[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: [email protected]. 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: 
[email protected].

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 [email protected].
    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