EPA/Nat'l Ctr Env Rsch: Novel Mechanistic Approaches in Human Hlth Rsk Assessment Funds

Gary Greenberg Gary.Greenberg at Duke.edu
Sun Jul 8 14:54:51 EST 2001

Issues in Human Health Risk Assessment: Novel Mechanistic Approaches
in Human Health Risk Assessment 


2001 Science to Achieve Results (STAR) Program 


Opening Date: June 01, 2001 

Closing Date: September 12, 2001 

The U.S. Environmental Protection Agency’s (EPA) Office of Research
and Development solicits grant applications for the development of
novel mechanistic approaches in human health risk assessment.  Risk
assessment is an essential tool for setting environmental and
occupational standards aimed at protecting human health.  However,
risk assessment is a relatively new discipline and currently available
methods and relevant information on the exposure to, and the toxicity
of, a given agent are frequently inadequate to fully satisfy the
demands for high quality characterizations of risk. Quantitative risk
assessment methods for both cancer and non-cancer endpoints have been
and continue to be developed.  However, the underlying bases and
approaches used to assess human health risk tend to differ, depending
on whether the response is a cancer or non-cancer health effect. 

In 1997, the Commission on Risk Assessment and Risk Management of the
National Research Council concluded that the simple dichotomy between
cancer and non-cancer risk assessment is not fully supported by
current scientific evidence (NRC, 1997).  They also stated that one
outcome of this dichotomy is expressions of risk that are not directly
comparable and that differ significantly in defining maximal exposures
considered to have negligible risk. In addition, the National Research
Council’s report on Science and Judgment in Risk Assessment (NRC,
1994) noted the importance of a risk assessment approach that is less
fragmented, more consistent in application of similar concepts, and
more holistic than endpoint-specific guidelines. 

It is now believed that some chemically-induced carcinogenic and
non-carcinogenic effects share common biological pathways or precursor
events. Identification of such common steps and their mechanistic
bases could lead to a more consistent approach in risk assessments. A
framework for how such mechanistic or mode of action information could
be used in risk assessments is lacking.  The EPA recognizes the need
to develop a consistent, yet flexible set of principles and guidelines
for using and drawing inferences from scientific information in risk
assessment.  This requires improved methods for more effectively using
toxicological information from both animals and humans for predicting
risk for both cancer and non-cancer outcomes. 

Regulatory agencies use a variety of methods to estimate the risks to
humans from environmental and occupational exposures to toxic agents. 
Many of these methods are based on toxicological data derived from
animal models, particularly rodents, and have limitations in their
ability to predict human risk.  Animal bioassay data are based on late
or terminal stages of complex sequences of events and processes that
are determined by both genotype and phenotype which differ
considerably between rodents and humans.  Also, animal bioassays are
generally carried out at doses that exceed relevant human exposures. 
Based on these and other criticisms, it is argued that risk
estimations based strictly on animal bioassay data may be
unnecessarily high in some cases and, in others, deceptively low and
not protective of human health. 

In order to improve the estimation of risks to humans from exposures
to toxic agents, it is important to continually evaluate all risk
assessment methods and practices in light of new scientific
information so that better risk assessment methodologies can be
developed.  A pivotal and emerging source of information that has
significant consequences for developing these new methodologies comes
from the fields of molecular and cellular biology.  Over the last
decade, these disciplines have increased our understanding of
biological mechanisms, including the basic pathways and processes that
control cell growth, differentiation, and death, and have provided new
insights into how these pathways and processes are subverted by toxic
agents.  While it is clear that some pathways and processes are common
to all eukaryotic cells, there are also clear phenotypic and genotypic
differences that cause responses at other levels of organization to be
cell type- and species-specific.  These differences can profoundly
affect how animals and humans respond to the same toxic agent. 

This Request for Applications (RFA) solicits studies that focus on the
development and characterization of new risk assessment methods,
approaches, and practices that take into account current understanding
of the commonalities and differences in the basic mechanisms through
which animals and humans respond to toxic agents.  This includes
studies that identify and characterize the key mechanisms, pathways,
and processes that control the effects of toxic environmental
chemicals on cell proliferation, differentiation, and death in both
humans and animal models.  Major emphasis should be on defining those
aspects that are the same or different from both qualitative and
quantitative aspects between animals and humans. Studies that
correlate comparisons between human and rodent primary tissue-specific
cells in vitro and the corresponding rodent tissue in vivo and which
focus on agents or metabolites that have previously tested positive in
animal models are encouraged.  Successful proposals will demonstrate
an improved understanding of a toxic response and use of that
knowledge in improving human health risk assessments. 

EPA is also interested in research on the use of mechanistic
information in risk assessments from the aspect of the types of
information necessary to: 

demonstrate that a substance acts via a particular mode or mechanism, 

demonstrate that two toxic manifestations caused by the same substance
are produced by different modes of action, and 

justify the approach for dose-response assessment for chemicals that
produce multiple toxic manifestations, but through similar or
different mode(s) of action.

The purpose of this research is eventually to allow the derivation of
a commonly accepted set of principles defining how mechanistic or mode
of action information can be used in risk assessments, particularly as
it relates to extrapolation issues across and within species, across
time, and from high-to-low doses.  Information derived from these
studies will help establish commonalities in the rationale for
interspecies default methods for cancer and non-cancer endpoints. It
will also be important to determine how differing exposure durations
and subsequent toxicity processes may indicate that different measures
of dose for a particular toxic agent, such as peak concentrations of a
particular metabolite, may be more appropriate than the integrated
value of the concentration of an unmetabolized parent compound. 
Therefore, comparative studies of chemicals having different metabolic
routes and the conditions influencing those different routes, such as
species, gender, and physiological status, will have a high priority. 
The EPA is particularly interested in proposals that address the
following areas: 

1. Differences and commonalities between rodents and humans in the
pathways, processes, and mechanisms that control the effects of toxic
chemicals in the environment on cell proliferation including cell
senescence and programmed cell death, cell cycle control mechanisms,
aspects of telomere/telomerase function, and mechanisms of apoptosis; 

2. Differences and commonalities in homologous gene function,
expression, and genomic organization between rodents and humans that
affect the pathways, processes, and mechanisms associated with the
effects of toxic chemicals in the environment; 

3. Biological markers (biomarkers) that provide direct human
dose-response data that will reduce the assumptions and uncertainties
that arise from interspecies and high-dose to low-dose extrapolations,
thereby making health risk assessments more reliable, meaningful,
realistic, and cost effective; 

4. Studies to determine if mode of action information can be used in a
more consistent way to improve dose-response assessment across types
of adverse health effects. This is true for both chemicals producing
different toxicities by a similar mode of action and chemicals that
produce multiple toxicities by different modes of action; and 

5. Case studies that assess the human health endpoints by evaluating
currently available information on cellular and molecular mechanisms
and modes of action, including studies that attempt to integrate
cancer and non-cancer risk assessment via statistical or computational
techniques.  These case studies should demonstrate the relevance and
application of the proposed approaches to improving human health risk

National Research Council (NRC). 1997. Building a Foundation for Sound
Environmental Decisions, Washington D.C., National Academy Press. 

National Research Council (NRC). 1994.  Science and Judgement in Risk
Assessment, Washington D.C., National Academy Press. 

Subject to the availability of funds, up to $6 million is expected to
be awarded in fiscal year 2002 in this program area.  The projected
award range is $200,000 to $300,000 per year total costs for up to 3

Academic and not-for-profit institutions located in the U.S., and
state or local governments, are eligible under all existing
authorizations.  Profit-making firms are not eligible to receive
grants from EPA under this program.  Federal agencies and national
laboratories funded by federal agencies (Federally-funded Research and
Development Centers, FFRDCs) may not apply. 

Federal employees are not eligible to serve in a principal leadership
role on a grant. FFRDC employees may cooperate or collaborate with
eligible applicants within the limits imposed by applicable
legislation and regulations.  They may participate in planning,
conducting, and analyzing the research directed by the principal
investigator, but may not direct projects on behalf of the applicant
organization or principal investigator.  The principal investigator's
institution may provide funds through its grant from EPA to a FFRDC
for research personnel, supplies, equipment, and other expenses
directly related to the research.  However, salaries for permanent
FFRDC employees may not be provided through this mechanism. 

Federal employees may not receive salaries or in other ways augment
their agency's appropriations through grants made by this program. 
However, federal employees may interact with grantees so long as their
involvement is not essential to achieving the basic goals of the
grant.1 The principal investigator’s institution may also enter into
an agreement with a federal agency to purchase or utilize unique
supplies or services unavailable in the private sector.  Examples are
purchase of satellite data, census data tapes, chemical reference
standards, analyses, or use of instrumentation or other facilities not
available elsewhere, etc.  A written justification for federal
involvement must be included in the application, along with an
assurance from the federal agency involved which commits it to supply
the specified service. 

1EPA encourages interaction between its own laboratory scientists and
grant principal investigators for the purpose of exchanging
information in research areas of common interest that may add value to
their respective research activities.  However, this interaction must
be incidental to achieving the goals of the research under a grant. 
Interaction that is “incidental” is not reflected in a research
proposal and involves no resource commitments. 

Potential applicants who are uncertain of their eligibility should
contact Jack Puzak in NCER, phone (202) 564-6825, E-mail:
puzak.jack at epa.gov. 


A set of special instructions on how applicants should apply for an
NCER grant is found on the NCER web site,
http://es.epa.gov/ncerqa/rfa/forms/downlf.html, Standard Instructions
for Submitting a STAR Application.  The necessary forms for submitting
an application will be found on this web site. 

Sorting Codes 

The need for a sorting code to be used in the application and for
mailing is described in the Standard Instructions for Submitting a
STAR Application.  The sorting code for applications submitted in
response to this solicitation is 2001-STAR-T1.  The deadline for
receipt of the application by NCER is no later than 4:00 p.m. ET,
September 12, 2001. 


Further information, if needed, may be obtained from one of the EPA
officials indicated below. E-mail inquiries are preferred. 

Chris Saint 202-564-6909 saint.chris at epa.gov 

or Nigel Field 228-688-1981 fields.nigel at epa.gov 

Gary N. Greenberg, MD MPH    Sysop / Moderator Occ-Env-Med-L MailList
gary.greenberg at duke.edu     Duke Occupat, Environ, Int & Fam Medicine
OEM-L Maillist Website:                      http://occhealthnews.net


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