United States Science Advisory EPA-SAB-EC-SS-021
Environmental Board (1400) September 1995
Protection Agency
&EPA AN SAB REPORT: A SECOND
LOOK AT DIOXIN
REVIEW OF THE OFFICE OF
RESEARCH AND DEVELOPMENT'S
REASSESSMENT OF DIOXIN AND
DIOXIN-LIKE COMPOUNDS BY THE
DIOXIN REASSESSMENT REVIEW
COMMITTEE
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September 29, 1995
EPA-SAB-EC-95-021
Honorable Carol M. Browner
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, B.C. 20460
Subject: Science Advisory Board's review of the Draft
Dioxin Exposure and Health Effects Reassessment
Documents
Dear Ms. Browner:
Dioxins are a group of anthropogenic chemical compounds created as unin-
tended by-products through a number of activities including: combustion, certain types
of chemical manufacture, chlorine bleaching of pulp and paper, and other industrial
processes. Dioxins are produced in very small quantities compared to other pollutants;
however, because this family of compounds 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 with a recommendation to
"...follow up on this excellent start..." by developing and validating new models for
human exposure and for cancer and non-cancer risk endpoints, and to pursue active
research programs resolve questions and incorporate new data. The Agency initiated
a significant effort addressing dioxin exposure and risk, and on September 13, 1994,
released for public review and comment (59 FR 46980) a 2,400 page draft reassess-
ment of the toxicity of, and human exposure to, dioxin.
In December, 1994, the EPA Office of Research and Development (ORD)
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requested that the SAB review the reassessment document, and submitted a draft
Charge addressing some 40 issues. The SAB Executive Committee approved the
creation of an ad hoc Dioxin Reassessment Review Committee (DRRC) and appointed
Drs. Morton Lippmann and Joan Daisey as Co-Chairs. The DRRC was developed by
building on the SAB's Environmental Health and Indoor Air Quality/Total Human
Exposure Committees, and adding (following an extensive review and recruitment
process) additional 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 Dioxin
Reassessment Review Committee.
A final Charge for the review, encompassing 43 specific questions was adopted
after discussions involving ORD and SAB staff, and the Co-Chairs (the detailed Charge
is provided in section 2.2 of the enclosed report). The DDRC subsequently met on May
15-16, 1995 in Herndon, Virginia to hear briefings by EPA staff, comments by Members
of the public, and to discuss the relevant issues of the Charge. Following the public
meeting, the Committee's report was developed through a series of mail reviews of
successive drafts. It was approved by the SAB Executive Committee on September 21,
1995.
The enclosed report provides a detailed discussion of each of the specific issues
raised by the Charge, and addresses some additional related questions which arose
during the course of the review. The following comments provide a synthesis and
overall perspective on the Committee's findings.
First, via-a-vis the Exposure Assessment draft document, the Committee wishes
to commend those responsible for doing a very credible and thorough job assembling,
integrating, and analyzing a very large body of data on dioxin source emissions,
environmental levels, exposures, and human body burdens, all within the framework of
human exposure assessment. The detailed recommendations of the DRRC largely
address refinements, corrections and clarifications, not substantive revisions.
The exposure reassessment identifies the major known sources of dioxins and
provides a reasonable estimate of total emissions. The Committee recommends that
new information on emissions from the incineration of medical waste (and other
sources) be incorporated if appropriate, and that the estimates of uncertainties in the
emissions inventory be improved for several emissions categories. 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
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exposures. The Committee agrees with the EPA position that current levels of di-
oxin-like compounds in the environment derive primarily from 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 important exposure pathways, e.g., point
source-to-water/sediments-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 compounds.
The document's estimate of average dioxin exposure is reasonable, but has
substantial uncertainties because of limited data; it thus cannot provide an estimate of
the complete distribution of exposures for the U.S. population. 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 on-going 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 Committee supports EPA's use of Toxic Equivalencies (TEQ) for exposure
analysis, but also recommends that EPA carefully review the draft Exposure Assess-
ment document 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 Health Assessment draft document, in its first seven (of nine) chapters,
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
agents to receptor sites, their metabolism and retention in tissues, and to biological
response at the cellular, organ, organ system, and whole body levels. The Committee
commends the EPA staff for this considerable accomplishment, and has made a
number of comments and suggestions for relatively minor changes that should sharpen
and clarify the content of the initial seven chapters. The Committee's most significant
recommendations concerning these seven chapters center on the Agency's use of
Toxic Equivalency Factors (TEF) to address the a broad range of dioxin-like com-
pounds 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 justifiable, 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 specifications
for TEFs of the various dioxin-like compounds for various health outcomes of concern,
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including the development of separate 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.
Chapter Eight, on modeling, must integrate both human and laboratory animal
data, and is critical to the reassessment's overall success. The human data typically
derives from accidents and industrial exposures, and are subject to many confounding
factors. Animal studies often involve high-to low-dose extrapolations 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 this 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 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, (pharma-
cokinetic) modeling, epidemiological, and bioassay data.
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 inci-
dence. The conclusion with respect to dioxin-like compounds is less firm. In the case
of dioxin, virtually all of the Committee believes that the animal studies would be
categorized as "sufficient" and the studies of humans as "limited," providing for an
overall categorization of B1; which would be expressed verbally as "Probably Carcino-
genic to humans with limited supporting information from human studies." The Commit-
tee (on the basis of similar effects) would support the same designation for dioxin-like
materials. PBBs and PCBs would receive ratings of B., and B2, respectively.
Chapter Nine, on risk assessment, was not as thoroughly peer-reviewed before
submission to the SAB as were the earlier chapters, and needs to be revised consider-
ably to reflect the changes being made in Chapters 1-8 and to deal with the areas of
weakness discussed below. The revised chapter would greatly benefit from an
external peer review by an appropriate group. More specifically, the Committee
identified, and wishes to emphasize to the Agency, particular areas of both strength
and weakness in Chapter 9.
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Three major strengths are apparent. First, by focusing serious attention on
various non-cancer effects (both human health and ecological 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 class of compounds, rather
than a single compound, the Agency has responded to 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 com-
pounds 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 document'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. Second, important uncertainties associated with the Agency's conclusions
are not fully identified and subjected to feasible analyses. Finally, the characterization
of non-cancer risk is not performed in a manner which can facilitate meaningful
analysis of the incremental benefits of risk management alternatives.
This letter can only highlight the major points of a detailed and extensive review
by 39 SAB Members and Consultants of a 2000+ page document. Perforce, the letter
cannot convey the many lesser, but important, findings and suggestions in the Commit-
tee's report. Also, it is important to note that although there is a broad consensus on
most issues, not every Member/Consultant on the Committee agreed fully with every
finding; such instances are noted in the report itself.
We appreciate the opportunity to review this document, and look forward to your
response to the issues we have raised.
-
Dr. Genevieve Matanoski, Chair
Science Advisory Board
Dr. Morton Lippmann, Co-Chair
Dioxin Reassesment Review
Committee
Dr. Joan Daisey, Co-Chair
Dioxin Reassessment Review
Committee
ENCLOSURE
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Distribution List
Administrator
Deputy Administrator
Assistant Administrators
Deputy Assistant Administrator for Pesticides and Toxic Substances
Deputy Assistant Administrator for Research and Development
Deputy Assistant Administrator for Water
EPA Regional Administrators
EPA Laboratory Directors
EPA Headquarters Library
EPA Regional Libraries
EPA Laboratory Libraries
Staff Director, Scientific Advisory Panel
Director, Science Policy Council
National Technical Information Service
Library of Congress
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.
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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.
VII
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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 (HOOF), 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, N J
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
VIM
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CONSULTANTS
Dr. Ronald Hites, Indiana University , Bloomington, IN
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 (HOOF) U.S. Environmental Protection
Agency, Washington, DC 20460
Mr. A. Robert Flaak, Science Advisory Board (HOOF), U.S. Environmental Protection
Agency, Washington, DC 20460
STAFF SECRETARY
Ms. Mary L. Winston, Environmental Protection Agency, Science Advisory Board
(HOOF) Washington, DC 20460
IX
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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 12
3. DETAILED FINDINGS-EXPOSURE DOCUMENT 21
3.1 Sources 21
3.1.1 Estimating and Apportioning Sources 21
3.1.2 Source Inventory 22
3.1.3 Dioxin Reservoirs 23
3.1.4 Local/Distant Contributions to Dioxin Levels in Food 24
3.1.5 Uncertainty in Deposition Estimates 24
3.2 Food and Media Levels 25
3.2.1 Problems in Estimating CDD/F Levels 25
3.2.2 Use of U.S. Food Data 26
3.2.3 Air/Plant/Animal Pathway and Other Food Chain Impacts 28
3.2.4 Smoking-An Additional Potential Exposure Pathway 29
3.3 Human Body Burdens 32
3.3.1 Uncertainty in Estimating Human Body Burdens 32
3.4 Background Exposures 33
3.4.1 Estimating Background Exposures via Food/Body Burden Data 33
3.5 Site-Specific Assessment Procedures 33
3.5.1 Steady-State Assumptions and Modeling 33
3.5.2 Mass-Balance Issues 33
3.5.3 Model Validation Issues 34
3.5.4 Photolysis and Atmospheric Transport 35
3.5.5 Air-to-Plant Transfer 37
3.5.6 Vapor/Particle Partitioning 37
3.5.7 Background Exposures and Site-Specific Evaluation .... 38
3.5.8 Evaluation of Multiple Sources 39
3.6 Overall Scientific Foundations of the Reassessment Document 40
4. DETAILED FINDINGS-HEALTH DOCUMENT 44
4.1 Disposition and Pharmacokinetics Issues 44
4.1.1 Strength of the database 44
4.1.2 Disposition and Pharmacokinetics 46
TABLE OF CONTENTS (CONTINUED)
4.1.3 Incremental Exposures and Bioaccumulation 48
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4.1.4 Uncertainties in Back Extrapolations of Body Burden 48
4.2 Mechanisms of Dioxin Action 49
4.2.1 Animal-to-Human Extrapolations of Receptor Structure/Function 49
4.3 Toxic Effects of Dioxin 52
4.3.1 Animal Models for estimating Human Risk 52
4.3.2 Variations in Human Sensitivity 54
4.4 Chloracne as an Indicator of Exposure 55
4.5 Cancer 55
4.5.1 Epidemiological Evidence 55
4.5.2 Carcinogenicity of Dioxin-like Compounds 59
4.5.3 Carcinogenic Activities of Dioxin and Dioxin-Like Compounds . . 60
4.5.4 Characterization of Dioxin/Dioxin-like Compounds as Human
Carcinogens 65
4.6 Developmental Toxicity and Animal NOAELs 67
4.7 Human/Animal Databases: Potential for Immunotoxicity 70
4.8 Other Effects 74
4.9 Dose-Response 74
4.9.1 Approaches to Dose-response Determination for Cancer 74
4.9.2 Use of the RfD in Evaluating Incremental Exposures 78
4.9.3 Continuum of Response Postulate 79
4.10 Use of Toxicity Equivalence Factors (TEFs) 80
4.11 Laboratory Animals/ Human Response 82
4.11.1 Animal Data/Weight-of-Evidence Conclusions for Human Risk 82
4.11.2 Animal vs. Human Data 83
4.12 Overall Scientific Foundations of the Health Reassessment Document . 85
4.12.1 Evaluation of the Risk Assessment Chapter 85
4.12.2 Evaluation of Major Conclusions 88
4.13 Other Issues and Future Steps 93
5. CONCLUSIONS 96
5.1 Exposure Assessment Document 96
5.2 Health Assessment Document 98
REFERENCES R-1
XI
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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, environmental 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 limitations in the
extant data described. Consequently, the recommendations of the Committee largely
address refinements, corrections, 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
information on emissions from incineration of medical waste and other sources be
incorporated 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
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 consider 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
comparing this estimate to the estimate obtained from measured and representative
deposition data. The Committee concurs with EPA's position (Volume II, p. 3-166) that
it is not scientifically valid to infer, based on the simple mass balance comparison, that
there are missing sources of 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 proce-
dure, which are given, be modified appropriately to reflect this revision.
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The Committee agrees with the EPA position that current levels of di-
oxin-like compounds in the environment are derived primarily from anthropo-
genic 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
important exposure pathways, e.g., point source-to-water-to-fish, and cigarette smok-
ing. 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 compounds.
The document's estimate of average dioxin exposure is reasonable, but has
substantial uncertainties due to limited data, and cannot provide an estimate of the
complete distribution of exposures for the U.S. population. In addition, although the
body burden data are clearly not adequate for rigorous time-trend analysis, there is
some evidence that exposure may be decreasing in the U.S. The Committee recom-
mends 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 contributions from reservoirs might indeed be
important and that these sources should be evaluated 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 concern is 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 recommends 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 guidance for performing "base-
line" exposure assessments, as well as assessments of the exposure increment from a
proposed facility.
Finally, although the Committee supports EPA's use of Toxic Equivalences
(TEQs) for exposure analysis, it also recommends that EPA carefully review the draft
Exposure Assessment report and ensure that the congener-specific data are used in all
instances (such as transport, transformation, and deposition processes) in which
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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.
1.2 Health Document
The document, in the first seven chapters, provides a comprehensive review of
the scientific literature on the biological mechanisms involved in the uptake of dioxin
and related compounds; the binding of these substances to receptor sites and 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 additional literature that should sharpen
and clarify the content of the initial seven chapters. The Committee's most
significant recommendations concerning 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 justifiable, 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 specifications for TEFs of the various dioxin-like compounds for various health
outcomes of concern, including the development of separate 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 confound-
ing 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
extrapolations 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
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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) modeling of factors such as deposition, tissue dose, and excretion, as
well as the epidemiological, and bioassay data.
Vis-a-vis cancer, the Committee notes that all of the evidence available 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 presumably mediated through the Ah receptor and
associated transduction 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 mutually exclusive and collectively exhaustive set of carcinogenicity categories
grossly oversimplifies the state of the science in most instances, excepting those
compounds for which there is an abundance of uniformly consistent evidence, 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; B., -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 categorization of B.,,
which would be expressed verbally as "Probably Carcinogenic to humans with
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.
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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 of B1 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 outstanding credentials and experience in
basic research and quantitative modeling of receptor-mediated processes. The review
group should also include other scientists with broad toxicological, epidemiological, and
public health experience to place the risks of dioxin and related compounds in perspec-
tive; and, as observers, risk managers who have to contend with concerns of the larger
public in addressing regulatory options.3
More specifically, the Committee identified, and wishes to emphasize to the
Agency, particular areas of both strength and weakness in Chapter 9.
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.
One Member of the Committee disagrees with the suggested composition of the peer review group, specifically 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.
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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 document'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 facili-
tate meaningful analysis of the incremental benefits of risk management alterna-
tives.
4
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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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
chemical manufacture, chlorine bleaching of pulp and paper, and other industrial
processes. For the purpose of this review, the terms "dioxin" and "dioxin-like com-
pounds" 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-substituted
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
emissions 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 recommendation to "..follow
up on this excellent start." by developing and validating new models 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 September
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
publication 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 determinant.
The document was based on information currently available to EPA regarding the
toxicity, sources, pathways of release to the environment, and the levels of these
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compounds 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 document, and submitted a draft
Charge addressing some 40 issues. Following discussions involving 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.
The SAB Dioxin Reassessment Review Committee (DRRC) was developed by
building on the SAB's Environmental Health and Indoor Air Quality/Total Human
Exposure Committees, and adding (following an extensive review and recruitment
process) additional 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 discus-
sions between the Committee Co-Chairs, SAB staff, and ORD staff. The questions are
displayed in italic textio differentiate them from the background material.
2.2.1 Exposure Document Charge
Overall Scientific Foundations 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?
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The exposure document was developed 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 reassessment document are to:
a) identify the sources that release dioxin-like compounds to the environment;
b) summarize data on the levels of these compounds in food and environmental
media;
c) summarize data on human body burdens;
d) estimate background exposure levels; 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 principal
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 atmospheric transport and deposition. Current
levels of these compounds in the environment are principally caused by anthropogenic
activities. The EPA reassessment document is based on an extensive literature review
which is complete through 1993 and includes a number of 1994 references. Over 1000
references 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 ap-
proaches 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
procedures 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 uncertainty around each estimate was
assumed. (Question 3) Does the Committee recommend any changes to this inven-
tory?
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2. The document concludes that the contribution 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 Committee 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
deposition. 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 judgments regarding unknown sources by comparison 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 mechanisms which result in food chain impacts?
4. The document concludes that environmental 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 compounds beginning in the first half of the
20th Century. Only low levels have been found in ancient tissue remains. (Question
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10) Does the Committee agree with the conclusion that environmental 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
studies are quite large (e.g., NHATS (National Human Adipose Tissue Survey)
collected samples from over 800 individuals), they may not be statistically representa-
tive of the entire U. S. population. (Question 11) Is this an important source of uncer-
tainty 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-calculating from body burden data. (Question
12) The Committee is asked to comment on the appropriateness of these calculations.
SITE-SPECIFIC ASSESSMENT PROCEDURES:
1. The food chain and other fate models used in this document are relatively simple,
steady-state approaches. They generally use partitioning 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 tendencies for these compounds to persist in the environment.
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-balance 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 concentra-
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tion to estimate tissue concentrations (plants, animals), tend to be simple to use.
Limited testing suggests that mass balance violations are unlikely as long as reason-
able 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 generally use approaches
and parameter values that were derived from field or laboratory observations. Chapter
7 of Volume III 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 modeling approaches compared with the approaches selected
for the assessment. Additionally comparisons were made of model predictions to field
measurements for 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 further exercises 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 compounds? If so, how does the toxic equivalency (TEQ) of the mixture change?
Some evidence exists that rapid photolysis can occur when these compounds are
present in a vapor phase. Testing, however, has not been conducted under true
atmospheric conditions. The degradation products have not been identified. The
possibility exists that higher chlorinated dioxins and furans will yield more toxic lower
chlorinated dioxins and furans. 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 coeffi-
cients 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
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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 reviews 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: molecular 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
background estimates for media concentrations and exposures (as presented in
Volume II). No additional details or suggestions are provided. (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?
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
compounds 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 demonstrate that exposure to dioxin and related compounds is associated with
subtle biochemical 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
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probability that exposure to dioxin-like compounds may be associated with other
serious health effects including cancer. Human 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
detectable in human population studies, is dependent 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, particularly in epithelial tissues.
These data, together with the collective body of information from animal and human
studies, when coupled with assumptions and inferences regarding extrapolation from
experimental animals to humans and from high doses to low doses, allow a character-
ization 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 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 this draft, adequately support the major conclusions of the
reassessment documents?
DISPOSITION AND 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 exposure. Data related to disposition and pharmacokinetics of dioxin and
related compounds and efforts to develop models to further understand tissue dosime-
try are described in detail in Chapter 1 of the Health Assessment document:
An understanding of the relationship between exposure and dose is an
important aspect of an adequate 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 weak-
nesses of the data base and draw appropriate inferences for this group of compounds?
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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
structurally related compounds. Estimates of half-life in the body facilitate the under-
standing 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 estimation of historical body burdens to comple-
ment effects analysis in human populations presumed to have high exposures in earlier
decades. (Question 5) Has the magnitude, implications 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 assumptions and models used to describe
possible responses to exposure to dioxin. In this document, the relatively extensive
database on dioxin action has been reviewed, with emphasis 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 subject. Discussion in this chapter focusses on aspects of our
understanding of mechanism(s) of dioxin action that are particularly important in
understanding and characterizing dioxin risk including:
the similarities at the biochemical level between humans and other animals with
regard to receptor structure and function;
the relationship of receptor binding to toxic effects; and
the role that the purported mechanism(s) of action might contribute to the diversity
of biological responses seen in animals and, to some extent, in humans.
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(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 knowl-
edge of the direct impact of these events on toxicity?
TOXIC EFFECTS OF DIOXIN:
General Issues
It is clear from the evaluation of the toxicologic literature that dioxin and related
compounds have the ability to produce a wide spectrum of responses in animals and,
presumably, 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 individual 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. Evaluation
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 position that,
although human data are limited, evidence suggests that animal models are appropri-
ate for estimating human risk if all available data are considered. (Question 7) Does
the Committee agree?
For purposes of the current assessment, 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,
recognizing 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
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Chloracne is the only clearly adverse health effect which is known to occur in
dioxin exposed humans. Recognition of chloracne has been associated with high level
exposure to these compounds, and as such, may represent a biomarker of exposure.
(Question 9) Does the Committee agree with the position stated in the Health Assess-
ment 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 epidemiologic studies remains controversial, it is the
view of this reassessment that this body of evidence supports the laboratory data
indicating 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 epidemiol-
ogy chapter suggested that the epidemiology data alone were still not adequate to
implicate dioxin and related compounds as "known" human carcinogens but that the
results from the human studies were largely consistent with observations from labora-
tory studies of dioxin-induced cancer and, therefore, should not be dismissed or
ignored. Other scientists, including those who attended the Peer Panel meeting, 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 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 carcinogenicity of dioxin and related compounds in
laboratory studies exists and is described in detail in Chapter 6. There is adequate
evidence 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 hexachlorodibenzodioxin (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. How-
ever, it is generally recognized that these compounds bioaccumulate and exhibit
toxicities similar to TCDD and are, therefore, also likely to be carcinogens (SAB, 1989).
(Question 11) Does the Committee have any additional comments on extending the
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inference of carcinogenicity of 2,3,7,8-TCDD to the broader class of dioxin-like com-
pounds 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 promoters of carcinogenicity
without traditionally defined genotoxic activity. (Question 12) Has the document
adequately characterized the carcinogenic 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 carcinogen
under the Agency's risk assessment guidance for carcinogens was based exclusively
on the adequacy of the animal carcinogenicity database. The current assessment
characterizes 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. Increased confidence is based
on the total weight of the evidence based on unequivocal animal evidence, limited
human evidence and mechanistic evidence supporting biological plausibility. (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? B,? B2?)
Developmental Toxicity
Since developmental toxicity following exposure to TCDD-like congeners occurs
in fish, birds, and mammals, it is likely to occur at some level in humans. It is not
currently 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 Chapter 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?
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Immunotoxicity
Evidence has accumulated to demonstrate 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. Epidemi-
ological 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 adequately characterized? Are the clinical
methods which have been applied to immune function 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 background 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 species 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 continuum of
response expected from these fundamental 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 response models for dioxin and related
compounds as a part of this reassessment has led to considerable and valuable
insights regarding 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 multi-
stage (LMS) procedure for estimating cancer potency or the uncertainty factor ap-
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proach 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 development 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 increments of exposure.
(Question 17) Does the Committee agree with the approaches to dose-response that
have been used in the Health Assessment? Given the evolving nature of this effort
should collaborative efforts to refine these techniques continue as a high priority?
The U.S. EPA has frequently defined a reference dose (RfD) for toxic chemicals
to 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 standard uncertainty factors to account for species 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 population. 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 assessment 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
severity of collective effects increases. This continuum provides a basis for inferring a
relationship 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, although 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
relationship of these mechanistic observations and prediction of potential for adverse
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effects in exposed humans. (Question 19) Does the Health Assessment document
provide a balanced perspective regarding the uncertainties embodied in this inference?
TOXICITY EQUIVALENCE FACTORS (TEFs):
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 compounds has
an empirical basis, is theoretically sound, and, in the absence of more complete data
sets on the toxicity of individual members of this class, is a useful procedure. This is
not to say that the use of TEFs is a certain procedure. Since 1986 when the first
Agency-wide consensus on the use of TEFs 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 predict-
ing effects of this class of compounds on wildlife species lends further support to the
use of this approach. This relatively simple, additive approach does not take into
account interactions between dioxin-like compounds 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 human studies both in vitro and in vivo, EPA has made the decision to use
laboratory animal data to contribute to weight-of- the-evidence conclusions on human
hazard and risk. (Question 21) Does the Committee agree that this decision is reason-
able?
Humans do not appear to be an unusual 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
ascribing hazard or risk, the lack of adequate human 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 scientists may disagree, in our estimation,
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the database on dioxin and related compounds regarding a wide range of responses
across animal species is one of the most comprehensive among all environmental
chemicals. The fundamental understanding of mechanisms of dioxin action provides a
unifying theory for the mechanisms for observed effects in laboratory animals and
humans, and for using a weight-of-the-evidence approach considering all relevant data
to infer the human health impacts 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 adequately characterize the data-
base, 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 understandable to decision-makers?
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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 contributions of each type of
source.
It should not be assumed that the fractional contributions of various types of
combustion sources to total emissions are identical or similar to their contributions to
human exposures for the population in general. 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
locations 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
estimate 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 urn), 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 com-
pounds 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
For the source estimation, only dioxins and furans were included.
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compounds, a global or hemispheric mass balance would be necessary. In order to do
a scientifically acceptable mass balance comparison of emissions and deposition for
the U.S., deposition of emitted dioxins must be estimated using atmospheric dispersion
and deposition modeling, and the deposition estimates from the emissions then
compared to measured deposition data. In addition, more representative measured
deposition data would be needed.
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 Question 3)
The dioxin emission inventory has identified 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 significantly
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 residential wood combustion should also be
reviewed and revised, as well as the estimates for dioxin emissions from the combus-
tion 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 emissions,
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
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cases. In addition, uncertainty classifications should attempt to build upon the classifi-
cation systems already used in existing EPA emissions factors databases.
There appear to be some sources identified in international inventories or by
com mentors which were not considered or were not assessed in the EPA Reassess-
ment Document. Some discussion of these sources is important to the completeness of
the report even if they are later determined to be negligible sources of CDD/CDF
emissions.
3.1.3 Dioxin Reservoirs (Charge Question 4)
The reassessment document indicated 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 document) 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 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 potential contributions from reservoirs
might indeed be important and should be evaluated. 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. 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 biological 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.
The Committee suggests a technique to evaluate the potential importance of
reservoir 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
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extent of reservoirs materials is not fully known, the analysis would provide some
assessment of the importance 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 contribution of local and distant sources to food levels
at a site is a difficult one to answer experimentally and would probably require exten-
sive studies at many sites. Furthermore, the answer 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 quality data are available, the Agency should consider using
geographic information 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 quantitative, this examination is likely
to produce some insights and testable hypotheses. Once the more current measure-
ments 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
3.1.5 Uncertainty in Deposition Estimates (Charge Question 6)
Various research groups have tried to balance the input of dioxins into the
atmosphere with their output from 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 effluxes 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 discrepancy between deposition from the atmosphere and inputs into
the atmosphere. This discrepancy indicates that 10-50 times more dioxins are being
deposited from the atmosphere than are being emitted into the atmosphere. 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) fraction of the
dioxins emitted within the continental United States are certainly transported by the
atmosphere and deposited beyond the borders. In addition, dioxin deposition can not
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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 deposition 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 geo-
graphically 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 products. Such estimates are appropriate and
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.
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a) The reported sample analyses were performed at different laboratories,
using different methods of analysis, and the samples were not all col-
lected 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, standard deviation). For
example, if environmental levels are declining, as indicated by sediment
samples, the samples may have a time variability which the reader might
not
recognize. Some cautions on these aspects of uncertainties 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 appropri-
ate. 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
becomes clear that there are not really significant differences between the
estimates for the U.S. and other countries given the uncertainties in the
estimates.
c) Although the reassessment document makes no unwarranted claims
about the accuracy of the food data for exposure assessment, it is impor-
tant 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
geographical or demographic trends in exposure. Nor are the currently
available 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 expo-
sures 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 background exposure to dioxin-like
compounds is presently inadequate, but the EPA is commended for its major
effort to obtain new data, on which the Committee was briefed, but did not specifically
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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 Administration) has gener-
ated 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 PCDD/PCDF may be less than 100 pg. Additional 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
statistically 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 differences.
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
information 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 probably overestimate measures of central
tendency. The Committee suggests that EPA explore alternative statistical approaches
to handling ND values in the future, particularly the well-established maximum likeli-
hood 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 detection limits for the penta-, and hexa- congeners (those for the hepta- and
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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 be-
comes 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 concentrations 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 engendered 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 opinion that the above study is inconclusive.
The individuals classified as vegetarians followed 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
consumption 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 expo-
sure 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
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.
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human exposure, foodfish (especially freshwater fish from the larger waterbodies) are
likely to be exposed to additional point sources of PCDDs/Fs such as publicly operated
treatment 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 populations eat larger quantities offish (e.g., anglers, Native Americans, etc.),
the water-fish pathway deserves additional discussion as an 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 concen-
trations between predicted and observed differ by a factor of 4 (8.15 to 2.13) and ratios
of observed to calculated values for individual congeners varies from 0.13 to 22,
roughly two orders-of-magnitude. 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 conge-
ners to make the comparison. For those five values, 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 generally consistent with observations, with the exception of the
OCDD and OCDF concentrations." 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 assumptions
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 available.
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3.2.4 Smoking-An Additional Potential Exposure Pathway7
There is an additional exposure pathway 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
document; although the Committee does not consider this omission to be a major flaw,
smoking should be considered in future revisions. There are now three papers in the
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)
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 mainstream 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 measurements are common, there is
reason to suspect that they may have had substantial losses in their sampling appara-
tus. 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 contribu-
tions 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.
3.2.5 Anthropogenic vs. Natural Sources of Dioxin (Charge Question 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 example,
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
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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environmental 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 exam-
ples) 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 contributors. 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 production of chlorinated
compounds. The Committee concurs strongly with the conclusion 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 literature 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.
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 atmosphere to lake sediments was at
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its highest around 1970. This decrease seems to be continuing, and it may well be
attributable to decreased emissions from large-scale combustion 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 etal., 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; therefore, 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. However, 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 Human Body Burdens
3.3.1 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 exposures using a pharma-
cokinetic 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 collected 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.
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The Committee believes that reliable nationally representative body burden
data are not available. The reassessment acknowledges that the NHATS data, the
most extensive available, cannot be considered as representative, and the smaller data
sets are even less likely to estimate average exposure accurately. Because the
exposure histories of the individuals included in the NHATS studies are unknown, the
average could be biased upwards by occupational exposures or residential 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
contaminated. On the other hand, the possibility remains that selection of the samples
may have been weighted towards more exposed persons. The reassessment docu-
ment 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 analysis. 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 Background Exposures
3.4.1 Estimating Background Exposures 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 Procedures
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3.5.1 Steady-State Assumptions and Modeling (Charge Question 13)
The Committee did not raise objections 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. Although 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 exposure 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 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 ignores 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
vegetative 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 surface-to-air-volume ratio of
the ground surface and vegetation surfaces are much larger relative to the atmosphere
than the surface-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
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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 chemical 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 here to 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 extensions 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 comparisons of model-estimated versus mea-
sured 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 overstatement of model validity and that a considerable 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 performed 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.
The Committee also discussed the distinction between model validity and model
system validity. The existing system of analysis 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 developed.
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)
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The relative abundance of the various dioxin homologues and congeners differs
between sources and the environment and environmental sinks. For example, most
combustion sources generate a dioxin mixture with relatively high concentrations of
tetrachloro- and pentachloro- dibenzofurans, whereas the environmental sinks are
dominated 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 degradation 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
particles). 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 atmospheric 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 minutes
under these conditions (Orth etal., 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 atmosphere. Thus, determining the rate constants
for reactions of dioxins with OH has been of considerable interest. Unfortunately,
experimental difficulties have precluded 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 indicate that the atmo-
spheric lifetimes of 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.)
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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 reactions 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
chlorinated compounds are degraded more rapidly than the higher chlorinated com-
pounds. For example, the tetrachloro- dioxins are probably degraded more rapidly than
the octachloro- dioxins. This estimate agrees with observations that the less chlori-
nated 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
compounds from the atmosphere to lakes or oceans. Photolysis on soil and on plant
surfaces must be considered as these compounds begin their movement into the
human food supply. In all of these cases, data on photolytic reactions are very sparse.
In addition, a knowledge of the products of these environmental transformations is not
available. Is it possible that congeners with low TEFs are being transformed in the
environment to congeners with higher TEFs? Clearly these are all areas in which
additional 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.
For EPA to understand the importance of the issue of air-to-plant transfer, the
fundamental physical and chemical properties 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 photolytic half-life should be near the top of the list
of data gaps that need to be filled to answer this question.
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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 concentra-
tions of CDD/Fs and CDD/Fs versus the concentration 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 laboratory studies because of the inability to replicate what happens in
the outdoor environment.
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 sampling
data. The inherent sampling artifacts (e.g., the use of heated filters to collect particles)
introduced by current stack monitoring methods were recognized as the main limitation
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 vapor/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
available data, however, are limited with respect to the particle size distribution and
environmental 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 limitation of these data is
that part of the particle-bound CDD/Fs collected by the filter may re-volatilize, particu-
larly when large volumes of air are moved through the filter. Consequently, 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 vapor/particle partition.
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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 limitations to this approach, such as the use
of solid phase vapor pressures at 25° C, whereas ambient temperatures could vary
significantly (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 vapor/particle partition trend in the ambient data, that is, the tetra- and penta-
substituted 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 per-
formed 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
specific 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
appropriate. Certainly the data on environmental concentrations of CDD/Fs presented
in Volume II demonstrate that there is significant variability in levels even among sites
which could be categorized in the same scenario.
The term "background" is also confusing 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 guidance for performing baseline exposure assessments for specific sites.
Such guidance may include the following recommendations for the user:
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a) use site-specific media concentrations rather than defaults whenever
possible;
b) if these data are unavailable, use information from a comparable site in
terms of the types and density of sources present, land-use conditions,
and geographic/atmospheric characteristics;
c) when site-specific or comparable site data are not available, use regional
data.
The Agency might consider including examples of how a site-specific baseline
evaluation might be performed. Consideration of site-specific baseline conditions
would obviously implicitly include the contributions from existing multiple sources.
3.5.8 Evaluation of Multiple Sources (Charge Question 20)
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 background 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 quantifi-
cation 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 air/deposition map currently in development by EPA will hopefully provide
information on regional deposition levels that can provide more localized background
level information.
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 Associated 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 compounds 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.
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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
compounds. 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 research 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 integrated
assessment, a number of industries are currently seeking to address gaps in emissions
measurement data.
The EPA has done a good job of evaluating the sources of dioxins, based on
available data, and significant sources of uncertainty have been qualitatively identified.
In addition, this document provides the foundations for a quantitative treatment of
uncertainties-a task that is, however, beyond the scope of the current reassessment
document. Although there is great uncertainty in the levels of dioxins in some environ-
mental 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 evidence, 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
emissions 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 accumulation mode particles (0.1 to about 2-3 urn) is of the order of many
days. Thus, a large proportion of the particles with dioxin-like compounds that are
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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 particulate dioxin-like
compounds, 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 recom-
mended 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
comparison 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
dioxin-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 mechanism 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; specifically, there are no experimental measurements of photodegradation
or degradation via reaction with hydroxyl radicals. Environmental measurements of
deposition of particulate 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 pathway for human exposure to dioxin-like
compounds is through the diet, with consumption of animal products accounting for the
dominant or overwhelming fraction of exposure, is also quite robust. The associated
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 population (about 25% of U.S. adults are smokers). If the
estimates of dioxin-like compounds in beef and pork presented in the report, based on
very limited data, are found to be too high, then cigarette smoking (for which the dioxin
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estimated are also based on very limited data) could account for a significant propor-
tion 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 "national average background 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 recommenda-
tions 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 national average background expo-
sure, as well as with increments in exposure from a specific 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 increase 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
atmospheric transport processes throughout the Northern Hemisphere and that more
global (or hemispheric) evaluations of mass balance should be undertaken.
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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
characterization 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 distribu-
tion of 2,3,7,8-TCDD in animals (Birnbaum, 1985; Gasiewicz etal., 1983; Neal etal.,
1982; Olson etal., 1983; Van den Berg etal., 1994). There are insufficient human data
to support deposition 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 environmental 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 particulate matter incorporating dioxin in a solid matrix (e.g., fly ash).
Although data on pulmonary absorption from a solid matrix are available (Nessel etal.,
1990; Nessel etal., 1992a; Nessel etal., 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
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obtained in non-human primates (Brewster and Birnbaum, 1988; Gallo etal., 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 absorption/distribution,
but did not characterize adequately the strengths and weaknesses of the data
base. Further, the inferences drawn leave some 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 exposures. 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 2,3,7,8-TCDD and 2,3,7,8-TCDD-like compounds, as well as those chlori-
nated compounds that are reviewed in the health assessment documents but are not
2,3,7,8-TCDD-like. In addition, to enhance further the value of the reassessment, 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 example, 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
document provides a generally balanced evaluation, 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 alterna-
tive approaches 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.
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4.1.2 Disposition and Pharmacokinetics (Charge Question 3)
In addition to the specific questions asked about disposition and pharmacokinet-
ics by the Charge, the introductory sentence leading into this issue must also be
evaluated. This sentence states " The evaluation of available data and the develop-
ment of physiologically-based models has led to a better understanding of the disposi-
tion and pharmacokinetics of dioxin and related compounds than for most other
environmental chemicals." This sentence implies that these models are well-estab-
lished 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 mechanism and models apply only to
2,3,7,8-TCDD or may it be extended to other related compounds? Cur-
rently 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 compounds (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 not generally derived from
studies conducted at low dose levels. There is significant controversy as
to the shape of the curve in the models 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 carcinogenesis are the gastrointes-
tinal tract and others. It is not clear that the models effectively describe
the exposure and metabolism of those possibly impacted tissues. Partic-
ular 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 determined from short-term or single-dose
studies, do these results apply to chronic studies and/or longer term
exposures? In particular, the chronic Kociba etal. (1978, 1979) studies,
which included low exposure levels, did not necessarily fit one of the
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models 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 compari-
sons 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
questions about the 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 specific 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 PBPK model in the risk assessment. Given the
issues noted above, this is understandable and not considered to be a particular
weakness by the Committee (however, opportunities do exist-see 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 incorporation of these models into the current
reassessment 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 e£a/.,1995a; 1995b) (which was not yet published at the time
the Health Reassessment was under development), for example , 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 effectively incorpo-
rated into the risk assessment through revisions to Chapter 8.
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4.1.3 Incremental Exposures and Bioaccumulation (Charge Question 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 (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
potential for toxicity can be made only if information is available regarding distribution,
metabolism, and half-lives of other major contributing 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 burdens may be as much as two
orders-of-magnitude 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 Extrapolations of Body Burden
(Charge Question 5)
The Committee's primary concern with the topic of the body burden back
extrapolation lies with EPA's treatment of uncertainty regarding the half life of dioxin,
and the exposition 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 the back extrapolation of
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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 addressed in the health document.
4.2 Mechanisms of Dioxin Action
4.2.1 Animal-to-Human Extrapolations of Receptor Structure/Function
(Charge Question 6)
Mechanisms of dioxin action are discussed in various parts of the Health
Assessment document. Overall, the presentations are very useful. Whether or not the
document 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 receptor 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 confu-
sion 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 finally lead to frank toxicity; the lack
of information in immunotoxicity is particularly limiting. Much of what is purported to
link the Ah receptor to specific toxic events is merely the demonstration of an associa-
tion between the binding of TCDD to the receptor and an eventual appearance of an
adverse effect some time later in some species (when the interspecies variation in
doses that produce 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
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process is truly elegant. The rest of the biological consequences of TCDD exposure
are yet to be described adequately and sequentially in mechanistic 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 achieve-
ment. How a planar polar compound such as TCDD binds with a cellular receptor,
followed by translocation into the nucleus, where transcriptional activity of DMA 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 Committee 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 scientifically testable hypotheses. In any future revisions,
EPA should present more clearly the major deficiencies that exist in the current
mechanism database and provide some discussion of any plausible alternative
hypotheses.
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
toxicity 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 assessments
based solely on Ah receptor activation or on the existing knowledge of CYP1A1
induction are unlikely to provide a biologically defensible prediction (quantitatively or
qualitatively) of likely toxic outcomes in humans, particularly under low exposure
scenarios.
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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 affinity for TCDD that is lower than the affinity in C57BL/6 mice or in
most laboratory rat strains. There may be at least a 10-fold range of variation among
the human 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 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 etal., 1993; Bertazzi etal., 1989; Mocarelli etal., 1986)
show significant excesses of multiple myeloma 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 spurious). In the exposed chemical plant
workers studied by the National Institute of Occupational Safety and Health (NIOSH)
(Fingerhut etal., 1991), there is no excess cancer of any kind in the less heavily
exposed 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.910
Some Committee Members suggest that this reduction may result from the anti-estrogenic effects of dioxin.
9
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 etal., 1988; Wu etal., 1984; Chang etal.,
1982a; Chang etal., 1982b: and Chang etal., 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 exposure to the people in the zones that are characterized as having excess cancers are far less than those
of the workers studied by Fingerhut etal., 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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4.3 Toxic Effects of Dioxin
4.3.1 Animal Models for estimating Human Risk (Charge Question 7)
The Committee believes that the EPA reassessment document reviewed
and summarized adequately the current knowledge base on the experimental
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
characterization. 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.
The Committee noted that although there were many interspecies consistencies
in response following exposure to the compounds 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 attributed 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 lesions, 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 studies involved lethal exposure levels. Therefore, 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
related 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"
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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 reassessment 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 and pharmacokinetic data would be needed
before making a conclusion that a given effect is directly attributable to TCDD or
related compounds. The degree of uncertainty 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 variances
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
definitive sentence on page 9-78 (see also the Committee's discussion of Charge
Question 1, in section 2.2.2 of this report) of the EPA document, 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 observed effects of
dioxin and related compounds 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, includ-
ing biochemical, cellular, and tissue-level changes in normal biological pro-
cesses. Binding to the Ah receptor appears to be necessary for all well studied
effects of dioxin but is not sufficient, in and of Itself, to elicit these responses."
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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 "neces-
sary" for the induction of several of the observed effects. This degree of uncer-
tainty needs to be stated in the document.
4.3.2 Variations in Human Sensitivity (Charge Question 8)
The issue of human sensitivity may be divided into two questions. First, are
human sensitivities so distributed that a representative 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 congeners will vary widely. Furthermore,
observations reported in human exposure studies as from Seveso, Italy (Bertazzi et al.,
1993; Bertazzi etal., 1989; Mocarelli etal., 1986) and the U.S. Air Force Ranch Hand
Study
(USAF, 1991; CDC, 1988a,b) as well as other studies of occupational cohorts clearly
indicate that wide variations in the frequency and severity of response occur.11
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 ability 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 re-
sponses in animals? 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, or the most
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 "clearly indicate that wide
variations in the frequency and severity of response occur."
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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
conservative approach to be employed with respect 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-populations be identified that are at
greatest risk to dioxin exposure? Such sub-populations might include pregnant women,
infants, and children 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 docu-
ment, the document (in the opinion of most of the Committee) does not (and
perhaps cannot, given that dioxin-specific effects beyond chloracne--see the
discussion below--are 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 document reflected adequately the
current knowledge base on chloracne as it relates to the subject compounds.
Chloracne is a clear indicator of exposure, but the absence of chloracne in an
exposed subject is not an indicator of low exposure. In fact, the Committee'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
Several Members have noted that they find the EPA emphasis on low-level exposures to be appropriate and consistent with
prudent public health practice.
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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 experimental or epidemiological result but a judgment made about the results.
In making such a judgment an epidemiologist takes into account the possibility that bias
and chance may play a part, but additionally examines the observed association in
terms of certain characteristics associated with "causal" relationships. 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
with time; e) biological gradient (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,
consistency, 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
interpreting so called "negative studies" (studies where no differences are apparent, or
where the differences are not "statistically significant"). Differences produced by real
effects can easily be masked by poor exposure classifications (misclassification bias),
Chance can appear as a possible explanation merely by virtue of a small population
Several Members of the Committee believe that recent research findings published after the Committee's public meeting
(e.g. Kogevinas etal. 1995; Huisman etal., 1995) establish some cancer and developmental effects in humans as outcomes of either
CDD orTCDD exposures.
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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 complicating 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 tower 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, sometimes 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
common, 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 no? 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.
The limits and extent of generalization 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
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a risk of soft tissue sarcoma (STS) (p. 7-74). Association of STS with dioxin exposure
was raised by Hardell and colleagues (Hardell etal., 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 misclassification, 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 picture of increased risks" fails to con-
clude 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 etal., 1991) which reported statistically significant increases in
respiratory 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 judgment, but considers that residual confounding 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 relationship in the presence of confounding by smoking and occupational
exposure to chemicals. 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 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
defensible. The document took into account many of the concerns of the broad
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scientific community and discussed them explicitly, but, of course, could not discuss all
significant alternative 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 reas-
sessment document (p. 7-77) refers to "uncertainties associated with the epidemiologic
evidence." 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. Observing some unintended or "natural" experiment 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 uncertainties are largely
associated with the questions of internal validity extensively discussed in the Assess-
ment itself (questions of bias, chance and real effect). The reassessment document did
not discuss remaining questions of external validity, the most important of which are
the high exposure to low exposure generalization. The EPA should comment on this
issue in any future revision, as well as on the relationships between agricultural and
forestry, and environmental exposure 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
compounds. The EPA reassessment document describes such congeners and some of
their metabolic and carcinogenic effects. A number 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 promoting 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 generalization
of the forestry and agricultural studies. At worst, they indicate that those studies are flawed.
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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 etal., 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 etal., 1993) at KD (the apparent equilibrium disassociation
constant for ligand binding to the Ah receptor) levels that approach that of TCDD.
However, the majority 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 sufficiently 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 mixtures,
there have been several studies of the carcinogenicity of such mixtures indicating
additivity of their promoting activity (Schrenk etal., 1994; Huff etal., 1991). In some
instances synergy of components of mixtures of biphenyls have been reported (Sargent
etal., 1991; 1992).
Although the discovery and characterization of the Ah receptor were delineated
using polycyclic hydrocarbons (halogenated or not) as ligands (Thorgeirsson and
Nebert, 1977), it has been assumed that naturally occurring and/or endogenous ligands
occur. Recent studies (Bjeldanes et al., 1991) identified some naturally occurring
indoles as effective 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 applica-
tion 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 Committee (albeit with several Members taking exception) recommends that the
polyhalogenated biphenyls, although having many similarities in their metabolic, toxic,
Several Members disagree strongly with this finding and recommend the inclusion of polyhalogenated biphenyls in the
assessment.
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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 promoting 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, however, emphasis
is placed on the fact that TCDD is carcinogenic well below the maximum 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 ef 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 mecha-
nism^) 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 capable 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 complete 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
readers direct mutational and clastogenic activity of the agent, which the evidence does
not support for TCDD.
The reassessment document also describes a second set of studies in which
TCDD was characterized as having promoting capabilities. TCDD is classified as an
"... extraordinarily strong promoter of liver and skin tumors." The following studies are
referenced in the EPA document as support for this statement:
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a) Liver studies:
1) Liver-tumor promotion by TCDD following initiating treatment with
partial hepatectomy/DEN (Diethylnitrosamine)was first described in
1980 (Pitot et al., 1980J. In female adult Charles River rats treated
with a high dose of TCDD following partial hepatectomy, five out of
seven eventually developed liver tumors vs. none out of four in
controls. This was accompanied 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). Accord-
ing 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
inappropriate comparison).
3) A third study (referenced several times in the EPA document) was
not published in the peer-reviewed literature (Clark etal., 1991)
and the complete data do not appear to have been published
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 analyzed by Fisher's Exact test, they
do not support the assertion that ovariectomy would provide a
"protective effect" 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 hy-
pothesis of a mitigation of effect in ovariectornized rats.
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4) Another study has become available in the open literature since
preparation of the EPA reassessment document (Sills etal., 1994).
The group sizes of animals used in this particular study provide
better statistical power (between 12 and 15 animals per group)
than do the previous studies. Despite the larger numbers, the
increased tumor incidence in initiated-TCDD treated female wean-
ling rats (five out of 15 animals) is not sufficiently high to demon-
strate a difference from the controls (1 out of 12 animals) at a
conventional level of statistical significance.
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 document. However, in all studies, there is evidence 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 significantly, and in a dose-depend-
ent manner, the presence of altered hepatic foci and other signs suggestive of a strong
promoting potential (Sills etal., 1994; Pitot etal., 1987; Dragan etal., 1992; Buchmann
etal., 1994; Flodstrom etal., 1991; Waern etal., 1991). A recent and extensive study
on the topic (Dragan etal., 1992) emphasizes the complexity of this particular endpoint.
The EPA document describes several mechanistic studies and attempts are made to
link the promoting activity of TCDD to such biochemical events as enzyme induction,
internalization of EGFR, estrogen receptors, and similar endpoints. A recent study on
inhibition of intercellular communication by TCDD might be added to this discussion
(DeHaan etal., 1994).
b) Skin studies
Promoting activity of TCDD was also shown in two skin studies:
1) In 1982, TCDD was described as promoting skin tumor development in
hairless mice (Poland etal., 1982a). 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
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indicate statistically significant observations. If the data are analyzed,
only the number 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 exception of the lowest-dose
TCDD group, all mice initiated with MNNG and treated with promoters had
an increased 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 docu-
ment. 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 receptor.
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 promoters or to comment on the validity of the
TEF 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 ovariectornized 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 etal., 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 significant however, when
analyzed with the appropriate test (uncorrected Chi-square).
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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.
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 promotion, in fact, only involves the
development of preneoplastic lesions ranging from enzyme altered foci in rodent liver
models to early papillomas in multistage epidermal carcinogenesis 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 transduction. Promot-
ing agents in various systems in vitro and in vivo inhibit programmed cell death and
apoptosis (Schulte-Hermann et al., 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 carcinogenic effect of prolonged TCDD
exposure is primarily, if not exclusively, the result of its action as a promoting
agent.
All of the evidence to date argues strongly that TCDD exerts its carcino-
genic 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 transduction
mechanisms. TCDD is not a complete carcinogen and thus to avoid confusion
should not be designated as such. Many structural 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 carcinogenesis 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
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may disappear when treatment is withdrawn; on 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 document. 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 linking dioxin exposure to the genesis of
malignant neoplasms is limited, and does not offer compelling evidence of carcinoge-
nicity to 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 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
conducted 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 evidence from human studies.
The Committee did not dispute the IARC judgement that PCBs and PBBs as likely to
cause human cancer under some conditions of exposure.
Several Members contend that no epidemiological study has produced evidence that is widely accepted by the scientific
community, including the IARC, as being convincing for the human carcinogenicity of dioxin.
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The Committee agrees that assignment of the dioxins, the PCBs, or PBBs
to one of a mutually exclusive and collectively exhaustive set of carcinogenicity
categories considerably oversimplifies the state of the science in most instances,
possibly excepting those compounds for which there is an abundance of uni-
formly 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 manage-
ment 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 carcinoge-
nicity of a compound is not measured in this manner, but is usually considered as a
categorical term. It is desirable that consistent criteria for this inevitable categorization
are employed.
Under the proposed revisions to EPA's guidelines, there are essentially three
alternative choices (unless "known to" is considered an alternative to "likely to"):
a) likely to cause cancer under some conditions
b) not likely to cause cancer
c) likelihood cannot be determined
In Chapter 9 of the reassessment document, the basis for a detailed multidimensional
assessment is described and the various caveats are underlined, but a choice between
these three alternatives (actually, between the first and the third-see below) is still
required.
Under the 1986 EPA cancer guidelines, three more levels of carcinogenic
evidence, with mutually exclusive descriptive terms are provided, giving regulators
more alternative choices. These choices include Group A - human carcinogen; B., -
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, even if the additional alternatives were provided, virtually
all of the Committee believes that the animal studies would be categorized as "suffi-
cient" and the studies of humans as "limited," providing for an overall categorization of
B1; which would be expressed verbally as "Probably Carcinogenic to humans with
limited
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supporting information from human studies." PBBs and PCBs would receive ratings of
B-i and B2, respectively.
There is some merit in the provision of a slightly more detailed set of alterna-
tives, 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 carcinogen-
esis 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 studies.
4.6 Developmental Toxicity and Animal NOAELs (Charge Question 14)
The specific issue of animal No Observed Adverse Effect Levels (NOAEL), as it
is framed in the Charge, is inconsistent with the question posed concerning the use of
the Reference Dose (RfD) in evaluating incremental 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 increment per arbitrary unit of exposure, ex-
pressed 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 situation-the
relationship between lead exposure (defined as blood lead level) and IQ-the risk is
better expressed as 0.25 IQ points for each 1//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 extracted
from the animal data, 1 ng/kg day"1 appears to lie in an ambiguous zone. Murray etal.
(1979), in a multi-generation study, found that 10 ng per kg"1 per day"1 of TCDD lowered
the body weights and food consumption of f1 and f2 rats and also affected postnatal
survival. At 1 ng per kg"1 per day"1 both increases and decreases were noted among the
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survival indices of f1 litters. A NOAEL of 1 ng per kg"1 per day"1 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 exposure 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, respec-
tively, from the initiation of exposure. Social behavior was assayed in the first cohort.
On the basis of total TCDD consumed by the time of birth, the mothers had 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 prenatal 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. Comparisons between acute and
steady-state exposures for endpoints such as those above have not been carried out
despite the significance 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
consume 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 accumulate 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 accumulation in fetal tissue. Moreover, the fetus will deplete the
mother of nutrients even at the cost of her own nutritional status. Lactation is another
situation in which lipophilic agents are released and consumed, as discussed in the
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document.18 The lead parallel 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 pharmacokinetics 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 vulnerability 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 developmental treatments in rats to the prenatal period may underestimate
the full impact in humans of gestational exposure. The behavioral 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.
Further, although sexual development has become a focus of TCDD toxicity
research, it is crucial to recognize that the complex unfolding of brain developmental
processes 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 developing brain and its virtual disappearance later in life argue that sexual develop-
ment is unlikely to be its only role. The report by Schantz and Bowman (1989) hints at
additional outcomes. Note, further, that copulatory behavior and genital structure reflect
only limited facets of sexual maturation. Copulatory behavior and reproductive morphol-
ogy 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.
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 planar PCBs were
associated with a higher incidence of hypotonia (Huisman et al., 1995).
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Chapter 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, etal., 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 develop-
ment. 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 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 associated 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 reproductive 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 developmental and
reproductive effects attributable to TCDD is necessarily quite limited. The
neurobehavioral studies on PCBs offer directions 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: Potential for Immunotoxicity
(Charge Question 15)
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.
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There was a consensus among most Committee Members that, overall,
Chapter 4 of the reassessment document provided an accurate, current summary
of the immunotoxicology associated with TCDD and related compounds in
humans and experimental animals. However, the Committee has some concerns
(and noted some omissions) pertaining to immunology and the interpretation of certain
experimental results, in Chapter 4, and particularly, Chapter 9. Although the overall
data suggest that dioxin and related compounds 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 background 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 experimental 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 characteriza-
tion of the populations that have been studied prevent definitive conclusions 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 immune effects in humans occurred in the Taiwan
population exposed to contaminated rice oil where both immunosuppression and
increased infections were observed, presumably resulting from exposure to furans and
PCBs (Wu etal., 1984; Chang etal., 1982a; Chang etal., 1982b: Chang etal., 1981).
Some studies have reported changes in immunoglobin (Ig) levels (Jennings etal.,
1988) and NKcell activity (Jennings etal., 1988; Svensson etal., 1991). Other studies
have reported no effects (such as the Ranch Hand (USAF, 1991) and Seveso studies
(Mocarelli etal., 1986; Mocarelli etal., 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, etal., 1981;
Bekesi et al., 1985) exposed to halogenated aromatic hydrocarbons (HAH), as well as
of monkeys (Hong eta\., 1989; Tryphonas etal., 1989), reported that a slight reduction
in CD4+ cells occurred. Although this may or may not translate to a significant health
effect, these cells are involved in regulating immune responses and reduced CD4/CD8
ratios are a hallmark of immunosuppression. It may be argued that any reduction in
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CD4 cells could lead to such potential health effects as increases in infectious disease,
given that a large population is affected. Of interest to this discussion is a recent study
by Oughton etal. (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 defined by
concomitant expression of Pgp-1 CD45RB. The clinical significance of this change on
immunocompetence is presently unclear. Similar changes in immune system function-
ing have, however, been suggested by some investigators to be significant to HIV
pathogenesis (Janossy etal., 1993; Lim etal., 1993; Cameron etal., 1994; Jaleco et
al., 1994), indicating that the decrease in these cells may be associated with a de-
crease in immunocompetence.
Although the immune system is a sensitive target to HAHs in experimental
animal species, as presented, the EPA document does not provide convincing evi-
dence to indicate that background or near background exposure levels to dioxin-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
reproduced 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 to two orders above
background is significant. 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-
standard" test (i.e., suppression of the primary antibody response following immuniza-
tion) was not employed in any of the human test panels, although this is a hallmark in
experimental animals. The exception to this is the as yet, unpublished study on the
Inuit population (Dewailly, in press).
Chapter Four discussions pertaining to in vitro effects, although complete,
concluded these tests have limited relevance as culture conditions may play a signifi-
cant role (i.e., serum effects). The Committee felt that this was not a legitimate
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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 evidence indicates that imununotoxicity (particu-
larly suppression of the antibody response) by dioxins is presumably Ah-receptor
dependent. 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 mechanism 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 animals. 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, rabbit, monkey, etc.). As such, it would be
more appropriate to indicate that differences in animal sensitivity exists rather than
"variability in response" as this suggests a different 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 reassess-
ment 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 experimental species, including mice and
monkeys, indicate that the antibody response to a T-dependent antigen is the most
sensitive and reproducible indicator for immunotoxicity in adult animals. The ED50 in
sensitive strains of mice is approx. 0.7 //g/kg. Several other responses have been
shown to be more sensitive but have not been confirmed or reproduced by other
research groups. Chapter 9 gives undue weight to these unconfirmed or limited
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studies (see Table 9-5), and fails to discuss the highly reproducible and widely
used primary antibody 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 mecha-
nism and relevance of these observations, which of course were not available 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 observation,
although additional studies are warranted 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 RFC primary response) which provide ED50, 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 text of these tables should include a critical review of the data,
the most reproducible 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 concerns 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 related members of this class, and in the whole
area of receptor biology and signaling biology, and these gains should be factored into
the revision.
4.9 Dose-Response
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.
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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 gener-
ated for that purpose. The Committee was disappointed to see that, in addition to data
from the Kociba et al. (1978) bioassay (which formed the basis for EPA's earlier
estimate of cancer potency for TCDD), the only additional data used in EPA's quantita-
tive analysis was from the Maronpot et al. (1993) gavage study.
The only use that EPA made of pharmacokinetic modeling in its quantitative
analysis was in making correlations between estimates of two-stage model parameters
and outputs of pharmacokinetic models (Appendix D of the reassessment document).
This is a very limited use of the physiological and pharmacokinetic information (al-
though 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); moreover, 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 analysis
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 under-
stood by the reader, to the point of reproducing the analysis if desirable. The
reasoning and analysis that led EPA to propose its preferred model must be clearly
explained. The sensitivity of the results to alternative models or assumptions must also
be presented. Unfortunately, EPA's description 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 para-
graph at the bottom of page 8-45. The resulting 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 analysis in sufficient detail to allow
the reader to understand 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.
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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. etal. involving initiation with DEN or the data not involving such initiation
were used in EPA's preferred analysis.
The focal lesion data used in developing EPA's cancer risk model are not from
the published Maronpot etal. (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 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 considerable 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 analysis. 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 determine 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.
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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-modeling 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 humans 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. There-
fore, 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
conceptually 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 summary measure should involve only prior exposures and not future exposures.
However, the summary exposure measure used by EPA is average lifetime exposure,
which involves 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 compensating ad hoc adjustment to the risk estimate obtained from the additive
risk model. The Committee recommends that both the additive and multiplicative
models be reformulated 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
Several Members of the Committee contend that the cancer risk model is not particularly "flawed," but represents an
acceptable approach.
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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 understanding 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 Incremental 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 epidemiologic 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
document needs to describe and evaluate this alternative dose response relation-
ship, 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 use of the linear multistage model (LMS) needs to be re-evaluated, the re-evalua-
tion consists of enhancing the LMS approach with a PBPK analysis and a 2-stage
analysis rather than a discussion of alterative approaches. A discussion of such
alternative approaches, and their results, should also be reflected in the appropriate
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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 complete carcinogen. Dioxin is a non-
genotoxic promotor which acts at least in part via the Ah receptor and exhibits numer-
ous U-shaped dose responses (Kociba, etal., 1978; Pitot etal., 1987; Fang etal., in
press; Maronpot etal., 1993; Teegaurden etal., 1995). Thus, the document cannot
ignore a possible threshold dose-response relationship 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
recommended 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 exposures, 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 incremental
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 ex-
pressed 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 number of specific case examples, but cannot be taken as
universally proven. Until a full mechanism of action has been mapped out, the reas-
sessment'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).
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The specific case developed by EPA to support this hypothesis was the binding
of ligand to the Ah receptor, which is then assumed 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 considered.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 responses. It is not
proven for all possible toxic endpoints; the association is strongest for enzyme induc-
tion 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 assessment 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 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 individ-
ual 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 published
literature were not considered in the document. The evidence for Ah receptor-
linked effects (and their role in toxicity), and (for balance) the evidence suggest-
ing 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 explanation, some
discussion of the merits and limitations, and an indication of the acceptance of this idea
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."
24
One of the Committee's immunologist participants believes that "The evidence for receptor independence from this data is
insufficient to contradict the majority of evidence for receptor dependence."
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in the scientific community. EPA needs to be more flexible in its statements, to allow
adaptability to scientific evidence that may be developed in the future.
4.10 Use of Toxicity Equivalence Factors (TEFs) (Charge Question 20)
In general, the Committee agrees that the use of a TEF is a valid approach
provided that the contribution to the TEQ from: a) TCDD; b) other dioxins and
furans; and c) coplanar PCBs are explicitly stated. However, when assessing the
toxicity of complex mixtures that are not well-defined, the Committee believes
that presenting the results using alternative methods may be warranted whenever
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 methods.
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 approach 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-
reviewed 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 acknowledges 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
constitute a small percentage of the total congeners present in an environmentally
relevant mixture. 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.
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New data, which became available since the release of the document have
resulted in adjustments to several of the TEF values. The Committee suggests
that a comprehensive review of all TEF values be summarized within the appen-
dix 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,
immunotoxicity) used to derive the TEF value. Finally, since TEF values can vary
dramatically based upon the species and response 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 position for the use of the
TEF/TEQ approach.
Although the reassessment recognized that humans are not overly sensitive or
resistant to the effects of dioxin-like compounds relative to other species, there is a lack
of discussion regarding the differences between human and rodent receptors. Such
information 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 discussion of
how this information is taken into account when assigning TEF values to congeners.
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 persis-
tent or bioaccumulative, but the precursor 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 anticarcinogenic effect (Bjeldanes et al., 1991;
Bradlow etal., 1991; Liu etal., 1994; and Wattenberg etal., 1978).
As mentioned in the health assessment document (p 9-70), "A more detailed
description of these issues is contained in U.S. EPA (1989)." This referenced
document (TITLE, EPA/625/3-89/016), once updated and modified 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 suggestions. In
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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, 001 b, 001 c) 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 addition 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 Response
4.11.1 Animal Data and Weight-of-Evidence Conclusions for Human 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 definition, a heavy reliance on the results
of numerous 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 humans show almost a
10,000-fold range in their response to dioxin exposure for a number 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 presumed to have the Ah receptor), but this breadth of sensitivity
may serve as an indicator 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 particular concern to this Committee. The
assignment of "oral intake risk-specific doses of slightly less than 0.01 pg
TCDD/kg/day, corresponding to unit risk estimates of 1 X 10"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 adequately 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
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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 extrapolation 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 species 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 humans, similar biochemical
responses in multiple 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 assessment. This position objects particularly to
the lack of cogent human data on indices such as sexual behavior, immune dysfunc-
tion, and others, and notes species heterogeneity in the Ah receptor. Lack of human
data, however, should not be interpreted to mean that humans 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.
The animal data indicate TCDD to be a potent developmental toxicant capable of
inducing functional and morphological aberrations in male rats (Mably et al., 1992;
Bjerke et al., 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 revised Chapter 9 should feature developmental
toxicity with as much emphasis as is allocated to cancer and reproductive toxicity.
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 supplemented
by the PCB data from the Lake Michigan (Jacobson and Jacobson, 1994) (as dis-
cussed in section 4.6.1) and North Carolina (Gladen et al., 1988) studies because,
unlike the Japanese and Taiwanese episodes, they are based on prevailing environ-
mental 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.
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A lamentable stimulus to this debate is the somewhat loose and impres-
sionistic 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 characteriza-
tion. Although the case for extrapolation 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 attempt 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 litera-
ture offer suitable models (e.g., Streissguth etal., 1990 re ethanol).
Chapter 9 needs to offer a balanced perspective on these issues, espe-
cially by recognizing that, for developmental toxicity, arguing from simple
homologous responses is unproductive. An appropriate translation, especially for
functional 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 (Wilson,
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 Document
4.12.1 Evaluation of the Risk Assessment Chapter (Charge Question 23)
The stated purpose of the Risk Characterization 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 management options ..." (pg. 9-2). The risk
management implications of the draft conclusions could certainly be significant. If there
are public health consequences of current exposures to dioxin-like compounds,
intensified regulatory actions may be appropriate. Given the large public health and
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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 managers 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 innova-
tive approach that the Agency has taken to deal with this class of compounds.
The weaknesses rest in the lack of discussion 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 conclusions, 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 responds 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 human 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 com-
pounds. In the final assessment, 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 (between 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.
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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" typically refers
to exposure levels that are not out of the ordinary experience. The
populations described by Jacobson and Jacobson (1994) (as dis-
cussed in section 4.6.1), Gladen etal. (1988), and Huisman etal.
(1995), which demonstrate associations between PCB (and in the
Huisman study, PBBs and dioxins) exposure and neuro-developmen-
tal deficits, would be classified at the high end of the "background'
distribution. 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 presenting any quantitative
estimates of anti-carcinogenic action (even though available data suggest
protective effects 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 recognized and subjected to feasible analyses. Examples of this
problem include instances in which:
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.
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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
provided (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 biologi-
cally 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 biologic 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 perspective.
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 manager is provided with no quantitative indication of how the
severity or frequency of non-cancer effects (e.g., reproductive and developmental
toxicity) in the human population might be affected by incremental reductions in either
intake rates or average body burdens. 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 managers with any means to perform dose-response 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 misinter-
preted. 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
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 performed 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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"Comments Section" should be added to the table to highlight key uncertainties in the
database on particular effects.
4.12.2 Evaluation of Major Conclusions (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
Chapters 1 through 7 and part of Chapter 8.
The comments following the quotation of each of Chapter 9's conclusions (in italic
text) presented below reflect the Committee's concerns with that conclusion.
a) The scientific community has identified 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.
Binding of dioxin-like compounds to a cellular protein called the Ah recep-
tor represents the first step in a 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
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. Consequently, the biological system responds 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 compounds
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 concern are receptor-associated provides the opportunity to draw
upon the principles of receptor action that have been developed and validated within
the disciplines of immunology, biochemistry, and pharmacology. These principles are
not unique to TCDD, but rather apply to all ligand receptor 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). Receptor theory provides the basis
for the development 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
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quantitative response as a function of receptor occupancy. The extremes range from
full agonist to antagonist. 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 antago-
nists need to be more fully considered-both qualitatively (What compounds are
present?) and quantitatively (in what amounts?). In the overall context of the exposure-
dose-response paradigm, 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 expo-
sure to adverse effects with increasing severity as exposure increases
above background levels. (Chapter 9, page 79).
Effects and exposure levels need to be specified. 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 an end-point specific
basis. For example, there is evidence from bioassays in rodents that TCDD could be
chemoprotective against breast cancer (Kociba etal., 1978) - although not all Mem-
bers of the Committee accept this finding. Recent studies from Seveso (Bertazzi et al.,
1993) seem to show a pattern of decreasing relative risk values for breast cancer in
women when comparing exposure zones R to B to A (i.e., from lower to higher esti-
mated 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.
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The overall impact of certain biochemical 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 toxicities
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 appropriate caveats) the total extant database.
c) In TCDD-exposed men, subtle changes in biochemistry and physiology,
such as enzyme induction, altered levels of circulating reproductive
hormones, or reduced glucose tolerance, have been detected in a limited
number of available studies. These findings, coupled with knowledge
derived from animal experiments, suggest the potential for adverse
impacts on human metabolism and developmental and/or reproductive
biology and perhaps, other effects in the range of current human expo-
sures. 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-burden 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 probability and severity as well as the spectrum 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 considerably
smaller than previously estimated.(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. Employment 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 additivity can be used. Experimental evidence
does not support the position of equal efficacy (which would rule out the presence of
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partial agonists or antagonists). With the knowledge that dioxin-like compounds have
differing receptor affinity, the well-documented 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 distribu-
tion and metabolism. Despite these caveats, the sense of almost all of the Com-
mittee was that the TEQ approach is, until some better alternative is developed,
the best available vehicle for performing 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 particu-
lar 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 margin 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 Committee) 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
suggests that dioxin and related compounds (CDDs, CDFs, and dioxin-like
PCBs are likely to present a cancer hazard to humans. While major
uncertainties remain, efforts of this reassessment to bring more data into
the evaluation of cancer potency have resulted in a risk-specific dose
estimate (1X 10~e) risk or one additional cancer in one million exposed of
approximately 0.01 pg TEQ/kg body weight/day, This risk-specific dose
estimate represents a plausible upper bound on risk based on the evalua-
tion 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 methodologies, 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 exposure levels within one or two orders-of-
magnitude above background is not well-supported by the existing human epidemio-
logic database.
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The previous (and apparently still current) position of the EPA has been to use a
linear extrapolation approach. This approach 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
considerable body of peer-reviewed data, including the bioassay data in Sprague-
Dawley rats (Kociba etal., 1978) and more recent studies on the TCDD-dependent
changes in hepatocyte proliferation (Fox etal., 1992) and preneoplasticfoci (Maronpot
etal., 1993), which challenges both of these assumptions. Thus, the risk-specific dose
estimate (at the 10"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
inference, a picture emerges of TCDD and related compounds as potent
toxicants in animals with the potential to produce a spectrum of effects.
Some of these effects may be occurring in humans 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 exposure have not yet been adequately demonstrated. The neuropsy-
chological abnormalities reported in the Lake Michigan (Jacobson and Jacobson, 1994)
(as discussed in section 4.6.1) and North Carolina (Gladen etal., 1988) PCB exposure
studies are suggestive, even though the exposures (albeit at "environmental 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 analysis of the animal data which form the basis of
the positions taken in the risk characterization.
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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 Committee's judgement that EPA has
not presented findings that support this conclusion adequately.
4.13 Other Issues and Future Steps
In the preceding text, the Health Panel of the Dioxin Reassessment Review
Committee responded to the 23 explicit questions contained in its charge. During the
course of the Panel's deliberations however, some generic issues not addressed in the
23 questions arose. These are:
a) The advantages and disadvantages of expressing overall risks for
2,3,7,8-TCDD, other dioxins and furans, and co-planar PCBs together
and separately.
The basis of this issue is, of course, the use of TEQ/TEF in formulating a risk
assessment for a broad range of related agents. Although there are many concerns
about the assumptions underlying the application of TEF/TEQ in this manner, neither
this Committee nor the public commentors who addressed this topic can propose an
approach better than that used by EPA. The sense of most of the Committee, devel-
oped 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 mixtures as a
whole.27 Having these risk assessment 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 (environmentally 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
exposure ranges for their consistency with its assumption of a linear, non-threshold
carcinogenic risk. In addition, the Committee (with several exceptions) believe that the
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.
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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 literature (albeit debatable, and
both pro and con) on the concept of hormesis and ionizing radiation biological effects;
this concept was not discussed during the review meeting, but is mentioned as a
possible area of future investigation.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
utilization of scientific knowledge in the preparation of the risk assess-
ment.
The Committee concluded that EPA reviews of the background and relevant
literature in Chapters 1-7 were thorough and objective, and that, subject to revision to
incorporate 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
judgments 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 implica-
tions of the ultimate judgments on the extent of these risks, the Committee recommends
that this further effort be undertaken as soon as possible.
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, submitting
the risk characterization chapter for external peer review prior to final review by the
SAB would serve to strengthen the document, 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 peer reviewed by a group of preeminent scientists, including some researchers from
outside the dioxin "community" before returning to the SAB. It is particularly important
Based on an analysis of data in Fingerhut et 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.
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to include individuals with outstanding credentials and experience in basic research
and quantitative modeling of receptor-mediated processes, as well as other scientists
with broad toxicological, epidemiological, and public health, perspectives in such a
review.
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5. CONCLUSIONS
5.1 Exposure Assessment Document
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, expo-
sures, 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 Committee
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 ques-
tions 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
comparing this estimate to the estimate obtained from measured and representative
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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 comparison) missing sources of 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 that the available scientific evidence strongly indicates
that current levels of dioxin-like compounds in the environment derive from anthropo-
genic 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 particulate 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 contributions from reservoirs might indeed be
important and that these sources should be evaluated 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 concern 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 guidance for performing "base-
line" 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 draft Exposure Assessment report and
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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 Exposure Assessment document provides a reasonable central estimate of
dioxin exposure but the estimate has substantial 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 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 commends 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 comprehen-
sive 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 additional 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 anthropo-
genic 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 reliability of the TEFs and the availability of
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representative and reliable exposure data. This review of the Health Assessment
Document calls for clarifications in the specifications for TEFs of the various dioxin-like
compounds for various health outcomes of concern. 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 deter-
mined with sufficient confidence for risk management decisions. In other words, when
the risk manager concludes that the overall health risk from dioxin and related com-
pounds 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
reduction for these several classes of compounds covered in this document.
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 and options for source and exposure reduction.
The eighth chapter on modeling is a critical one in the document. The interpre-
tation 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
interpretation of the human experience, largely (but not exclusively) from relatively high
dose industrial workers exposures and acute exposures of populations to accidental
releases, requires knowledge of, and corrections for, dose-related 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 human health risks of chronic,
low-dose environmental exposures to dioxin and related compounds, models that are
based on all of the relevant data are essential.
The modeling chapter does an adequate 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 Committee, 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, primarily the low-dose data of Kociba etal. (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 recommend that the
feasibility of such a model be discussed in the revised draft chapter.
103
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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 including: scientists active in dioxin research; other scientists with
broad toxicological (including experience in basic research and modeling of receptor-
mediated processes); and scientists with epidemiological and public health perspec-
tives, to place the risks of dioxin 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
Several Committee Members believe that EPA should consider in a threshold model the possibility of other toxic effects
occurring in the "threshold region."
104
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