....... 71
4.12.1 Evaluation of the Risk Assessment Chapter 71
4.12.2 Evaluation of Major Conclusions 74
4.13 Other Issues and Future Steps 78
5. CONCLUSIONS 81
5.1 Exposure Assessment Document 81
5.2 Health Assessment Document 83
REFERENCES . 85
VII
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PAGE 1
1. EXECUTIVE SUMMARY
1.1 Exposure Document
The EPA and its staff have done a very
credible and thorough job, and are commended for
assembling, integrating, and analyzing a very large
body of data on dioxin source emissions, environ-
mental levels, exposures, and human body burdens,
within the framework of human exposure assessment.
In general, the data and analyses have been
clearly presented, and uncertainties and limi-
tations in the extant data described. Conse-
quently, the recommendations of the Com-
mittee largely address refinements, correc-
tions, and clarifications, not substantive
revisions.
The reassessment identifies the major
known sources of dioxins and provides a
reasonable estimate of total emissions. The
Committee recommends that the new infor-
mation on emissions from incineration of
medical waste and other sources be incorpo-
rated if appropriate. The Committee also
recommends adding an explicit statement to
the final document noting that the fractional
contributions of various types of emissions
sources to total emissions cannot be assumed
to be identical to the fractional contributions
of those sources to human exposures.
At present, it is difficult to evaluate the
relative contributions of local and more dis-
tant sources to the levels of dioxin in food.
When better data become available from on-
going EPA measurements of dioxin concentra-
tions in food, the Committee suggests that the
Agency consider using a Geographical Infor-
mation System (CIS) for analysis of these
data. With such a system, the geographic
distributions of dioxin emissions sources and
dioxin levels in food could be mapped and
quantitative questions asked (and tested
statistically) regarding the probable influences
of local and more distant sources.
In the Exposure document, total esti-
mated dioxin-like emissions for the U.S. have
been directly compared to an estimate of the
total amount of dioxin deposited to the sur-
face of the U.S., based on available measured
deposition factors. However, a scientifically-
valid mass balance comparison would require
estimating deposition of the emitted dioxins
using atmospheric dispersion and deposition
modeling and then comparing this estimate to
the estimate obtained from measured and
representative deposition data. The Commit-
tee concurs with EPA's position (Volume II, p.
3-166) that it is not scientifically valid to
infer, based on the simple mass balance com-
parison, that there are missing sources of
... the recommendations of the
Committee largely address
refinements, corrections, and
clarifications, not substantive
revisions.
dioxins. The Committee also recommends
that this section of the document be modified
substantially so that the simple direct mass
balance comparison is not provided, and that
the scientific problems with this procedure,
which are given, be modified appropriately to
reflect this revision.
The Committee agrees with the EPA
position that current levels of dioxin-like compounds
in the environment are derived primarily from
REASSESSING DIOXIN
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PAGE 2
anthropogenic sources, and, based on available data,
that the air-to-plant-to-animal pathway is most
probably the primary way in which the food chain is
impacted and humans are exposed. EPA should,
however, take note of other potentially impor-
tant exposure pathways, e.g., point source-to-
water-to-fish, and cigarette smoking. There is
also a very large gap in our understanding of
the potential atmospheric transformation of
vapor-phase dioxin-like compounds and of the
air to plant transfer coefficients of these com-
pounds.
... the potential contributions
from reservoirs might indeed
be important and that these
sources should be evaluated
more thoroughly.
The document's estimate of average
dioxin exposure is reasonable, but has substan-
tial uncertainties due to limited data, and
cannot provide an estimate of the complete
distribution of exposures for the U.S. popula-
tion. In addition, although the body burden
data are dearly not adequate for rigorous time-
trend analysis, there is some evidence that
exposure may be decreasing in the U.S. The
Committee recommends that these points be
noted clearly and explicitly in the Summary
volume for the benefit of policy makers and
the public. The Committee commends and
fully supports EPA's efforts to develop better
data on concentrations of dioxins in food and
in human tissue and regards these as very high
priority research needs.
The reassessment document indicated
that it is possible that dioxins from historic
reservoir sources might be re-introduced
through various exposure pathways. The
Committee agrees that the potential contribu-
tions from reservoirs might indeed be impor-
tant and that these sources should be evalu-
ated more thoroughly.
The Exposure document defines a
"background" exposure based on existing
monitoring data obtained from sites removed
from known contaminant sources (or from
food representative of the general supply).
The Committee has two concerns with the
"background exposures" as so defined. The
first is that this term be used consistently
throughout the document. The second con-
cern is that the comparison of estimated expo-
sures from a single planned facility to this
"background" might not be adequate if the
region already had a higher level of exposure
than the "background" due to the presence of
multiple existing sources. The Committee
recommends that a "baseline" exposure assess-
ment also be made for the local area or region
for comparison to the "background," and that
the Agency consider providing guidance for
performing "baseline" exposure assessments,
as well as assessments of the exposure incre-
ment from a proposed facility.
Finally, although the Committee sup-
ports EPA's use of Toxic Equivalences (TEQs)
for exposure analysis, it also recommends that
EPA carefully review the draft Exposure As-
sessment report and ensure that the congener-
specific data are used in all instances (such as
transport, transformation, and deposition
processes) in which differences in the physical
and chemical properties of the congeners are
likely to be important. The Committee has
noted several such cases in this report.
THE SCIENCE ADVISORY BOARD
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PAGE 3
1.2 Health Document
The document, in the first seven chap-
ters, provides a comprehensive review of the
scientific literature on the biological mecha-
nisms involved in the uptake of dioxin and
related compounds; the binding of these
substances to receptor sites and their metabo-
lism and retention in tissues; and cellular,
organic, and whole body responses. The
Committee commends the EPA staff for this consid-
erable accomplishment, and has made a number of
comments and suggestions for relatively minor
changes, corrections, and citations to additional
literature that should sharpen and clarify the
content of the initial seven chapters. The Commit-
tee's most significant recommendations con-
cerning these seven chapters center on the
Agency's use of Toxic Equivalency Factors
(TEF) to address the broad range of dioxin-
like compounds having the common property
of binding to the Ah receptor and producing
related responses in cells and whole animals.
The use of the TEFs as a basis for developing an
overall index of public health risk is clearly justifi-
able, but its practical application depends on the
reliability of the TEFs and the availability of
representative and reliable, exposure data. The
Committee calls for clarifications in the speci-
fications for TEFs of the various dioxin-like
compounds for various health outcomes of
concern, including the development of sepa-
rate TEFs for the major compound classes,
i.e., 2,3,7,8-TCDD, other dibenzodioxins and
furans, and coplanar PCBs. The Committee is
confident that final versions of Chapters One
through Seven will not need further review by the
SAB.
The eighth chapter on modeling is
critical to the reassessment's overall success.
The modeling must deal with both human
and laboratory animal data. The human data
are usually based on accidents and industrial
exposures and are subject to confounding
factors such as exposures to other toxicants,
differences in population distributions of age,
sex, ethnic background, diet, etc. Animal
studies often involve high-to low-dose extrap-
olations as well as cross-species extrapolation.
Both types of such data are inadequate, by
themselves, for estimating the human health
risks of chronic, low-dose environmental
exposures to dioxin and related compounds.
Although the modeling chapter reflects a great deal
of effort, several Members of the Committee found
the exposition of important points to be unclear.
Chapter Eight is also weakened by its reliance on
the standard EPA default assumption of a linear
non-threshold model for carcinogenic risk. The
Committee suggests that EPA consider, in future
revisions, alternative risk models, allowing for
minimal response at low environmental levels of
exposure, and which would be consistent with the
body of available physiological (and, with the
opportunities now arising, pharmaco-kinetic) model-
ing of factors such as deposition, tissue dose, and
excretion, as well as the epidemiological, and bioas-
say data.
... the assignment of the
dioxins, the PCBs, or PBBs to
one of a mutually exclusive and
collectively exhaustive set of
carcinogenicity categories
grossly oversimplifies the state
of the science in most
instances...
Vis-a-vis cancer, the Committee notes
that all of the evidence available argues
strongly that TCDD exerts its carcinogenic
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PAGE 4
effect primarily through its effectiveness as a
promoting agent stimulating cell replication in
a reversible manner, and inhibiting apoptosis,
both mechanisms presumably mediated
through the Ah receptor and associated trans-
duction mechanisms. TCDD is thus not a
complete carcinogen, and, to avoid confusion should
not be designated as such in the EPA document.
Almost all Members of the Committee do concur
with EPA's judgment that 2,3,7,8-TCDD, under
some conditions of exposure, is likely to increase
human cancer incidence.2 The conclusion with
respect to dioxin-like compounds is less firm. The
Committee notes that the assignment of the
dioxins, the PCBs, or PBBs to one of a mutu-
ally exclusive and collectively exhaustive set of
carcinogenicity categories grossly oversimpli-
fies the state of the science in most instances,
excepting those compounds for which there is
an abundance of uniformly consistent evi-
dence, but that EPA must make such an
assignment. Under the 1986 EPA cancer
guidelines, levels of carcinogenic evidence,
with mutually exclusive descriptive terms are
provided. These choices include Group A
human carcinogen; Bt -probable human
carcinogen on the basis of limited information
from human studies as well as animal studies;
Group B2 probable human carcinogen on
the basis of animal studies only; Group C
possible human carcinogen; Group D - not
classifiable; and Group E -- evidence of non-
carcinogenicity for humans. In the case of
dioxin, virtually all of the Committee believe
that the animal studies would be categorized
as "sufficient" and the studies of humans as
"limited," providing for an overall categoriza-
tion of Bp which would be expressed verbally
as "Probably Carcinogenic to humans with
limited supporting information from human
studies." The Committee (on the basis of similar
effects) would support the same designation for
dioxin-like materials. PBBs and PCBs would
receive ratings ofBt and B2, respectively.
Chapter Nine, on risk assessment,
was not as thoroughly peer-reviewed as were
the preceding chapters. It needs to be revised
considerably to reflect the changes being made
in Chapters 1-8 and the areas of weakness
discussed below. The chapter would greatly
benefit from an external peer review by a
group including some scientists active in
dioxin research and individuals with outstand-
ing credentials and experience in basic re-
search and quantitative modeling of receptor-
mediated processes. The review group should
also include other scientists with broad toxico-
logical, epidemiological, and public health
experience to place the risks of dioxin and
related compounds in perspective; and, as
observers, risk managers who have to contend
with concerns of the larger public in address-
ing regulatory options.3
More specifically, the Committee
identified, and wishes to emphasize to the
Agency, particular areas of both strength and
weakness in Chapter Nine.
One Member contends that no epidemiological
study has produced evidence that is widely accepted by the
scientific community, including the International Agency for
Research on Cancer, as being convincing for the human
carcinogenicity of dioxin.
One Member of the Committee disagrees with
the suggested composition of the peer review group, specifi-
cally the inclusion of public health experts and risk managers.
He believes that the presence of such participants would
divert the focus of the review from science to other issues.
These comments apply also to the proposals for peer review
which appear in sections 4.1.3 and 5.2 of this report.
THE SCIENCE ADVISORY BOARD
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Three major strengths are apparent.
First, by focusing serious attention on various non-
cancer effects, the Agency has dispelled any mis-
impression that EPA's risk assessment process is
overly preoccupied with carcinogenic effects. Second,
by evaluating an entire group of compound classes
(with a common attribute), rather than a single
compound, the Agency responds to the generally-
mistaken criticism that its risk assessment process
can only address issues on a chemical-by-chemical
basis. Third, a useful comparative perspective is
provided in the draft conclusions where the Agency
highlights the fact that the margin of safety (between
background exposures and levels of exposure where
effects have been observed in test animals) for dioxin-
like compounds is smaller than that EPA usually
accepts for many other compounds.
' PAGE 5
Three major weaknesses were also
noted. First, almost all of the Members of the
Committee conclude that the presentation of
scientific findings portrayed in the draft docu-
ment's conclusions is not balanced vis-a-vis the
possible risks posed by exposure to dioxin, with a
tendency to overstate the possibility for danger.4
Second, important uncertainties associated with
the Agency's conclusions are not fully identified
and are not subjected to feasible analyses.
Finally, the characterization of non-cancer risk is
not performed in a manner that can facilitate
meaningful analysis of the incremental benefits of
risk management alternatives.
However, several Members of the Committee
do not agree with this statement and regard the EPA
presentation as appropriately conservative within the context
of public health protection.
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PAGE 81
5. CONCLUSIONS
5.1 Exposure Assessment Docu-
ment
EPA has done a very credible and
thorough job on a large and complex task.
The Agency is commended on the work
that has been done to assemble, integrate,
and analyze a very large body of data on
source emissions, environmental levels,
exposures, and human body burdens in a
framework of human exposure assessment.
In so doing, they have uncovered key data
gaps and issues, developed some reasonable
priorities for future efforts, and begun
research efforts to address key information
gaps. In general, the work has been clearly
presented, and uncertainties and limitations
in the data are generally well described.
Thus, the recommendations of the Commit-
tee largely address refinements, corrections
and clarifications that should be made to
the Exposure Assessment draft document
rather than substantive revisions.
In general, the emissions inventory
has identified the major known sources of
dioxins and provided a reasonable estimate
of total emissions, given the available data.
The Committee recommends that the new
information on emissions from incineration
of medical waste, which became available
after this draft document was prepared, be
reviewed and the emissions estimates be
revised if appropriate. The Committee also
recommends adding an explicit statement to
the final document noting that the frac-
tional contributions of various types of
emissions sources to total emissions cannot
be assumed to be identical to the fractional
contributions of those sources to human
exposures.
At present, it is difficult to evaluate
the relative contributions of local and more
distant sources to the levels of dioxin in
food. When better data become available
from on-going EPA measurements of dioxin
concentrations in food, the Committee
suggests that the Agency considering using
a Geographical Information System (CIS)
for analysis of these data. With such a
system, the geographic distributions of
dioxin emissions sources and dioxin levels in
food could be mapped and quantitative
questions asked (and tested statistically)
regarding the probable influences of local
and more distant sources.
In the Exposure document, total
estimated dioxin-like emissions for the U.S.
have been directly compared to an estimate
of the total amount of dioxin deposited to
the surface of the U.S., based on available
measured deposition factors. However, a
scientifically-valid mass balance comparison
would require estimating deposition of the
emitted dioxins using atmospheric dispersion
and deposition modeling and then compar-
ing this estimate to the estimate obtained
from measured and representative deposition
data. The Committee's concurs with EPA's
position (Volume II, p. 3-166) that it is not
scientifically valid to infer that there are
(based on the simple mass balance compari-
son) missing sources of dioxins. The Com-
mittee also recommends that this section of
the document be modified substantially so
that the simple direct mass balance compari-
son is not provided, and that the scientific
problems with this procedure, which are
given, be modified appropriately to reflect
this revision.
REASSESSING DIOXIN
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PAGE 82 =
The Committee agrees that the avail-
able scientific evidence strongly indicates that
current levels of dioxin-like compounds in the
environment derive from anthropogenic
sources and that the air-to-plant-to-animal
pathway is most probably the primary way in
which the food chain is impacted and humans
are exposed. However, the environmental
data are limited and EPA should not loose
sight of other potentially important exposure
pathways that may impact on some parts of
the population, e.g., point source to water to
fish, and cigarette smoking. Furthermore,
there is a very large gap in our understanding
of the potential atmospheric transformation of
vapor-phase dioxin-like compounds and of the
air to plant transfer coefficients of these
compounds. Environmental measurements of
deposition of paniculate and vapor-phase
dioxin-like compounds to the surface are also
extremely limited, although we understand
that there'are now some efforts to address this
lack.
The reassessment document indicated
that it is possible that dioxins from historic
reservoir sources might be re-introduced
through various exposure pathways. The
Committee agreed that the potential contribu-
tions from reservoirs might indeed be impor-
tant and that these sources should be evalu-
ated more thoroughly.
The Exposure document defines a
"background" exposure based on existing
monitoring data obtained from sites removed
from known contaminant sources (or from
food representative of the general supply).
The Committee had two concerns with the
"background exposures" as so defined. The
first is that this term be used consistently
throughout the document. The second con-
cern was that the comparison of estimated
exposures from a single planned facility to this
"background" might not be adequate if the
region already had a higher level of exposure
than the "background" due to the presence of
multiple existing sources. The Committee
recommended that a "baseline" exposure
assessment also be made for the local area or
region for comparison to the "background,"
and that the Agency consider providing guid-
ance for performing "baseline" exposure
assessments, as well as assessments of the
exposure increment from a proposed facility.
Although the Committee supports
EPA's use of TEQs for exposure analysis, it
also recommends that EPA carefully review
... the available scientific
evidence strongly indicates that
current levels of dioxin-like
compounds in the environment
derive from anthropogenic
sources...
the draft Exposure Assessment report and
ensure that trie congener-specific data are
used in all instances (such as transport, trans-
formation, and deposition processes) in which
differences in the physical and chemical prop-
erties of the congeners are likely to be impor-
tant. The Committee has noted several such
cases in this report.
The Exposure Assessment document
provides a reasonable central estimate of
dioxin exposure: but the estimate has substan-
tial uncertainties at this time because of to the
very limited data that are available. The
assessment does not (and, given currently
available data, cannot) provide an estimate of
the complete distribution of exposures for the
U.S. population which is needed to provide a
strong scientific basis for a judging whether
THE SCIENCE ADVISORY BOARD
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PAGE 83
there are currently significant adverse health
risks to the U.S. population from the dioxins.
Nor are the body burden data adequate for
time trend analysis. The Committee com-
mends and fully supports EPA's efforts to
develop more current and representative data
on concentrations of dioxins in food and in
human tissue. These are very high priority
research needs.
5.2 Health Assessment Document
The first seven chapters of this three-
volume document present a comprehensive
and careful review of the scientific literature
on the biological mechanisms leading to:
uptake of dioxin and related compounds; their
binding to receptor sites; their metabolism
and retention in tissues; and cellular, organic,
and whole body responses. The Committee
commends the EPA staff for this considerable
accomplishment, and has made a number of
comments and suggestions for relatively minor
changes, corrections, and citations to addi-
tional literature that should sharpen and
clarify the content of these chapters further.
It is confident that EPA will use this guidance
to produce improved final versions of these
chapters that will not need further review by
SAB.
The document represents a departure
from the earlier EPA risk assessment for
dioxin, which dealt primarily with 2,3,7,8-
TCDD. In addressing a broad range of
dioxin-like compounds having the common
property of binding to the Ah receptor, and
producing related responses in cells and whole
animals, it creates opportunities for a holistic
assessment of the cumulative impacts of these
broadly distributed anthropogenic pollutants.
Thus, while the environmental concentrations
of each compound alone may be too low to
produce effects of concern, the combined
exposures may be producing effects that
warrant concern. The use of the concept of
toxicity equivalence factors (TEFs), and the
concentrations of the compounds in foods and
environmental media, to produce an overall
index of public health risk is clearly justifiable.
Its practical application depends on the reli-
ability of the TEFs and the availability of
representative and reliable exposure data.
This review of the Health Assessment Docu-
ment calls for clarifications in the specifica-
tions for TEFs of the various dioxin-like com-
pounds for various health outcomes of con-
cern. Having such specifications on TEFs,
combined with exposure data for the specific
compounds, the contributions to the overall
risk of the various compounds and compound
classes can then be determined with sufficient
confidence for risk management decisions. In
other words, when the risk manager concludes
that the overall health risk from dioxin and
related compounds requires a decision to
reduce the risk, such decisions can be based
on knowledge of which control options can
produce the greatest increments of risk reduc-
tion for these several classes of compounds
covered in this document.
The document ... creates
opportunities for a holistic
assessment of the cumulative
impacts of these broadly
distributed anthropogenic
pollutants.
It is on the basis of the preceding
discussion that the Committee calls for more
explicit treatment, in the revised document, of
the major compound classes, i.e., 2,3,7,8-
TCDD, other dibenzodioxins and furans, and
coplanar PCBs. Each has different sources
REASSESSING DIOXIN
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PAGE 84
and options for source and exposure reduc-
tion.
The eighth chapter on modeling is a
critical one in the document. The interpreta-
tion of the available bioeffects data from
controlled exposure studies in the laboratory
depends largely on cross-species and high dose
to-low dose extrapolations. The interpreta-
tion of the human experience, largely (but not
exclusively) from relatively high dose indus-
trial workers exposures and acute exposures of
populations to accidental releases, requires
knowledge of, and corrections for, dose-re-
lated responses, and for the influence of
confounding factors such as exposures to
other toxicants, differences in population
distributions of age, sex, ethnic background,
diet, etc. Since each set of relevant data is
inadequate, by itself, for estimating the hu-
man health risks of chronic, low-dose environ-
mental exposures to dioxin and related com-
pounds, models that are based on all of the
relevant data are essential,
The modeling chapter does an ade-
quate job summarizing the current state-of-
the-art of modeling relevant to dioxin and
related compounds. Its major deficiency,
from the perspective of the SAB review Com-
mittee, was its reliance on the standard EPA
default assumption of a linear non-threshold
model for carcinogenic risk. Many Members
of the Committee were impressed by the
possibility of using the available data, primar-
ily the low-dose data of Kociba et al. (1976;
1978; 1979) for rats, and the Bertazzi et al.
(1993) data for humans, to construct an
alternate model allowing for minimal response
at low environmental levels of exposure that
would be consistent with the body of available
epidemiological and bioassay data, and recom-
mend that the feasibility of such a model be
discussed in the revised draft chapter.
The final chapter on risk assessment
had, of necessity, the limitations imposed on
it by its reliance on the contents of the first
eight chapters. Also, having been prepared
after the external peer reviews devoted to the
earlier chapters, it was not as thoroughly
reviewed as were the preceding chapters. It
needs to be revised to reflect, the changes
being made in Chapters 1-8, and the areas of
weakness discussed above in Sections 4.12.1
and 4.12.2. Chapter 9 would greatly benefit
from an external peer review by a group in-
cluding: scientists active in dioxin research;
other scientists with broad toxicological (in-
cluding experience in basic research and
modeling of receptor-mediated processes); and
scientists with epidemiological and public
health perspectives, to place the risks of di-
oxin and related compounds in perspective. It
may also be desirable to invite, as observers,
risk managers, who may have to contend with
concerns of the larger public in addressing
regulatory options for these compounds.30
30
Several Committee Members believe that EPA
should consider in a threshold model the possibility of other
toxic effects occurring in the "threshold region."
THE SCIENCE ADVISORY BOARD
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= PAGE 85
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2. INTRODUCTION
2.1 Background
Dioxins are a group of anthropogenic
chemical compounds created as unintended
by-products through a number of activities
including: combustion, certain types of chemi-
cal manufacture, chlorine bleaching of pulp
and paper, and other industrial processes. For
the purpose of this review, the terms "dioxin"
and "dioxin-like compounds" are used to refer
to the family of dioxins, furans, and dioxin-like
PCBs, and comprises 2,3,7,8-TCDD and other
2,3,7,8-substituted dioxins, 2,3,7,8-substi-
tuted furans, and those PCB congeners with at
least four chlorine atoms which can assume a
planar conformation and have dioxin-like
activity, including the non ortho, mono ortho,
and a few di ortho PCB congeners. Dioxins are
produced in very small quantities (the emis-
sions estimates in Table II-3 of Volume 1 of
the Exposure Assessment sum to about 25
pounds or 11.3 kilograms annually) compared
to other pollutants ; however, because they are
thought to be highly toxic, they have been
treated as significant environmental pollutants
since the early 1970's.
In 1988, EPA released two documents
addressing risks from dioxins (A Cancer Risk-
Specific Dose Estimate for 2,3,7,8-TCDD and
Estimating Exposure to 2,3,7,8-TCDD) and
requested that the Science Advisory Board
(SAB) review them. The SAB report (SAB,
1989), released in November 1989, although
not agreeing with several of the conclusions in
the two documents, concluded that "both
documents were carefully constructed and well
written." The SAB report concluded a recom-
mendation to "..follow up on this excellent
start." by developing and validating new mod-
els for human exposure and for cancer and
non-cancer risk endpoints, and to pursue
active research programs to resolve questions
and incorporate new data.
The Agency initiated a significant
effort addressing dioxin risk, and on Septem-
ber 13, 1994, released for public review and
comment a 2,400 page draft reassessment of
the toxicity of and exposure to dioxin (see 59
FR 46980). The development of this "public
review draft" involved outside scientists as
principal authors of several chapters, several
public meetings to take comment on the
Agency's plans and progress, and the publica-
tion of earlier drafts for public comment and
review. The draft reassessment broadened its
focus beyond 2,3,7,8-TCDD to include other
dioxins, furans, and coplanar PCBs on the
basis of equivalence of response in terms of
Ah-receptor binding. Such receptor binding
was considered an essential, if not sole deter-
minant. The document was based on informa-
tion currently available to EPA regarding the
toxicity, sources, pathways of release to the
environment, and the levels of these com-
pounds in the environment. It recognized that
these compounds vary in potency and used
toxicity equivalents based on experimental
data to develop overall risk estimates.
In December 1994, the EPA Office of
Research and Development (ORD) requested
that the SAB review the reassessment docu-
ment, and submitted a draft Charge addressing
some 40 issues. Following discussions involv-
ing ORD and SAB staff, and the Co-Chairs
appointed by the SAB Executive Committee to
lead the review, a final Charge with 43 issues
(see Section 2.2 following) was adopted.
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The SAB Dioxin Reassessment Review
Committee (DRRC) was developed by build-
ing on the SAB's Environmental Health and
Indoor Air Quality/Total Human Exposure
Committees, and adding (following an exten-
sive review and recruitment process) addi-
tional Consultants to fill gaps in needed
expertise and to add depth in key scientific
areas. In addition to the Co-Chairs, 37
scientists were appointed to the Committee.
The DDRC met on May 15-16, 1995 in
Herndon, Virginia to hear briefings by EPA
staff and comments by Members of the
public, and to discuss the relevant issues of
the Charge. Following the public meeting,
the present report was developed through a
series of mail reviews of successive drafts,
continuing until consensus was reached, or
statements of both majority and minority
viewpoints were incorporated.
2.2 Charge
Sections 2.2.1 and 2.2.2 following
display the detailed Charge for the review.
The Charge consists of background material
supplied by EPA Office of Research and
Development (ORD) staff, and the specific
questions agreed upon following discussions
between the Committee Co-Chairs, SAB
staff, and ORD staff. The questions are
displayed in italic text to differentiate them
from the background material.
2.2.1 Exposure Document Charge
OVERALL SCIENTIFIC FOUNDA-
TIONS OF THE REASSESSMENT
DOCUMENT
(Question 1) Overarching the specific issues
addressed below and not withstanding any specific
finding of the Committee(s), do the available data
and the analyses of these data, as presented in the
draft, adequately support the major conclusions of
the reassessment documents?
The exposure document was devel-
oped by EPA's Exposure Assessment Group
with contract support from Versar, Inc. The
effort began in 1992 and has included several
internal review cycles and one external review.
The primary objectives of the exposure reas-
sessment document are to:
a) identify the sources that release
dioxin-like compounds to the envi-
ronment;
b) summarize data on the levels of
these compounds in food and envi-
ronmental media;
c) summarize data on human body
burdens;
d) estimate background exposure lev-
els; and
e) provide procedures for estimating
human exposure as a result of site-
specific releases
The key findings of the exposure
document include the following: The princi-
pal pathway by which people are exposed to
dioxin-like compounds is through the diet,
with the consumption of animal products
contributing over 90% of the average daily
intake. It is hypothesized that the principal
mechanism by which dioxin-like compounds
enter the terrestrial food chain is via atmo-
spheric transport and deposition. Current
levels of these compounds in the environment
are principally caused by anthropogenic activi-
ties. The EPA reassessment document is
based on an extensive literature review which
is complete through 1993 and includes a
REASSESSING DIOXIN
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PAGE 8
number of 1994 references. Over 1000 refer-
ences were used.
EPA is seeking comment from the SAB
in each of the above five areas, as well as
posing this general question: (Question 2) Are
currently available models and approaches for
estimating and apportioning the impacts of various
sources adequate for this purpose - i.e., addressing
the specific issue areas enumerated below? Have the
best extant approaches been employed?
SOURCES
1. An inventory of CDD/F (chlorinated
dibenzo-dioxins and furans) emissions to land,
air, and water is presented in the document.
In general, the inventory is based on proce-
dures and supporting data comparable to
similar inventories conducted by a number of
European countries. A qualitative uncertainty
classification (low, medium, or high) was
given to each estimate, and a range of uncer-
tainty around each estimate was assumed.
(Question 3) Does the Committee recommend any
changes to this inventory?
2. The document concludes that the contri-
bution of historical sources ("reservoirs") to
current exposures is unknown. (Question 4)
Can the Committee suggest new ways or identify
new data to evaluate further the importance of these
sources?
3. It is unknown whether local or distant
sources contribute most to food levels at a
particular location. (Question 5) Can the Com-
mittee suggest new ways or identify new data to
evaluate further this issue?
4. A number of investigators from other
countries have evaluated the possible exis-
tence of unknown sources by comparing
estimates of emissions to estimates of deposi-
tion. Such an analysis is provided for the U.S.
in this document. It concludes that too much
uncertainty exists in both the emission and
deposition estimates to make any firm judg-
ments regarding unknown sources by compari-
son of these two estimates. (Question 6) Does
the Committee agree with this position?
FOOD AND MEDIA LEVELS
1. The uncertainty in the estimates of CDD/F
levels in U.S. is difficult to characterize. The
document highlights the limited number of
samples used to derive averages and presents
standard deviations (where possible to derive).
Also, an analysis is presented showing the
impact of deriving averages assuming
nondetects equal zero versus assuming
nondetects equal half of the detection limit.
Finally, comparisons are made to European
studies. (Question 7) Has this uncertainty, due
both to the possible varied quality of the data and
the limited number of samples, been adequately
emphasized and characterized?
2. Some reviewers have suggested that the
current U.S. food data should not be used to
make preliminary estimates of background
levels, even with the caveats. (Question 8)
Does the Committee agree with the document's
approach?
3. The document proposes the hypothesis
that the air-to-plant-to-animal pathway is the
primary way that the food chain is impacted.
(Question 9) Does the Committee concur with the
rationale used to develop this hypothesis? Can the
Committee offer further elaborations on the mecha-
nisms which result in food chain impacts?
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PAGE 9
4. The document concludes that environmen-
tal levels appear to be primarily a product of
anthropogenic activities. This is based on
trends seen in sediment data, which show a
rise in the concentration of dioxin-like com-
pounds beginning in the first half of the 20th
Century. Only low levels have been found in
ancient tissue remains. (Question 10) Does the
Committee agree with the conclusion that environ-
mental levels are primarily a product of human
activities in the 20th Century?
HUMAN BODY BURDENS
Human body burden data are presented from
several studies. Although some of these stud-
ies are quite large (e.g., NHATS (National
Human Adipose Tissue Survey) collected
samples from over 800 individuals), they may
not be statistically representative of the entire
U. S. population. (Question 11) Is this an
important source of uncertainty for projecting
background body burdens?
BACKGROUND EXPOSURES
Background exposures are estimated in two
ways: a) using levels in food and standard
consumption estimates; and b) by back-calcu-
lating from body burden data. (Question 12)
The Committee is asked to comment on the appro-
priateness of these calculations.
SITE-SPECIFIC ASSESSMENT PROCE-
DURES
1. The food chain and other fate models used
in this document are relatively simple, steady-
state approaches. They generally use parti-
tioning techniques to model media transfers
without consideration of the mass of the
compartments. Accordingly, mass balance
violations are theoretically possible. The
general issues associated with these models
can be grouped into three areas:
(Question 13) Is the steady-state assumption valid?
Using steady state models is felt to be justified based
on the assumption that the release rates of dioxin-
like compounds are relatively constant and tenden-
cies for these compounds to persist in the environ-
ment. The additional benefit of such models is that
they tend to be less data intensive, and information
was found for all parameters for the dioxin-like
compounds. Does the Committee generally agree
with the use of simple, steady state approaches for
modeling the fate-and-transport of dioxin-like
compounds? Does the Committee have comments on
specific models or model parameters?
(Question 14) Is the lack of an explicit mass-bal-
ance derivation of the models an important concern?
The current models have the advantage of being
relatively easy to use. For example, bioaccumulation
factors, which are multiplied by media concentration
to estimate tissue concentrations (plants, animals),
tend to be simple to use. Limited testing suggests
that mass balance violations are unlikely as long as
reasonable parameter values are used. Also, the
general recommendation is included to conduct mass
balance checks after modeling. Is this sufficient or
are more complex approaches needed?
(Question 15) Have the models been sufficiently
validated? Most aspects of these models were not
derived on the basis of theory. Rather, they gener-
ally use approaches and parameter values that were
derived from field or laboratory observations.
Chapter 7 of Volume HI details several exercises
that are meant to address the validity of the models
used in these procedures. Some of these exercises are
the description and application of alternate model-
ing approaches compared with the approaches
selected for the assessment. Additionally compari-
REASSESSING DIOXIN
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PAGE 10
sons were made of model predictions to field mea-
surements/or the effluent discharge model, air-to-
beef food chain model, and others. Although model
validation is generally an ongoing concern, can the
Committee make any statements as to the extent and
merit of the validation exercises presented in Chapter
7? Can they make suggestions about farther exer-
cises which could be done? Can the Committee make
statements as to the proper use of these models in
light of the validation work presented in Chapter 7?
2. In addition to the general issues discussed
above, three more specific fate model issues
were highlighted:
(Question 16) Does significant photolysis occur
during atmospheric transport of dioxin-like com-
pounds? If so, how does the toxic equivalency
(TEQ) of the mixture change? Some evidence exists
that rapid photolysis can occur when these com-
pounds are present in a vapor phase. Testing,
however, has not been conducted under true atmo-
spheric conditions. The degradation products have
not been identified. The possibility exists that higher
chlorinated dioxins andfurans will yield more toxic
lower chlorinated dioxins andfurans. Given the lack
of tests and unknowns about changes in TEQs, the
document recommends assuming no degradation
during atmospheric transport.
(Question 17) Have the air-to-plant transfer
coefficients been appropriately estimated? These
transfer factors are critical components of the dioxin
food chain model. The document concludes that
transfers of dioxins in the vapor phase dominate
above ground vegetative concentrations, particularly
feeds of livestock. The transfer coefficients were
derived from laboratory studies on the transfer of
2,3,7,8-TCDD vapors onto grass leaves and other
vegetation. Questions remain, however, regarding
extrapolation to other congeners, extrapolation to
other vegetation, effects of photolysis, wash-off rates
of deposited contaminants, etc.
(Question 18) Has the vapor/particle partitioning
been appropriately estimated? The document re-
views adsorption theory and provides a procedure to
estimate the degree that dioxin-like compounds
partition between the vapor and particle phases in
the ambient air. The controlling factors are: molecu-
lar weight, chemical-specific vapor pressure, ambient
temperature, and concentration of total suspended
particulate. Does the Committee recommend any
changes to this approach?
3. The procedures presented in Volume III
are specifically designed for assessing the
incremental impacts from specific sources.
Two aspects of such assessments were not
addressed in detail:
The general advice provided on considering
background exposures when evaluating the
impacts from a specific site is that incremental
impacts can be compared to national back-
ground estimates for media concentrations
and exposures (as presented in Volume II).
No additional details or suggestions are pro-
vided. (Question 19) Does the Committee agree
with this approach? Does the Committee have any
specific recommendations?
The general advice provided on evaluating
impacts from multiple sources of release is that
point sources can be modeled individually and
impacts summed at points of interest, but no
additional details or suggestions are provided.
(Question 20) Does the Committee agree with this
approach, or would the Panel recommend that
multiple sources be more explicitly discussed in
Volume III? And if so, does the Panel have any
specific recommendations for such inclusions?
THE SCIENCE ADVISORY BOARD
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PAGE 11
2.2.2 Health Document Charge
Chlorinated dibenzo-p-dioxins and
related compounds (commonly known simply
as dioxins) are contaminants present in a
variety of environmental media. These com-
pounds are extremely potent in producing a
variety of effects in experimental animals
based on traditional toxicology studies at
levels hundreds or thousands of times lower
than most other chemicals of environmental
interest. In addition, human studies demon-
strate that exposure to dioxin and related
compounds is associated with subtle biochem-
ical and biological changes whose clinical
significance is as yet unknown, and with
chloracne, a serious skin condition associated
with high level exposure to these and similar
organic chemicals. Laboratory studies suggest
the probability that exposure to dioxin-like
compounds may be associated with other
serious health effects including cancer. Hu-
man data, while often limited in their ability
to answer questions of hazard and risk, are
generally consistent with the observations in
animals. Whether the adverse effects noted
above are expressed in humans, or are detect-
able in human population studies, is depen-
dent on the dose absorbed and the intrinsic
sensitivity of humans to these compounds.
Recent laboratory studies have provided new
insights into the mechanisms involved in the
impact of dioxins on various cells and tissues
and, ultimately, on toxicity. Dioxins have
been demonstrated to be potent modulators
of cellular growth and differentiation, particu-
larly in epithelial tissues. These data, together
with the collective body of information from
animal and human studies, when coupled with
assumptions and inferences regarding extrapo-
lation from experimental animals to humans
and from high doses to low doses, allow a
characterization of dioxin hazards.
EPA is seeking comment from the
SAB in the following areas of the Health
Assessment document:
OVERALL SCIENTIFIC FOUNDATIONS
OF THE REASSESSMENT DOCUMENTS
(Question 1) Overarching the specific issues ad-
dressed below and not withstanding any specific
finding of the Committee(s), do the available data
and the analyses of these data, as presented in this
draft, adequately support the major conclusions of
the reassessment documents?
DISPOSITION/PHARMACOKINETICS
The disposition and pharmacokinetics of
2,3,7,8-TCDD and related compounds have
been investigated in several species and under
various exposure conditions. These data and
models derived from them are critical in
understanding the sequelae of human expo-
sure. Data related to disposition and phar-
macokinetics of dioxin and related com-
pounds and efforts to develop models to
further understand tissue dosimetry are
described in detail in Chapter 1 of the
Health Assessment document:
An understanding of the relation-
ship between exposure and dose is an impor-
tant aspect of ai\ adequare characterization of
risk. The data base relating to this issue is
extensive for 2,3,7,8-TCDD but is lacking for
many of the related compounds, (Question 2)
Does the document adequately characterize the
strengths and weaknesses of the data base and
draw appropriate inferences for this group of
compounds?
REASSESSING DIOXIN
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PAGE 12
The evaluation of available data and
the development of physiologically based
models has led to a better understanding of
the disposition and pharmacokinetics of
dioxin and related compounds than for most
other environmental chemicals. (Question 3)
Has this understanding been well integrated into
other aspects of the assessment such as route of
exposure, toxicity equivalence, dose to the fetus, etc?
This assessment relies extensively on
estimates of body burden that are a function
of the uptake, distribution, metabolism, and
excretion of this complex mixture of structur-
ally related compounds. Estimates of half-life
in the body facilitate the understanding of
bioaccumulation as a function of intake over
a life-time, and of the impact of incremental
exposures on blood or tissue levels both over
the short and long term. (Question 4) Have
these issues been adequately dealt with in the health
assessment document?
Body burden data allow some estima-
tion of historical body burdens to complement
effects analysis in human populations pre-
sumed to have high exposures in earlier de-
cades. (Question 5) Has the magnitude, implica-
tions and uncertainty of these back extrapolations
been adequately described?
MECHANISMS OF DIOXIN ACTION
Knowledge of the mechanisms of dioxin
action may facilitate the risk assessment
process by imposing bounds upon the assump-
tions and models used to describe possible
responses to exposure to dioxin. In this docu-
ment, the relatively 'extensive database on
dioxin action has been reviewed, with empha-
sis on the contribution of the specific cellular
receptor for dioxin and related compounds
(the Ah receptor) to the mechanism(s) of
action. Other reviews referenced in Chapter
2 provide additional background on the sub-
ject. Discussion in this chapter focusses on
aspects of our understanding of mechanism(s)
of dioxin action that are particularly impor-
tant in understanding and characterizing
dioxin risk including:
a) the similarities at the biochemical
level between humans and other
animals with regard to receptor
structure and function;
b) the relationship of receptor binding
to toxic effects; and
c) the role that the purported mecha-
nism^) of action might contribute
to the diversity of biological re-
sponses seen in animals and, to
some extent, in humans.
(Question 6) Has the Health Assessment provided
a useful summary and balanced perspective on these
issues? Is the advance in knowledge of details of
early cellular events in response to dioxin exposure
clearly distinguished from our paucity of knowledge
of the direct impact of these events on toxicity?
TOXIC EFFECTS OF DIOXIN
General Issues
It is clear from the evaluation of the toxico-
logic literature that dioxin and related com-
pounds have the ability to produce a wide
spectrum of responses in animals and, pre-
sumably, in humans, if the dose is high
enough. Relatively few chronic effects related
to exposure to dioxin-like compounds have
been observed in humans. The epidemiologic
data are limited due to a number of possible
factors: the absence of many, specific individ-
THE SCIENCE ADVISORY BOARD
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PAGE 13
ual measurements of dioxin exposure for the
general population; a limited number of cross-
sectional and prospective studies of more
highly exposed populations; the limited ability
of epidemiologic studies to detect significant
differences 'between exposed and relatively
unexposed populations when the outcomes
are relatively rare, the exposures are low, and
the population under study is small; and the
difficulty in quantifying the impact of all
potentially confounding exposures. Evalua-
tion of hazard and risk for dioxin and related
compounds must rely on a weight-of-the-
evidence approach in which all available data
(animal and human) are examined together.
This process often requires extrapolation of
effects across various animal species, as well as
to humans.
The reliability of using animal data
to estimate human hazard and risk has
often been questioned for this class of
compounds. The document takes the posi-
tion that, although human data are limited,
evidence suggests that animal models are
appropriate for estimating human risk if all
available data are considered. (Question 7)
Does the Committee agree?
For purposes of the current assess-
ment, unless there are data to identify a
particular species as being representative of
humans for a particular effect, average
humans can be reasonably assumed to be of
average sensitivity for various effects, recog-
nizing that individuals in the population
might vary widely in their sensitivity to
individual effects. (Question 8) Is this a
reasonable position to take given the available
data? Is the rationale for this assumption clearly
stated?
Chloracne
Chloracne is the only clearly adverse
health effect which is known to occur in
dioxin exposed humans. Recognition of
chlofacne has been associated with high
level exposure to these compounds, and as
such, may represent a biomarker of expo-
sure. (Question 9) Does the Committee agree
with the position stated in the Health Assessment
that, because of the wide variability of the
chloracnegenic response in humans and its varied
persistence, the absence of chloracne is not a
reliable indicator of low exposure to dioxin and
related compounds?
Cancer
While the data base from epidemio-
logic studies remains controversial, it is the
view of this reassessment that this body of
evidence supports the laboratory data indicat-
ing that TCDD probably increases cancer
mortality of several types. The Peer Panel
that met in September, 1993, to review an
earlier draft of the cancer epidemiology chap-
ter suggested that the epidemiology data alone
were still not adequate to implicate dioxin and
related compounds as "known" human carcin-
ogens but that the results from the human
studies were largely consistent with observa-
tions from laboratory studies of dioxin-in-
duced cancer and, therefore, should not be
dismissed or ignored. Other scientists, includ-
ing those who attended the Peer Panel meet-
ing, felt either more or less strongly about the
weight of the evidence from epidemiology
studies, representing the range of opinion that
still exists on the interpretation of the cancer
epidemiology studies. (Question 10) Does the
Health Assessment document adequately reflect
those views? Have uncertainties in the epidemiology
REASSESSING DIOXIN
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PAGE 14
data base been well characterized? Would the
Committee care to add its view to those already
stated in the document?
An extensive data base on the carcino-
genicity of dioxin and related compounds in
laboratory studies exists and is described in
detail in Chapter 6. There is adequate evi-
dence that 2,3,7,8-TCDD is a carcinogen in
laboratory animals. Few attempts have been
made to demonstrate the carcinogenicity of
other dioxin-like compounds. Other than a
mixture of two isomers of hexachloro-
dibenzodioxin (HCDDs) which produced liver
tumors in both sexes of rats and mice (NTP,
1980), the more highly chlorinated CDDs and
CDFs have not been studied in long-term
animal cancer bioassays. However, it is gener-
ally recognized that these compounds
bioaccumulate and exhibit toxicities similar to
TCDD and are, therefore, also likely to be
carcinogens (SAB, 1989). (Question II) Does
the Committee have any additional comments on
extending the inference of carcinogenicity of 2,3,7,8-
TCDD to the broader class of dioxin-like compounds
as defined in the assessment document?
The Health Assessment document
describes dioxin and related compounds as
complete carcinogens, based on their ability to
produce tumors in all animals tested in the
absence of exogenous initiating agents. At the
same time, it recognizes that these compounds
can be described operationally as potent pro-
moters of carcinogenicity without traditionally
defined genotoxic activity. (Question 12) Has
the document adequately characterized the carcino-
genic activity of these compounds so as to distinguish
between these descriptors?
The EPA's 1985 classification of
2,3,7,8-TCDD as a "probable" human carcino-
gen under the Agency's risk assessment guid-
ance for carcinogens was based exclusively on
the adequacy of the animal carcinogenicity
database. The current assessment character-
izes 2,3,7,8-TCDD and related compounds as
likely to be human carcinogens under some
conditions of exposure, and re-affirms the
classification of "probable" carcinogens but
with greater confidence than in 1985. In-
creased confidence is based on the total weight
of the evidence based on unequivocal animal
evidence, limited human evidence and mecha-
nistic evidence supporting biological plausibil-
ity. (Question 13) Does the Committee agree with
this characterization of the cancer hazard of dioxin
and related compounds? Given efforts underway to
revise the Agency's Cancer Guidelines, should this
class of compounds be assigned an alphanumeric
classification according to the 1986 Guidelines? (A?
Bf?B2?)
Developmental Toxicity
Since developmental toxicity follow-
ing exposure to TCDD-like congeners occurs
in fish, birds, and mammals, it is likely to
occur at some level in humans. It is not cur-
rently possible to state exactly how or at what
levels humans in the population will respond
with adverse impacts on development or
reproductive function. Data analyzed in Chap-
ter 5 and Chapter 7 suggest, however, that
adverse effects may be occurring at levels lower
than originally thought to represent a "no
observed adverse effect level (NOAEL)" in
animals. Traditional toxicology studies had
led to the conclusion that the NOAEL was in
the range of intake values of 1 ng TEQ/kg/day.
(Question 14) Does the Committee agree that
current data would suggest that the NOAEL in
animals should be lower?
THE SCIENCE ADVISORY BOARD
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PAGE 15
I mmunotoxicity
Evidence has accumulated to demon-
strate that the immune system is a target for
toxicity of TCDD and structurally related
compounds. The evidence has derived from
numerous studies in various animal species.
Animal studies suggest that some
immunotoxic responses may be evoked at very
low levels of dioxin exposure. Epidemiological
studies also provide conflicting evidence for
the immunotoxicity of these compounds in
humans. Few changes in the immune system in
humans associated with dioxin body burdens
have been detected when exposed humans
have been studied. Both direct and indirect
(e.g., hormonally mediated) impacts on the
immune system have been hypothesized to be
the basis of dioxin immunotoxicity. (Question
15) Has the significance of the human data been
adeauately characterized? Are the clinical methods
which have been applied to immune junction in
humans exposed to dioxin sufficiently sensitive to
detect immunotoxicity? Does the Health Assessment
provide sufficient discussion of the strengths and
weaknesses of the animal data on immune function
to support its conclusions regarding the potential for
immunotoxicity in humans exposed at or near back-
ground levels?
Other Effects
A number of other effects of dioxin and
related compounds have been discussed in
some detail throughout the chapters in this
assessment. While they serve to illustrate the
wide range of effects produced by this class of
compounds, some may be specific to the spe-
cies in which they are measured and may have
limited relevance to the human situation. On
the other hand, they may be indicative of the
fundamental level at which dioxin produces its
biological impact and may represent a contin-
uum of response expected from, these funda-
mental changes. While all may not be adverse
effects (some may be adaptive and of neutral
consequence), several effects have been noted
in human studies or in primates and have been
given special mention. (Question 16) Are there
other important effects that should be highlighted?
DOSE-RESPONSE
Development of biologically-based dose re-
sponse models for dioxin and related com-
pounds as a part of this reassessment has led
to considerable and valuable insights regard-
ing both mechanisms of dioxin action and
dose response relationships for dioxin effects.
These are described in some detail in Chapter
8. These efforts have provided additional
perspectives on traditional methods such as
the linearized multistage (LMS) procedure for
estimating cancer potency or the uncertainty
factor approach for estimating levels below
which non-cancer effects are not likely to
occur. These methods have also provided a
biologically based rationale for what had been
primarily statistical approaches. The develop-
ment of models like those in Chapter 8 allows
for an iterative process of data development,
hypothesis testing, and model development.
These efforts have resulted in incorporation of
more of the available biological data into
models to predict human risk at low incre-
ments of exposure. (Question 17) Does the
Committee agree with the approaches to dose-re-
sponse that have been used in the Health Assess-
ment? Given the evolving nature of this effort
should collaborative efforts to refine these techniaues
continue as a high priority?
The U.S. EPA has frequently defined
a reference dose (RfD) for toxic chemicals to
DIOXIN
-------
PAGE 16
represent a scientific estimate of the dose
below which no appreciable risk of non-cancer
effects is likely to occur following chronic
exposures. In the case of dioxin and related
compounds, calculation of an RfD based on
human and animal data and including stan-
dard uncertainty factors to account for spe-
cies differences and sensitive sub-populations
would result in reference intake levels on the
order of 10-100 times below the current
estimates of daily intake in the general popu-
lation. For most compounds where RfDs are
applied, the compounds are not persistent,
background exposures are generally low, and
are not taken into account. Dioxin and
related compounds present an excellent
example of a case where background levels in
the general population are likely to have
significance for evaluation of the relative
impact of incremental exposures associated
with a specific source. Since RfDs refer to
the total chronic dose level, the Health
Assessment document takes the position that
the use of the RfD in evaluating incremental
exposures in the face of a background intake
exceeding the RfD would be inappropriate.
(Question 18) Does the Committee agree? Is the
rationale for this position clear?
Observations described in this assess-
ment suggest a continuum of response to
exposure to dioxin-like chemicals. By a
continuum of response, we suggest that as
dose increases the probability of occurrence
of individual effects increases and the sever-
itv of collective effects increases. This con-
^
tinuum provides a basis for inferring a rela-
tionship between some early events which
are not necessarily considered to be adverse
effects with later events which are adverse
effects. Considerable uncertainty remains in
inferring how these events are related, al-
though we know more about how dioxin-like
compounds may elicit effects than we know
about the mechanisms of action for most
chemicals. This inference may be the most
contentious of all and it is likely that a wide
range of opinion will be provided by the
scientific community regarding the relation-
ship of these mechanistic observations and
prediction of potential for adverse effects in
exposed humans. (Question 19) Does the
Health Assessment document provide a balanced
perspective regarding the uncertainties embodied in
this inference?
TOXICITY EQUIVALENCE FAQ
TORS (TEFsl
The EPA and the international scientific
community have agreed that the use of
toxicity factors (TEFs) to predict relative
toxicities of mixtures of this class of com-
pounds has an empirical basis, is theoreti-
cally sound, and, in the absence of more
complete data sets on the toxicity of individ-
ual members of this class, is a useful proce-
dure! This is not to say that the use of TEFs
is a'tlertain procedure. Since 1986 when the
firstc "Agency-wide consensus on the use of
TEFsk was published, additional refinements
to the data bases and to the use of TEFs
have occurred. Published revisions in accord
with international agreement appeared in
1989. In the course of this reassessment,
critical data were collected and agreement
was reached regarding the contribution of
dioxin-like PCBs to overall TEQs. Additional
validation of the TEQ concept in predicting
effects of this class of compounds on wildlife
species lends further support to the use of
this approach. This relatively simple, addi-
tive approach does not take into account
interactions between dioxin-like compounds
THE SCIENCE ADVISORY BOARD
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PAGE 17
and other chemical exposures. (Question 20)
Does the Committee agree with the EPA's use of
TEFs in the Health Assessment document? Have
the uncertainties and the assumptions intrinsic to
the use of TEFs been clearly described? Should
EPA consider presenting the assessment results in
an alternative manner?
LABORATORY ANIMALS/ HUMAN
RESPONSE
Based on our knowledge of the biochemical
and biological similarities between laboratory
animals and humans, our understanding of
some of the fundamental impacts of this class
of compounds on biological systems, and
comparable responses from animal and hu-
man studies both in vitro and in vivo, EPA
has made the decision to use laboratory ani-
mal data to contribute to weight-of- the-evi-
dence conclusions on human hazard and risk.
(Question 21) Does the Committee agree that this
decision is reasonable?
Humans do not appear to be an un-
usual responder for dioxin effects; that is,
humans do not, on average, appear to be
either refractory to or exquisitely sensitive to
the effects of dioxin-like compounds. While
positive human data are preferable for ascrib-
ing hazard or risk, the lack of adequate hu-
man data to demonstrate causality for many
suspected dioxin effects is assumed not to
negate the findings from laboratory animal
and in vitro studies. Although some
scientistsmay disagree, in our estimation, the
database on dioxin and related compounds
regarding a wide range of responses across
animal species is one of the most comprehen-
sive among all environmental chemicals. The
fundamental understanding of mechanisms
of dioxin action provides a unifying theory for
the mechanisms for observed effects in labo-
ratory animals and humans, and for using a
weight-of-the-evidence apptcoh considering
a 1 1
relevant data to infer the human health im-
pacts of dioxin and related compounds.
(Question 22) Have the strengths and weaknesses
of this position been well articulated?
OVERALL CONCLUSIONS
The final chapter of the Health Assessment
document integrates information on exposure
and effects relating to the impact of dioxin
and related compounds on human health. It
also contains overall conclusions on this issue.
As such, it represents a risk characterization.
(Question 23) Does this chapter adeauately charac-
terize the database, assumptions, and uncertainties
relating to the potential health effects of dioxin and
related compounds? Does it provide the information
in enough of a public health context to be under-
standable to decision-makers?
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PAGE 18
3. DETAILED FINDINGS-EXPOSURE DOCUMENT
3.1 Sources
3.1.1 Estimating and Apportioning
Sources (Charge Question 2)
The approach for estimating and
apportioning the relative contributions of.
various types of sources is to multiply average
emission factors for each source type by the
mass flow (i.e., the amount of combustion) in
each category to estimate the total emissions
of dioxin and dioxin-like compounds5 to the
environment for each source category, then
sum the totals and examine the relative contri-
butions of each type of source.
It should not be assumed that the
fractional contributions of various types of
combustion sources to total emissions are
... it is thus not scientifically
valid to infer from such a
comparison that there are any
missing sources of dioxins.
identical or similar to their contributions to
human exposures for the population in gen-
eral. This distinction should be explicitly
stated. It is quite possible that the major
sources of dioxin in food may not be those
that represent the largest fractions of total
emissions in the U.S. The geographic loca-
tions of sources relative to the farms from
which much of the beef, pork, milk, and fish
come, is important to consider. That is, the
farm lands which produce much of our food
may not be necessarily located near the major
sources of dioxin and related compounds.
Total estimated dioxin-like emissions
for the U.S. have been compared to an esti-
mate of the total amount of dioxin that is
deposited to the surface of the U.S. based on
available deposition factors. The ranges of the
two estimates overlap, giving some suggestion
of a mass balance for the U.S. as a whole.
Although such mass balance comparisons have
been published in the literature, there is a
significant scientific problem with doing this
very simple comparison on a continental or
regional scale without doing atmospheric
dispersion and deposition modeling of the
emissions. Specifically, the atmospheric
lifetime of the accumulation mode particles
(0.1 to about 2-3 Aim), in which much of the
dioxins and dioxin-like compounds are found,
is on the order of many days. Thus, a large
proportion of the particles with dioxin-like
compounds that are emitted in the eastern
U.S. are likely to be deposited in the Atlantic
Ocean, Canada, Europe, or even the Arctic,
depending upon source locations and weather
patterns. Given the long atmospheric half-life
of the particulate dioxin-like compounds, a
global or hemispheric mass balance would be
necessary. In order to do a scientifically
acceptable mass balance comparison of emis-
sions and deposition for the U.S., deposition
of emitted dioxins must be estimated using
atmospheric dispersion and deposition model-
ing, and the deposition estimates from the
emissions then compared to measured deposi-
tion data. In addition, more representative
measured deposition data would be needed.
were included.
For the source estimation, only dioxins and furans
THE SCIENCE ADVISORY BOARD
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PAGE 19
The Committee recommends that this
section of the report be modified so that
this simple direct mass balance comparison
is not provided, and the scientific reason for
not doing so be explained. The Committee
agrees with EPA's statement (Volume II, p.
3-166) that it is thus not scientifically valid
to infer from such a comparison that there
are any missing sources of dioxins.
3.1.2 Source Inventory (Charge Ques-
tion 3)
The dioxin emission inventory has identi-
fied the major known sources and has, in general,
made a reasonable estimate of the total emissions
from each source category. However, some
revisions should be made.
The incineration of medical waste
was estimated to be the largest source of
dioxin emissions. After this estimate was
made, new information became available
that indicates that current emissions from
medical waste incineration might be signifi-
cantly lower than initially estimated by EPA.
The EPA should review these (and any
other) new data that becomes available, and
revise the estimates as appropriate. The
emission estimates for industrial and residen-
tial wood combustion should also be re-
viewed and revised, as well as the estimates
for dioxin emissions from the combustion of
diesel fuel.
The Agency should assess the time-
frame for the emission inventory. Also, EPA
needs to evaluate more thoroughly the
emissions data and define more carefully the
width of the uncertainty range based upon
engineering assessments and data availabil-
ity.
Due to the uncertainties in dioxin
emissions data, and the variability in emis-
sions, there is significant uncertainty in the
emission estimates. The EPA has estimated an
uncertainty range of either a factor of five or
a factor of ten for each dioxin source category,
based primarily on the uncertainty in the
estimated emission factors. The Committee
thinks that the uncertainty in emissions has
been underestimated in some cases. In addi-
tion, uncertainty classifications should at-
tempt to build upon the classification systems
already used in existing EPA emissions factors
databases.
There appear to be some sources
identified in international inventories or by
commentors which were not considered or
were not assessed in the EPA Reassessment
Document. Some discussion of these sources
is important to the completeness of the report
even if they are later determined to be negligi-
ble sources of CDD/CDF emissions.
3.1.3 Dioxin Reservoirs (Charge Ques-
tion 4)
The reassessment document indi-
cated that in addition to exposures from
sources that are currently emitting CDD/CDF,
it is possible that CDD/CDF from historic
reservoir sources are being re-introduced to
exposure media. The assessment conducted
on this issue (section 3.7 of the EPA docu-
ment) was a simple evaluation of the relative
importance of one year's emissions from
currently emitting sources to those from
preexisting reservoirs. This simple assessment,
based upon an assumption of first-order
dissipation rates and an assumed half-life of
dioxin in the reservoir, indicated the large
potential size of the CDD/CDF reservoirs
REASSESSING DIOXIN
-------
PAGE 20
relative to annual deposition rates. Given
that heretofore, the presence of CDD/CDF in
subsurface lake and ocean sediments had
generally been considered to be innocuous
deposits, no attempt was made to quantify
further the contribution of the reservoirs to
human exposure.
The Committee concluded that the poten-
tial contributions from reservoirs might indeed be
important and should be evaluated. It is im-
portant to be able to evaluate the relative
contributions of reservoirs and currently
emitting sources, particularly in light of the
fact that emitting sources appear to be in
decline. Thus the relative contribution of
these reservoir sources may become even
more important. A limiting case which may
be particularly informative is an assessment
of exposure in the absence of currently
emitting sources. Some of the reservoirs,
such as sediments, may act as a relatively
minor continuous source from surface bio-
logical processes, but become much more
significant during major storm events,
cleanup, or navigational dredging. Other
reservoirs may be relatively active and their
continuing contribution to exposure should
be assessed in order to account for all
sources of exposure.
It is important to be able to
evaluate the relative
contributions of reservoirs and
currently emitting sources,
particularly in light of the fact
that emitting sources appear to
be in decline.
The Committee suggests a technique
to evaluate the potential importance of reser-
voir material to exposure. EPA could evaluate
the plausibility of different reservoir materials
re-entering exposure scenarios through the
use of engineering estimates and limited case
analysis. Although this analysis would not be
quantitative since the actual extent of reser-
voirs materials is not fully known, the analysis
would provide some assessment of the impor-
tance of particular reservoirs and exposure
scenarios.
3.1.4 Local/Distant Contributions to
Dioxin Levels in Food (Charge
Question 5)
The question of the relative contribu-
tion of local and distant sources to food levels
at a site is a difficult one to answer experimen-
tally and would probably require extensive
studies at many sites. Furthermore, the an-
swer could well be different in different parts
of the U.S.
In the future, better data and new or
revised models may make such activities more
feasible, and lead to a full understanding of
the movement of contaminants from emission
sources to food pathways.
When better ouality data are available,
the Agency should consider using geographic infor-
mation systems (GIS) for their analysis. With
such systems, the geographic distributions of dioxin
emissions and food (beef, pork, chicken, milk) could
be mapped and compared. Although not quanti-
tative, this examination is likely to produce
some insights and testable hypotheses. Once
the more current measurements of dioxins in
food become available, these can also be
mapped and quantitative questions can be
asked and tested statistically regarding the
probable influences of local, regional, and
distant sources.
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3.1.5 Uncertainty in Deposition Esti-
mates (Charge Question 6)
Various research groups have tried to
balance the input of dioxins into the atmo-
sphere with their outputfrom the atmosphere.
The input calculations are based on source
inventories, done on a national, region, and
international scale. The output estimates are
based on calculations and measurements of
fluxes from the atmosphere. Most of these
data (summarized in Volume II, pages 3-4, 3-
5, and 3-166 to 3-168) indicate a large dis-
crepancy between deposition from the atmo-
sphere and inputs into the atmosphere. This
discrepancy indicates that 10-50 times more
dioxins are being deposited from the atmo-
sphere than are being emitted into the atmo-
sphere. However, the simple mass balance
comparison of the estimates of emissions and
deposition fails to take into account the
atmospheric lifetimes of accumulation mode
particles and their long range transport in the
atmosphere. Thus a certain (unknown) frac-
tion of the dioxins emitted within the conti-
nental United States are certainly transported
by the atmosphere and deposited beyond the
borders. In addition, dioxin deposition can
not be expected to be geographically uniform;
in consequence, this very simple mass balance
comparison cannot be used to infer unknown
sources.
There is another technical problem
with this comparison. These deposition rate
estimates are based on direct measurements of
wet and dry deposition by several research
groups. However, these measurements have
been converted to TEQ values in order to
compare them to emission estimates. This
conversion is justified by the overall strategy
of the dioxin reassessment; however, it is
strictly correct only when the ratios of the
various congeners is the same in the various
samples. To be technically rigorous, the deposition
calculations and emission estimates should be based
on individual congeners and isomers, perhaps
focusing on a few of the most abundant compounds.
The Committee, however, agrees with
EPA that there is much value in an evaluation
of the mass balance comparison of emissions
and deposition. Such a comparison (which we
are pleased to learn from EPA staff is now
underway by the Agency), however, must
involve modeled estimates of dispersion,
transport, and finally deposition from sources
within a given region. The modeled
emissions-based estimate of deposition could
then be compared to measured deposition for
the region.
Improved measurements of deposi-
tion fluxes for the U.S. is a fruitful area for
investigation. Most published studies have
taken samples in highly industrialized and
urbanized regions of the world. It is risky to
extrapolate these measurements to the entire
United States. A strategy in which deposition
fluxes are calculated from geographically
diverse samples taken throughout the United
States could lead to a more accurate and
precise estimate of the total deposition rate to
the United States.
3.2 Food and Media Levels
3.2.1 Problems in Estimating CDD/F
Levels (Charge Question 7)
A very limited number of samples are
available to make the preliminary estimates of
CDD/CDF in air, water, soil, and food prod-
ucts. Such estimates are appropriate and
REASSESSING DIOXIN
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PAGE 22
useful, and EPA has tried to provide some
idea of the uncertainties and variability in the
data. However, there are some refinements
and additions that can and should be made in
revising the report.
a) The reported sample analyses were
performed at different laboratories,
using different methods of analysis,
and the samples were not all collected
and analyzed in the same time period.
Thus, there are some underlying
sources of uncertainty and variability
which are not adequately represented
by using simple statistics (mean, stan-
dard deviation). For example, if envi-
ronmental levels are declining, as indi-
cated by sediment samples, the sam-
ples may have a time variability which
the reader might not recognize. Some
cautions on these aspects of uncertain-
ties should be added to the report.
b) It is recommended that the reported
data be examined with respect to the
number of significant figures used and
that these be reduced as appropriate.
For example, the daily intake should
not be reported as 119 pg/day TEQ
but as being on the order of 100. By
handling the results this way, it be-
comes clear that there are not really
significant differences between the
estimates for the U.S. and other coun-
tries given the uncertainties in the
estimates.
c) Although the reassessment document
makes no unwarranted claims about
the accuracy of the food data for expo-
sure assessment, it is important that
policy makers be fully aware of the
limitations of the use of the results in
the policy arena. For example, the
Committee does not believe that
these data are appropriate for trends
analysis of body burdens or for geo-
graphical or demographic trends in
exposure. Nor are the currently avail-
able data sufficient to characterize
the variability of exposures in the
U.S. population. In the summary
volume, it would be very helpful to
policy makers to explicitly point out
these kinds of limitations and to note
that the exposure estimate is only an
estimate of the central tendency of
exposures within the U.S.
In the future, as better measured data
become available, the data analyses should
include use of probability techniques, not just
simple statistics.
3.2.2 Use of U.S. Food Data (Charge
Question 8)
U.S. food data for the estimation of back-
ground exposure to dioxin-like compounds is presently
inadequate, but the EPA is commended for its major
effort to obtain new data, on which the Commit-
tee was briefed, but did not specifically review.
Shortcomings aside, the available information
from the U.S. along with that from other
countries indicates a central trend or mean for
background food exposure of about 100 pg per
day. A very recent food study effort by EPA
(with contributions from the U.S. Department
of Agriculture and the Food and Drug Admin-
istration) has generated significant data on the
TEQ content of beef (Winters et al, 1994).
The new value is considerably (3 to 4 times)
lower than that used in the document. This
would suggest that the overall daily intake of
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PAGE 23
PCDD/PCDF may be less than 100 pg. Addi-
tional data gathering is now in progress for
milk samples, and is planned for pork, poultry,
eggs, and vegetable oils.
Current information on the variation
or distribution of this value within the U.S. is
imprecise, however. The sampling part of the
EPA program is quite strong as it is statisti-
cally planned, and the distribution within the
U.S. is being studied, as well as production
within various regions. From this initial
undertaking, it appears that sources of food
for much of the U.S. are widely distributed
geographically, and that exposure is national
in scope with only limited regional differ-
ences.
The Committee was of the opinion
that, in the cases where analyses showed non-
detectable numbers (ND), the best estimate of
the true value, with currently available infor-
mation and methodology, was to use one-half
the limit of detection. The effect of using this
approach on measures of central tendency of
a distribution depends, however, on the actual
detection limit (which is a function of sample
properties and analytical procedures) and the
proportion of values in the distribution at or
below the detection limit. For example, if the
detection limit is relatively high, and a large
proportion of the values in the distribution
are at or below the limit of detection, then
using one-half the detection limit will proba-
bly overestimate measures of central ten-
dency. The Committee suggests that EPA
explore alternative statistical approaches to
handling ND values in the future, particularly
the well-established maximum likelihood
method. This approach requires only that the
parametric form of the underlying distribution
be known.
The food study program underway by
EPA shows a good detection limit for TCDD
(0.05 ppt on a fat basis or about 0.01 ppt on
a whole weight basis) but significantly higher
values (0.5 ppt fat or 2.5 ppt whole weight)
for the penta-, hexa-, and hepta- congeners.
For example the food data of Schecter et al.
(1993) have been criticized for its lack of
controlled sampling but the detection limits of
the analytical method are lower than those of
EPA. In order to minimize the variation in
estimation of the PCDD/PCDF content of
foods by this uncertainty in detectability, EPA
should try to improve their analytical detec-
tion limits for the penta-, and hexa- congeners
(those for the hepta- and octa- are not as
important since they contribute less to the
TEQ). In this activity, there is a tradeoff
between reliability of analytical levels and the
detection limit. In general, the closer one
approaches the detection limit of a method,
the less certain one becomes of the value, and
the further one is removed from the detection
limit, (usually) greater confidence is given to
the analytical value. The Committee believes
that EPA, in measuring PCDD/PCDF concen-
trations in foods, should take the necessary
steps to obtain detection limits on the samples
as low as technically feasible. Such an ap-
proach will minimize the uncertainty engen-
dered by using one-half of the detection limit
for ND results. The Committee considers
that EPA is putting (correctly) more weight on
the latter. It is also desirable that EPA report
data on both a whole-weight and fat basis to
compare to other studies.
A number of public comments related
to a paper presented at Dioxin 93 (Welge et
al., 1993) showing that the PCDD/F content
of blood was the same for vegetarians and
non-vegetarians. The Committee is of the
REASSESSING DIOXIN
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PAGE 24
opinion that the above study is inconclusive.
The individuals classified as vegetarians fol-
lowed such a diet between 5 and 10 years
(median values). Classification as a vegetarian
was based on non-consumption of both meat
and fish. The diet was not verified by any
means, and the study did not address con-
sumption of milk, dairy products, and eggs --
all known food sources of PCDD/PCDFs.
3.2.3 Air/Plant/Animal Pathway and
Other Food Chain Impacts
(Charge Question 9)
Given the existing data, it is probably
premature to conclude that the air-to-plant-to-
animal pathway6 is the primary way the entire food
chain is impacted. Nonetheless, this is a reasonable
hypothesis, one that is consistent both with the
extant data and existing models. Based on the
analysis of the existing and very limited food
measurement data, EPA has focused on the
air-to-plant-to-animal exposure pathway. It is
important that EPA not lose sight of other
potentially significant exposure pathways such
as emissions from point sources- to-water-to-
fish and possible exposures from cigarette
smoking.
In terms of concentrations, existing
data suggest that fish have a higher average
concentration than any other food, although
the ingestion rate is lower. In terms of human
exposure, foodfish (especially freshwater fish
from the larger waterbodies) are likely to be
exposed to additional point sources of
After deposition on plants, particles are washed
into the soil by precipitation and plants die and decay into
soil, so that ultimately the deposited dioxins accumulate in
the soil; consequently, for grazing animals, this pathway
includes intake of dioxin via ingestion of both plants and soil.
PCDDs/Fs such as publicly operated treat-
ment works, as well as to air emissions. For
this human exposure scenario, such sources
may be of equal or greater importance than
the air emissions. Given that some popula-
tions eat larger quantities of fish (e.g., anglers,
Native Americans, etc.), the water-fish path-
way deserves additional discussion as an
J
important exposure pathway.
The weaknesses in the conclusion
that the air-plant-food pathway is dominant
are carefully examined in Volume III, Chapter
7. One major conclusion about beef concen-
trations is that the "Total TEQ concentrations
compare favorably with observed total TEQ at
0.48 ppt and predicted TEQ at 0.36 ppt."
One concern is using TEQs to support this
conclusion. This comparison, using the sum
of 17 values, each of which is multiplied by a
factor ranging from 1 to 0.0001, is misleading.
The total TEQ concentrations between pre-
dicted and observed differ by a factor of 4
(8.15 to 2.13) and ratios of observed to calcu-
lated values for individual congeners varies
from 0.13 to 22, roughly two orders-of-magni-
tude. Here, and throughout the document,
the EPA must move away from the TEQ
comparison and begin to assess by individual
congener comparisons. When this is done, the
strength of a number of EPA's conclusions
about exposure and consequent human risk
decreases. Another way to compare these
results is to note that 9 out of the 17 or about
53 percent of the congener values differ by a
factor of 5 or more.
The same type of analyses are carried
out for the air-to-hay pathway calculations.
Unfortunately, there are only observed (other
than non-detect) values for five congeners to
make the comparison. For those five values,
THE SCIENCE ADVISORY BOARD
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the observed concentrations are greater than
the modeled ones. The analysis concludes
that, "Given the range of the detection limit,
0.31-6.4 ppt for the hay sampling, the model's
predictions of grass concentrations are gener-
ally consistent with observations, with the
exception of the OCDD and OCDF concentra-
tions." Two of the five comparisons are
OCDD and OCDF, and the lack of data for
the other comparisons cannot verify the
model or conclusions.
The fairly good agreement in TEQs, the
sum of the total concentrations, and the fact that
most of the individual congener comparisons agree
within an order- of-magnitude, all support the
conclusion that the air-plant-animal pathway is the
major input to the food chain. As noted above, this
is a worthwhile hypothesis and may well be true;
but given the lack of data and the number of as-
sumptions needed, it can not be proved at this time.
The document should state this fact explicitly and
might also note that no good alternatives are avail-
able.
3.2 A SmokingAn Additional Potential
Exposure Pathway7
There is an additional exposure path-
way that should be considered. Cigarette
smoking may account for a very significant
fraction of dioxin exposures for some of the
population (25% of adults). Smoking has not
been considered in the reassessment docu-
ment; although the Committee does not
consider this omission to be a major flaw,
smoking should be considered in future revi-
sions. There are now three papers in the
, PAGE 25
literature that report that dioxin is present in
mainstream cigarette smoke. Muto &.
Takizawa (1989) estimated that a pack-a-day
smoker has a daily intake of about 4.3 pg of
polychlorinated dibenzo-dioxins per kg of
body weight. Lofroth and Zebuhr's (1992)
The Agency should also
consider possible
contributions to exposure from
environmental tobacco smoke
(ETS).
measurements of mainstream smoke imply an
intake of 18 pg TEQ per day per person for a
pack-a-day smoker. This is about 13% of the
daily median intake estimated from other
sources in the EPA exposure assessment.
There is also a paper by Ball et al. (1990)
which reports dioxin emissions for main-
stream smoke that are about an order-of-
magnitude lower than those reported in the
other two publications. Although differences
of an order-of-magnitude in dioxin measure-
ments are common, there is reason to suspect
that they may have had substantial losses in
their sampling apparatus. Beck et al. (1994)
found no differences in PCDD/PCDF content
of human breast milk between smokers and
non-smokers. Nonetheless, given that the
exposures are actually distributions, and that
some members of the population are heavy
smokers, this source should be considered.
The Agency should also consider possible
contributions to exposure from environmental
tobacco smoke (ETS). It would be useful to
know if any good data on the dioxin content
(or lack of dioxin content) in sidestream
smoke exist.
This discussion does not relate to a specific
question in the Charge. The issue of smoking as a possible
exposure pathway arose during the preparation of this report.
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PAGE 26
3.2.5 Anthropogenic vs. Natural
Sources of Dioxin (Charge Ques-
tion 10)
The background for this question is
the observation in the late 1970s that dioxins
are produced by the combustion of many
common materials, including municipal solid
waste. This led some scientists to suggest
that dioxins had been with us since "the
advent of fire" and that dioxins could be
produced by natural combustion (for exam-
ple, by forest fires). At that time, there were
some suggestions that observed levels of
dioxins were primarily the result of coal
combustion or perhaps of wood burned in
small stoves. This speculation was largely
refuted by sediment core studies, both in the
United States (primarily in the Great Lakes)
and in Europe, which indicated that environ-
mental dioxin levels increased significantly
beginning about 1935-40 (see Volume II,
pages 3-92 to 3-94). Since the advent of fire
clearly predated this time, it can be concluded
that dioxins were largely anthropogenic and
associated with events taking place around
1935-40. What were these events? Coal
combustion could be ruled out because the
consumption of coal in the United States was
essentially constant from the turn of the
century until about 1970; this record did not
agree with the sediment core data. The
explanation is likely to be the introduction of
chlorinated organic compounds (polyvinyl
chloride and chlorinated pesticides are but
two examples) in the 1935-40 time-frame.
Other sources such as leaded gasoline (which
commonly contained ethylene dichloride and
ethylene dibromide), diesel emissions, and
PCBs are also possibly significant contribu-
tors. Although the details of dioxin formation
are not yet quantitatively understood, the
introduction of these chlorinated products
into wastes that were combusted appears to
be the most likely cause of the increased
dioxin deposition measured in sediments.
These sediment core data are now
numerous. Several such studies have been
published for lakes from throughout the world,
and these studies have not been challenged in
the scientific literature. Therefore, it is very
clear that dioxins are a Twentieth Century
phenomenon closely correlated with the pro-
duction of chlorinated compounds. The
Committee concurs strongly with the conclu-
sion that "environmental levels of dioxins are
primarily a product of human activities in the
twentieth century." The draft document could
make this point even more persuasively by
citing all of the sediment core studies that
have been published, even though some of
them have been for lakes outside of the U.S.
Incidentally, there is an undercurrent
of opinion (which has also been expressed in
the public comments received about the draft
reassessment) which says that "forest fires are
possibly the major source of dioxin in the
environment." The Committee concludes that
this contention is not correct. Many of the
sediment core studies in the scientific litera-
ture span times during which forests in the
lake's watershed were burned by natural
causes. There was no elevation of dioxins in
the sediment record at the time of these forest
fires. A recent study by Buckland et al. (1994)
found no difference in soil dioxin levels in
Australian conservation areas before and after
brush fires. Consequently, the Committee
concludes that environmental levels of dioxins
are primarily a product of human activities in
the Twentieth Century.
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PAGE 27
There is one other feature of these
sediment core data that warrants comment.
Most of the sediment records show a decrease
in dioxin deposition starting around 1970; in
other words, dioxin deposition from the atmo-
sphere to lake sediments was at its highest
around 1970. This decrease seems to be
continuing, and it may well be attributable to
decreased emissions from large-scale combus-
tion systems; regulations for such systems are
not thought to have had major impacts prior
to the early 1980s; consequently, the origin of
the decline is still unclear.
Beyond the sediment core studies, the
history of dioxin emissions has been addressed
by two studies (Ligon et al, 1989; Schecter,
1988) of mummified human tissue (see
Volume II, pages 3-149 to 3-150). These
results suggest that dioxins were present only
at very low levels in humans at the time these
individuals were mummified (about 2800
years ago in the Ligon study, and 400 years
ago in the Schecter report). The presence of
these compounds in modern humans at much
higher concentrations is well known; there-
fore, these ancient tissue analyses support the
concept that dioxins have not been with us
since "the advent of fire," but are a more
recent addition to our environment. How-
ever, unlike sediment core studies, these tissue
measurements, in addition to being limited to
only two samples, do not tell us when dioxins
became an important part of the environment.
3.3 Uncertainty in Estimating Human
Body Burdens (Charge Question
11)
Body burden data are presented in
Chapter 5, pages 5-18 to 5-27 of the exposure
reassessment document. These data provide
one index of exposure to dioxins; the data on
body burden are also used to estimate expo-
sures using a pharmacokinetic model that
back calculates the dose needed to achieve the
observed adipose tissue levels (assuming
steady state exposure/dose). The principal
U.S. data come from the National Human
Adipose Tissue Survey (NHATS). Table 5-8
presented mean adipose tissue data for a
number of congeners for 865 samples col-
lected in 1987 and analyzed as 48 composites,
each containing an average of 18 specimens.
Analyses are reported as showing increasing
levels with increasing age and as being lower,
in 1987 in comparison with previous findings
from 1982. Except for one congener there
was no variation by region and no variation
for any congener by race and sex. Additional
data are provided from U.S. reports by
Patterson (1994) and Schecter (1991). Data
from Germany and elsewhere are also cited.
The report assumes a level of 2,3,7,8 -TCDD
in adipose tissue of 5.0 to 6.7 ppt for the
purpose of estimating typical exposure.
The Committee believes that reliable
nationally representative body burden data
are not available. The reassessment acknowl-
edges that the NHATS data, the most exten-
sive available, cannot be considered as repre-
sentative, and the smaller data sets are even
less likely to estimate average exposure accu-
rately. Because the exposure histories of the
individuals included in the NHATS studies
are unknown, the average could be biased
upwards by occupational exposures or residen-
tial exposures from smoking. However, there
would be little impact on the mean unless
exposure markedly increased levels, given the
sample size of 885 samples in NHATS. The
Committee anticipates that only a small
proportion of the population would be heavily
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PAGE 28
contaminated. On the other hand, the
possibility remains that selection of the
samples may have been weighted towards
more exposed persons. The reassessment
document does not attempt to estimate the
potential for such bias nor its consequences.
Although the NHATS data may be
sufficiently robust to provide a reasonable
estimate of the mean, the range of tissue
concentrations is not provided by these data
because the samples were pooled for analy-
sis. Further, because of the modest sample
size, the data are not adequate for trends
analysis and would have limited statistical
power for any comparisons across groups,
whether defined by race, sex, or geography.
Thus, the findings of the analysis on these
factors should be given little weight.
3.4 Estimating Background Expo-
sures via Food/Body Burden
Data (Charge Question 12)
The Committee agrees that it is
appropriate to use food data and food
factor information to estimate exposure to
the 2,3,7,8-TCDD. It is also appropriate to
use body burden data on TCDD to estimate
daily uptake from all sources (half-life of
about 7.5 yr).
As noted earlier, the food analysis
data are too limited to extrapolate the
results to reflect the distribution for the
entire U.S. population. Data obtained from
different geographical areas, with a statistical
emphasis on those foods that contain the
bulk of the dioxins and furans, are needed
before these data can be used to estimate
uptake. The Committee also recommends
that EPA evaluate cigarette smoking as a
possible exposure pathway for dioxins (see
discussion in section 3.2.4).
3.5 Site-Specific Assessment Proce-
dures
3.5.1 Steady-State Assumptions and
Modeling (Charge Question 13)
The Committee did not raise objec-
tions to or have comments on the validity
of the steady-state approach or challenge
the model selection. It was noted, however,
that in future efforts it would be desirable
to have some estimate of the importance of
long-term accumulation in sinks such as
sediments or soil.
There were also some concerns about
the potential input of harbor dredging and
storm events on re-suspended solids. Al-
though these occurrences probably have
minor impacts on the exposure of the total
population, they might impact on certain
sub-populations with high fish intakes. This
comment is intended to point out the need
for future work and to describe potential
risks that may not be addressed in the
present system of analysis.
3.5.2 Mass-Balance Issues (Charge
Question 14)
On page 3-55 to 3-57 of the expo-
sure reassessment document, where the use
of the COMPDEP model is described, it is
stated that the model should be run with
no deposition for gas-phase contaminants,
and with both wet and dry deposition
included for particles. Given the nature of
atmospheric dispersion models, this implies
that, for gas-phase CDD/Fs, the plume
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PAGE 29
disperses with full reflection at the ground
surface, and for particles there is a loss at the
ground surface based on the flux attributable
to the wet and dry deposition. This reflects
the state-of-the art in atmospheric dispersion
modeling. Nevertheless, this approach ig-
nores some significant mass balance and
energy balance issues with regard to the
dispersed CDD/F species. To understand
these issues, the gas-phase CDD/Fs at the
interface between air and the soil, at vegeta-
tive surfaces, or at surface water with which
they come in contact, must be considered.
This is especially true, since EPA believes that
this is the predominant mechanism for the
contamination of food. Even though these
gas-phase contaminants are not expected to
"deposit" physically onto these surfaces, a
partitioning in response to the tendency of
natural systems to maintain thermodynamic
equilibrium is expected. Consider that in the
atmosphere both the particles and pure gas
phase provide comparable reservoirs for
CDD/F congeners. Since the sur-
face-to-air-volume ratio of the ground surface
and vegetation surfaces are much larger rela-
tive to the atmosphere than the sur-
face-to-volume ratio of air particles, how can
the partitioning of CDD/F compounds at
air/plant and air/soil interfaces be ignored? In
an air/soil, air/plant, or air/water system,
chemical thermodynamics is likely to favor a
relatively large fraction of the chemical in the
non-air compartment. Consequently, there is
a fairly strong chemical potential likely to
drive the chemicals from air into these other
media, where they are likely to be retained,
transformed, and re-emitted, either in the gas
phase or bound to particles.
These types of processes cannot be
captured using the COMPDEP (Complex
Deposition) model but instead require chem-
ical potential models. At this time, we
cannot ascertain the magnitude of any errors
thus introduced to the output of the
COMPDEP model, or their significance to
the assessment. In order to explore the
significance of the omissions of mass-balance
in the COMPDEP model, there is a need
also to develop a regional-scale chemical
potential model and apply it individually to
the CDD/F compounds. It is important hereto
emphasize that these types of transport and
transformation processes are compound- and
congener- specific and therefore should not be
estimated on a TEQ basis. Until such exten-
sions can be developed and applied, the use
of COMPDEP remains the best alternative.
3.5.3 Model Validation Issues (Charge
Question 15)
The Committee considered the com-
parisons of model-estimated versus measured
environmental contaminant concentrations.
It was noted that the narrative material in
the reassessment document described seven
such comparisons, and no generalizations
about model function could be easily drawn.
It appears that there has been no overstate-
ment of model validity and that a consider-
able effort has been made to uncover all
useful methods for validating the models
with the existing data. It was noted by
EPA that the validation exercise for the beef
bioconcentration model algorithm was per-
formed and that the results supported the
model. There were no suggestions for
alternative model use, but the review of the
earlier SAB guidance on peer review and
model validation (SAB, 1989) should be
discussed in the document.
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PAGE 30
The Committee also discussed the
distinction between model validity and model
system validity. The existing system of analy-
sis will not answer questions of long-term
contaminant accumulation in sinks and would
be difficult to adapt for use with multiple
sources. The Committee suggests that if these
other important questions are to be addressed,
a different framework will have to be devel-
oped.
It is important to note that the above
comments are not intended to suggest that
the current framework is inappropriate,
inaccurate, or in need of revision for its
stated use as a data and methodology
resource for risk assessment.
3.5.4 Photolysis and Atmospheric
Transport (Charge Question 16)
The relative abundance of the vari-
ous dioxin homologues and congeners differs
between sources and the environment and
environmental sinks. For example, most
combustion sources generate a dioxin mix-
ture with relatively high concentrations of
tetrachloro- and pentachloro- dibenzofurans,
whereas the environmental sinks are domi-
nated by relatively high concentrations of
octachlorodioxin. It has been suggested
that the lesser chlorinated compounds are
degraded between the source and the sink
and that the mechanism for this degrada-
tion is photolysis (see Volume II, pages 2-
30 to 2-35 of the exposure document).
The significance of photolysis is a difficult
question for the Committee (or the EPA) to
answer because there are virtually no data
on this subject. Photolysis is probably
important, but all evidence on this point is
qualitative and indirect.
During the atmospheric transport of
dioxins, they can exist in one of two forms:
either in the vapor-phase (in which the
compounds are airborne as individual mole-
cules) or in the particle-phase (in which the
dioxins are sorbed onto atmospheric parti-
cles). Photolysis of dioxins in each of these
two phases proceeds at different rates and
by different mechanisms. Unfortunately,
there are very few data on either of these
mechanisms. Data on the photolysis of
dioxins from the atmospheric particle-phase
are limited to one study, which indicates
that dioxins associated with fly-ash are
stable when exposed to simulated atmo-
spheric photolysis conditions. Of course,
this is only one study which needs to be
replicated.
Two mechanisms for the degradation
of dioxins in the vapor phase are possible.
The first is direct photolysis, in which the
molecule of interest reacts with a photon.
The very limited extant data indicate that
2,3,7,8-TCDD has a half-life of a few min-
utes under these conditions (Orth et al,
1989). The second mechanism, which is
probably the most important, is the reaction
of dioxins with hydroxyl (OH) radicals.
Most atmospheric chemists consider this to
be the primary mechanism by which organic
compounds are removed from the atmo-
sphere. Thus, determining the rate con-
stants for reactions of dioxins with OH has
been of considerable interest. Unfortu-
nately, experimental difficulties have pre-
cluded the direct measurement of these
values. In the absence of experimental
data, models (based on various substituant
effects) have been used (Atkinson, 1987;
Atkinson, 1991). These calculations indi-
cate that the atmospheric lifetimes of
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dioxins and furans are in the range of 1 to
40 days. The tetrachloro- congeners are at
the low end of that range, and the
octachloro- congeners are at the high end.
Reactions with OH are considerably slower
than those induced by direct photolysis.
(Incidentally, this work on OH reactions
was not presented in the draft reassessment
document, and it should be added.)
There are clearly insufficient data on
which to base any firm conclusions about the
general issue of atmospheric photolysis. It
seems likely that important loss processes in
the atmosphere are photolytic and that reac-
tions with OH are important. However, rate
constants for none of these reactions are
known, and it is impossible to assess their
significance.
Based on the modeled rate constants
cited above, it is likely that the lower chlori-
nated compounds are degraded more rapidly
than the higher chlorinated compounds. For
example, the tetrachloro- dioxins are probably
degraded more rapidly than the octachloro-
dioxins. This estimate agrees with observa-
tions that the less chlorinated dioxins and
furans are reduced in relative concentration
between environmental sources and sinks.
However, it should be emphasized that this is
all mere speculation in the absence of any
data on the relative rates of the pertinent
reactions.
Photolysis may also be important in
other parts of the environmental transport
scenario for dioxins. Photolysis in water must
be considered after deposition of these com-
pounds from the atmosphere to lakes or
oceans. Photolysis on soil and on plant sur-
faces must be considered as these compounds
begin their movement into the human food
supply. In all of these cases, data on pho-
tolytic reactions are very sparse. In addi-
tion, a knowledge of the products of these
environmental transformations is not avail-
able. Is it possible that congeners with low
TEFs are being transformed in the environ-
ment to congeners with higher TEFs?
Clearly these are all areas in which addi-
tional research is needed.
3.5.5 Air-to-Plant Transfer (Charge
Question 17)
As stated in the Charge, the question of
the importance of air-to-plant transfer is too
difficult to answer at this time with the
available data. The air-to-plant transfer
coefficients suggested by EPA are reasonable
for 2,3,7,8-TCDD (given the available data),
but there are insufficient data to support the
assumptions for the transfer coefficients for
the other PCDDs and PCDFs.
It is widely thought that some
fraction ofPCDD taken up by
grazing animals will normally be
associated with ingestion of
contaminated soil.
For EPA to understand the impor-
tance of the issue of air-to-plant transfer, the
fundamental physical and chemical proper-
ties for most PCDDs and PCDFs need to be
determined (and confirmed). Values for K^
(the octanol/water partition coefficient) and
vapor pressure, water solubility, and photol-
ytic half-life should be near the top of the
list of data gaps that need to be filled to
answer this question.
REASSESSING D1OXIN
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PAGE 32
It is not possible to work backward
from concentrations of CDD/Fs in cows to
estimate what was on the plant which the
animals ingested, because of the significant
contribution of soil ingestion by grazing cows
to the total uptake. It is widely thought that
some fraction of PCDD taken up by grazing
animals will normally be associated with
ingestion of contaminated soil. Ideally, a high
quality field study of air concentrations of
CDD/Fs and CDD/Fs versus the concentra-
tion in vegetation would be the basis for the
air-to-plant transfer coefficient estimate. This
type of study would probably be performed in
several agricultural areas. Some Committee
Members preferred this approach over labora-
tory studies because of the inability to repli-
cate what happens in the outdoor environ-
ment.
3.5.6 Vapor/Particle Partitioning
(Charge Question 18) .
The EPA document presents three
alternative approaches for the estimation of
vapor/particle partitioning and discusses the
limitations of each. It is important to note
that actual measurements of vapor/particle
partitioning in air are technically difficult.
Lacking such data, the model proposed by
Bidleman (1988) was selected by EPA for
estimating partitioning as the best of the
three approaches.
One approach considered was to
derive partition estimates from stack sam-
pling data. The inherent sampling artifacts
(e.g., the use of heated filters to collect parti-
cles) introduced by current stack monitoring
methods were recognized as the main limita-
tion of this approach. A further limitation is
the need for modeling the changes in va-
por/particulate partitioning downwind from
the source, as the plume components undergo
dilution, condensation, and coagulation.
Given the effects of these processes on va-
por/particle partitioning of CDD/Fs, the
model estimates would be quite unreliable
and must be considered to be preliminary
estimates.
Another approach consists of using
current ambient monitoring data. The avail-
able data, however, are limited with respect
to the particle size distribution and environ-
mental condition represented. Furthermore,
these data have been typically obtained with
high-volume samplers such as the PS-1;
particles are collected with a filter while the
vapor-phase compounds not retained in the
filter are captured by a sorbent trap located
downstream from the filter. The main limita-
tion of these data is that part of the particle-
bound CDD/Fs collected by the filter may re-
volatilize, particularly when large volumes of
air are moved through the filter. Conse-
quently, the fraction of the CDD/Fs collected
by the sorbent trap may overestimate the
vapor phase fraction actually found in the
atmosphere. Nonetheless, these data could
provide an upper bound estimate of va-
por/particle partition.
The third approach, and the one
selected (as noted above) for estimating
vapor/particle partitioning (a choice which
the Committee considers acceptable), is the
model proposed by Bidleman (1988), which
is largely based on fundamental properties of
the CCD/Fs. Phase partitioning is assumed
to be conserved between the source and
downwind receptor. There are some limita-
tions to this approach, such as the use of
solid phase vapor pressures at 25° C, whereas
THE SCIENCE ADVISORY BOARD
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PAGE 33
ambient temperatures could vary signifi-
cantly (the EPA document applies the model
for 20° C). This could be the major reason
why the calculated data in table 3-5, page
3-42 agree so poorly with the measured
data. However, the model results appear to
be in general agreement with the va-
por/particle partition trend in the ambient
data, that is, the tetra- and penta- substi-
tuted congeners tend to partition to the
vapor phase, and hexa/hepta chlorinated
compounds are mainly particle-bound. Since
vapor/particle partition depends on ambient
temperature, further evaluation of the results
from the model could be performed by
comparing ambient data obtained during the
temperature extremes of winter and summer.
The Committee recommends that EPA
undertake such an effort.
3.5.7 Background Exposures and Site-
Specific Evaluation (Charge
Question 19)
The definition of "background" as
applied in the current assessment is given on
page 5-1 of Volume II as: "...background
exposures estimated in this chapter are based
on monitoring data obtained from sites
removed from known contaminant sources
(or food data representative of the general
food supply.)" On the other hand, the site
specific assessment is directed at estimating
incremental exposure resulting from a spe-
cific source. There seems to be an implicit
contradiction in these two statements, since
the implications of an increment in exposure
from the emissions of a given source are a
function of existing conditions (i.e., the
presence or absence of other similar or
different sources). Depending on those
specific sources, the "background" default
assumptions of the six scenarios presented in
Chapter 5 of Volume III may not be appro-
priate. Certainly the data on environmental
concentrations of CDD/Fs presented in
Volume II demonstrate that there is signifi-
cant variability in levels even among sites
which could be categorized in the same
scenario.
The term "background" is also con-
fusing because, in spite of the preferred
definition stated above, it is used in the rest
of the document to represent other concepts.
For the purpose of site-specific assessments,
the term "baseline conditions" appears to be
more appropriate than "background." The
Agency might then consider providing guid-
ance for performing baseline exposure assess-
ments for specific sites. Such guidance may
include the following recommendations for
the user:
a) use site-specific media concentra-
tions rather than defaults whenever
possible;
b) if these data are unavailable, use
inforrnation from a comparable site
in terms of the types and density
of sources present, land-use condi-
tions, and g ^graphic/atmospheric
characteristics;
c) when site-specific or comparable
site data are not available, use re-
gional data.
The Agency might consider including
examples of how a site-specific baseline
evaluation might be performed. Consider-
ation of site-specific baseline conditions
would obviously implicitly include the con-
tributions from existing multiple sources.
REASSESSING DIOXIN
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PAGE 34
3.5.8 Evaluation of Multiple
(Charge Question 20)
Sources
For the reasons discussed in detail in
section 3.5.7 above, it may not be appropriate
to utilize the national background exposure
estimates presented in Volume II of the draft
report as representing the site-specific back-
ground levels.
Where a site is impacted by multiple
existing sources of dioxin-like compounds, it is
appropriate to model the contribution of each
individual existing source and then sum their
emissions and depositions for the purpose of
calculating a baseline quantification of total
exposure for that site. Whenever possible,
baseline calculations should be developed on a
media-specific basis. This baseline exposure
calculation may differ significantly from the
national background levels discussed in
Volume II. The dioxin ambient ait/deposition
map currently in development by EPA will
hopefully provide information on regional
deposition levels that can provide more local-
ized background level information.
The EPA has done a good job
of evaluating the sources of
dioxins, based on available
data...
The SAB Indoor Air Quality/Total
Human Exposure Committee has previously
raised the concern in the context of its review
of the EPA draft document "Addendum to the
Methodology for Assessing Health Risks Asso-
ciated with Indirect Exposure to Combustor
Emissions" that a more regional approach be
adopted for evaluation of exposure and health
risks from indirect exposures to combustor
emissions (SAB, 1994). Dioxin-like com-
pounds were among the pollutants of concern
with respect to these sources. The Committee
recommends that guidance be provided in Volume III
to indicate that a regional, as well as site-specific,
exposure assessment be undertaken in areas with
multiple existing sources of dioxin-like compounds.
Currently, the draft report provides
little information for the reader regarding how
to assess baseline exposures at a site with
multiple existing sources of dioxin-like com-
pounds. The inclusion of a case-study example
would make the report more informative.
3.6 Overall Scientific Foundations of
the Reassessment Document
(ChargeQuestion 1)
The EPA staff has done a very credible
and thorough job on a large and complex task.
They are to be commended on the work that
they have done to assemble, integrate, and
analyze a very large body of data on source
emissions, environmental levels, exposures,
and human body burdens in the framework of
human exposure assessment. In so doing,
they have uncovered key data gaps and issues,
developed some reasonable priorities for
future efforts, and begun to implement re-
search efforts to address information gaps. In
general, the work has been clearly presented
and the documents are well written. It should
also be noted that, as a result of this inte-
grated assessment, a number of industries are
currently seeking to address gaps in emissions
measurement data.
The EPA has done a good job of evalu-
ating the sources of dioxins, based on avail-
able data, and significant sources of uncer-
THE SCIENCE ADVISORY BOARD
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PAGE 35
tainty have been qualitatively identified. In
addition, this document provides the founda-
tions for a quantitative treatment of
uncertainties--a task that is, however, beyond
the scope of the current reassessment docu-
ment. Although there is great uncertainty in
the levels of dioxins in some environmental
samples, these levels are consistent with the
emission inventory; that is, comparison of the
emission inventory and environmental levels
does not imply that there are significant
unknown sources. There is also some evi-
dence, i.e., decreases in concentrations of
dioxins in surface sediments and human tissue
samples, that indicates that emissions of
dioxin are decreasing. Further environmental
and human monitoring is, however, required
to confirm this.
In assessing sources of dioxin-like
compounds, the total estimated dioxin emis-
sions for the U.S. have been compared to an
estimate of the total amount of dioxin that is
deposited to the surface of the U.S. based on
available deposition factors. The difference
between the two estimates has raised some
concerns about possible "missing sources."
There is a serious scientific problem with
trying to perform such a simplified mass
balance on a continental or regional scale.
That is, the atmospheric lifetime of accumula-
tion mode particles (0.1 to about 2-3 pirn) is of
the order of many days. Thus, a large propor-
tion of the particles with dioxin-like com-
pounds that are emitted in the eastern U.S.,
for example, are likely to be deposited in the
Atlantic Ocean, Canada, Europe, or even the
Arctic, depending upon source locations and
weather patterns. Given the long atmospheric
half-life of the participate dioxin-like com-
pounds, a global or hemispheric mass balance
is necessary. A second, and perhaps even
more serious concern, is that the mass balance
calculations have been performed using only
two data points for deposition in the U.S.
(Bloomington, Indiana and Green Lake, New
York). These locations are unlikely to be
representative of average deposition in this
country. Given these problems, it is strongly
recommended that the sections of the report in which
the very simplified mass balance comparison of the
emissions inventory and the deposition mass are
compared be modified so that a direct comparison is
not made and it is made clear that such a compari-
son is not scientifically valid. In addition, these
findings also mean that the simple mass balance
presented here cannot be used to infer "missing
sources."
The available scientific evidence
strongly indicates that current levels of di-
oxin-like compounds in the environment are
largely derived from anthropogenic sources
(see section 3,2.5). There is also considerable
scientific evidence that the principal mecha-
nism by which dioxin-like compounds enter
the terrestrial food chain is via atmospheric
transport and deposition. However, there is a
very large gap in our understanding of the
potential atmospheric transformation of
vapor-phase dioxin-like compounds; specifi-
cally, there are no experimental measurements
of photodegradation or degradation via reac-
tion with hydroxyl radicals. Environmental
measurements of deposition of paniculate and
vapor-phase dioxin-like compounds to the
surface are also extremely limited, although
we understand that there are now some efforts
to address this data gap.
The evidence that the principal path-
way for human exposure to dioxin- like com-
pounds is through the diet, with consumption
of animal products accounting for the
REASSESSING DIOXIN
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PAGE 36
dominant or overwhelming fraction of
exposure, is also quite robust. The associ-
ated air/plant/animal pathway hypothesis
has considerable support, although it has
not been proven unequivocally, particularly
in view of the very limited available data.
It is also important not to lose sight of
other potentially significant dietary exposure
pathways, such as emissions from point
sources to water or sediment, and then to
food. In addition, cigarette smoking should
be evaluated as a potentially significant
exposure source for smokers in the popula-
tion (about 25% of U.S. adults are smok-
If the estimates of dioxin-like com-
ers
pounds in beef and pork presented in the
report, based on very limited data, are
found to be too high, then cigarette smok-
ing (for which the dioxin estimated are also
based on very limited data) could account
for a significant proportion of exposure for
smokers.
Estimates of human exposures,
based on currently available information
from exposure analysis and analyses of
human tissue samples, are consistent and
are likely to provide a reasonable central
estimate of the distribution of exposures for
the population. Existing measurements of
dioxin-like compounds in food, however, are
very limited. Consequently, we lack data
that would allow an estimate to be made of
the distribution of exposures for the U.S.
population.
The Committee found the term
"background" somewhat confusing and
suggests that" the national average back-
ground exposure," or some similar
explicit term should be used in future drafts
for greater clarity.
The Committee also believes that the
very brief discussion and recommendations
on multiple sources should be substantially
expanded and that more detail should be
provided. Of the two approaches suggested,
it was felt that the better approach would be
to model multiple sources in a region and
then make comparisons of the potential
exposure contributions of a new source to
local exposures. The results might be termed
"baseline," and considered along with na-
tional average background exposure, as well
as with increments in exposure from a spe-
cific facility.
Understandably, the focus of the
report is on site-specific models, which are
needed for regulatory purposes, e.g., to
answer questions such as "Is a proposed
facility likely to result in a significant in-
crease in exposure above background?"
Ongoing work to refine, test, and validate
these models can be considered a "micro-
scopic" approach. It would, however, also be
very useful to have a macroscopic approach,
including more regional and global mass
balances and multimedia modeling. That is,
other types of models should be used to
examine other issues. For example, the very
similar levels of these compounds which
have been found in food and humans in a
number of countries, suggests that they
probably are widely distributed via atmo-
spheric transport processes throughout the
Northern Hemisphere and that more global
(or hemispheric) evaluations of mass balance
should be undertaken.
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PAGE 37
4. DETAILED FINDINGS-HEALTH DOCUMENT
4.1 Disposition and Pharmacokinetics
Issues
4.1.1 Strength of the database (Charge
Question 2)
The Charge for this review (see section
2.2) states that "An understanding of the
relationship between exposure and dose is an
important aspect of an adequate characteriza-
tion of risk." A specific concern is how the
extant data are used to predict tissue dose
levels of 2,3,7,8-TCDD in humans under low
exposure conditions.
There is a an extensive animal data
base relating exposure to tissue dose for
2,3,7,8-TCDD (although data are lacking for
many of the related compounds), and there is
a substantial (and generally solid) body of
data on the absorption and distribution of
2,3,7,8-TCDD in animals (Bimbaum, 1985;
Gasiewicz <*«/., 1983; Neal etai, 1982; Olson
etal, 1983; Van den Berg etal, 1994). There
are insufficient human data to support deposi-
tion and tissue dose modeling however, and
this data gap severely restricts animal (largely
rodent) to human extrapolation. Further,
there are only a limited number of animal
studies that reflect accurately likely environ-
mental exposure scenarios for humans. For
example, gastrointestinal absorption of
2,3,7,8-TCDD is influenced by the presence
of other compounds, the nature of the matrix,
and the very limited aqueous solubility of
2,3,7,8-TCDD. These and other factors
relevant to the partitioning of 2,3,7,8-TCDD
and gut absorption are of critical concern,
given the fact that foodstuffs are considered
by EPA to represent a major source of chronic
low level human exposure to dioxins .
The pulmonary exposure data base is
based on the pulmonary absorption of
2,3,7,8-TCDD from solution; absorption by
this route is known to be high. The most
likely non-dietary human exposure to 2,3,7,8-
TCDD, however, would be through inhalation
of paniculate matter incorporating dioxin in
a solid matrix (e.g., fly ash). Although data on
pulmonary absorption from a solid matrix are
available (Nessel et al, 1990; Nessel et al,
1992a; Nessel et al., 1992b), these data are
not addressed in the reassessment document.
Given the large data base, a more thorough
analysis of the biological determinants of tissue
absorption and deposition (particularly with low
dose exposure) should be carried out. For example,
mice show a different pattern of distribution
to the skin than rats, with the former more
accurately reflecting data obtained in non-
human primates (Brewster and Birnbaum,
1988; Gallon/., 1992; Rahman etal., 1992).
The hepatic distribution patterns of
2,3,7,8-TCDD in animals appears to be dose-
dependent and saturable. This is an area that
needs further study, particularly with regard
to potential interspecies differences and the
development of valid human physiologically-
based pharmacokinetic (PBPK) models.
In general, the reassessment document has
drawn extensively from the existing animal data
relating exposure/tissue dose and absorp-
tion/distribution, but did not characterize ade-
quately the strengths and weaknesses of the data-
base. Further, the inferences drawn leave some
REASSESSING DIOXIN
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PAGE 38
issues unaddressed. A greater effort needs to be
made to describe the long-term effects of the
decrease of PCDD- and PCDF levels in the
environment, and in turn, in human expo-
sures. This description should provide an
improved estimate of the mix of chemicals in
the TEQ and their capacity to be both
agonists and antagonists (or synergists) in the
overall biological effects of 2,s',7,8-TCDD and
2,3,7,8-TCDD-like compounds, as well as
those chlorinated compounds that are re-
viewed in the health assessment documents
but are not 2,3,7,8-TCDD-like. In addition,
to enhance further the value of the reassess-
ment, a greater effort is needed to provide a
better understanding of the consequences and
possible interaction of employing both the
receptor model for risk assessment and the
utilization of the concept of TEQ. For exam-
ple, what can be expected in this context with
a range of halogenated chemicals that may
interact in various ways as either agonists or
antagonists? What can be expected from a
mixture of such compounds, when considering
both additive or non-additive effects, with
constant or changing concentrations of those
individual components which contribute to
both response and the TEQ value?
In chapters I through 7, which mainly
review the current research data, the docu-
ment provides a generally balanced evalua-
tion, and inferences from these chapters are
appropriate except as noted above. However,
Chapter 8 presents an incomplete review of
the dose response model (Linear Multi-Stage
[LMS] and modified LMS) approach, with no
consideration of alternative models used by
other agencies, nor discussion of the literature.
This is reflected in the summary chapter.
Thus, the Committee recommends that EPA provide
either additional discussion of alternative ap-
proaches and their implications for risk assessment
in Chapter 8, or present a clear justification for
choosing this particular dose-response approach over
others. Chapter 9 should also be modified to reflect
these additions.
4.1.2 Disposition and Pharmacokinet-
ics (Charge Question 3)
In addition to the specific questions
asked about disposition and pharmacokinetics
by the Charge, the introductory sentence
leading into this issue must also be evaluated.
This sentence states " The evaluation of
available data and the development of
physiologically-based models has led to a
better understanding of the disposition and
pharmacokinetics of dioxin and related com-
pounds than for most other environmental
chemicals." This sentence implies that these
models are well-established and ready for
incorporation into the current assessment. It
is the Committee's consensus, however, that there
are several issues that should be addressed before
these models can be used effectively in the risk
assessment. The following questions should be
addressed in a revised assessment document:
a) Does the database to determine mecha-
nism and models apply only to 2,3,7,8-
TCDD or may it be extended to other
related compounds? Currently the
great majority of data on physiologically
based kinetic models is derived from
2,3,7,8-TCDD research, but about 90%
of estimated "risk" is from related com-
pounds (as stated in the reassessment
document, p. 9-81).
b) Do the models proposed extend to all
dose ranges, particularly to low dose?
The data used in current models were
THE SCIENCE ADVISORY BOARD
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PAGE 39
not generally derived from studies conducted
at low dose levels. There is significant contro-
versy as to the shape of the curve in the mod-
els proposed at the low dose levels.
c) Are all organs effectively addressed in
the models? The models appear to
focus on liver and fat concentrations
in rodents; however, the target organs
in the epidemiology studies for carci-
nogenesis are the gastrointestinal tract
and others. It is not clear that the
models effectively describe the expo-
sure and metabolism of those possibly
impacted tissues. Particular questions
may exist with respect to the lung for
carcinogen exposures that occur by the
respiratory route (although this route
is probably of minor significance for
most of the population, it could be of
concern for occupational exposures).
d) If models have primarily been deter-
mined from short-term or single-dose
studies, do these results apply to
chronic studies and/or longer term
exposures? In particularf;the chronic
Kociba et al. (1978, 1979) studies,
which included low exposure levels,
did not necessarily fit one of the mod-
els proposed, whereas the dose finding
studies did. A question then exists
concerning the model's efficacy for the
real life-low exposure situation.
e) Do the models apply across relevant
mammalian species?
f) What is the relationship between
"dose" as used in the dose-response
models and tissue or body burden that
the EPA uses in many comparisons
between human and animal exposures
and risks?
Lastly, the variability of the half-life of
2,3,7,8-TCDD in the human leads to ques-
tions about trie precision of the models. The
estimated half-life discussed varied from five
to 11.3 years. The range given here may
represent a difficult communication issue, and
affects the precision of the model.
In the body of the health reassessment
document, the issue of PBPK modeling is
discussed in three chapters (1,8, and 9).
However, there is little evidence of actual
integration of any of these models into spe-
cific portions of the document. The concept
of physiologic-based modeling is discussed
separately in the risk assessment portions of
the document, and is conceptually a part of
the process. Scrutiny of the document (and
oral discussions with the document's authors
at the public meeting) however, yielded no
evidence of use of a specific P%PK model in the
risk assessment. Given the issues noted
above, this is understandable and not consid-
ered to be a particular Weakness by the Com-
mittee (however, opportunities do existsee
the discussion below), but future revisions of
the document should be clear as to the degree
to which such, modeling has been incorporated
into the assessment process.
Notwithstanding the lack of incorpora-
tion of these models into the current reassess-
ment and the significant questions noted
above, the database on dioxin could provide
an opportunity to utilize state-of-the-art PBPK
models. The Carrier-Brunet-Brodeur model
(Carrier et a/.,1995a; 1995b) (which was not
yet published at the time the Health Reassess-
ment was under development), for example,
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incorporates non-linear elimination rates; as
body burden declines, half-life increases. The
applicability of this model and its implications
should be discussed in any future revision of
the reassessment document. The opportunity to
utilize the Ah receptor binding in modeling is
significant, and these models should be more effec-
tively incorporated into the risk assessment through
revisions to Chapter 8.
4.1.3 Incremental Exposures and
Bioaccumulation (Charge Ques-
tion 4)
The EPA reassessment document
provides a large amount of animal and human
data regarding bioaccumulation of 2,3,7,8-
TCDD. However, it is readily apparent that
a large gap exists in our knowledge regarding
the pharmacokinetics of common, environ-
mentally occurring congeners of 2,3,7,8-
TCDD. If Toxicity Equivalency Factors
... the Committee anticipates
that future revisions of the
reassessment document will
incorporate the latest data set
from the Ranch Hand study...
(TEF) are going to be used to assess human
toxicity, and if approximately 10% of the total
exposure to dioxins is attributable to 2,3,7,8-
TCDD, an accurate estimation of total poten-
tial for toxicity can be made only if informa-
tion is available regarding distribution, metab-
olism, and half-lives of other major contribut-
ing components (See discussion in section
4.13). It is not possible to make a general
estimate of toxicity if we know nothing of the
pharmacokinetics of the majority of the
dioxin-like compounds to which humans are
exposed. The reassessment is silent on this
issue, but data from autopsy evaluations have
been published by Schecter (1991) and
should be used (if possible) to extend our
knowledge of the pharmacokinetics of these
compounds.
Major shortcomings are evident in the data
base and the relevant issues have not been dealt
with adequately. For example, no attention has
been given to reviewing the half-lives of many
of the important compounds that constitute
the TEQ. Data from studies concerning
exposures of subsistence fishermen appear to
be in conflict with the EPA estimation of body
burden (Columbia River Intertribal Fish
Commission, 1993; Dewailly et al, 1994;
Svensson et al., 1991). These studies suggest
that the reassessment's estimated body bur-
dens may be as much as two orders-of-magni-
tude higher than actual levels; this difference
may be related to errors introduced by not
accounting for the various half-lives of the
agents included in the TEQ.
4.1.4 Uncertainties in Back Extrapola-
tions of Body Burden (Charge
Question 5)
The Committee's primary concern with
the topic of the body burden back extrapola-
tion lies with EPA's treatment of uncertainty
regarding the half life of dioxin, and the expo-
sition of the methods for the back calculation
in the health document.
As discussed at the public meeting, the
Committee anticipates that future revisions of
the reassessment document will incorporate
the latest data set from the Ranch Hand
study, which should narrow considerably the
range of estimates for dioxin half-life, and so
reduce the uncertainty (from that source) in
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the back extrapolation of body burden. In
addition, we expect that EPA will revise the
discussion on the back calculation method to
include material covered in Chapter 6 of the
exposure document, but not currently ad-
dressed in the health document.
4.2 Mechanisms of Dioxin Action
4.2.1 Animal-to-Human Extrapolations
of Receptor Structure and Func-
tion (Charge Question 6)
Mechanisms of dioxin action are dis-
cussed in various parts of the Health Assess-
ment document. Overall, the presentations
are very useful. Whether or not the docu-
ment addresses all the relevant information
and alternatives depends, however, on the
section that is being read. Chapter 2 offers an
unequivocal assessment that "...the Ah recep-
tor mediates the biological effects of TCDD."
Yet, when reading Chapters 3, 4 and 5 dealing
with specific toxic events, it becomes clear
that numerous fundamental uncertainties
occur and mechanisms of action for the toxic
events beyond receptor binding are largely
unknown. In Chapter 9, however, there is a
return to the acceptance presented in Chapter
2. This may indicate that the authors of
Chapter 9 are willing to go along with the Ah
receptor information as it exists today.
One major difficulty lies with the use
of the term "mediator" and perhaps confusion
about what constitutes a "mechanism of
action." Other than what is described in the
sections dealing with developmental toxicity
(e.g., cleft palate, hydronephrosis), very little
is known about the biological steps that fi-
nally lead to frank toxicity; the lack of infor-
mation on immunotoxicity is particularly
limiting. Much of what is purported to link
the Ah receptor to specific toxic events is
merely the demonstration of an association
between the binding of TCDD to the receptor
and an eventual appearance of an adverse
effect some tune later in some species (when
the interspecies variation in doses that pro-
duce lethality can be over 8,000-fold, based
on the data provided in Table 3-1, Volume 1,
of the reassessment document). But the
possible "downstream" events, if they exist,
between Ah receptor binding and the final
toxic manifestation are not well established.
"Mechanism of action" should mean that at
least some of the intermediate steps, after Ah
receptor binding and leading to the pathologic
processes involved, are known to some extent.
The loose use of the term "mediator" implies
that the association apparently observed is in
reality the initiator of the process. In actual
fact, the only mechanism of action involving
the Ah receptor that has been worked out
sufficiently well to be called the biological
sequence that describes a "mechanism of
action' is the induction of cytochrome P450.
What is known about the induction process is
truly elegant. The rest of the biological conse-
quences of TCDD exposure are yet to be de-
scribed adequately and sequentially in mecha-
nistic terms.
The document (Chapter 2) presents an
excellent review of what is known about the
Ah receptor and the multiple steps involved in
TCDD-induced cytochrome P450 induction.
Research findings during the last 10 or so
years that have identified the structure and
mode of action of the Ah receptor represent
a major scientific achievement. How a
planar polar compound such as TCDD binds
with a cellular receptor, followed by translo-
cation into the nucleus, where transcriptional
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activity of DNA is influenced, is very well
understood. On the other hand, there is a
large intellectual chasm between the elegant
science describing the details of the TCDD
receptor and its mechanism of initiating a
cellular response, and the poorly understood
manifestations of the toxic events associated
with an alteration of the homeostasis of an
animal. The linkage between Ah receptor
action and specific cellular toxicity remains
undefined. Several Members of the Commit-
tee noted that the possibility that the Ah
receptor system may be a sensing pathway to
protect the cell is not considered, nor are
there other attempts to put forth scientifi-
cally testable hypotheses. In any future
revisions, EPA should present more clearly
the major deficiencies that exist in the cur-
rent mechanism database and provide some
discussion of any plausible alternative hy-
potheses.
Although the Ah receptor is likely
involved in producing TCDD toxic effects of
potential concern to humans, there are
multiple levels of regulation of the receptor
pathway. The induction of CYP1A1 does
not serve as a good model for all receptor-
mediated responses to dioxin, particularly
those that result in altered patterns of
growth and differentiation. The studies of
Poland and Knutson (1982b) in hairless
mice indicated that for responses such as
epidermal hyperkeratinization and skin
tumor promoting activity, the Ah receptor is
necessary, but not sufficient. Two implications
from these studies are: a) that toxicity is
under multiple genetic control, and b) the
most sensitive response in animal models is
not necessarily the most valid predictor of
toxicitv in humans. Chloracne remains the
^
most definitive response documented in
humans and clearly occurs at high exposure
levels. However, there are relatively few
animal models for chloracne. Most of the
"mechanistic data" support the involvement
of the Ah receptor, but say little (in the
context of toxicity), about how the activation
of this protein alters normal physiologic
function and/or development. Risk assess-
ments based solely, on Ah receptor activation
or on the existing knowledge of CYP1A1
induction are unlikely to provide a biologi-
cally defensible prediction (quantitatively or
qualitatively) of likely toxic outcomes in
humans, particularly under low exposure
scenarios.
Regarding the Ah receptor in humans,
there is adequate evidence that, in overall
function, the human Ah receptor mechanism
essentially acts the same as the Ah receptor
in rodents,and in other laboratory species.
The Ah receptor in humans, however, has an
The linkage between Ah receptor
action and specific cellular
toxicity remains undefined.
affinity for TCDD that is lower than the
affinity in C57BL/6 mice or in most labora-
tory rat strains. There may be at least a
10-fold range of variation among the hu-
man population in the affinity with which
the Ah receptor binds TCDD. Induction of
CYP1A1 exhibits classical sigmoidal log-dose
response curves in several human cell lines
in culture.
The EPA document's phrase "...and
the role that the purported mechanisms of
action might contribute to the diversity of
biological response seen in animals and, to
some extent, in humans?" in this question
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can be better posed as "...how convincing is
the evidence for the purported mechanisms
that link receptor binding to toxic effects in
humans?" Unfortunately, the evidence is
quite mixed. There is only limited evidence
for toxic effects in the Ranch Hand study
(USAF, 1991; CDC, 1988a,b). Studies of
the Seveso population (Bertazzi et al., 1993;
Bertazzi et al, 1989; Mocarelli et al, 1986)
show significant excesses of multiple my-
eloma and hepatobilliary tract cancer in
women, and lymphoreticulosarcoma in men
in zone B, and soft tissue sarcoma in men
in zone R. These lesions, however, were
seen in the zones of lower, not higher,
estimated exposure. Conversely, and further
clouding the issue, these same studies also
report decreases in breast8 and other cancers
in females (although the number of cases is
very small and the decrease may be spuri-
ous). In the exposed chemical plant work-
ers studied by the National Institute of
Occupational Safety and Health (NIOSH)
(Fingerhut et al, 1991), there is no excess
cancer of any kind in the less heavily ex-
posed workers (i.e., those who were exposed
for less than one year). Workers with over
one year's exposure showed statistically
significant increases in respiratory system
cancer, but they were exposed to a wide
variety of potentially carcinogenic agents in
addition to dioxin. Given the possible
confounding, and the somewhat equivocal
links of dioxin to excess cancer
in the group as a whole, it is difficult to
document a dioxin-cancer relationship.9 10
4.3 Toxic Effects of Dioxin
4.3.1 Animal Models for estimating
Human Risk (Charge Question 7)
The Committee believes that the EPA reas-
sessment document reviewed and summarized
adequately the current knowledge base on the experi-
mental disease(s) produced by TCDD and related
compounds in animals,
The Committee agreed that, because
there is a limited amount of human data, EPA
will have to rely on the results of animal
studies for some portion of its risk character-
ization. However, the Committee also finds
that it is probably not appropriate for the
Agency to single out the results of a given
study (unless it is of a seminal nature) for
decision making. The EPA would be better
served to employ a weight-of-the-evidence
approach, using the totality of the data.
Some Committee Members suggest that this
reduction may result from the anti-estrogenic effects of
dioxin.
Several Members of the Committee suggest that
EPA has neglected other human exposure studies of interest,
particularly the health effects seen in the Taiwan rice oil PCB
poisoning episode (as reported in Rogan et al., 1988; Wu et
al., 1984; Chang it al, 1982a; Chang et al, 1982b: and
Chang et al, 1981) which could reduce the reliance on
animal-to-man extrapolation.
Noting that cancer excesses were seen in the
Fingerhut et al. (1990; 1991) studies only in workers with 20
or more years of latency, one Committee Member argues that
the Bertazzi study should be discounted as uninformative. It
was carried out only ten years after exposure, the levels of ex-
posure to the people in the zones that are characterized as
having excess cancers are far less than those of the workers
studied by Fingerhut et al. In this Member's opinion, both
the reported excesses and deficits are more likely to result
from chance than from any dioxin effect.
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The Committee noted that although
there were many interspecies consistencies in
response following exposure to the com-
pounds in question, there were also many
significant inconsistencies. The Committee
questions whether some of the interspecies
differences were "true" differences or were a
reflection of the dose levels used in the
different studies. A portion of the
interspecies Inconsistencies may be attrib-
uted to the fact that some of the animal
studies involved lethal exposure levels but
that other studies did not. For example,
some of the effects noted in animals (see
Table 9-2 of the reassessment document),
e.g. "wasting disease," chloracne, testicular
atrophy, hepatotoxicity, cardiovascular le-
sions, hypoglycemia, edema, and porphyria,
were found primarily in animals that died.
Many of these effects were not observed in
cows, however, and none of the cattle stud-
ies involved lethal exposure levels. There-
fore, the lack of interspecies comparability
may indeed be a reflection of the dose levels
used in particular species/studies.
Another apparent inconsistency which
may be a reflection of study design is re-
lated to the carcinogenicity of TCDD.
Although TCDD has not been reported to
be carcinogenic in guinea pigs, rabbits,
chickens, cows, or monkeys, none of the
studies were of sufficient length to ascertain
whether it is indeed carcinogenic or not in
these species. Additionally, the lack of
observed chloracne in a given species may be
related to anatomical differences; many of
the tested species have "fur" rather than true
"hair" follicles as are found in monkeys and
humans. Also, a feather follicle (chicken) is
anatomically quite different than a hair
follicle. Some discussion of these points
would be beneficial to readers of the reas-
sessment document.
The Committee also suggests that the
document discuss "primary" versus "secondary"
effects of exposure. For example, some of the
effects related to TCDD exposure (testicular
atrophy, cardiovascular pathology, edema, and
porphyria) may not be directly related to the
compound, but may rather be a reflection of
the "sick animal" syndrome. Comparative
mechanistic arid pharmacokinetic data would
be needed before making a conclusion that a
given effect is directly attributable to TCDD
or related compounds. The degree of uncer-
tainty in this regard needs to be discussed in
the document and needs to be reflected by
using "?" marks in Table 9-2.
The Committee believes that Table 9-2
is extremely important and is very likely to be
used by the casual reader; consequently it
should be made as accurate as possible.
Members of the Committee have noted errors
in the Table, and we suggest that the tabular
material in the document be reviewed for
accuracy.
In summary, the Committee finds that there
is evidence of both inter-species consistency and
inconsistency in the EPA document. These vari-
ances need to be addressed in an objective manner in
the document, and discussed in conjunction with all
the uncertainties inherent in the various endpoints.
In addition, the Committee felt strongly that an
examination of the totality of the animal data will
be required in the final hazard characterization.
Finally, nearly all of the Members of the
Committee take strong exception to the defin-
itive sentence on page 9-78 (see also the Com-
mittee's discussion of Charge Question 1, in
THE SCIENCE ADVISORY BOARD
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section 2.2.2 of this report) of the EPA docu-
ment, which states:
"The scientific community has identified and
described a series of common biological steps
that are necessary for most If not all of the
j
observed effects of dioxin and related com-
pounds in vertebrates, including humans.
Binding of dioxin-like compounds to the
cellular protein Ah receptor represents the
first step in the series of events attributable to
exposure to dioxin-like compounds, including
biochemical, cellular, and tissue-level changes
in normal biological processes. Binding to the
Ah receptor appears to be necessary for all
well studied effects of dioxin but is not suffi-
cient, in and of Itself, to elicit these re-
sponses."
This pronouncement is too strong. Virtually
all the Committee believes that it is more accurate to
state that binding of TCDD and related compounds
to the Ah receptor is a marker of exposure, but has
not yet been established to be "necessary" for the
induction of several of the observed effects. This
degree of uncertainty needs to be stated in the
document.
4.3.2 Variations in Human Sensitiv-
ity (Charge Question 8)
The issue of human sensitivity may be
divided into two questions. First, are human
sensitivities so distributed that a representa-
tive average can be assumed? Secondly, do
humans on average yield a response which
might be considered to be average relative to
the spectrum of responses in animals?
Wide variations in response to dioxins
are well documented in animal studies, with
at least a three-fold order-of-magnitude being
reported for some responses between animal
species and even within a given animal species
such as rats and mice, or between very young
hamsters and adult hamsters. Responses of
humans are known to vary by several orders-
of-magnitude with respect to the exposure to
many exogenous substances as drugs, where
some individuals are known to be responders
while others are considered non-responders.
It is reasonable to assume, therefore, that
responses of humans to TCDD and its conge-
ners will vary widely. Furthermore, observa-
tions reported in human exposure studies as
from Seveso, Italy (Bertazzi et al., 1993;
Bertazzi et al., 1989; Mocarelli et al., 1986)
and the U.S. Air Force Ranch Hand Study
(USAF, 1991; CDC, 1988a,b) as well as other
studies of occupational cohorts clearly indi-
cate that wide variations in the frequency and
severity of response occur.''
The Committee finds that there is no
single animal model that could accurately
predict human responses. EPA, in its revision,
should identify clearly the limitations of
existing animal models in terms of their abil-
ity to predict the various health outcomes that
may occur in humans as a result of exposure
to dioxin and dioxin-like compounds. Are
humans expected to yield an average response
relative to the spectrum of responses in ani-
mals? Humans could be as sensitive as the
most sensitive mouse species, or insensitive as
the least sensitive mouse species to TCDD.
Based on the available human data, it is
debatable whether the most sensitive species,
One Member of the Committee objects to this
statement, citing findings in this review which assert that the
only adverse human health effect tied to dioxin is chloracne.
Given this latter finding, he does not accept that studies
"dearly indicate that wide variations in the frequency and
severity of response occur."
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or the most representative animal species,
should be used when selecting an animal
model to predict TCDD toxicity in humans.
Ideally, if a high degree of confidence in the
model existed, one should use the animal
species that is most representative of humans.
If no single model is appropriate, animal
models should be selected that permit a con-
servative approach to be employed with re-
spect to extrapolation to human subjects.
What is unclear with respect to the
question regarding average sensitivity is what
constitutes an average response in humans who
exhibit an average sensitivity, and at what level
of exposure, both acute and chronic, does this
occur?
When considering toxicity to humans,
one must always consider the most sensitive
population. Can highly sensitive sub-popula-
tions be identified that are at greatest risk to
dioxin exposure? Such sub-populations might
include pregnant women, infants, and chil-
dren or members of a population with an
above average exposure as populations whose
subsistence diet consists largely of fish.
Although variations in response are reported
and presented in the document, the document (in the
opinion of most of the Committee) does not (and
perhaps cannot, given that dioxin-specific effects
beyond chloracnesee the discussion beloware not
established) concisely articulate that wide variations
in human sensitivity to dioxin exposure occur and
should be anticipated. The emphasis is heavily
placed on low level exposures that might cause
toxicity in some individuals.12
4.4 Chloracne as an Indicator of
Exposure (Charge Question 9)
The Committee believes that the EPA docu-.
ment reflected adequately the current knowledge base
on chloracne as it relates to the subject compounds.
Chloracne is a ckar indicator of exposure, but the
absence of chloracne in an exposed subject is not an
indicator of low exposure. In fact, the Commit-
tee's consensus is that chloracne is the only
lesion of note clearly established as being
related to TCDD exposure; in the absence of
sufficient data on human tissue levels at peak
development of chloracne, however, a dose-
response relationship is difficult to ascertain.13
The Committee also noted that chloracne has
also been found in people exposed to related
compounds such as dibenzofurans and PCBs.
4.5 Cancer
4.5.1 Epidemiological Evidence
(Charge Question 10)
When a difference between compared
groups is observed, "causation" may still not
be imputed. Similarly, when no difference is
seen, it cannot be concluded that the study
variable is not associated (noting, of course,
that the presence of "association" does not
impute causation) with some outcome or is
not "causal." Causation is not itself an experi-
mental or epidemiological result but a judg-
ment made about the results. In making such
a judgment an epidemiologist takes into
account the possibility that bias and chance
12
Several Members have noted that they find the
EPA emphasis on low-level exposures to be appropriate and
consistent with prudent public health practice.
Several Members of the Committee believe
that recent research findings published after the Committee's
public meeting (e.g. Kogevinas et al. 1995; Huisman et al.,
1995) establish some cancer and developmental effects in
humans as outcomes of either CDD or TCDD exposures.
THE SCIENCE ADVISORY BOARD
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PAGE 47
may play a part, but additionally examines the
observed association in terms of certain
characteristics associated with "causal" rela-
tionships. These are sometimes referred to as
the Hill criteria (for A. Bradford Hill, who
first codified them). They are: a) strength of
the association; b) consistency; c) specificity;
d) relationship witJh time; e) biological gradi-
ent (dose-response relationship); f) biological
plausibility; g) coherence of the evidence; h)
observed change following some intervention;
and i) analogous findings.
The reassessment document mentions
three of the Hill criteria (gradient, consis-
tency, and strength) but does not explicitly
use them as a tool to organize its discussion
of causality. The Committee does not regard
this as a failing, since the Hill criteria are not
so much "rules," as viewpoints to aid in
interpretation. The EPA response is that
causation judgments were not explicitly part
of Chapter 7, although the Committee notes
conclusions of Chapter 7 were used as a
partial basis for Chapter 9. We find this
acceptable, since the entire discussion is couched in
terms of characteristics of causal associations.
Understanding the operation of bias
and chance is especially important in inter-
preting so called "negative studies" (studies
where no differences are apparent, or where
the differences are not "statistically signifi-
cant"). Differences produced by real effects
can easily be masked by poor exposure classi-
fications (misclassification bias), Chance can
appear as a possible explanation merely by
virtue of a small population available for
study (poor statistical power), and potential
risks can be undetectable by observing the
exposed population for too short a time (bias
produced by failure to account for adequate
latency), to name just a few factors compli-
cating interpretation of such outcomes. On
the other hand, factors that can produce
spurious increases in exposed groups in
environmental epidemiological studies are
much less common, most forces operating to
lower the observed risks, not raise them. The
reassessment document does a quite good job of
taking these limitations into account, but could
still benefit from additional discussion of the effects
of confounding factors. Specifically, EPA should
incorporate in a revised Chapter 9 the means
of addressing confounding factors discussed
by Agency staff at the review meeting.
To summarize the above discussion,
evaluating internal validity requires the
assessment of the roles played by bias,
chance and real effect. Each can operate,
sometimes reinforcing other factors, some-
times offsetting other factors. There is often
disagreement about studies among experts,
stemming from differing weights each places
on the influence of bias, chance and real
effect. Such differences in science are com-
mon, both in and out of the regulatory
process. The Assessment is explicit about
the judgments it makes, allowing others to
differ if they feel that other emphases are
warranted. The Committee feels this is
preferable to merely cataloging variant points
of view.
An evaluation of internal validity helps
a scientist in deciding how much to rely on
the specific result of the experiment or study.
It does not tell a scientist how much to
extend that result to contexts or situations
different than the one studied, i.e., how
much to generalize the result. A separate
evaluation for external validity is needed.
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The limits and extent of generaliza-
tion are given by a study's external validity.
In our context the question is whether a
proposition developed in one context (e.g., a
high dose occupational study like that of
Fingerhut et al., 1990) can be generalized to
cover other contexts (e.g., environmental
exposures). Unfortunately, there are no rules
for how far to generalize, if at all. Each
study must be evaluated in a specific context
to determine the extent to which it can be
generalized.
Cross-species generalization is not a
problem for the epidemiological studies, but
the question of generalizing to environmental
doses remains. Interestingly, Chapter 7A of
the Assessment (Epidemiological Data, Part
A Cancer Effects) does not comment on the
applicability of the epidemiologic data to
environmental exposures, satisfying itself
with answering the question of whether
TCDD and related compounds have the
capacity to cause cancer in humans under
any conditions. It answers in the affirmative,
citing several studies of "sound design and
adequate size" that have found a risk of soft
tissue sarcoma (STS) (p. 7-74). Association
of STS with dioxin exposure was raised by
Hardell and colleagues (Hardell et al, 1979;
Hardell, 1981a,b; Hardell and Eriksson,
1988; Hardell, 1993) and, according to the
reassessment, has "stood up to extensive
criticism and a great deal of subsequent
research." (pp. 7-73, 7-74). The document
also notes that the entirety of the association
in these studies may be"real" and not "due
to selection bias, differential exposure mis-
classification, confounding, or chance."
Although there are differing opinions about
the validity of the Swedish studies, most
Members of the Committee find that the
Assessment clearly discusses the direction
and degree of influence of the various
sources of bias in these studies.
The reassessment similarly discusses
non-Hodgkin's Lymphoma (NHL) and, based
upon a lack of a "minimally consistent pic-
ture of increased risks" fails to conclude at
this time that dioxin exposure is related to
NHL. This conclusion was arrived at by a
clearly stated and scientifically defensible
argument that is adequately supported.
The reassessment also states that the
epidemiologic data suggest that lung cancer
might also be related to dioxin exposure, and
cites the findings of the NIOSH study
(Fingerhut et al., 1991) which reported
statistically significant increases in respira-
tory system cancer (for those with over one
year's exposure and a 20 year latency period.
Because of possible uncontrolled confounding
by smoking, as well as by exposure to many
other carcinogens in the workplace, the EPA
document is more tentative on this judg-
ment, but considers that residual confound-
ing is insufficient to explain the observed
increase in respiratory system cancer risk.
Here the basis for the EPA's position is
weaker, reflecting the current lack of data on
the possible nature of a dioxin/cancer rela-
tionship in the presence of confounding by
smoking and occupational exposure to chem-
icals. Although the Committee does not
reject the EPA's position, neither can it
reject the alternative explanations which
some Members of the Committee think have
more merit.
The document found insufficient data
to make conclusions regarding stomach
cancer, generally increased risk of all types of
THE SCIENCE ADVISORY BOARD
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cancer, and sex differences in cancer risk.
The Committee agrees.
In summary, almost all Members of
the Committee found that the reassessment's
judgments on the epidemiology data (subject
to the caveats noted) to be generally defensi-
ble. The document took into account many
of the concerns of the broad scientific com-
munity and discussed them explicitly, but, of
course, could not discuss all significant alter-
native viewpoints.14
The Committee does have some
concerns about the ways and the extent to
which uncertainties in the epidemiological
data base were characterized. The reassess-
ment document (p. 7-77) refers to "uncertain-
ties associated with the epidemiologic evi-
dence." Some of these uncertainties are the
usual ones attendant upon a subject where
much research remains to be done and many
questions are still unanswered. The more
important uncertainties are those connected
with the epidemiologic method itself. Ob-
serving some unintended or "natural" experi-
ment in the real world, which is the essence
of observational studies like epidemiology,
has the enormous advantage that it involves
human beings living under conditions similar
to ones of concern to regulators and public
health officials. For epidemiology, the uncer-
tainties are largely associated with the ques-
tions of internal validity extensively discussed
in the Assessment itself (questions of bias,
chance and real effect). The reassessment
document did not discuss remaining ques-
tions of external validity, the most important
of which are the high exposure to low expo-
sure generalization. The EPA should com-
ment on this issue in any future revision, as
well as on the relationships between agricul-
tural and forestry, and environmental expo-
sure levels (as well as varying exposure routes
and patterns and associated environmental
conditions and chemicals in these situations)
and the cancers observed at those exposure
levels.15
4.5.2 Carcinogenicity of Dioxin-like
Compounds (Charge Question
11)
TCDD is one member of a large family
of halogenated polycyclic aromatic com-
pounds. The EPA reassessment document
describes such congeners and some of their
metabolic and carcinogenic effects. A num-
ber of other studies have demonstrated the
effectiveness of other dibenzodioxins and
dibenzofurans, both individually and in
mixtures, as promoting agents in the rat liver
model (e.g. Nishizumi and Masuda, 1986;
Waern et al, 1991; Shrenk et al, 1994).
Although the data is as yet too sparse to
make any extensive generalizations, it is
reasonable to hypothesize that many of these
congeners of TCDD will be effective promot-
ing agents and thus carcinogenic at some
dose.
14
Likewise, the Committee did not discuss in its
public meeting, or address in this report, all the relevant
epidemiological studies noted in the reassessment document
or the extant literature.
One Member of the Committee notes that the
reported effects of low-level exposure to forestry and
agricultural workers predicts overwhelming incidence of
certain tumors in the far more highly exposed production
workers. Those tumors are not in excess or are barely in
excess (see above) in the production workers. At least, this
absence of external validation casts doubt on the general-
ization of the forestry and agricultural studies. At worst, they
indicate that those studies are flawed.
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PAGE 50
Another large class of closely related
halogenated aromatic hydrocarbons are the
polyhalogenated biphenyls. Many of the
members of this class are promoting agents in
the rat liver system (Sargent et al., 1991;
Jensen and Sleight, 1986; Luebeck et al.,
1991; Preston et al., 1985) and in other organ
systems as well (Anderson et al., 1994). In
addition many, but not all, polyhalogenated
biphenyls interact specifically with the Ah
receptor (Kafafi et al., 1993) at KD (the appar-
ent equilibrium disassociation constant for
ligand binding to the Ah receptor) levels that
approach that of TCDD. However, the ma-
jority of the Committee concluded that the
structure, metabolism, gene regulation and
toxicities of this class, while overlapping with
some of the characteristics of dibenzodioxins
and dibenzofurans (Safe, 1990) are suffi-
ciently different from those of the latter to
argue that polyhalogenated biphenyls not be
a part of this document.16 They may be
considered for future studies on assessments
using this document as a model.
Since many dibenzodioxins and
dibenzofurans occur as components of mix-
tures, there have been several studies of the
carcinogenicity of such mixtures indicating
additivity of their promoting activity (Schrenk
et al, 1994; Huff et al., 1991). In some in-
stances synergy of components of mixtures of
biphenyls have been reported (Sargent et al.,
1991; 1992).
Although the discovery and character-
ization of the Ah receptor were delineated
using polycyclic hydrocarbons (halogenated or
not) as ligands (Thorgeirsson and Nebert,
16
Several Members disagree strongly with this
finding and recommend the inclusion of polyhalogenated
biphenyls in the assessment.
1977), it has been assumed that naturally
occurring and/or endogenous ligands occur.
Recent studies (Bjeldanes et al., 1991) identi-
fied some naturally occurring indoles as effec-
tive ligands. However, the contribution of
such agents to the "dioxin burden" as ligands
of the Ah receptor is unknown. Clearly more
studies in this area are needed.
In summary, dibenzodioxins and
dibenzofurans which have been studied as
congeners of TCDD, exhibit qualitatively
similar toxicities, ligand reactivity with the Ah
receptor, and show carcinogenic potential as
promoting agents. However, the data in this
field are too incomplete at this time to make
generalizations in the direct application of
findings with one member of the class, e.g.,
TCDD, to all others. Promoting activity of
mixtures of this class can be additive and, in
some cases, may be synergistic. The Commit-
tee (albeit with several Members taking excep-
tion) recommends that the polyhalogenated
biphenyls, although having many similarities
in their metabolic, toxic, and carcinogenic
effects to TCDD, should be considered in a
separate class and not considered in depth in
this document.
4.5.3 Carcinogenic Activities of Dioxin
and Dioxin-Like Compounds
(Charge Question 12)
The EPA reassessment document, in
describing the experimental evidence, makes
a clear distinction between studies that imply
TCDD as a multi-site, complete carcinogen, as
opposed to studies that emphasize the pro-
moting properties of the agent. The principal
animal assays that evaluated the carcinogenic
potential of TCDD and some of its congeners
are adequately reviewed. On occasion, how-
ever, emphasis is placed on the fact that
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PAGE 51
TCDD is carcinogenic well below the maxi-
mum tolerated doses; what should also be
noted is that quite often the response was
statistically not significant (e.g., skin tumors in
hamsters (Rao etal, 1988) and liver tumors in
mice (Sugar rt a/., 1979)).
In the document, the classification of TCDD
as a complete carcinogen is done on an operational,
not mechanistic basis. This is confusing since the
classical definition of a complete carcinogen
necessarily involves a consideration of the
mechanism(s) whereby the agent effects its
action. The term "complete carcinogen" has
been reserved, until the advent of this and
other recent documents on the carcinogenicity
of TCDD (Huff et al, 1994), for agents capa-
ble of inducing all stages of cancer develop-
ment, initiation, promotion, and progression
(Boyland, 1980; Pitot, 1990). TCDD, as
documented in the reassessment (as well as
from other sources), is incapable of initiating
cells in multiple in vitro and in vivo studies, and
has never been satisfactorily demonstrated to
have progressor activity. It should not be
classified as a complete carcinogen any more
than phenobarbital, phorbol esters, uracil or
galactosamine would be considered as com-
plete carcinogens. Thus, if the term "complete
carcinogen" is to be retained as a classification
of the carcinogenic action of TCDD, a full
definition of the term as used in the document
must be given to prevent the confusion noted
above. Furthermore, designation as a complete
carcinogen implies in the minds of most read-
ers direct mutational and clastogenic activity
of the agent, which the evidence does not
support for TCDD.
The reassessment document also de-
scribes a second set of studies in which TCDD
was characterized as having promoting capa-
bilities. TCDD is classified as an "... extraordi-
narily strong promoter of liver and skin
tumors." The following studies are refer-
enced in the EPA document as support for
this statement:
a) Liver studies:
1) Liver-tumor promotion by TCDD
following initiating treatment with
partial hepatectomy/DEN (Di-
ethylnitrosamine)was first described in
1980 (Pitot et al., 1980). In female
adult Charles River rats treated with a
high dose of TCDD following partial
hepatectomy, five out of seven eventu-
ally developed liver tumors vs. none
out of four in controls. This was ac-
companied by an increase of enzyme-
altered foci. No effects were seen in
five animals treated with a low dose of
TCDD. The findings are significant
when a one-tailed Fisher's exact test is
applied.
2) In another study with adult female
rats, a single dose of DEN was used as
initiator and TCDD as a promoting
agent (Graham et al, 1988). This
study also suffers from low statistical
power, and tumor data, at 60 weeks,
are only available for one (the highest)
out of three TCDD doses studied (5/8
vs. 1/5 in controls). According to the
authors, "The number of animals was
not sufficient to determine whether the
incidence in DEN initiated/TCDD-
promoted rats was different from that
seen in rats treated with DEN alone."
(A significant effect was claimed when
DEN/TCDD-treated animals were
compared to animals that had not
received DEN - clearly an inappropri-
ate comparison).
^TREASSESStNG DIOXtN
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PAGE 52
3) A third study (referenced several times
in the EPA document) was not pub-
lished in the peer-reviewed literature
(Clark et al, 1991) and the complete
data do not appear to have been pub-
lished elsewhere. The report should be
specific in this regard. Data on tumor
incidence are only given for intact and
for ovariectornized animals initiated
with DEN and treated with TCDD;
apparently only one TCDD dose was
used. No control data (rats initiated
with DEN and treated with solvent)
are presented. "When the available
data on liver tumor incidence are ana-
lyzed by Fisher's Exact test, they do
not support the assertion that ovariec-
tomy would provide a "protective ef-
fect" against liver tumor development.
However, analysis of the same data
with an uncorrected chi-square test,
which is more appropriate for such an
application (D'Agostino et al., 1988)
results in highly significant support
(p<.01) for the hypothesis of a mitiga-
tion of effect in ovariectornized rats.
4) Another study has become available in
the open literature since preparation
of the EPA reassessment document
(Sills et al., 1994). The group sizes of
animals used in this particular study
provide better statistical power (be-
tween 12 and 15 animals per group)
than do the previous studies. Despite
the larger numbers, the increased tu-
mor incidence in initiated-TCDD
treated female weanling rats (five out
of 15 animals) is not sufficiently high
to demonstrate a difference from the
controls (1 out of 12 animals) at a
conventional level of statistical signifi-
cance.
It is interesting to note that, taken
individually, two of the four studies on rat
liver tumor promotion by TCDD cannot
demonstrate a statistically significant effect, a
point that should be addressed in the docu-
ment. However, in all studies, there is evi-
dence of a TCDD effect and, if the data from
the four studies are pooled using appropriate
statistical methodologies, the promoting effect
of TCDD becomes highly significant.
Furthermore, there is a substantial data
base wherein, although no direct data on
tumor incidence or multiplicity are provided,
convincing evidence is given that treatment of
initiated animals with TCDD increases signifi-
cantly, and in a dose-dependent manner, the
presence of altered hepatic foci and other
signs suggestive of a strong promoting poten-
tial (Sills et al, 1994; Pitot et al., 1987;
Dragan et al, 1992; Buchmann et al, 1994;
Flodstrom et al, 1991; Waemrta/., 1991). A
recent and extensive study on the topic
(Dragan etal, 1992) emphasizes the complex-
ity of this particular endpoint. The EPA
document describes several mechanistic stud-
ies and attempts are made to link the promot-
ing activity of TCDD to such biochemical
events as enzyme induction, internalization of
EGFR, estrogen receptors, and similar end-
points. A recent study on inhibition of inter-
cellular communication by TCDD might be
added to this discussion (DeHaan et al,
1994).
b) Skin studies:
Promoting activity of TCDD was also
shown in two skin studies:
1) In 1982, TCDD was described as pro-
moting skin tumor development in
hairless mice (Poland et al, 1982a).
WE SCIENCE ADVISORY BOARD
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PAGE 53
The data presented in this paper fully
support the assertion that TCDD is a
skin tumor promoter.
2) A second experiment (Hebert et al.,
1990) claimed to confirm some of
Poland's observations, but when read
carefully actually did not quite do so.
The table reporting the incidence of
proliferative lesions does not indicate
statistically significant observations. If
the data are analyzed, only the num-
ber of mice with papillomas in the
lowest TCDD group is statistically
higher than in controls. This is in
contrast to the description of the data
given by the authors: "With the excep-
tion of the lowest-dose TCDD group,
all mice initiated with MNNG and
treated with promoters had an in-
creased number of papillomas and
nodules" (p. 366). The document
should be corrected. Significant skin
tumor-promoting responses were seen
with the congeners PCDF and HCDF,
but there was a paradoxical dose-effect
relationship throughout (e.g., lower
doses produce higher responses), and
this anomaly should also be pointed
out.
One aspect of this particular study is
incorrectly represented in the EPA document.
On page 6-23 of the EPA document, line 4-8,
it is stated:
"Results (of the Hebert study) demonstrated
that 2,3,4,7,8-CDF was 0.2 to 0.4 times as
potent as TCDD and that 1,2,3,4,7,8-CDF
was 0.08 to 0.16 times as potent as TCDD.
These data suggest that the tumor-promoting
potencies of structural analogues of TCDD,
like the promotion of liver tumors, reflect
relative binding properties of the Ah recep-
tor."
This statement is in contrast to what Hebert
et al. (op cit.) said about the same data (p.
366): "The lack of a clear dose-response
makes it impossible to compare the relative
potencies of the three compounds as promot-
ers or to comment on the validity of the TEF
j
approach for promotion as an endpoint."
The potency estimates of 0.2 to 0.4 or
0.08 to 0.16, attributed mistakenly in the
EPA document to promoting activity, are
derived from a comparison of the relative
changes in body weight and organ/body
weight ratios (op cit. p. 372). This error
should be corrected in the revised document.
c) Lung tumors:
The claim that TCDD promotes lung
tumors is based on one experiment in which it
was found that in ovariectomized rats, treated
with DEN and given TCDD, lung tumors
developed (four in 39 rats), whereas none
were found in 37 intact animals treated with
DEN and TCDD (Clark et al., 1991). No
data on animals treated with DEN alone are
available. The study was not published in the
open literature (which should be noted in the
document). The effect is statistically signifi-
cant however, when analyzed with the appro-
priate test (uncorrected Chi-square).
A second study on the promotion of
lung tumors in mice by TCDD (Beebe et al.,
1995) reported that TCDD enhances tumor
multiplicity in the lungs of mice treated with
DMN. This study needs to be discussed
within the larger context of the murine lung
tumor model being a representative system for
tumor promotion.
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PAGE 54
Although the EPA document provides a
good over-all view on the studies done on liver and
skin tumor promotion by TCDD, both a more
critical analysis of the database and a more in-
depth discussion of mechanisms underlying tumor
promotion, should be added, Although some
investigators believe that tumor promotion
must result in neoplasms, the stage of promo-
tion, in fact, only involves the development of
preneoplastic lesions ranging from enzyme
altered foci in rodent liver models to early
papillomas in multistage epidermal carcino-
genesis in the mouse. In model systems
wherein the stage of promotion can be studied
independent of the stage of progression, a
number of characteristics of the stage and of
the effects of promoting agents have been
delineated (Yuspa and Poirier, 1988;
Rahmsdorf and Herrlich, 1990; Pitot, 1993).
Primary among these characteristics is the
reversibility of the stage both at the level of
gene expression and lesion growth. Promoting
agents themselves typically exert their effects
via receptor mechanisms and signal transduc-
tion. Promoting agents in various systems in
vitro and in vivo inhibit programmed cell death
and apoptosis (Schulte-Hermann etal., 1991;
Magnuson et al, 1994; Wright et al, 1994).
Although there are some other promoter hallmarks
not yet established for TCDD, it conforms to all the
characteristics of promoting agents noted above, and
thus one is led to the conclusion that any carcino-
genic effect of prolonged TCDD exposure is primar-
ily, if not exclusively, the result of its action as a
promoting agent.
All of the evidence to date argues strongly
that TCDD exerts its carcinogenic effect primarily
through its effectiveness as a promoting agent,
stimulating cell replication in a reversible manner
and inhibiting apoptosis, both mechanisms presum-
ably mediated through the Ah receptor and associ-
ated transduction mechanisms. TCDD is not a
complete carcinogen and thus to avoid confusion
should not be designated as such. Many struc-
tural congeners of TCDD appear to act in a
similar manner to dioxin but there are as yet
insufficient data to make any generalizations
with respect to mechanisms of cartinogenesis
or toxicity for all such structurally related
chemicals.
Finally, EPA needs to consider to what
extent data on female rat liver foci should be
used in modeling the tumorigenic activity of
TCDD, be it as a promoting agent or as an
"incomplete" carcinogen. The ratio of foci to
tumors is far from being 1:1. Many foci may
disappear when treatment is withdrawn; on
... any carcinogenic effect of
prolonged TCDD exposure is
primarily, if not exclusively, the
result of its action as a
promoting agent.
the other hand, it is impossible that foci can
grow to the size suggested by mathematical
models, since one focus would occupy the
entire liver, a fact pointed out in the docu-
ment. Attempts to incorporate data into
models and risk assessments will require a
critical in-depth analysis of the biology of
altered hepatocyte foci.
4.5.4 Characterization of
Dioxin/Dioxin-like Compounds as
Human Carcinogens (Charge
Question 13)
Dioxin has been shown to produce
malignancies in rats and mice of both sexes
Although the epidemiological evidence Unking
dioxin exposure to the genesis of malignant
neoplasms is limited, and does not offer
compelling evidence of carcinogenicity to
THE SCIENCE ADVISORY BOARD
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PAGE 55
humans when taken by itself, this evidence is
by no means inconsistent with such an effect.
Almost all Members of the Committee therefore
concur with the judgment that 2,3,7,8-TCDD,
under some conditions of exposure, is likely to
increase human cancer incidence.17 The conclusion
with respect to dioxin-like compounds is less firm.
Since the information from animal studies is
much less robust, and that from human
studies often Limited by uncertainties about
exposure, the judgment depends wholly on
the similarity between the chemical effects of
s
dioxin and those of its congeners, the
dibenzofurans and other related compounds.
For the congeners and dibenzofurans, enough
evidence indicating similarity of biologic
action exists to adopt the presumption that
they too are likely to be carcinogenic to
humans under some conditions (although in
nearly all instances the doses required to
produce the same incidence would be higher
than those for dioxin).
With respect to the polyhalogenated
biphenyls which share only some of the
physical characteristics and activities of
dioxin, the degree of carcinogenicity has not
been formally assessed in the present EPA
document. However, at least one other
authoritative body, the International Agency
for Research on Cancer (IARC), has con-
ducted such a formal assessment and judged
both polychlorinated (IARC, 1974; 1978a;
1987a) and polybrominated (IARC, 1978b;
1986; 1987b) biphenyls to be probable
human carcinogens, both on the basis of
animal studies as conclusive as those for
dioxin, and, in the case of PBBs, with limited
17
Several Members contend that no epidemi-
ological study has produced evidence that is widely accepted
by the scientific community, including the IARC, as being
convincing for the human carcinogenicity of dioxin.
evidence from human studies. The Commit-
tee did not dispute the IARC judgement that
PCBs and PBBs as likely to cause human
cancer under some conditions of exposure.
The Committee agrees that assignment of the
dioxins, the PCBs, or PBBs to one of a mutually
exclusive and collectively exhaustive set of carcinoge-
nicity categories considerably oversimplifies the
state of the science in most instances, possibly
excepting those compounds for which there is an
abundance of uniformly consistent evidence.
However, prudent regulators must act and
cannot base their regulation on ambiguous or
inconsistent detail. They must make every
effort to treat dangers of similar magnitude
evenhandedly, even when there are limited
management options. Although the level of
exposure and the potency of the agent are
measured on a meaningful continuous scale
and can be incorporated into decisions on
the basis of unambiguous continua, the
degree of uncertainty re the human carcino-
genicity of a compound is not measured in
this manner, but is usually considered as a
categorical term. It is desirable that consis-
tent criteria for this inevitable categorization
are employed.
Under the proposed revisions to EPA's
guidelines, there are essentially three alterna-
tive choices (unless "known to" is considered
an alternative to "likely to"):
a) likely to cause cancer under some con-
ditions;
b) not likely to cause cancer; and
c) likelihood cannot be determined.
In Chapter 9 of the reassessment docu-
ment, the basis for a detailed multidimen-
sional assessment is described and the vari-
ous caveats are underlined, but a choice
REASSESSING DIOXIN
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PAGE 56 =
between these three alternatives (actually,
between the first and the third-see below) is
still required.
Under the 1986 EPA cancer guide-
lines, three more levels of carcinogenic evi-
dence, with mutually exclusive descriptive
terms are provided, giving regulators more
alternative choices. These choices include
Group A -- human carcinogen; B, probable
human carcinogen on trie basis of limited
information from human studies as well as
animal studies; Group B: -- probable human
carcinogen on the basis of animal studies only;
Group C - possible human carcinogen; Group
D not classifiable; and Group E evidence
of non-carcinogenicity for humans.
In the case of dioxin, even if the addi-
tional alternatives were provided, virtually all
of the Committee believes that the animal
studies would be categorized as "sufficient"
and the studies of humans as "limited," pro-
viding for an overall categorization of Blf
which would be expressed verbally as "Proba-
bly Carcinogenic to humans with limited
supporting information from human studies."
PBBs and PCBs would receive ratings of El
and B2, respectively.
There is some merit in the provision of
a slightly more detailed set. of alternatives, but
the provision of Group E, as well as of the
proposed revised scheme category of "not
likely to cause cancer" may be ill-advised.
Since all mechanisms of cartinogenesis are not
completely understood, and all sets of study
conditions (species, dosage, co-carcinogens,
etc.) cannot be foreseen, it seems unwise to
suggest that evidences of non-carcinogenicity
could ever be universally generalizable, at least
as worded (with no reservations). Were one
to employ a restrictive phrase such as "under
study conditions judged to replicate most
recognized conditions of human exposure,"
the class would be more defensible, although
one still would need to draw a difficult line
based on the conditions of the negative stud-
ies.
4.6 Developmental Toxicity and Ani-
mal NOAELs (Charge Question 14)
The specific issue of animal No Ob-
served Adverse Effect Levels (NOAEL), as it is
framed in the Charge, is inconsistent with the
question posed concerning the use of the
Reference Dose (RiD) in evaluating incremen-
. ..the animal studies would be
categorized as "sufficient" and
the studies of humans as
"limited," providing for an
overall categorization of B1...
tal exposures (see health question 18), and on
pages 9-69 ff of the reassessment document.
The latter question derives from the argument
that RfDs (which are based on NOAELs), are
inappropriate for the current assessment
because background levels may be significant.
If that argument is sound, why should it not
apply to animal models?
Furthermore, even if the effect level
procedure could be defended for animals, is it
the optimal metric? The basis for Charge
question 18 is the reasoning that the proper
evaluation of risk in this context is the incre-
ment per arbitrary unit of exposure, expressed
as some measure of body burden. This is one
instance in which dose-response modeling, as
by Benchmark doses, may confer a substantial
advantage. What is gained by using NOAELs
and RfDs? In a somewhat analogous situa-
tion-the relationship between lead exposure
THE SCIENCE ADVISORY BOARD
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PAGE 57
(defined as blood lead level) and IQ--the risk
is better expressed as 0.25 IQ points for each
l//g/dL than as an RfD. This would be a
more appropriate model for TCDD because,
as with lead, the location of a threshold for
developmental outcomes is rather uncertain.
If, for consistency with traditional
EPA practices, a NOAEL were to be ex-
tracted from the animal data, 1 ng/kg day'
appears to lie in an ambiguous zone. Murray
et al. (1979), in a multi-generation study,
found that 10 ng per kg'1 per day"1 of TCDD
lowered the body weights and food consump-
tion of f 1 and f2 rats and also affected post-
natal survival. At 1 ng per kg"1 per day"1 both
increases and decreases were noted among
the survival indices of f 1 litters. A NOAEL of
1 ng per kg~l per day~l would be a reasonable
figure if based on these data.
On the basis of other endpoints,
however, it may not be as reasonable. Mon-
keys whose mothers were undergoing expo-
sure to TCDD in food (Schantz et al, 1989)
were impaired, relative to controls, in a
behavioral task called reversal learning. They
also displayed differences from controls in
social behaviors (Schantz and Bowman,
1992). The mothers had been fed a diet
containing 5 ppt of TCDD. The offspring
tested for learning, from two cohorts, were
born a mean of 16 months or 36 months,
respectively, from the initiation of exposure.
Social behavior was assayed in the first
cohort. On the basis of total TCDD con-
sumed bv the time of birth, the mothers had
j
been exposed to about 0.125 ng/kg daily.
Copulatory behavior in male rats and
measures of morphological and endocrine
development showed adverse effects of prena-
tal exposure to TCDD at a dose of 64 ng/kg
to the mother on gestation day (GD) 15
(Mably et al., 1992). If a half-life in rats of
24 days was assumed for 1 ng/kg day'1,
steady state would be reached in about 120
days, and total body burden would be about
34 ng/kg. For this reason, because 64 ng/kg
is actually a frank effects level (PEL), 1
ng/kg/day would be a dubious NOAEL. The
problem lies in distinguishing between the
acute effects of a dose delivered on GD 15
and an equivalent body burden stored largely
in fat tissue. TCDD stored in this way might
be viewed as functionally dormant, although'
the Schantz and Bowman data cited above
argue against such an interpretation. Com-
parisons between acute and steady-state
exposures for endpoints such as those above
have not been carried out despite the signifi-
cance of this issue. Such studies should be
relatively straightforward, though tedious, to
conduct.
In humans, TCDD and other lipophilic
agents could enter the blood if fat stores
were to be drawn upon during periods of
caloric deficit. Weight-loss diet books con-
sume enormous shelf space in bookstores and
weight-loss regimens are not a guarantee
against pregnancy. Although the increment
in blood level of lipophilic toxicants during
such a regimen may be small, it may not be
insignificant, and fetal tissue might accumu-
late these increments. Release of such agents
during gestation, in the small proportion of
cases in which the mother fails to consume
adequate nutrition, might lead to their accu-
mulation in fetal tissue. Moreover, the fetus
will deplete the mother of nutrients even at
the cost of her own nutritional status. Lacta-
tion is another situation in which lipophilic
agents are released and consumed, as
REASSESSING DIOXIN
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PAGE 58
discussed in the document.18 The lead paral-
lel should again be considered. During
pregnancy, lead is released from bone as a
consequence of to hormonal changes. The
same mechanism would not pertain to
TCDD, but the details of gestational phar-
macokinetics is a question that deserves to
be further pursued.
Endpoints other than those discussed
above (sexual function in rats and learning in
monkeys) should also be considered. The role
that developmental toxicity has assumed in
risk assessment stems from an extensive body
of literature indicating the exquisite vulnera-
bility of the fetus. The developing brain is
especially sensitive. But the rodent brain may
not reflect all aspects of this sensitivity.
Recall that rats are born, from the standpoint
of brain development, at the end of the
second human trimester. Processes that
occur in humans during the third trimester,
such as synaptogenesis and the maturation of
neurotransmitter systems, occur postnatally
in rats. For this reason, confining develop-
mental treatments in rats to the prenatal
period may underestimate the full impact in
humans of gestational exposure. The behav-
ioral pharmacology literature offers many
examples of the sensitivity of the neonatal
period in rodents and Bjerke et al. (1994)
and Bjerke and Peterson (1994) reported
that lactational as well as prenatal exposure
proved necessary to induce feminization of
male rat copulatory behavior.
A study just published, and not available to
the Committee at the time of the review, reports that higher
levels of PCBs, PCDDs, and PCDFs in breast milk were
related to reduced neurological optimality, and higher levels
of pknar PCBs were associated with a higher incidence of
hypotonia (Huisman et al., 1995).
Further, although sexual development
has become a focus of TCDD toxicity re-
search, it is crucial to recognize that the com-
plex unfolding of brain developmental pro-
cesses in the presence of certain levels of
TCDD could also exert an impact on other
indices of brain function and structure. The
substantial levels of the Ah receptor in devel-
oping brain and its virtual disappearance
later in life argue that sexual development is
unlikely to be its only role. The report by
Schantz and Bowman (1989) hints at addi-
tional outcomes. Note, further, that copula-
tory behavior and genital structure reflect
only limited facets of sexual maturation.
Copulatory behavior and reproductive mor-
phology may not be the best endpoints to
examine for prenatally-exposed females.
Other sexually dimorphic behaviors, based on
cognitive function, for example, might also
reveal consequences of TCDD exposure if
examined. And, for males, sexual motivation
is an arena independent of copulation itself.
The preceding comments presume that
the total exposure is to TCDD. They make
no assumptions about the validity of TEQs,
which is a separate, but related issue. Chap-
ter 5 of the reassessment document neither
cited nor discussed the findings of several
researchers on the effects of PCBs (e.g.,
Jacobson and Jacobson, 1994 and Gladen, et
al, 1988). Jacobson and Jacobson (1994)
reported that higher gestational exposure to
PCBs, as reflected by cord serum levels and
maternal consumption of Lake Michigan fish,
was correlated with lower scores on tests of
psychological development. A large cohort in
North Carolina was reported by Gladen et al.
to show also evidence of poorer performance
associated with higher prenatal exposure to
PCBs. Jacobson and Jacobson suggested that
the PCBs themselves, particularly the
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PAGE 59
coplanar PCB congeners, could be more
responsible for such effects than the much
lower concentrations of dioxins or
dibenzofurans in these mixtures, but the
relative potency issue would have to be
clarified. PCDFs in the Yusho and YuCheng
exposures are currently held to be primarily
responsible for the observed toxicities. The
North Carolina and Lake Michigan studies,
however, are significant because they indicate
adverse neurobehavioral development associ-
ated with current environmental levels of this
class of compounds.19
Another reason for reevaluating the
current NOAEL are data strongly suggesting
that TCDD is a more potent teratogen in
mice than previously supposed, and that this
effect occurs at doses considerably lower than
those causing liver enzyme induction. (Bjerke
et al., 1994) These data are coupled with
findings from various laboratories showing
changes in hormone levels controlling repro-
ductive and developmental processes and
reproductive success in offspring of treated
animals.
In summary, the current NOAEL of 1
ng/kg day'1 rests on a debatable foundation, and it
would be appropriate to reevaluate it.20 One
reason for a fuller examination of these issues
is that such a NOAEL is likely to be used in
evaluating the risks of human exposures,
given that crude clinical evidence for develop-
mental and reproductive effects attributable
to TCDD is necessarily quite limited. The
19
These findings were not discussed at the
Committee's public meeting, but came to light during the
preparation of this report.
Several Members of the Committee suggest
that the immediate inference of this statement is that the
NOAEL should be lowered.
neurobehavioral studies on PCBs offer direc-
tions for additional research, but forcing such
studies into an effects level mold, as noted
earlier, is a premature use of the data.
4.7 Human/Animal Databases: Poten-
tial for Immunotoxicity (Charge
Question 15)
There was a consensus among most Com-
mittee Members that, overall, Chapter 4 of the
reassessment document provided an accurate,
current summary of the immunotoxicology associ-
ated with TCDD and related compounds in
humans and experimental animals. However,
the Committee has some concerns (and
noted some omissions) pertaining to immu-
nology and the interpretation of certain
experimental results, in Chapter 4, and
particularly, Chapter 9. Although the overall
data suggest that dioxin and related com-
pounds can produce immune effects, there
are insufficient supporting data to establish
fully whether these effects can occur at or
near two orders-of-magnitude above back-
ground levels.
The document hedges on whether there
was sufficient evidence to state that this class
of compounds can cause immune effects in
humans. In some instances there was a
"YES" and in other sections a statement of
"UNSURE." Based upon the extensive experi-
mental animal, and the very limited human,
database the majority of the Committee agreed
that sufficient data exist to indicate immune effects
could occur in the human population from exposure
to dioxin or dioxin-like agents at some dose levels.
However, the large variability in the immune
response in humans, the limited numbers of
tests conducted, and the poor exposure
characterization of the populations that have
been studied prevent definitive conclusions
REASSESSING DIOXIN
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PAGE 60
as to sensitivity. This is not to say that
humans are more or less sensitive than other
species, only there are not sufficient clinical
data to assess human sensitivity.
The most notable documented im-
mune effects in humans occurred in the Tai-
wan population exposed to contaminated rice
oil where both immunosuppression and in-
creased infections were observed, presumably
resulting from exposure to furans and PCBs
(Wu et al, 1984; Chang et al, 1982a; Chang
et al., 1982b: Chang et al., 1981). Some
studies have reported changes in
immunoglobin (Ig) levels (Jennings et al.,
1988) and NK cell activity (Jennings et
fl/.,1988; Svenssonrtfl/., 1991). Other studies
have reported no effects (such.as the Ranch
Hand (USAF, 1991) and Seveso studies
(Mocarelli et al, 1986; Mocarelli et al.,
1991)). but, as with the positive studies, the
actual exposure levels and study design, were
not adequately addressed in the document nor
were they critically reviewed.
Although not well-established, several
studies of humans (Chang, et al., 1981; Bekesi
et a/,,1985) exposed to halogenated aromatic
hydrocarbons (HAH), as well as of monkeys
(Hong et al, 1989; Tryphonas et al., 1989),
reported that a slight reduction in CD4"1" cells
occurred. Although this may or may not
translate to a significant health effect, these
cells are involved in regulating immune re-
sponses and reduced CD4/CD8 ratios are a
hallmark of immunosuppression. It may be
argued that any reduction in CD4 cells could
lead to such potential health effects as in-
creases in infectious disease, given that a large
population is affected. Of interest to this
discussion is a recent study by Oughton et al.
(1995) which found no decrease in total
CD4+ cells in TCDD-treated mice following
low-level chronic exposures. However, within
the CD4+ subset, a modest decrease was
observed in the proportion of CD4+ memory
cells as denned by concomitant expression
ofPgp-1 CD45RB. The clinical significance of
this change on immunocompetence is pres-
ently unclear. Similar changes in immune
system functioning have, however, been
suggested by some investigators to be signifi-
cant to HIV pathogenesis (Janossy et al.,
1993; Lim et al., 1993; Cameron et al., 1994;
Jaleco et al., 1994), indicating that the de-
crease in these cells may be associated with a
decrease in immunocompetence.
Although the immune system is a sensi-
tive target to HAHs in experimental animal
species, as presented, the EPA document does
not provide convincing evidence to indicate
that background or near background exposure
levels to dioxm-like compounds in industrial
countries are sufficient to affect the immune
system. Given the current methods available
for testing, it would be unlikely that this could
even be determined in humans, and one would
have to rely on experimental animal data or
highly exposed populations to determine
effects at the low-end of the dose-response
curve, or in vitro approaches using primary
isolated human lymphocytes and human
lymphoid cell lines. Changes reported at very
low levels of exposure in two or three of the
experimental animal studies are certainly of
concern, but need to be confirmed and repro-
duced and, until then, cannot yet be used to
support a "background" level effect. However,
the No Observed Eeffects Level (NOEL) and
ED50 (dose effective for 50% of the recipients)
for suppression of the T-dependent antibody
response, in sensitive mouse strains, has been
reproduced in many labs using different
experimental designs and can be used to help
support or refute that "background" or one
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PAGE 61
to two orders above background is signifi-
cant. In this respect, the recent paper by
McGrath et a/. (1994) is relevant to this issue.
Human studies undertaken to study
the immune system of exposed populations
have not used the appropriate test battery
for this class of chemicals. The "gold-stan-
dard" test (i.e., suppression of the primary
antibody response following immunization)
was not employed in any of the human test
panels, although this is a hallmark in experi-
mental animals. The exception to this is the
as yet, unpublished study on the Inuit popu-
lation (Dewailly, in press).
Chapter Four discussions pertaining
to in vitro effects, although complete, con-
cluded these tests have limited relevance as
culture conditions may play a significant role
(i.e., serum effects). The Committee felt
that this was not a legitimate argument as
numerous investigators have successfully
reproduced in vivo observations using well-
defined in vitro culture conditions. The in
vitro studies have provided considerable
understanding of the cellular and molecular
mechanisms of TCDD and should not be
understated.
Although data exist suggesting that
non-Ah receptor mechanisms may play some
role in immunotoxicity, definitive evidence
for this is lacking and will require using
novel approaches such as receptor knockout
mice or pure binding antagonists. The
Committee agreed that the majority of evi-
dence indicates that imununotoxicity (partic-
ularly suppression of the antibody response)
by dioxins is presumably Ah-receptor depen-
dent. The disappearance of quantitative
differences in immunosuppression between
Ah-low and Ah-high responsive mice after
sub-chronic exposure suggests that chronicity
can override acute exposure resistance and
may suggest an even "greater" hazard. Based
upon existing evidence, the involvement of
an endocrine-related non-Ah receptor mecha-
nism impacting on immunocompetence may
be overstated in the document.
Numerous studies suggest that the
immune system is a sensitive target for
dioxin-like compounds in experimental ani-
mals. There are species/strain differences in
the sensitivity, but the effects tend to be
similar with the most sensitive indicator (at
least in adult animals) being changes in the
primary antibody responses; similar effects
occur in many test species (guinea pig, rab-
bit, monkey, etc.). As such, it would be
more appropriate to indicate that differences
in animal sensitivity exists rather than "vari-
ability in response" as this suggests a differ-
ent meaning. One might expect that similar
variability would also exist in the human
population, but this has not been examined
when the limited clinical studies have been
undertaken.
Multiple cellular targets exist for
immunotoxicity by dioxin-like compounds
including both T and B lymphocytes as well
as lymphoid-associated tissue (e.g., thymus
epithelium) and marrow stromal elements.
Debate exists as to the "most sensitive" or
"most proximate" target and not which cell
is the target. The reassessment document
should be more clear on this point. (Table 9-
2 is incorrect as the immune system of
rabbits and fish are also affected).
Studies conducted in a number of exper-
imental species, including mice and monkeys,
indicate that the antibody response to a T-
dependent antigen is the most sensitive and
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PAGE 62
reproducible indicator for immunotoxicity in
adult animals. The ED50 in sensitive strains of
mice is approx. 0.7 Mg/kg. Several other
responses have been shown to be more sensi-
tive but have not been confirmed or repro-
duced by other research groups. Chapter 9
gives undue weight to these unconfirmed or limited
studies (see Table 9-5), and fails to discuss the
highly reproducible and widely used primary anti-
body suppression studies.
Results for the host resistance tests are,
for the most part, consistent with the immune
affects. One obvious exception to this are the
influenza challenge studies conducted in mice
(G. Burelson, in press), where disease occurs
at much lower dose levels than do immune
changes. As this directly relates to human
health, the mechanism and relevance of these
observations, which of course were not avail-
able when the reassessment was developed,
need to be addressed in the future revision.
The recent observations reported by the same
author in rats (G. Burleson, in press) should
also be discussed.21 This new study helps
increase the validity of the preceding observa-
tion, although additional studies are war-
ranted to help elucidate the mechanism. It
would argue that a very specific component
(perhaps immune/perhaps not) is altered, and
at extremely low concentrations.
Chapter 9 should also include a table of
confirmed laboratory results (i.e., the PFC pri-
mary response) which provide EDSO, ED,, and/or
NOELs. A separate table for suggestive
results (not yet extended at low doses) can
then be included and identified as such.
The two in-press studies noted here were not
available to most Members of the Committee during the
review process; several Members therefore cannot endorse
these specific findings at this time.
The text of these tables should include a
critical review of the data, the most repro-
ducible and sensitive indicators, and a clear
and logical presentation of how these data
were used to determine that exposures at 1
or 2 orders-of-magnitude above background
levels have potential human health effects.
4.8 Other Effects (Charge Question
16)
The Committee had no specific con-
cerns with the manner in which the topic of
"other effects" is covered in the reassessment
document. There has been considerable
expansion of the knowledge base since the
document was issued, however, and these
gains should be addressed in any revision.
Specifically, major growth has taken
place in our understanding of the biological
and biochemical effects of TCDD and re-
lated members of this class, and in the whole
area of receptor biology and signaling biol-
ogy, and these gains should be factored into
the revision.
4.9 Dose-Response
4.9.1 Approaches to Dose-response
Determination for Cancer
(Charge Question 17)
There was public expectation that the
reevaluation of the carcinogenic potency of
dioxin would be comprehensive and would
incorporate extensive new data generated for
that purpose. The Committee was disap-
pointed to see that, in addition to data from
the Ko'ciba et al. (1978) bioassay (which
formed the basis for EPA's earlier estimate of
cancer potency for TCDD), the only addi-
tional data used in EPA's quantitative analy-
' THE SCIENCE ADVISORY BOARD
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sis was from the Maronpot et al. (1993)
gavage study.
The only use that EPA made of
pharmacokihetic modeling in its quantitative
analysis was in making correlations between
estimates of two-stage model parameters and
outputs of pharmacokinetic models (Appen-
dix D of the reassessment document). This
is a very limited use of the physiological and
pharmacokinetic information (although the
Committee is aware of the problems involved
in using the extant PBPK models-see the
discussion in sections 4.1.1 and 4.1.2); more-
over, the description provided in Appendix D
is not sufficient to enable the reader to
understand what was done. This lack of
clear exposition needs to be corrected in the
revised document.
Not only is EPA's risk assessment of
dioxin extremely important in its own right,
it represents EPA's first application of so-
called "biologically based" models. Conse-
quently, it may set a precedent for future
analyses. It is thus important that the analy-
sis be clearly presented .so that its scientific
justification and usefulness can be assessed.
EPA should describe its analysis in sufficient detail
that it can be fully understood by the reader, to the
point of reproducing the analysis if desirable. The
reasoning and analysis that led EPA to pro-
pose its preferred model must be clearly
explained. The sensitivity of the results to
alternative models or assumptions must also
be presented. Unfortunately, EPA's descrip-
tion of its analysis is lacking in clarity, in
details, and in supporting documentation.
The description of the analysis relied
upon by EPA consists of a single paragraph
at the bottom of page 8-45. The resulting
. PAGE 63
model is described in broad terms as the
"most parsimonious two-stage model" that
agrees with the tumor incidence data and
focal lesion data. EPA must describe its analy-
sis in sufficient detail to allow the reader to under-
stand how EPA arrived at its preferred model and
how robust those results are - i.e., to what extent
would other assumptions be reasonable, adequately
fit the data, and lead to different levels of risk.
For example, EPA's preferred analysis uses
data from a feeding study and a gavage study
and thus had to make assumptions in order
to combine data from two different types of
studies. EPA does not describe how this
issue was handled, nor detail the necessary
assumptions.
Also, EPA does not describe clearly
what data were used in its preferred analysis.
It states only that the tumor incidence data
from the Kociba et al. (1978) study and the
focal lesion data from Maronpot et al. (1993)
were used. The precise form of the tumor
data (whether individual animal time-to-
tumor data or summary data) is not stated.
Similarly, the reader is not informed as to
whether the data from Maronpot. et al.
involving initiation with DEN or the data
not involving such initiation were used in
EPA's preferred analysis.
The focal lesion data used in develop-
ing EPA's cancer risk model are not from the
published Maronpot et al. (1993) paper but
are unpublished results from that study.
That fact should be clearly indicated. More
importantly, the actual data used by EPA
should be made accessible to the reader, by
including them in an appendix, if necessary.
If time-to-tumor data were used, an
assumption was required as to the context in
which the hepatocellular tumors from the
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PAGE 64
Kociba et al. (1978; 1979) studies were
observed (whether incidental, fatal or some
combination). This assumption is not stated,
and it may have an important effect upon
EPA's conclusions regarding the fits to the
data of various models.
Appendix C contains additional details
of some analyses, but not the ones used to
derive EPA's preferred cancer model. A con-
siderable portion of Appendix C is devoted to
discussing the non-identifiability of some
parameters in certain applications of the two-
stage model. In some of these instances, EPA
is attempting to estimate up to 16 parameters
from what are essentially four data points. It
is not surprising that some of the parameters
are not identifiable. The last paragraph in
Appendix C is particularly disturbing. It
starts with the assertion that the calculations
have "hidden assumptions" that can have a
bearing on the interpretation of the results. It
then goes on to list some of these "hidden
assumptions" and ends with the statement
that the analysis is very sensitive to the choice
of values for the radius of a cell and to the
(assumed) minimum size of a detectable
focus. This paragraph (and particularly the
last statement re sensitivities of the analysis)
raises serious questions as to the reliability of
EPA's cancer risk assessment. No information
is provided on the cell radius or minimum
detectable focus size assumed in EPA's analy-
sis. In fact, this is the only mention that
either of these two quantities are required at
all in the analysis. EPA must provide enough
detail in its analysis to permit the reader to deter-
mine how these values were used in the analysis,
how EPA selected those values, what values were
selected, and the sensitivity of EPA's risk assessment
to those selections.
EPA must clearly distinguish between
what is being assumed (i.e., what is going into
the modeling) and what is being concluded as
a result of the modeling. Although EPA's
preferred dose response model is linear, it seems clear
that a threshold model would provide an equivalent
or nearly equivalent description of the data. This is
the most important issue in the dose response-model-
ing and should be thoroughly explored in EPA's
analysis.
Even if EPA's risk assessment based on
the animal data is correct, without additional
assumptions regarding the relative sensitivities
to dioxin of various types of tumors in hu-
mans and animals, the risk assessment based
upon animal data only provides estimates of
the risk of liver tumors in a single strain of
female rats. Therefore, despite limitations in
the human data for dioxin, it would have been
appropriate for EPA to have conducted a more
comprehensive analysis of the human data.
EPA's risk assessment based on human data is
derived from the published data from three
studies. Reliance on these published data
necessitated a number of assumptions and
approximations by EPA that could have been
avoided by use of the raw data from other
studies. The Committee also recommends
that the data from the Ranch Hand cohort,
when published, be considered for inclusion in
this analysis.
The cancer risk assessment models
applied to the human data by EPA are con-
ceptually flawed.22 Both the additive and
multiplicative models express the cancer
mortality rate at a given age as a function of a
summary measure of exposure. Clearly, this
Several Members of the Committee contend
that the cancer risk model is not particularly "flawed," but
represents an acceptable approach.
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PAGE 65
summary measure should involve only prior
exposures and not future exposures. How-
ever, the summary exposure measure used by
EPA is average lifetime exposure, which in-
volves both past and future exposures. A
practical consequence of this model
misspecification is that in the case of the
additive model, the increased mortality rate
under constant exposure is independent of age
(e.g., a person has the same probability of
dying of a dioxin-induced cancer between the
ages of one and two as between the ages of 70
and 71), which is clearly inappropriate. EPA
appeared to recognize this and made a com-
pensating ad hoc adjustment to the risk esti-
mate obtained from the additive risk model.
The Committee recommends that both the
additive and multiplicative models be refor-
mulated to incorporate more biologically
plausible summary exposure measures (e.g.,
cumulative past exposure).
In EPA's cancer risk calculations based
upon epidemiological data, exposures in
dioxin-exposed subcohorts were summarized
by the median exposure. The stated reason
for choosing the median (over, say, the mean)
was that body levels were "quite variable and
not symmetrically distributed." Neither of
these assertions appear to be supported by the
draft document. At any rate, these are not
appropriate reasons for selecting the median
over the mean as a summary measure of
exposure, and there appears to be no clear
reason stated for preferring the median over
the mean. This choice would not be required
if the raw data were used in the analysis,
which illustrates an advantage of basing an
analysis upon the raw data.
Given the problems and limitations
identified with the analysis, it is not clear that
this work added significantly to our under-
standing of the dose-response for TCDD.
Rather than giving a high priority to refining
these techniques at the present time, the
Committee recommends that EPA review this
effort, and communicate clearly the strengths
and limitations of the work. The Agency
should evaluate critically the potential for
future work in this area to elucidate the dose-
response for TCDD in humans.
4.9.2 Use of the RfD in Evaluating In-
cremental Exposures (Charge
Question 18)
The question of possibly rejecting of the
Reference Dose (threshold) approach for
evaluating incremental exposure because of
the existing background levels relates also to
health Charge questions 14 and 17 (as noted
earlier). All three issues are part of a more
fundamental problem which has not been
addressed and needs to be included to provide
balance to the reassessment document. This
fundamental issue concerns the basis for the selection
of the dose response relationship to be used in
assessing the (non-cancer) adverse effects of dioxin.
The selection of the dose response function
clearly distinguishes the EPA approach from
that of some (but not all) other agencies and
bodies which have carried out similar risk
assessments on dioxin. Although all of these
groups used the same toxicologic and epidemi-
ologic data bases as EPA, all except EPA have
elected to use some type of threshold and
safety factor methodology for their health risk
evaluation. Chapter 8 of the reassessment docu-
ment needs to describe and evaluate this alternative
dose response relationship, discuss the approaches
and findings of the other relevant agencies, and
justify the basis for selecting another approach.
Although the Agency concludes (page 8-
13 of the reassessment document) that the
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PAGE 66
use of the linear multistage model (LMS)
needs to be re-evaluated, the re-evaluation
consists of enhancing the LMS approach
with a PBPK analysis and a 2-stage analysis
rather than a discussion of alterative ap-
proaches. A discussion of such alternative
approaches, and their results, should also be
reflected in the appropriate places in the
summary chapter 9. As noted earlier in this
report (see sections 4.5.2 and 4.5.3), dioxin
is not an initiator and thus is not a com-
plete carcinogen. Dioxin is a non-genotoxic
... the available information on
TCDDs suggest that use of the
benchmark approach, rather
than the reference dose, is
probably more appropriate.
promotor which acts at least in part via the
Ah receptor and exhibits numerous U-
shaped dose responses (Kociba et al., 1978;
Pitot et al, 1987; Maronpot et al, 1993;
Teegaurden et al, 1995; Fang et al, in
press). Thus, the document cannot ignore
a possible threshold dose-response relation-
ship and claim to be comprehensive in its
presentation.
As noted in the Committee's response
to health question 14 (section 4.6.1), the
available information on TCDDs suggest
that use of the benchmark approach, rather
than the reference dose, is probably more
appropriate. This approach has been recom-
mended in several previous SAB reports
(SAB, 1990; SAB, 1995). The EPA, along
with the International Life Sciences Institute
(ILSI), has sponsored workshops on this
topic, and various EPA staff are among the
most progressive and knowledgeable experts
in the use of this methodology.
The Committee (with the exception of
one Member) agrees that, in concept, the
reference dose is not designed to evaluate the
risk from incremental exposures (however, if
background exposures are not accounted for in
the population from which data are obtained
for calculating a reference dose, the resulting
reference dose may represent doses in excess
of that background). Although EPA's current
methodology for cancer risk assessment allows
one to assess risks from incremental expo-
sures, the RfD methodology is not well-suited
for this particular use. The Committee recom-
mends that EPA work towards developing and
implementing a methodology that would allow the
assessment of non-cancer risk resulting from incre-
mental exposures.
4.9.3 Continuum of Response Postulate
(Charge Question 19)
EPA postulates a continuum of response
from events seen at low doses that are not
toxic but cause the subsequent development
of toxic effects. This idea is expressed several
times in the document, but it is not supported
by a full discussion. As it stands now, the
basis for this statement regarding a continuum
of responses is unclear. The statement is far
too general and could be taken as implying
that all (or any) early changes will necessarily
lead to ultimate toxicity. The statement is
only defensible in reference to a limited num-
ber of specific case examples, but cannot be
taken as universally proven. Until a full
mechanism of action has been mapped out,
the reassessment's position remains unproved
in general. The statement should not be
presented as a "postulate" (which is widely
accepted as a universal truth not requiring
proof) but as a "current hypothesis" (subject
to change as new data are discovered).
THE SCIENCE ADVISORY BOARD
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PAGE 67
The specific case developed by EPA to
support this hypothesis was the binding of
ligand to the Ah receptor, which is then as-
sumed to lead to all, or most, of the toxic
responses. The possibility that the Ah
receptor system may be a sensing pathway
to protect the cell, not an integral part of
the machinery associated with the toxic
response of a cell to TCDD, is not consid-
ered.23 Only in the mechanism of action
chapter is there any suggestion that this
association may not be universally accepted.
However, Ah receptor binding may not be
the ultimate mechanistic step in all re-
sponses. It is not proven for all possible
toxic endpoints; the association is strongest
for enzyme induction in mice, but may not
hold in other species. Different strains of
rat show remarkably diverse sensitivities to
dioxin while possessing active Ah receptors.
Although enzyme induction in mice is the
classic Ah receptor mediated response, there
may be other responses that do not involve
Ah receptor. For example, although some
immuno-responses are Ah associated in mice,
others are apparently not.24 Ah receptor
binding may not be a rate-limiting response.
The recent development of "knock out"
mice lacking functional Ah receptors may
help clarify these points. EPA needs to
leave itself some flexibility so that the as-
One Member of the Committee asserts that
"The Ah receptor system is probably part of the normal
cellular second messenger regulating systems and its
inappropriate activation by dioxin (and dioxin-like
compounds) can lead to assorted toxic outcomes through a
variety of pathways. Any suggestion that this inappropriate
activation has positive outcomes is strictly speculative at this
time."
One of the Committee's immunologist
participants believes that "The evidence for receptor
independence from this data is insufficient to contra-
dict the majority of evidence for receptor dependence."
sessment can remain valid in light of future
discoveries.
The EPA response at the public review
meeting suggested that Ah receptor binding
could be considered as "necessary but not
y
sufficient." Other events may well also be
needed for toxicity to occur. Because of this,
TEFs should be based solely on Ah receptor
data only when other data are unavailable.
There are a variety of individual effects
yielding a likelihood of response, a cascade of
events.
The Committee is not taking the position
that EPA is wrong in its view that Ah receptor
binding is a critical early event leading to eventual
toxicity, but rather that the Agency stated the idea
too strongly and without sufficient consideration of
toxic immune system effects that have not been
shown to be Ah receptor associated. Alternative
mechanisms that have been suggested in the pub-
lished literature were not considered in the docu-
ment. The evidence for Ah receptor- linked effects
(and their role in toxicity), and (for balance) the
evidence suggesting a lack of involvement of Ah
receptor binding in some effects, should be discussed
in the document to support acceptance of this
continuum as a current hypothesis. Furthermore,
the continuum theory needs further explana-
tion, some discussion of the merits and
limitations, and an indication of the accep-
tance of this idea in the scientific commu-
nity. EPA needs to be more flexible in its
statements, to allow adaptability to scientific
evidence that may be developed in the fu-
ture.
4.10 Use of Toxicity Equivalence Fac-
tors (TEFs) (Charge Question 20)
In general, the Committee agrees that the
use of a TEF is a valid approach provided that the
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contribution to the TEQfrom: a) TCDD; b) other
dioxins and furans; and c) coplanar PCBs are
explicitly stated. However, when assessing the
toxidty of complex mixtures that are not well-defined,
the Committee believes that presenting the results
using alternative methods may be warranted when-
ever possible. It must be noted however, that
other than the suggestion (see Section 4.13
below) to apply TEQs separately for 2,3,7,8-
TCDD, other dioxins and furans, and co-
planar PCBs, as well as for environmental
mixtures as a whole, the Committee has no
specific proposals for such alternative meth-
ods.
Although the assessment acknowledges
some of the uncertainties associated with the
use of TEFs/TEQs, these issues have not been
satisfactorily addressed. Since the TEQ ap-
proach has been used throughout the assessment
document, and many of its conclusions (e.g.,, the
position that levels 10-100 times over background
pose a possible human health hazard) hinge on the
validity of the TEF values and assumptions used,
the Committee advises EPA to include a peer-re-
viewed appendix that will comprehensively review
EPA's use of the TEF/TEQ approach in the exposure
and health assessment documents. This appendix
should clearly outline the assumptions and
TEF values used throughout the documents as
well as address the following issues:
The reassessment document acknowl-
edges that dioxin-like compounds other than
TCDD represent greater than 90% of the
calculated TEQ value in some instances.
Consequently, the applicability of using TEFs
for mixtures containing PCBs with partial
agonist and antagonist activities should be
addressed. The EPA assumes that there is
additivity among TEQs calculated from the
TEF values for 7 of the 75 dioxins, 10 of the
135 dibenzofurans, and 13 of the 209 PCBs.
However, these dioxin-like congeners consti-
tute a small percentage of the total congeners
present in an environmentally relevant mix-
ture. Therefore, the EPA should address the
issue of possible interactions, since there is
evidence that non-dioxin-like PCBs antagonize
several biochemical (e.g. enzyme induction)
and toxic responses (e.g., teratogenic and
immunotoxic effects) elicited by more potent
congeners. Possible synergies should also be
considered.
New data, which became available since the
release of the document have resulted in adjustments
to several of the TEF values. The Committee sug-
gests that a comprehensive review of all TEF values
be summarized within the appendix for each congener
that has previously been assigned a value. In
addition, EPA should clearly state the species
and responses (e.g., ligand binding, enzyme
induction, imrnunotoxicity) used to derive the
TEF value. Finally, since TEF values can vary
dramatically based upon the species and re-
sponse examined, EPA should justify the TEF
value that has been selected for evaluating
human risk.
EPA should document clearly the
studies that demonstrate additivity among
dioxins, dibenzofurans and PCBs and that the
TEF/TEQ approach accurately predicts both
short-term (e.g., immunotoxic effects, enzyme
induction) and long-term (e.g., carcinogenic,
teratogenic, reproductive effects) responses
elicited by these complex mixtures. In the
event there are insufficient data demonstrating
the applicability of the approach for specific
toxic endpoints, EPA should justify its posi-
tion for the use of the TEF/TEQ approach.
Although the reassessment recognized
that humans are not overly sensitive or resis-
tant to the effects of dioxin-like compounds
THE SCIENCE ADVISORY BOARD
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relative to other species, there is a lack of
discussion regarding the differences between
human and rodent receptors. Such informa-
tion should be included in the appendix. EPA
should also outline how this information is
taken into account when assigning TEF values
to congeners. Also, recent studies indicate
that there are differences in congener uptake,
metabolism, elimination, and storage. This
should be acknowledged followed by a discus-
sion of how this information is taken into
account when assigning TEF values to conge-
ners.
The reassessment document lacks
discussion regarding naturally occurring
dioxin-like compounds such as
benzo[a]pyrene and indole[3,2-b]carbazole.
The EPA should comment on the exclusion of
these compounds. These agents are not
persistent or bioaccumulative, but the precur-
sor of indole[3,2-b]carbazole is present at
high levels in the diet, and this constant level
of exposure should be reported. Furthermore,
there is (very preliminary) evidence that some
of these compounds (e-g->
indole[3,2-b]carbazole) may have an anticar-
cinogenic effect (Bjeldanes et al., 1991;
Bradlow et al., 1991; Liu et al, 1994; and
Wattenberg et al., 1978).
As mentioned in the health assessment
document (p 9-70), "A more detailed descrip-
tion of these issues is contained in U.S. EPA
(1989)." This referenced document (TITLE,
EPA/625/3-89/016), once updated and modi-
fied to address the issues listed above, and
peer reviewed, could be used as a basis for the
appendix and therefore, could reasonably
accommodate the Committee's above sugges-
tions. In addition, a balanced comprehensive
review should clearly state the assumptions
and limitations of the TEF/TEQ approach as
well as highlight the areas that warrant further
investigation. Examination of the Summary
of the Public Comments related to the
Exposure and Health documents
(EPA/600/6-88/005Ca, Cb, Cc and
EPA/600/BP-92/001a, 00Ib, 00Ic) indicates
that EPA is already aware of the concern
surrounding this issue (i.e. the statement that
"This issue was the single most addressed
issue among all of the comments on the risk
characterization" on page 25 of the Health
Comments Summary). Therefore, the addi-
tion of a peer reviewed appendix dealing with
the TEF/TEQ approach should satisfy several
of the concerns raised, or at least indicate
which items are still points of contention.
4.11 Laboratory Animals/ Human Re-
sponse
4.11.1 Animal Data and Weight-of-
Evidence Conclusions for Hu-
man Risk (Charge Question
21)
The present state of our knowledge of
TCDD as a toxic agent is largely derived from
studies with animals. Thus, there is, by defini-
tion, a heavy reliance on the results of numer-
ous animal studies designed to define the
plethora of effects of TCDD. By default one is
compelled to use these animal data. However,
these data must be used in perspective.
Studies using animals as surrogates for hu-
mans show almost a 10,000-fold range in
their response to dioxin exposure for a num-
ber of different adverse effects, depending on
the animal species and endpoints selected.
The reasons for these large differences in
response by different species of animals are
not known (even though they are all pre-
sumed to have the Ah receptor), but this
breadth of sensitivity may serve as an indica-
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tor of the range of response that might be
seen in the human population.
The use of animal data to establish a
potency value for TCDD which may then be
used for calculating human risk is of particu-
lar concern to this Committee. The assign-
ment of "oral intake risk-specific doses of
slightly less than 0.01 pg TCDD/kg/day,
corresponding to unit risk estimates of 1 x
1Q-4 per pg TCDD/kg/day" (pages 9-67 and
9-83) must be rigorously analyzed to satisfy
the scientific community that these values,
derived solely from animal studies, are ade-
quately justified and defensible. These
critical values will serve as the elements for
human risk assessment calculations by risk
managers when determining acceptable levels
of human exposure. It is not obvious how
these values of potency were derived and
how vigorously the value can be defended as
the critical number used for human risk
calculations. The document requires a more
extensive discussion (in Chapter 9) of how this
calculation was derived, which default assumptions
were used, and why daily dose is the proper
dosimetric parameter.
4.11.2 Animal vs. Human Data
(Charge Question 22)
The strengths and weaknesses of ex-
trapolation to humans are discussed in the
dioxin document, in the responses by those
submitting comments, and in the TCDD
literature. In general terms, the arguments
advanced from both positions are widely
recognized. Little is novel in the TCDD
context and the debate: remains relatively
superficial. EPA's assertions in favor of spe-
cies extrapolation are based on the
weight-of-evidence argument, which points to
some shared mechanisms among species, the
presence of a functional Ah receptor in hu-
mans, similar biochemical responses in multi-
ple species, and the correspondence in certain
outcomes of high dose exposures, primarily
chloracne, in both humans and animals.
Commonalities in certain outcomes among
several species of laboratory animals (but not
yet humans), particularly in the growing
developmental literature, also support this
position.
The opposing position asserts that
postulating homologous outcomes among
species is not a fruitful avenue to risk assess-
ment. This position objects particularly to the
lack of cogent human data on indices such as
sexual behavior, immune dysfunction, and
others, and notes species heterogeneity in the
Ah receptor. Lack of human data, however,
should not be interpreted to mean that hu-
mans are unaffected, because appropriate
human studies are yet to be performed.
Although it will be a difficult task, EPA should
perhaps consider, in future revisions, what
human studies might be undertaken to shed
light on this issue.
... a revised Chapter 9 should
feature developmental toxicity
with as much emphasis as
is allocated to cancer and
reproductive toxicity.
The animal data indicate TCDD to
be a potent developmental toxicant capable
of inducing functional and morphological
aberrations in male rats (Mably et «/., 1992;
Bjerke et a!., 1994; Bjerke and Peterson,
1994). Because such outcomes can occur at
low doses, and therefore are much more
relevant to general environmental levels,
most Committee Members think that a
THE SCIENCE ADVISORY BOARD
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PAGE 71
revised Chapter 9 should feature develop-
mental toxitity with as much emphasis as is
allocated to cancer and reproductive toxic-
ity. Animal data will have to be relied on
for developmental questions linked to
TCDD because the human database is so
limited. These data, however, can be supple-
mented by the PCB data from the Lake
Michigan (Jacobson and Jacobson, 1994) (as
discussed in section 4.6.1) and North
Carolina (Gladen et al, 1988) studies be-
cause, unlike the Japanese and Taiwanese
episodes, they are based on prevailing envi-
ronmental levels and were revealed by
neuropsychological indices rather than
clinical abnormalities. The evolution of our
understanding of the developmental toxicity
of lead should be cited as a model.
A lamentable stimulus to this debate is
the somewhat loose and impressionistic manner in
which Chapter 9 is framed. Had its tenets been
offered in a more precise, organized manner, with
appropriate documentation and depth, and with
a clear presentation and evaluation of conflicting
points of view, it could have served as a structure
on which to build a more defensible risk charac-
terization. Although the case for extrapola-
tion is argued more cogently in Chapter 8,
its fragmentation in Chapter 9 leads to
questions about its validity. In defense of
EPA, however, the insistence on human
evidence for every assertion about a possible
hazard based on animal data is unrealistic.
One comment submitted to EPA contends
that clinical evidence of disordered human
sexual behavior, corresponding to Mably et
al. (1992), has yet to appear (however,
complaints of impotence have been received
from exposed workers, although adults seem
to be a rather less sensitive population). It
further argues that the preponderance of
social and environmental determinants in
human sexual behavior makes it unlikely
that effects homologous to Mably et al.
would ever emerge as a consequence of
prenatal TCDD exposure. No cogent at-
tempt to make such a comparison has been
carried out; in addition, it would be naive
to expect exactly the same outcomes. If
such studies are undertaken seriously, they
should be designed to illuminate small
functional differences; the lead, ethanol, and
PCB literature offer suitable models (e.g.,
Streissguth et al, 1990 re ethanol).
Chapter 9 needs to offer a balanced
perspective on these issues, especially by recogniz-
ing that, for developmental toxicity, arguing from
simple homologous responses is unproductive. An
appropriate translation, especially for func-
tional endpoints, is essential. Chapter 9
should be organized in accordance with
Wilson's principle, i.e., that functional
effects of gestational exposure are likely to
emerge at lower dose levels than those
provoking overt structural teratologies (Wil-
son, 1977). Chapter 5 might also benefit
by a wider discussion of developmental
questions beyond the narrow domain of
TCDD.
4.12 Overall Scientific Foundations of
the Health Reassessment Docu-
ment
4.12.1 Evaluation of the Risk As
sessment Chapter (Charge
Question 23)
The stated purpose of the Risk Char-
acterization Chapter (9) is to provide "a
balanced picture of the scientific findings of
the health and exposure assessments for use
by risk managers in selecting risk manage-
ment options ..." (pg. 9-2). The risk
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management implications of the draft conclu-
sions could certainly be significant. If there
are public health consequences of current
exposures to dioxin-like compounds, intensi-
fied regulatory actions may be appropriate.
Given the large public health and economic
stakes in the dioxin reassessment, the Agency
is well-advised to make sure that its final
conclusions about dioxin-like compounds
have a high degree of support within the
scientific community. Otherwise, risk manag-
ers will not be in a strong position to perform
their roles with competence and credibility.
Overall, the analytic strengths of the draft
conclusions rest in the innovative approach that the
Agency has taken to deal with this class of com-
pounds. The weaknesses rest in the lack of discus-
sion of alternative low-dose models and serious
uncertainties, and the absence of quantitative
information that can be useful to risk managers in
comparing the incremental benefits of regulatory
alternatives aimed at reducing exposures to dioxin-
like compounds.
Looking at the strengths of the conclu-
sions, three major points are apparent. First,
by focusing serious attention on various non-
cancer effects, the Agency has dispelled any
mis-impression that EPA's risk assessment
process is overly preoccupied with carcinogenic
effects. In order to emphasize this point,
the Agency may want to reorder the
discussion of health effects on pp. 9-39
through 9-53, so that the discussions of
non-cancer effects precede that of the
cancer effects.
Second, by evaluating an entire group of
compound classes (with a com- mon attribute),
rather than a single compound, the Agency re-
sponds to the generally-mistaken criticism that its
risk assessment process can only address issues on
a chemical-by-chemical basis. In this case, the
compound classes are defined in terms of
common biological responses, since the hu-
man body is presumed to be responding to
the cumulative exposure to numerous agents
that act through a common mechanism
involving the Ah receptor. This leads to the
Agency's use of TEFs as a numerical device to
describe the relative importance of various
dioxin-like compounds. In the final assess-
ment, EPA should emphasize further the
ambitious and somewhat speculative nature
of this ground-breaking approach to risk
assessment, as well as the consequences of
not using a TEQ. approach.
Third, in the opinion of most Committee
Members, a useful comparative perspective is
provided in the draft conclusions where the Agency
highlights the fact that the margin of safety (be-
tween background exposures and levels of exposure
where effects have been observed in test animals) for
dioxin-like compounds is smaller than the EPA
usually sees for many other compounds.
Three major weaknesses were also
noted. First, the presentation of scientific findings
portrayed in the draft conclusions is not balanced.25
A tendency to overstate the evidence of
danger is apparent in the following:
a) There is an inference that humans are at
risk from background and near- background
exposures. The term "background," because
of its implications in ordinary discourse,
needs to be amplified in the context of the
dioxin reassessment. "Background" typi-
Several Members of the Committee do not
agree with this statement and regard the EPA presentation
and the inferences (drawn as appropriately conservative
within the context of public health protection.
THE SCIENCE ADVISORY BOARD
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PAGE 73
cally refers to exposure levels that are not out of
the ordinary experience. The populations de-
scribed by Jacobson and Jacobson (1994) (as
discussed in section 4.6.1), Gladen et al.
(1988), and Huisman et al. (1995), which
demonstrate 'associations between PCB (and in
the Huisman study, PBBs and dioxins) exposure
and neuro-developmental deficits, would be classi-
fied at the high end of the "background" distribu-
tion. This distinction needs to made clear by
EPA.
b) The Agency's decision to propose a
uniform carcinogen classification for
all dioxin-like compounds (even
though the weight-of-the-evidence on
TCDD is more persuasive than for
many other compounds included in
the report).
c) The Health Reassessment document's
presentation of quantitative estimates
of carcinogenic potency without pre-
senting any quantitative estimates of
anti-carcinogenic action (even though
available data suggest protective ef-
fects are occurring at low levels of
exposure) and biological plausibility
for such effects (As noted in section
4.2.1 however, several Members of
the Committee suggest that possible
protective effects may be related to
anti-estrogenic activity, rather than
any general chemoprotective effect.
One Member does not believe that
the evidence for protective effects is
statistically significant.).
Second, important uncertainties associated
with the Agency's conclusions are not fully recog-
nized and subjected to feasible analyses. Examples
of this problem include instances in which:
a) The document did not acknowledge
the biologic plausibility of a threshold
model for some or all of the effects.
b) Sensitivity analyses of the TEF values
reported in Table 9.1 were not pro-
vided (incorporation of such analyses
were suggested and illustrated in the
comments provided by the public).
c) The document repeatedly referred to
"average body burden" as a biologically
meaningful dose metric, even though
other measures of dose associated with
peak intake may be more important
for some effects, and that "area under
the curve" is the preferred dosimetric
for dealing with agents with long bio-
logic half-lives.
d) The document reported "conservative"
numerical values (e.g., for the potency
figure) without any realistic or central
estimates to provide a broader perspec-
tive.
Finally, the characterization of non-cancer
risk is not performed in a manner that allows
meaningful analysis of the incremental benefits of
risk management alternatives.26 The risk man-
ager is provided with no quantitative indica-
tion of how the severity or frequency of non-
cancer effects (e.g., reproductive and develop-
mental toxicity) in the human population
might be affected by incremental reductions
in either intake rates or average body bur-
26
A minority within the Committee finds the
non-cancer risk characterization to be appropriate for use
within a public health perspective. However, they agree that
the reassessment document's characterization is not per-
formed in a manner which will be very useful in the analysis
of the incremental benefits of risk management alternatives
by those who are also concerned with the micro-level
economic costs.
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dens. Although the Agency is correct in
pointing out the weaknesses in a traditional
"reference dose" approach to this class of
compounds, it has not provided risk manag-
ers with any means to perform dose-re-
sponse analyses of the non-cancer effects.
Unless such information is provided, there is
a danger that the real possibility of non-
cancer effects will be downplayed or ignored
or, conversely, overstated, in regulatory
impact analyses and future cost-benefit
analyses.
From a presentational perspective,
more thought needs to be given to how the
information is presented in Tables 9-3
through 9-5. These are arguably the most
important tables in the entire report, but
they are not constructed in a manner that is
helpful to the reader looking for information
about how responses are related to dose
range. Without information about dose
range, the effects reported are easily misin-
terpreted. One fruitful idea might be to
start with background exposures, report the
most sensitive endpoint first, and then order
all of the effects along a continuum of dose.
A "Comments Section" should be added to
the table to highlight key uncertainties in
the database on particular effects.
4.12.2 Evaluation of Major Conclu-
sions (Charge Question 1)
Five major conclusions related to the
health effects of 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD or dioxin) are contained in
Chapter 9. These conclusions purport to
draw on the extensive data base on TCDD
and related compounds presented in Chap-
ters 1 through 7 and part of Chapter 8.
The comments following the quotation
of each of Chapter 9's conclusions presented
below reflect the Committee's concerns with
that conclusion.
a) "The scientific community has identi-
fied and described a series of common
biological steps that are necessary for
most (if not all) of the observed effects
of dioxin and related compounds in
vertebrates, including humans. Bind-
ing of dioxin-like compounds to a cel-
lular protein called the Ah receptor
represents the first step in a series of
events attributable to exposure to
dioxin-like compounds, including bio-
chemical, cellular, and tissue level
changes in normal biological processes.
Binding to the Ah receptor appears to
be necessary for all well-studied effects
of dioxun but is not sufficient, in and of
itself, to elicit these responses. This
reassessment concludes that the effects
elicited by exposure to 2,3,7,8-TCDD
are shared by other chemicals that
have a similar structure and Ah
receptor-binding characteristics. Con-
sequently, the biological system re-
sponds to the cumulative exposure of
Ah receptor-mediated chemicals rather
than to the exposure to any single
dioxin-like compound." (Chapter 9,
page 78)
The conclusion that some responses
to TCDD and structurally related com-
pounds are initiated by binding to (and
activation of the Ah receptor) is clearly
supported by an extensive body of data on
many, if not all, relevant endpoints. The
acceptance that toxicities of potential con-
cern are receptor-associated provides the
opportunity to draw upon the principles of
receptor action that have been developed
SCIENCE ADVISORY BOARD
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PAGE 75
and validated within the disciplines of
immunology, biochemistry, and pharmacol-
ogy. These principles are not unique to
TCDD, but rather apply to all ligand recep-
tor interactions (however, see the discussion
in section 4.2.1 concerning the relationship
of the binding of TCDD to the Ah receptor
and the manifestation of toxicity). Recep-
tor theory provides the basis for the devel-
opment of quantitative descriptions of these
interactions that take into account both the
affinity of the ligand for its cognate receptor
and efficacy. The latter is based on the
experimental observation that not all ligands
produce the same quantitative response as
a function of receptor occupancy. The
extremes range from full agonist to antago-
nist. Although the conclusion that TCDD
toxicity is receptor-associated is straight-
forward and supported by the data, the
broader implications for environmental
mixtures that contain synergists, agonists,
partial agonists, and antagonists need to be
more fully consideredboth qualitatively
(What compounds are present?) and quanti-
tatively (in what amounts?). In the overall
context of the exposure-dose-response para-
digm, it is necessary also to incorporate
pharmacokinetic data that will allow a
qualitative and quantitative description of
the presence of the various compounds (and
their metabolites) in potential target tissues.
Clearly, not all dioxin-like compounds are
alike in their metabolic stability, tissue
distribution patterns, or biologic half-life.
The conclusion that "the biological
system responds to the cumulative exposure
of Ah receptor-mediated chemicals" needs to
be more specifically defined to incorporate
the above concerns. The implication of
simple additivity ignores individually and
collectively the chemical and biological
properties of these chemicals as well as the
well-established and experimentally verified
principles of receptor-ligand interactions.
b) "There is adequate evidence based on
all available information, including
studies in human populations as well
as in laboratory animals and from
ancillary experimental data, to support
the inference that humans are likely to
respond with a broad spectrum of
effects from exposure to dioxin and
related compounds--if exposures are
high enough. These effects will likely
range from adaptive change at or near
background levels of exposure to ad-
verse effects with increasing severity as
exposure increases above background
levels. "(Chapter 9, page 79).
The implication of simple
additivity ignores individually
and collectively the chemical
and biological properties of
these chemicals as well as the
well-established and
experimentally verified
principles of receptor-ligand
interactions.
Effects and exposure levels need to be
specified. For example, are all effects nega-
tive as implied by the term increasing severity?
Here, it is imperative that the entire database
be explicitly considered in the document, on
an end-point specific basis. For example, are
all effects negative as implied by the term
increasing severity? Here, it is imperative that
the entire database be explicitly considered in
the document, on there is evidence from
bioassays in rodents that TCDD could be
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chemoprotective against breast cancer
(Kociba et al, 1978) -- although not all
Members of the Committee accept this find-
ing. Recent studies from Seveso (Bertazzi et
al, 1993) seem to show a pattern of decreas-
ing relative risk values for breast cancer in
women when comparing exposure zones R to
B to A (i.e., from lower to higher estimated
exposure). It must be noted, however, that
these relative risk estimates are extremely
unstable, and, as is the case with cancer
exceedences, are based on very small numbers
(e.g., one case of breast cancer in zone A).
In addition, no other epidemiological studies
have reported such effects, so the issue of the
nature of effects remains problematical.
The overall impact of certain biochemi-
cal changes (e.g., increased levels of phase I
and phase II metabolizing enzymes) seen at
lower levels is not fully understood at this
time. Current knowledge of the mechanisms
of TCDD toxicity has not identified the
biological determinants of specificity that
would allow one to extrapolate toxitities
across species with confidence.
In summary, there is not reason nor
sufficient evidence to reject completely the
EPA's statement above, but it should be
revised to sharpen its message, better indicate
areas of uncertainty, and reflect (with appro-
priate caveats) the total extant database.
c) "In TCDD-exposed men, subtle
changes in biochemistry and physiol-
ogy, such as enzyme induction, altered
levels of circulating reproductive hor-
mones, or reduced glucose tolerance,
have been detected in a limited num-
ber of available studies. These find-
ings, coupled with knowledge derived
from animal experiments, suggest the
potential for adverse impacts on hu-
man metabolism and developmental
and/or reproductive biology and per-
haps, other effects in the range of cur-
rent human exposures. Given the
assumption that TEQ intake values
represent a valid comparison with
TCDD exposure, some of these adverse
impacts may be occurring at or within
one order of magnitude of average
background TEQ intake or body-bur-
den levels (equal to .3-6 pg TEQ/kg
body weight/day or 40-60 to 600 ppt
in lipid). As body burdens increase
within and above this range, the proba-
bility and severity as well as the spec-
trum of human non-cancer effects
most likely increase. It is not currently
possible to state exactly how or at what
levels humans in the population will
respond, but the margin of exposure
(MOE) between background levels and
levels where effects are detectable in
humans in terms of TEQs is consider-
ably smaller than previously esti-
mated." (Chapter 9, page 81)
Potential adverse effects are stated
without a clear definition of the doses or
exposure levels at which they occur. EPA's
revision should attempt to provide a range of
exposures linked to a range of adverse effects,
much like it has done with lead toxicity, and
incorporate some identification as to what
adverse effects could be expected.
A critical issue throughout the risk
characterization chapter is the assumption of
the validity of the TEQ approach. Employ-
ment of TEQs assumes that all dioxin-like
compounds have equal efficacy and in the
context of the receptor occupancy theory
(i.e., linear stimulus transfer), simple
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additivity can be used. Experimental evi-
dence does not support the position of equal
efficacy (which would rule out the presence
of partial agonists or antagonists). With the
knowledge that dioxin-like compounds have
differing receptor affinity, the well-docu-
mented difference in the levels of the Ah
receptor in various tissues would determine
whether synergism or antagonism would
predominate. Finally, in vivo, dioxin-like
compounds differ significantly in their distri-
bution and metabolism. Despite these caveats,
the sense of almost all of the Committee was that
the TEQ approach is, until some better alternative
is developed, the best available vehicle for perform-
ing risk assessment involving complex mixtures of
dioxins, furans, and co-planar PCBs. To address
the caveats noted above, EPA should conduct a
peer review of the TEF/TEQ approach, with
particular attention to the role of partial agonists
and antagonists.
The last sentence of the above quoted
EPA conclusion ("It is not currently possible
to state exactly how or at what levels humans
in the population will respond, but the mar-
gin of exposure (MOE) between background
levels and levels where effects are detectable
in humans in terms of TEQs is considerably
smaller than previously estimated.") is (in the
opinion of most, but not all of the Commit-
tee) thought to be speculative and needs to
be reexamined. In effect, it states that we
don't know what will occur, or at what level
this unknown [response] will occur, but we
know that it will occur (in terms of TEQs)
closer to background levels than previously
estimated.
d) "With regard to carcinogenicity, a
weight-of-the-evidence evaluation sug-
gests that dioxin and related com-
pounds (CDDs, CDFs, and dioxin-like
PCBs are likely to present a cancer
hazard to humans. While major un-
certainties remain, efforts of this reas-
sessment to bring more data into the
evaluation of cancer potency have
resulted in a risk-specific dose estimate
(1 X 10"6 ) risk or one additional can-
cer in one million exposed of approxi-
mately 0.01 pg TEQ/kg body
weight/day, This risk-specific dose
estimate represents a plausible upper
bound on risk based on the evaluation
of animal and human data. "True"
risks are not likely to exceed this value,
may be less, and may even be zero for
some members of the population."
(Chapter 9, page 85)
Existing epidemiological methodolo-
gies, coupled with the available database,
simply do not have the power to identify
possible cancer/dioxin links at background
levels. Consequently, the conclusion that
dioxin and related compounds are likely to
present a cancer hazard to humans at expo-
sure levels within one or two orders-of-magni-
tude above background is not well-supported
by the existing human epidemiologic data-
base.
The previous (and apparently still
current) position of the EPA has been to use
a linear extrapolation approach. This ap-
proach employs TEQ additivity and, to some
extent, is contrary to the principles applicable
to the quantitative modeling of receptor-
mediated processes, most of which assume the
absence of a threshold. There is a consider-
able body of peer-reviewed data, including the
bioassay data in Sprague-Dawley rats (Kociba
et al., 1978) and more recent studies on the
TCDD-dependent changes in hepatocyte
proliferation (Fox et al., 1992) and
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PAGE 78
preneoplastic foci (Maronpot et al., 1993),
which challenges both of these assumptions.
Thus, the risk-specific dose estimate (at the
lO'6 level of risk) of 0.01 pg, TEQ/kg body
weight/day is not supported by the available
data.
All of the above notwithstanding, the
main cancer hazard issue for EPA and other
risk managers is to identify and gain a better
understanding of those conditions of exposure
wherein dioxin can be a human carcinogen.
The Agency should revise its conclusions so as
to state background risk in terms of a range
from lower to higher, and should identify the
range of risks for specific exposures above
background exposures that may pose a human
hazard.
e) "Based on all of the data reviewed in
this reassessment and scientific infer-
ence, a picture emerges of TCDD and
related compounds as potent toxicants
in animals with the potential to pro-
duce a spectrum of effects. Some of
these effects may be occurring in hu-
mans at very low levels, and some may
be resulting in adverse impacts on
human health." (Chapter 9, page 87)
TCDD is a potent animal toxicant,
producing a spectrum of effects dependent on
the dose, context of exposure, and the genetic
background. Not all responses in animals can
be classified as adverse. In humans under
conditions of high exposure, the most well-
documented response is chloracne. Adverse
effects attributable to chronic low level expo-
sure have not yet been adequately demon-
strated. The neuropsychological abnormalities
reported in the Lake Michigan (Jacobson and
Jacobson, 1994) (as discussed in section
4.6.1) and North Carolina (Gladen et al.,
1988) PCB exposure studies are suggestive,
even though the exposures (albeit at "environ-
mental levels") are probably higher than one
would consider to be near general background
levels. The overarching issue here is the
validity of extrapolation of animal data on
dioxin to humans (which assumes rodents and
humans to be equivalent in sensitivity) and
the default assumptions applied to the analy-
sis of the animal data which form the basis of
the positions taken in the risk characteriza-
tion.
It is difficult to determine what EPA is
inferring in the last sentence in the above-
cited conclusion. If it is intended to state that
adverse effects in humans may be occurring
near current exposure levels, it is the Commit-
tee's judgement that EPA has not presented
findings that support this conclusion ade-
quately.
4.13 Other Issues and Future Steps
In the preceding text, the Health Panel
of the Dioxin Reassessment Review Commit-
tee responded to the '. explicit questions
contained in its charge. -ing the course of
the Panel's deliberation Avever, some ge-
neric issues not addressed in the 23 questions
arose. These are:
a) The advantages and disadvantages of
expressing ove: 1 risks for 2,3,7,8-
TCDD, other cL
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PAGE 79
mittee nor the public commentors who ad-
dressed this topic can propose an approach
better than that used by EPA. The sense of
most of the Committee, developed as this
review was prepared, was that EPA and other
interested parties would be better served if the
risk assessments for 2,3,7,8-TCDD, other
dioxins and furans, and co-planar PCBs were
done separately, as well for environmental mix-
tures as a whole.27 Having these risk assess-
ment calculations provided side-by-side in a
single document will help risk managers, since
control strategies and options may differ
substantially for the separate categories, while
recognizing that most human exposures will
be to complex mixtures.
b) The implications to the risk assessment
of alternate forms for the exposure-
response relationship at low (environ-
mentally relevant) levels of exposure.
The Committee urges EPA to examine
fundamental principles of receptor theory,
and the evidence from the epidemiological
and toxicological data bases in the low expo-
sure ranges for their consistency with its
assumption of a linear, non-threshold carcino-
genic risk. In addition, the Committee (with
several exceptions) believe that the Agency
should at least consider the suggestions from
the public28 regarding evidence for reduced
cancer risks associated with very low levels of
exposure. Although such a concept seems to
be counterintuitive, there is a body of litera-
Several Committee Members believe that
keeping dioxin-like PCBs together with the dioxins and
furans in a single overall reassessment is appropriate and
consistent with EPA's role of managing health risks to the
general public.
ture (albeit debatable, and both pro and con)
on the concept of hormesis and ionizing radia-
tion biological effects; this concept was not
discussed during the review meeting, but is
mentioned as a possible area of future investi-
gation
29
c) The extent to which revisions in the
draft reassessment document will be
needed to warrant the endorsement of
SAB in terms of the appropriate utiliza-
tion of scientific knowledge in the prep-
aration of the risk assessment.
The Committee concluded that EPA
reviews of the background and relevant litera-
ture in Chapters 1-7 were thorough and objec-
tive, and that, subject to revision to incorpo-
rate changes made in response to specific
technical input from the Committee and
others, no further SAB review was needed.
By contrast, the Committee concluded
that more substantial revisions would be
needed in Chapter 8 on modeling, and in
Chapter 9 on risk assessment, and a further
SAB public review session would be needed
before any SAB endorsement of EPA's judg-
ments on the extent of health risk posed by
2,3,7,8-TCDD, other dioxins and furans, and
co-planar PCBs. In view of the major public
health and economic implications of the ulti-
mate judgments on the extent of these risks,
the Committee recommends that this further
effort be undertaken as soon as possible.
28
Based on an analysis of data in Fingerhut ef a/.,
1990.
29
Several Members of the Committee believe that
the evidence of "hormesis" for dioxin-lime compounds is not
statistically or experimentally significant at this time, and that
until more solid evidence is obtained, this issue is irrelevant.
These Members also contend that the putative "hormesis"
effects are occurring at the levels of exposure at which the
developmental and immunological alterations are seen
REASSESSING DIOXIN
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PAGE 80
The importance of this revision to the
reassessment of dioxin risks demands that the
highest standards of peer-review extend to the
risk characterization itself. Although
it can be argued that this is in fact being
carried out by this SAB Committee, submit-
ting the risk characterization chapter for
external peer review prior to final review by
the SAB would serve to strengthen the docu-
ment, and assure a greater likelihood of its
acceptance by the scientific community-at-
large. It is recommended strongly that: a) the
risk characterization chapter undergo major
revision; and b) the revised document be
peerreviewed by a group of preeminent scien-
tists, including some researchers from outside
thedioxin "community" before returning to
the SAB. It is particularly important to in-
clude individuals with outstanding creden-
tials and experience in basic research
and quantitative modeling of receptor-medi-
ated processes, as well as other scientists with
broad toxicological, epidemiological, and
public health, perspectives in such a review.
THE SCIENCE ADVISORY BOARD
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