United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington, D.C. 20460
Research and Development
EPA/600/S9-87/013 August 1988
SEPA Project Summary
Report of the EPA
Workshop on the
Development of Risk
Assessment Methodologies for
Tumor Promoters
Jan Connery
At a workshop sponsored by the
EPA Office of Research and Devel-
opment in February 1987, thirteen
expert panelists discussed research
needed to support the development
of risk assessment methodologies
for tumor promoters. The panelists
exchanged current data on
promotion, identified data gaps, and
formulated general and specific
research recommendations. Avail-
able data suggest that there are
probably at least three stages of
carcinogenesis - initiation, promo-
tion and progression - and that there
are agents that are associated pre-
dominantly with these three stages.
The panelists agreed that the
mechanism of promotion is not
currently understood, and they sug-
gest that there may be several
different mechanisms of promotion.
Available data suggest that pro-
motion is substantially different from
initiation and that traditional risk as-
sessment models for carcinogens
are not appropriate for promoters.
The panelists agreed that not enough
data are currently available to assess
the risks of promoters and that
substantial research is needed in
several areas, including: mech-
anisms of initiation, promotion and
progression; the behavior of
promoters in humans, especially
epidemiological studies; develop-
ment and validation of statistical
models for initiation/promotion
systems; the behavior of promoters
in organs other than the skin and the
liver, interspectes differences in
promotion; expansion of the chemical
data base for known and potential
promoters; synergism among pro-
moters; and development validation
of in vitro screening models for
known experiment promoters.
Trt/s Project Summary was
developed by EPA's Office of Health
and Environmental Assessment,
Washington, DC, to announce key
findings of the research project that is
fully documented in a separate report
of the same title (see Project Report
ordering information at back).
Introduction
In recent years, there has been a
growing recognition that risk assessment
of tumor promoters is important but is
precluded by a lack of data. In 1982, the
U.S. Environmental Protection Agency
(EPA) Office of Toxic Substances held a
workshop to examine how information on
promoter activity could be incorporated
into risk assessment. Participants agreed
that such information should be
incorporated into risk assessment but
could not offer the Agency guidance on
how to do this. Recently, both the
Science Advisory Board in its review of
perchloroethylene and the EPA Office of
Pesticides and Toxic Substances' panel
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on dioxin recommended that the EPA
consider integrating promotional activity
into the traditional risk assessment.
With regard to promoters, the current
EPA Guidelines for Carcinogen Risk
Assessment state:
Agents that are positive in long-term animal
experiments and also show evidence of
promoting or cocarcinogenic activity in
specialized tests should be considered as
complete carcinogens unless there is
evidence to the contrary because it is, at
present, difficult to determine whether an
agent is only a promoting or cocarcinogenic
agent. Agents that show positive results in
special tests for irritation, promotion or
cocarcinogenicity and no indication or tumor
response in well conducted and well
designed long-term animals studies should
be dealt with on an individual basis.
While this approach was not felt to be
wholly satisfactory, there was not enough
consensus to develop an alternative
approach in terms of either a qualitative
judgment of how likely an agent is to be
a promoter, or, quantitatively, of how
great a cancer risk a promoter might
pose for given levels of exposure.
As a first step towards risk
assessment for tumor promoters, the
EPA Office of Research and De-
velopment convened a workshop on
"Development of Risk Assessment
Methodologies for Tumor Promoters" on
February 3-5, 1987, in Bethesda,
Maryland. The workshop provided an
opportunity for expert scientists to pool
their knowledge and set research goals
to improve the scientific bases for risk
assessment of promoters. The group was
asked not to address specific chemicals,
but rather to identify research concerning
promoters as a class of substances, and
to prioritize this research according to its
impact and utility for risk assessment.
The workshop was chaired by Dr. Roy
Albert (University of Cincinnati Medical
Center), Dr. Robert Langenbach (National
Institute of Environmental Health
Science), and Dr. William Farland (EPA
Carcinogen Assessment Group).
The full report is based solely on the
workshop discussion and panelist
comments. As such, it reflects the
opinions and data of a limited number of
participants exchanged over a brief
period of time and therefore does not
provide a comprehensive treatment of
the various subject areas. The amount of
information provided on a particular topic
in the report does not indicate its relative
importance, and there may be important
aspects of tumor promotion that are not
touched on in the report.
Discussion
At the workshop the panelists agreed
that available data suggest that there are
probably at least three stages of
carcinogenesis - initiation, promotion and
progression - and that there are agents
that are associated predominantly with
these three stages. Initiation was
described as a sudden change probably
involving DMA that is irreversible over a
long period of time. There is a growing
body of data suggesting that the initiation
stage is relatively common and involves
nonspecific damage to DNA. There is
also evidence that there may be a
spectrum of initiated cells that vary in
their degrees of initiation and thus in
their susceptibility to promotion.
Promotion was defined as "the reversible
selective clonal expansion of initiated
cells and the reversible alteration of gene
expression." A list of criteria for
chemicals that can only promote was
developed. Progression was defined by a
majority of panelists as "an irreversible
change in DNA towards malignancy."
The panelists agreed that the
mechanism of promotion is not currently
understood, and they suggested that
there may be several different
mechanisms of promotion. Available data
suggest that promotion is substantially
different from initiation and that traditional
risk assessment models for carcinogens
are not appropriate for promoters.
Promoters appear to show more
extreme differences in species and strain
responses than carcinogens. The
panelists agreed that much more work
needs to be done to understand these
differences from a mechanistic stand-
point. Epidemiological studies should be
conducted to obtain human data, and
existing epidemiological data on pro-
motion should be examined as a
potential source of information on human
promoters. Although no agents have
been unequivocally classified as human
promoters, data indicate that several
chemicals may be working as human
promoters.
Available data suggest that promotion
is reversible in the liver and skin, but
currently there are not enough data to
ascertain whether reversibility is char-
acteristic of all promoters in all systems.
There was concern that there may be
synergism among promoters. Research
is needed to study this phenomenon and
to identify the kinds of promoters that are
likely to interact.
There is a need to develop and
validate statistical models for promotion
and to develop data to test the models.
The two-stage birth-death-mutation
model, developed by Moolgavkar,
Venzon and Knudson, was discussed at
the workshop. The panelists agreed that
it appears to provide a good theoretical
framework from which to propose and
interpret studies on promotion. Various
approaches to validating the model were
discussed, including an initiation/promo-
tion/initiation protocol using multiple
doses of both the initiating and promoting
agents.
The panelists agreed that not enough
data are currently available to assess the
risks of promoters and that substantial
research is needed in several areas.
including:
• Mechanisms of initiation, promotion
and progression, particularly data on
dose-response and frequency of
response.
• The behavior of promoters in humans.
Epidemiological studies of promoters
in humans are a high priority The
panelists suggested several pop-
ulations for epidemiological studies.
• Development and validation of
statistical models for initiation/ pro-
motion systems.
• The behavior of promoters in organs
other than the skin and the liver.
• Interspecies differences in promotion.
• Expansion of the chemical data base
for known and potential promoters
The panelists offered several sug-
gestions of chemicals to study.
• Synergism among promoters.
• Development and validation of in vitro
screening models for known
experimental promoters. If successful.
the in vitro approach should expedite
the selection of chemicals for in vivo
study.
The full report summarizes the dis-
cussion at the workshop. The first day of
discussion focused on current knowledge
of promotion. Panelists exchanged data
and identified data gaps. On the second
and third days, general and specific
research needs were identified.
The full report is organized into 13
sections that reflect the major themes of
discussion at the workshop. Each sec-
tion has been synthesized from many
different parts of the discussion that
pertain to the topic. A list of the panelists
and observers can be found in Appendix
A. The agenda is provided in Appendix
B, and premeeting comments prepared
by the panelists can be found ir
Appendix C.
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Jan Cannery is with the Eastern Research Group, Inc., Arlington, MA 02174
Hugh L Spitzer is the EPA Project Officer (see below).
The complete report, entitled "Report of the EPA Workshop on the Development
of Risk Assessment Methodologies for Tumor Promoters," (Order No. PB
88-230 743/AS; Cost: $25.95, subject to change) will be available only
from:
National Technical Information Service
5285 Port Royal Road
Springfield, VA 22161
Telephone: 703-487-4650
The EPA Project Officer can be contacted at:
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Washington, D.C. 20460
United States
Environmental Protection
Agency
Center for Environmental Research
Information
Cincinnati OH 45268
Official Business
Penalty for Private Use $300
EPA/600/S9-87/013
0000329 PS
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