December 23, 1996
EPA-SAB-EHC-LTR-97-002
Honorable Carol M. Browner
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W
Washington, DC 20460
Subject: Science Advisory Board Review of the Risk Assessment Forum's draft
document Assessment of Thyroid Follicular Cell Tumors
Dear Ms. Browner:
In 1988 the Science Advisory Board (SAB), in conjunction with the FIFRA
Scientific Advisory Panel, reviewed a position document covering the risk assessment of
agents that produce thyroid tumors in laboratory rodents. This document departed from
precedent in that it proposed that some thyroid carcinogens were operating through
perturbation in thyroid-pituitary function that would show dose thresholds instead of
possible low-dose linearity. The Board embraced the Agency's science review of thyroid
carcinogenesis and supported the science policy guidance on the risk assessment
process, but requested that the Agency provide more details as to the progression in the
development of cancer that may underlie a dose threshold. The Board also requested
that EPA develop some case studies that demonstrate how the Agency will use informa-
tion in the risk assessment process for thyroid cancer. In April, 1996, EPA's Risk
Assessment Forum completed a draft document updating the thyroid cancer policy and
responding to the SAB's earlier request for additional information. The Forum then
requested that the SAB review the updated document.
On July 19, 1996 the SAB's Environmental Health Committee (EHC) met in
Washington, DC to review the subject draft document. The Committee membership for
this review was augmented to include the Chair and one Member of the Scientific
Advisory Panel. The meeting was structured around a detailed Charge (Enclosure A)
addressing seven major issues. One of these issues (the first) addressed the overarch-
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ing consideration of the overall scientific adequacy of the document; the other six dealt
with specific technical questions. The following discussion addresses each of these
issues in turn.
a) Overall Scientific Adequacy
The Committee was positive regarding the overall scientific adequacy of the policy
document. Each of the criteria iterated in the document is supported by a robust science
base and supports the basic policy position that a disruption in thyroid pituitary status in
the rodent is associated with increases in thyroid cancer risk in a non-linear dose related
fashion. There are adequate scientific data in the case studies and in the incorporated
science reviews to guide a risk assessor to appropriate conclusions within the context of
the proposed policy, but the Committee believes that addressing some of the technical
issues raised in the following discussion would improve the utility of the document.
b) Specific Technical Issues
1) Adequacy of the rodent model in relation to human hazard potential
The science underpinning the EPA position is robust and voluminous. The review
of the science as presented at the SAB meeting was outstanding. The update since
1988 was expansive and complete. There was a good comparison between primate and
rodent responses to thyrotoxic agents; an excellent discussion regarding the role of
growth factor(s) in thyroid disease; and an outstanding presentation of a mechanistic
explanation of thyroid carcinogenesis as a secondary (compensatory) response to insult.
The scientific review and the conclusions present a course of action that is clear,
concise and realistic. The definition of antithyroid action for the class of compounds in
question is very pointed and notes that the required "evidence" must include: thyroid
hypertrophy, changes in hormone levels, specific site(s) of action, a dose correlation, a
time correlation, a lesion progression pathway, and structure activity relationships.
There are some minor caveats. Section 1.3 of the draft document would be
enhanced by the incorporation of explanatory graphics such as were used in the
presentation at the public meeting. It would be useful to emphasize the concept of
biomarkers by adding a statement such as "Figure 1 illustrates that several hormones
critical to thyroid homeostasis are measurable in circulating blood and can be used as
biomarkers of disruption to the homeostatic process. Use of the T3 (triododo thyro-
nine),T4 (thyroxine), and Thyroid Stimulating Hormone (TSH) appears appropriate.
These are the clinical markers used in patient diagnoses and management and are
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important in experimental animals as markers. When coupled with the "definition of
antithyroid action," presented above, the biomarkers serve as markers of both exposure
and effect; however, because of feedback and compensation, it may be necessary to
make measurements at critical time periods to show either exposure or effect.
2) Relative sensitivities of rodents and humans
The report takes the position that rodents appear to be more sensitive than
humans to the carcinogenic influences of thyroid-pituitary disruptions. The correspond-
ing proposed science policy position is that
"Evaluations of human thyroid cancer hazard and risk potential that pro-
duce thyroid (and related pituitary) tumors from long-term perturbations of
thyroid- pituitary functioning in rodents should (a) incorporate consider-
ations about potential interspecies differences in sensitivity, and (b)
evaluate the applicability of potential human exposure patterns relative to
animal cancer findings."
Requiring consideration of interspecies differences in sensitivity and human
exposure pattern is reasonable. Given the proposed and well-justified qualitative
presumption that rodent thyroid tumorigens may pose carcinogenic hazards and risks to
humans, the evaluations of differing species sensitivity and its impact should be quanti-
tative and data driven. It appears that data may be sufficient for assessments in several
cases. For cases where data are inadequate for such an assessment, presumptions of
equivalent species sensitivity and equivalent response for similar exposure patterns
seem reasonable. A suggestion for the science policy guidance provided on page 7 of
the SAB Review Draft would be to begin point number 2 at the bottom of the page with
the language:
"Where data are sufficient to quantitatively assess, evaluations of human
thyroid cancer risk from chemicals..."
and to end point number 2 with:
"In the absence of data sufficient to quantitatively assess species differ-
ences, equivalent sensitivity will be assumed."
Evidence suggests increased sensitivity in rodents in nearly all cases. The
Committee suggests adding a caveat in this regard to the first sentence in the second
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paragraph on page 7 (e.g., ".... but definitive human studies have not been performed...
") and to rewrite the second to the last sentence of that paragraph to state clearly the
position that "However, quantitatively, humans appear to be less sensitive to the
thyrotoxic effects of some chemicals than rodents."
In this regard, more care should be taken in the discussion in section 1.4 of the
report. Comparisons of rodent and human tumors, both in background incidence, as well
as in response to identified disturbances in thyroid functioning, have not been made.
Comparable levels of tissue sampling and histological examination of individuals are
typically not performed in the rodent bioassay and human epidemiological investigations;
the descriptive and analytic epidemiologic investigations to date are also limited by many
other factors, and are difficult to compare with rodent findings; and an explanation for
comparable background levels of thyroid tumors for rodents and humans in light of the
case being made is not given. Because of these variables, the Committee recommends
that the following sentence be added to the end of the paragraph at the top of page 5 of
the draft document: "These differences between studies in animals and studies in
humans with regard to histology and function, as well as the limiting factors in descriptive
and analytical epidemiological investigations, emphasize the lack of definition provided
by human data and the uncertainties for comparison with animal data." Finally, regard-
ing the discussion of species differences due to pharmacokinetics/half-life on page 6,
differences in pharmacodynamics, species size, and relative lifespan need to be
considered before statements regarding overall species differences in susceptibility can
be made. Although there are observed species differences for pharmacokinetics/half-
life, additional differences in pharmacodynamics, species size, and relative lifespan
should be considered before statements regarding overall species differences in
susceptibility can be made.
3) Importance of thyroid-pituitary status
The draft policy document takes the position that disruption in thyroid-pituitary
status may be associated with increases in thyroid cancer risk, and that there would not
be elevated risks for antithyroid chemicals under conditions of thyroid-pituitary homeo-
stasis. These positions are reasonable and justified, given that nonlinear dose-response
considerations will be incorporated into thyroid (and relevant pituitary) tumor assess-
ments for chemicals that disrupt thyroid hormone economy and have no mutagenic
activity relevant to the carcinogenicity. Agents regulated in this manner will have a
substantial data base to support the position of anti-thyroid activity resulting in imbal-
ances of the pituitary-thyroid axis. This will include evidence for enhanced thyroid growth
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(increased thyroid weights, hypertrophy/hyperplasia of follicular cells); changes in serum
thyroid (decreased thyroxine and triiodothyronine) and pituitary (increased
thyroid-stimulating hormone) hormone levels; data on the site of action of the compound
(direct thyroid effect or extrathyroidal effect on the peripheral metabolism of thyroid
hormones); and correlative data that documents doses of the compound that perturb
thyroid hormone economy result in appropriate morphologic changes in thyroid follicular
cells.
Nonlinear (threshold) considerations would not be applied to thyroid neoplasia
dose-response assessments for chemicals operating by mechanisms that do not disrupt
thyroid-pituitary homeostasis and where there is an absence of (or inadequate) mode of
action data. The four case presentations in the draft document demonstrate clearly how
the process will be accomplished with chemicals that act by several different
mechanisms.
It is important that any short-term mechanistic studies conducted to determine if a
compound has anti-thyroid activity leading to hormonal imbalances be carefully designed
and include multiple doses above and below the level producing thyroid tumors in
chronic studies. If possible, the final thyroid cancer policy document should include
selected literature citations and brief methodological considerations that will assist
sponsors in the development of a high-quality, data-rich information base for use in
making decisions regarding risk assessment of xenobiotic chemicals that produce
thyroid tumors in rodents.
4) Factors affecting antithyroid activity
The report provides seven factors for assessing whether or not a chemical has
antithyroid activity and sets the minimal criteria for making such a determination.
Thyroid growth and hormone changes are considered to be the sine qua nor? for
evidence of antithyroid activity. These changes show that the homeostatic mechanism
to control the metabolic role of thyroid hormones has been challenged and the
physiological controls are operational. The Committee agrees with this position, but
recommends that the following sentence be added to the second paragraph of section
2.2 (next to the last sentence) of the draft document: "It is important to provide for careful
timing of the measurements for TSH, T3, and T4, because of the compensatory action of
the homeostatic mechanism and because the measurements of rodent TSH are variable
and a true increase over control levels may be difficult to show after compensation
occurs."
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The next most important of the seven factors are the dose correlations. Changes
in growth may increase slightly as the homeostatic mechanism is challenged, but it is
important to show where the growth curve for the thyroid gland deviates from the normal
growth pattern. This shows that the anti-thyroid effect has caused an abnormal re-
sponse, even though the hormone changes may be normal due to compensation. With
regard to the dose-response correlations, the Committee suggests the deletion of Figure
A-3 for Compound 1 from the case study presentation. This figure appears to display an
inappropriate transformation of data and could be omitted since Table A-7 makes the
point adequately.
Although the site of action factor may not be absolutely necessary for document-
ing anti-thyroid effect, it is important to understand the basis for the adverse effect and
the Committee agrees that it should be listed as required evidence.
With regard to lesion progression, the document's position that cellular hypertro-
phy should be noted as a confirmation of thyroid growth is correct. However, hyperpla-
sia and stages of neoplasia may be difficult to note as they may only be seen near the
termination of a chronic study and further studies to show progression may not be
necessary.
The other studies listed under factor 6 can be useful, but not necessary, except
for reversibility. Reversibility during the early changes of thyroid growth and hormone
changes is important, and should be required.
Structure-activity analyses can certainly add strong support to the evidence on a
specific compound, and should be noted when available.
5) Margin-of-exposure considerations
The report proposes a default assumption that the significance of human expo-
sure to thyroid carcinogens should be evaluated by margin-of-exposure considerations
unless biologically based models and data are available (The margin of exposure is the
ratio of an estimate of the critical No Observed Adverse Effects Level (NOAEL) and
estimated human exposure). According to the proposed EPA cancer risk assessment
guidelines, the margin of exposure will be based upon the lower confidence limit of a
dose producing an excess tumor incidence of 10% or lower, not from the NOAEL for
tumors. To be compatible with those guidelines, the thyroid cancer policy document
should rely on the same procedure. Since there are several biological effects or markers
that may impact on tumor production (T3, T4, TSH, hyperplasia, thyroid weight), all of
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these endpoints should be examined, not just a single " critical" effect" on which a
NOAEL is typically based. The important issue is the shape of the dose-response curve
in the low-dose region. More than just the NOAELs should be identified. It would be
informative to risk assessors to calculate benchmark doses for all important biological
effects. Furthermore, the difficulty of measuring some of these "critical endpoints" with
precision argues against use of the NOAEL.
In addition, the final document should discuss reasons why the additivity to
background argument with low-dose linearity does not apply to rodent or human thyroid
tumors. Since there apparently is only a single critical mechanism, increased TSH, this
is a possibility. To argue for nonlinearity, it must be demonstrated that homeostasis
prevents increases in TSH in sensitive animals or sensitive thyroid cells at low doses of
an exogenous chemical.
6) Adequacy and utility of case studies
The Thyroid Risk Assessment Policy Document describes four case studies of
hypothetical chemicals that may act as thyroid carcinogens within the proposed frame-
work of chemical carcinogenesis for follicular thyroid tumors in rodents, i.e., either
through antithyroid activity or mutagenic activity. Each case study indicates the types of
data that might be available on a given chemical and the process that might be em-
ployed in assessing their significance for thyroid carcinogenesis. The policy document
places emphasis on assessing the site and mode of action of a chemical and on
assessing which dose-response relationships might be used to carry out low dose
extrapolations in animal studies. The four case studies are described in extensive detail
and illustrate very well the range of information that may be available (or not) for
potential thyroid carcinogens. Although the four case studies may not cover all possibili-
ties that may occur in practice, they are sufficient for purposes of illustrating the process
of assessing the significance of the data for carcinogenesis in rodents and for assessing
the type of low-dose extrapolation that might be appropriate in a given scenario. One
minor caveat is noted: there is a need to clarify the dose-response relationship between
the untransformed dose of Compound 1 and TSH levels as given in Figure A-3 of the
document.
The document also provides guidance for using the case study information in risk
assessment. This guidance suggests that: a risk assessor attempt to classify a chemical
as much as possible by its site and mode of action using the available data and provides
information on conducting low-dose extrapolations in animal studies. Overall, the
guidance provided by the four case studies is more than adequate and sufficient as an
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example of the process. Several minor changes would enhance further the value of the
document. The Committee suggests that the document include a brief comment on
whether animals with chronic thyroid stimulation (e.g., iodide deficiency, inhibition of
thyroid peroxidase) are susceptible to the development of thyroid tumors from additional
exposure to any one of the four hypothetical compounds described, and whether this
might suggest the need to consider the possibility of a category of susceptible
subpopulation in humans. In addition, the four detailed case studies, which are a critical
component of this policy document, should be designated as an Appendix to which a
reader can readily refer as needed.
We appreciate having been given the opportunity to address these issues, and
look forward to receiving your response to our comments.
Sincerely,
Dr. Genevieve Matanowski, Chair
Science Advisory Board
Dr. Ernest McConnell, Acting Chair
Environmental Health Committee, and
Chair, Scientific Advisory Panel
ENCLOSURES
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ENCLOSURE A
THYROID CANCER RISK ASSESSMENT POLICY DOCUMENT
CHARGE
In 1988 the EPA Science Advisory Board, in conjunction with the FIFRA Scientific
Advisory Panel, reviewed a position document covering the risk assessment of agents
that produce thyroid tumors in laboratory rodents. This report departed from precedent
in that it proposed that some thyroid carcinogens were operating through perturbation in
thyroid-pituitary functioning that would show dose thresholds instead of possible low-
dose linearity. The Board embraced the Agency's science review of thyroid carcinogen-
esis and supported the science policy guidance but wanted more details as to the steps
in the development of cancer that may underlie a dose threshold and some case studies
that show how the Agency will use information in the risk assessment process. After
several false starts, EPA has produced an update of the thyroid cancer policy. The
report has been reviewed by the Risk Assessment Forum and a number of outside
reviewers (attached). The revised document has been transmitted for evaluation and
comment by a combined Science Advisory Board/FIFRA Scientific Advisory Panel review
group.
The revised document comprises several parts. The body is composed of a free
standing summary of the science which sets the stage for the science policy, followed by
the highlights of the case studies. Several attachments support the policy including:
Appendix 1 is the detailed 1988 Agency science review, and Appendix 2 is an EPA
science update through 1992. Note that a preliminary search of the literature into 1996
failed to find papers that would significantly alter the science policy positions developed
in the report. Appendix 3 is an exemplary listing of chemical classes and individual
compounds that are known to produce effects upon the thyroid and, finally, Appendix 4
presents four case studies that illustrate the types of mode of action data that may be
available and how to use them in risk assessments. A copy of the October 15, 1988
SAB letter to the Administrator on their review of the original thyroid document is
included as Appendix 5.
The Agency is interested in comments on each of the following aspects of the
document, in addition to any other comments the review group may have:
1. Overall Adequacy
a. Do the scientific data provide a creditable basis for the science policy
positions?
b. Are the case studies appropriate to serve as illustrative guidance for risk
assessors?
A-1
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c. Are the science reviews (especially the update) reflective of current infor-
mation and adequate for their purpose?
2. Specific Issues for Discussion:
a. There is ample information in rodents to show that disruption in thyroid-
pituitary status leads to thyroid cancer. For humans, however, there is
conflicting and incomplete information on the role of thyroid-pituitary
imbalance in thyroid carcinogenesis. The document takes the position that
the rodent model cannot be totally disregarded in regard to human hazard
potential. Comment on the review of the relevant science and its support of
the proposed science policy position.
b. Assuming the relevance of the rodent model to human cancer hazard
potential, the report takes the position that rodents appear to be more
sensitive than humans to the carcinogenic influences of thyroid-pituitary
disruption. Risk assessors could provide guidance to risk managers as to
the interpretation of this information. Comment on the summary of the
state of knowledge regarding potential susceptibility for thyroid cancer
development and the proposed science policy position.
c. The Agency position is that disruption in thyroid-pituitary status may be
associated with increases in thyroid cancer risk. Likewise, there would not
be elevated risks for antithyroid chemicals under conditions of thyroid-
pituitary homeostasis. Comment on the reasonableness of this science
policy position.
d. The report develops guidance for assessing whether or not a chemical has
antithyroid activity. Comment on the seven factors included and the
minimal criteria for making such a determination.
e. The report proposes a default that the significance of human exposure to
antithyroid carcinogens should be evaluated by margin-of-exposure
considerations unless biologically based models and data are available.
The margin of exposure is the ratio of an estimate of the critical NOAEL
and estimated human exposure. Is this a reasonable position given the
state of knowledge? Address the proposed use of certain biomarkers (e.g.,
TSH levels, hyperplasia) to estimate potential NOAELs for antithyroid
activity and for estimating estimates of cancer risk.
The case studies illustrate some of the range of information that may be
available for thyroid carcinogens and the ways one may use such informa-
A-2
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tion in risk assessments. Comment on the nature, adequacy and com-
pleteness of the case studies and of the guidance for using the information.
A-3
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Distribution List
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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
ENVIRONMENTAL HEALTH COMMITTEE MEETING
July 19, 1996 - Thyroid Cancer Policy Document Review
CHAIR
Dr. Ernest E. McConnell,* Raleigh N.C
MEMBERS
Dr. Charles Capen (SAP), The Ohio State University, Columbus OH
Dr. Adolfo Cornea, The Johns Hopkins University , Baltimore, MD
Dr. Michael A. Gallo, UMDNJ-Robert Wood Johnson Medical School, Piscataway NJ
Dr. Emil Pfitzer, Research Institute for Fragrance Materials, Inc., Hackensack NJ
Dr. Mark J. Utell, University of Rochester Medical Center, Rochester NY
Dr. Lauren Zeise, California Environmental Protection Agency, Berkeley CA
CONSULTANTS
Dr. Steven C. Lewis, Exxon Biomedical Sciences, Inc., East Millston NJ
Dr. Bernard Weiss, University of Rochester Medical Center, Rochester NY
FEDERAL EXPERT
Dr. David Gaylor, National Center for Toxicological Research, Jefferson, AR
DESIGNATED FEDERAL OFFICIAL
Mr. Samuel Rondberg
Executive Secretary
Environmental Health Committee
Science Advisory Board (HOOF)
U.S. Environmental Protection Agency
Washington, D.C. 20460
STAFF SECRETARY
Ms. Mary L. Winston
Environmental Protection Agency
Science Advisory Board (HOOF)
Washington, D.C. 20460
*Chair of the Scientific Advisory Panel
**Member, Scientific Advisory Panel
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