[Federal Register Volume 61, Number 236 (Friday, December 6, 1996)]
[Notices]
[Pages 64739-64741]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-31058]
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ENVIRONMENTAL PROTECTION AGENCY
[FRL-5660-5]
Investigator-Initiated Grants on Health Effects of Arsenic
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: The purpose of this notice is to solicit public comment on the
four research topics in the draft Request for Applications (RFA) on the
health effects of low levels of arsenic in drinking water. EPA staff
and academic researchers identified these arsenic research topics as
important for reducing the uncertainty regarding the health risks of
ingested arsenic at low levels. The Safe Drinking Water Act Amendments
of 1996 directed EPA to develop a plan for study to support arsenic
rulemaking that would reduce the uncertainty of health risks of
arsenic. Congress directed EPA to consult with Federal Agencies and
interested public and private entities in conducting the study and
authorized EPA to work with interested parties to carry out the study
plan. At a later date, EPA will hold a public meeting(s) on the arsenic
study plan.
DATES: Comments are requested on the wording, scope of the topics, and
the appropriateness of the research topics presented in this draft RFA.
Comments must be received on or before January 6, 1997. EPA plans to
issue the RFA a month after the close of the comment period.
ADDRESSES: Comments must be submitted to Dr. Sheila Rosenthal at EPA,
(8723), 401 M Street, SW., Washington, DC 20460.
FOR FURTHER INFORMATION CONTACT: For questions or comments regarding
the solicitation process, contact Dr. Sheila Rosenthal, telephone
number (202) 260-7334, EPA (8723), 401 M Street, SW., Washington, DC
20460, electronic mail address: rosenthal.sheila@epamail.epa.gov. For
questions or comments regarding the arsenic research topics, contact
Ms. Irene Dooley, telephone number (202) 260-9531, EPA (4607), 401 M
Street, SW., Washington, DC 20460, electronic mail address:
dooley.irene@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA's National Center for Environmental
Research and Quality Assurance (NCERQA) is preparing to issue a joint
solicitation for research on the health effects of low levels of
arsenic in drinking water. Funding for this joint solicitation will be
provided by EPA, the American Water Works Association Research
Foundation (AWWARF), and the Association of California Water Agencies
(ACWA) for a total of approximately $3 million. Any proposal submitted
will be considered for an EPA grant or AWWARF contract, unless the
proposal stipulates otherwise. EPA will fund approximately $2 million
worth of grants, and AWWARF/ACWA will fund approximately $1 million
worth of contracts. It is expected that three to six applications, each
with a project period of up to 3 years, will be funded under this joint
solicitation.
NCERQA will receive, process, and distribute the proposals to the
peer reviewers; convene the peer review sessions in conformance with
existing EPA and AWWARF guidelines; and record the review discussion
for each proposal. No EPA or ACWA or AWWARF employees will serve as
peer reviewers. The funding parties will discuss their respective
research agendas for the sole purpose of ensuring that any one proposal
is not funded by both EPA and AWWARF. The funding parties will ensure
annual review of
[[Page 64740]]
projects being funded separately by the parties, and promote
dissemination of results and communication of research findings to
appropriate regulatory bodies and other stakeholders.
The description of the request for applications is as follows:
ARSENIC HEALTH EFFECTS RESEARCH
Background
Risk management policies for arsenic in the United States (U.S.)
have changed with increases in knowledge, as evidenced by the U.S.
Environmental Protection Agency's (EPA's) divergent guidance for
arsenic under the Safe Drinking Water Act and the Clean Water Act.
EPA's drinking water standard, or maximum contaminant level (MCL), of
50 g/l was developed by the Public Health Service in the mid-
1940s. In 1980, EPA established a human health water quality criterion
for arsenic at 0.018 g/l for a one in a million (10-6)
cancer risk level under the Clean Water Act. Researchers have since
developed a substantial amount of data (toxicologic, epidemiologic, and
some mechanistic) about the potential human health effects of arsenic
(As) following ingestion.
The existing information has been used to develop a risk
assessment. EPA's 1988 arsenic risk assessment (Special Report on
Ingested Inorganic Arsenic: Skin Cancer; Nutritional Essentiality EPA/
625/3-87/013) has undergone peer review, inside and outside the Agency.
The risk assessment has led to the identification of several areas of
uncertainty. Given the high costs associated with reducing the level of
arsenic in drinking water systems, it has been decided that research to
reduce the uncertainty in the risk assessment is warranted.
The EPA, American Water Works Association Research Foundation
(AWWARF), and Association of California Water Agencies (ACWA) are
jointly requesting grant and contract applications for research on
human health effects associated with low level arsenic exposure via
ingestion.
While there are several possible approaches to improving our
understanding of the molecular basis of the carcinogenicity of arsenic,
additional data on the baseline exposure, metabolism of arsenic, and
role of arsenic in carcinogenesis are critical research priorities.
Exposure data on arsenic from dietary sources other than drinking water
would help determine the relative significance of arsenic from drinking
water. This would be important information in future risk assessments
for arsenic in drinking water and provide much needed exposure
information for future epidemiological studies. Furthermore, on-going
epidemiological feasibility studies being funded by EPA and AWWARF plus
several studies in Mexico, South America, and Asia should provide
needed health effects data and improve future epidemiological study
designs. This is the reason epidemiological studies are not requested
as a part of this RFA. Understanding the mechanism of arsenic
carcinogenesis and the variability in arsenic metabolism may ultimately
be used to determine the shape and slope of dose response curves,
including possible threshold effects, and reduce the uncertainty in
these curves. Research proposals in the following four topic areas are
invited. Proposals may address one or more than one topic area.
1. Contribution of Arsenic From Dietary Sources
In order to understand the possible health impacts of exposure to
arsenic from drinking water ingestion, it is essential to know the
relative contributions from different media. Since air exposures
typically are low, the amount and variability of exposures from food
and beverages need to be quantified for various populations, taking
into account demographic variabilities. This could be done by using
market-basket surveys for U.S. populations, as well as analyses of
dietary intakes for specific individuals. In conducting these studies
it is also essential to address availability of arsenic absorption from
ingested foods, as well as arsenic speciation (chemical form and
oxidation state). Information on specific food sources should be
determined in addition to total dietary contributions.
2. Determinants of Variability in Arsenic Metabolism
Given the critical role of methylation in the disposition of
arsenic, further characterization of the enzymatic basis of arsenic
methylation is required. To date, human arsenic methyltransferase has
not been isolated, but transferases are generally polymorphic.
Understanding the factors affecting human sensitivity would improve the
arsenic risk assessment. The objective of this section is to evaluate
variations in arsenic metabolism as reflected in variations in urinary
metabolites or other biomarkers of exposure as associated with the
exposure level, nutritional status, genetic factors, and other
variables. Included in this area are studies to improve mass balance
data on typical human metabolism of arsenic at various doses and
chemical forms. There is a need for the development and refinement of
assay procedures to characterize arsenic methyltransferases in human
tissues. In addition, these studies would compare biomarkers of arsenic
metabolism in individuals exposed to varying levels of arsenic with
differences that include, but are not limited to, nutritional status,
age, sex, and genetic variations.
3. Development of Animal Models for Determining Mechanisms for Arsenic
Carcinogenesis
Currently, EPA's cancer risk assessment is based on a low-dose
linearity and multistage extrapolation model, because there is not
enough information on the mechanism of arsenic to do otherwise. In
order to understand how arsenic causes cancer, it is first necessary to
have a model system in laboratory animals. This model system can then
be dissected to determine the molecular mechanism of the
carcinogenesis. Understanding of the mechanism can often be used to
identify biomarkers that would be useful for developing dose-response
relationships, including possible threshold effects, and for detecting
human populations sensitive to arsenic.
4. Biologically Based Quantitative Models
Quantitative models are key to extrapolation issues. They are
critical not only to the description of experimental results but also
in the generation of additional research. Physiologically based
pharmacokinetic (PBPK) models, which incorporate measurable
physiological and biochemical parameters, can be used to describe the
bioavailability, uptake, tissue distribution, metabolism, and excretion
of a chemical. By varying the biological parameters, one can predict
across routes, exposure scenarios, high-to-low doses, and even species.
The relationships among readily measured endpoints (e.g., blood levels,
urinary metabolites, etc.) can be described. PBPK models can be linked
to response models to predict how a specific tissue concentration can
result in biological effect.
A major question in arsenic health effects is the relationship
among exposure, dose, and response. PBPK models should be developed
using either animal or human data and appropriately validated. Exposure
via one route should be modeled and validated for another route. The
ability to back-predict exposure, as well as tissue concentration, from
readily
[[Page 64741]]
measured surrogates should be investigated.
Funding
Funding for this joint solicitation is provided by the U.S. EPA,
AWWARF, and ACWA for a total of approximately $3 million. Any proposal
submitted will be considered for an EPA grant or AWWARF contract,
unless the proposal stipulates otherwise. EPA will fund approximately
$2 million worth of grants, and AWWARF/ACWA will fund approximately $1
million worth of contracts. It is expected that three to six
applications, each with a project period of up to 3 years, will be
funded under this joint solicitation.
Eligibility
Academic and not-for-profit institutions located in the U.S. and
state or local governments are eligible under all existing EPA
authorizations. Profit-making firms are not eligible to receive
assistance from EPA under this program, but are eligible to receive
funding from AWWARF. Researchers in federal agencies other than EPA may
submit applications, but federal employees may not request salary
reimbursement. Federal employees may cooperate or collaborate with
other eligible applicants within the limits imposed by applicable
legislation and regulations.
Researchers who are late in any ongoing AWWARF sponsored studies
without an approved no cost extension will not be eligible for funding
by AWWARF; however, they may be eligible for funding by EPA. Potential
applicants who are uncertain of their eligibility for an AWWARF
contract should contact their AWWARF project manager.
AWWARF and EPA have a policy of non-discrimination and abide by all
laws, rules, and executive orders governing equal employment
opportunity. All entities receiving funding under this solicitation
will be required to agree not to discriminate on the basis of age, sex,
race, religion, color, national origin, handicap or veteran status.
AWWARF expects its contractors to be equal opportunity employers who
accept the goal of having a workforce that generally reflects the
minority composition of the community in which it is located. It is the
policy of AWWARF to encourage proposals from qualified minority owned
or directed institutions.
Funding Mechanism
The funding mechanism for all awards issued under this solicitation
will consist of grants from EPA and contracts from AWWARF and depends
on the availability of funds. In accordance with Public Law 95-224, the
primary purpose of a grant is to accomplish a public purpose of support
or stimulation authorized by Federal statute rather than acquisition
for the direct benefit of the Agency. In issuing a grant agreement, EPA
anticipates that there will be no substantial EPA involvement in the
design, implementation, or conduct of the research funded by the grant.
However, EPA will monitor research progress, based in part on annual
reports provided by awardees. ACWA and AWWARF will receive the annual
progress reports for the EPA grants.
The mission of AWWARF is to ``advance the science of water to
improve the quality of life.'' Contracts with AWWARF are managed by an
assigned AWWARF project manager and a volunteer Project Advisory
Committee (PAC). PACs are organized by AWWARF for each funded project
to provide guidance, review all reports and significant materials, and
generally monitor project performance on behalf of AWWARF and the water
utility industry. EPA will appoint a member to each AWWARF project
advisory committee funded from this joint solicitation. Periodic
reports for AWWARF are required every four months. In addition, a final
report and intellectual property rights as outlined in the ``Standard
AWWARF Funding Agreement'' are required under all AWWARF contracts. The
``Standard AWWARF Funding Agreement'' is available on the AWWARF home
page at http://www.awwarf.com. For general information regarding the
``Standard AWWARF Funding Agreement,'' contact Kathy Garretson at 303-
347-6118 or by E-mail at kgarretson@awwarf.com.
The final RFA will also include instructions to potential
applicants on the specific format to be used for applications. These
instructions will be similar to such instructions found in other EPA/
ORD solicitations which may be reviewed on the Internet at http://
www.epa.gov/ncerqa.
Dated: November 27, 1996.
Approved for publication:
Joseph K. Alexander,
Acting Assistant Administrator for Research and Development.
[FR Doc. 96-31058 Filed 12-05-96; 8:45 am]
BILLING CODE 6560-50-P
