CARCINOGENICITY OF DRINKING WATER DISINFECTION BY-PRODUCTS

Release Date:  July 8, 1999

RFA:  ES-99-007

National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  August 16, 1999
Application Receipt Date:  September 13, 1999

PURPOSE

Environmental health research carried out by the National Institute of
Environmental Health Sciences (NIEHS) provides a solid scientific foundation for
understanding interrelationships between environment, genetics and temporal
factors as they relate to human disease and dysfunction. The NIEHS Division of
Extramural Research and Training is responsible for developing and directing the
investigator-initiated hypothesis-driven, mechanistically-based research related
to the NIEHS mission. Research conducted by the National Toxicology Program
(NTP), centered at the NIEHS, focuses on evaluation of environmental/industrial
agents for their toxic effects using a broad array of assays and test systems,
and generates data to strengthen the scientific foundation for risk assessment. 
The goal of the Request for Applications (RFA) is to support investigator-
initiated research that will provide data to aid the NIEHS in defining the
mechanisms of action of agents under study by the NTP. Such information will
improve the risk assessment process, and, thereby, better protect the public
health.

This RFA, utilizes the R03 Small Grants Program to encourage investigator-
initiated applications that will utilize animal/tissues/sera from NTP studies
involving exposure to drinking water disinfection by-products (DBP).  It is
anticipated that this investigator-initiated research will complement the NTP
contract toxicity/carcinogenicity studies of DBPs by providing additional
information on their mechanism of action. An understanding of the mechanism of
toxicity/carcinogenicity will improve the ability to extrapolate from data
collected in rodents to humans. It will also help in extrapolation from the
higher concentrations used in the rodent studies to concentrations that occur in
the drinking water. Thus, research on the mechanisms of toxicity for these DBPs
will improve the use of the NTP study data for risk assessment by policy makers.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000", a PHS-led national
activity for setting priorities. This RFA, Carcinogenicity of Drinking Water
Disinfection By-Products, is related to the priority area of environmental
health, specifically the Section 11.9, People Receiving Safe Drinking Water. 
Potential applicants may obtain a copy of "Health People 2000" (Full Report:
Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through
the Superintendent of Documents, Government Printing Office, Washington, DC
20402-9325 (telephone: (202) 512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State or local governments and eligible agencies of the
Federal government.  Foreign institutions and organizations are not eligible. 
Applications from minority individuals and women are encouraged. Submission of
an application precludes concurrent submission of a regular research grant
application (R01) containing essentially the same research proposal. In addition,
small grant research support may not be used to supplement projects concurrently
supported by Federal or non-Federal funds or to provide interim support for
projects under review by the Public Health Service.

MECHANISM OF SUPPORT

This RFA will use the NIH Small Grants Program (R03) awards. Responsibility for
the planning, direction and execution of the proposed project will be solely that
of the applicant. The requested costs and project period will be a maximum of
$50,000 per year (direct cost) for a maximum of two years. Small grants are not
renewable but may be extended for an additional year with no additional funds at
the discretion of the applicant organization.  Funds for this RFA must be
requested in modules of $25,000 (direct cost) with a maximum of two modules per
year.  A feature of this modular grant concept is that no escalation is provided
for future years. In addition, only limited budget information is required. A
description of the modifications in the budget and biographical sketch pages
needed for submitting a modular grant will be found in the application procedure
section.

FUNDS AVAILABLE

The total estimated funds for this small grants program is $450,000 which will
support approximately four to six awards.  This level of support is dependent on
the receipt of a sufficient number of applications of high scientific merit.
Although this program is provided for within the financial plans of the NIEHS,
awards pursuant to the RFA are contingent upon the availability of funds for this
purpose.

RESEARCH OBJECTIVES

Background

The availability of safe drinking water is an important health concern. The
introduction of water chlorination resulted in a large drop in mortality from
infectious disease from contaminated water and is a major public health advance. 
However, there has been some concern about the safety of the disinfectants and
disinfectant byproducts (DBPs) that occur as a result of water treatment. The
disinfection by-products (DBPs) are a diverse group of chemicals that occur in
the drinking water following chlorination, chloramination, addition of chlorine
dioxide or ozone treatment of source water containing organic compounds such as
humic acid, typically present in surface water. The DBPs that occur in drinking
water in the highest concentrations include the trihalomethanes (THM) and
haloacetic acids (HAA). Sodium chlorate may occur at high concentrations when an
alternative disinfectant, chlorine dioxide is used MX, 3-chlore-4-
(dichloromethyl)-5-hydroxy-2(5h)-furanone occurs in low concentrations but
accounts for approximately 50% of the "mutagenicity found in drinking water". The
concentrations of these by-products vary with the method of disinfection, organic
content of the water and other variables such as temperature, type of piping and
distance from the site of disinfection.  The study of DBPs is important because
of the widespread exposure to these chemicals in the drinking water and in the
air. It is important to understand the risk/benefit ratio of the various
disinfection processes, since water disinfection is essential to control
waterborne diseases and since DBP exposure is not easily avoided (showers,
swimming, preparing food may result in significant exposure to volatile
trihalomethanes.

In 1996, Congress reauthorized the Safe Drinking Water Act requiring the U.S. EPA
to promulgate a Stage I disinfectants/disinfectants byproducts (D/DBP) rule by
November 1998. The stage I (interim) rule established a Maximum Contaminant Level
(MCL), 80 ug/L for total trihalomethanes (THMs) and 60 ug/L total for the five
(5) major haloacetic acids (HAAs), (mono-, di-, and trichloroacetic acid and
mono- and dibromoacetic acid), as well as standards for disinfectants and some
other DBPs.  A Stage II rule (i.e. final guidelines) is proposed that would lower
the THM level to 80 ug/L and the HAA levels to 40 ug/L.  However, there is
currently insufficient scientific data for precise establishment of these DBP
standards.

Thus, the NIEHS, in collaboration with the U. S. Environmental Protection Agency
(EPA), is conducting short-term and long-term toxicity studies of DBPs in
traditional rodent models with additional studies in genetically modified
(transgenic) mice. Four (4) DBPs long-term toxicity studies are planned, or are
under way. These include bromodichloromethane, sodium chlorate, 3-chloro-4-
(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), and dibromoacetic acid.

These studies all use the drinking water route of exposure with high dose
concentrations but they also will include lower concentrations closer to human
exposure levels.

Bromodichloromethane is selected for study since this trihalomethane was
associated with a high incidence of colon cancer in rats in NTP studies when
given by corn oil gavage. In a U. S. EPA study, where bromodichloromethane was
given by drinking water, liver cancer, but not colon cancer, was found
(unpublished study).  The reason for this discrepancy is not understood.  The
second most important family of DBPs, based on frequency of occurrence and
concentrations in the drinking water, is the haloacetic acids.  Dichloroacetic
acid and trichloroacetic acid cause liver cancer in rodents at 0.5 g/L and
higher.  Dibromoacetic acid was selected for study because it occurs quite
commonly and much less toxicology data is available on this haloacetic acid. It
would be reasonable to expect that liver tumors may be associated with exposure
to high levels of this chemical.

MX (3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone), a DBP accounting for
up to 50% of the mutagenicity of chlorinated water, caused thyroid and liver
tumors in rats. This chemical is being evaluated at lower concentrations in both
rats and mice in the proposed NTP studies.

Sodium chlorate is being evaluated since it may occur in milligram quantities in
the drinking water following the use of chlorine dioxide, an alternate drinking
water disinfectant. Short-term NTP studies and EPA studies indicate that sodium
chlorate in the drinking water causes thyroid follicular cell hyperplasia in rats
but not mice.  Two-year studies are underway at doses that cause thyroid
follicular hyperplasia and at lower concentrations that do not. These NTP
toxicity/carcinogenicity studies will also address species specificity (mice vs.
rats) toxicokinetics, metabolism and disposition of the chemicals as well as dose
responses including doses that are environmentally relevant.

Research Goals

To aid the NTP in developing the scientific data necessary to define the
mechanisms of tumor development by bromodichloromethane, sodium chlorate, 3-
chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), and dibromoacetic acid,
the NTP, in coordination with the Division of Extramural Research and Training,
proposes to add additional investigator-initiated studies from this RFA to the
four NTP DBP studies.

Projects that will provide biochemical/biological endpoints that are related to
(or predict) potential carcinogenicity of bromodichloromethane, sodium chlorate,
3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), and dibromoacetic acid
are requested. Emphasis should be on whether lower concentrations, which may not
cause cancer in rodents, can be either expected to pose a human health hazard or
may be considered of minimal risk for the human population, including sensitive
subpopulations. Projects may include but are not limited to:

o  cellular effects/biochemical changes (in DNA methylation, glucose 6-
phosphatase activity, alterations in growth factors, changes in cell cycle
control) in liver, kidney or thyroid relative to exposure and how this is related
to DBP-induced (bromodichloromethane, sodium chlorate, 3-chloro-4-
(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), or dibromoacetic acid)
carcinogenicity,

o  the relationship between exposure to bromodichloromethane, sodium chlorate,
3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), or dibromoacetic acid
and the formation of DNA adducts and mutations and their role in carcinogenicity,

o  the relationship between exposure to bromodichloromethane, sodium chlorate,
3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), or dibromoacetic acid
and DNA repair enzyme activity, oxidative DNA damage and carcinogenicity induced
by these DBPs, and

o  the relationship between gene expression and exposure to bromodichloromethane,
sodium chlorate, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), or
dibromoacetic acid and DBP-induced carcinogenicity.

Research applications should be hypothesis driven, mechanistically-based and must
be justified as to how the NTP DBP studies (bromodichloromethane, sodium
chlorate, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), or
dibromoacetic acid) are unique in providing tissues needed for the studies
proposed, how the proposed studies will complement the NTP studies, and how the
data will aid in understanding the mechanisms of DBP carcinogenicity. The
application should explicitly state how the proposed studies will aid the U.S.
EPA in improving the scientific basis for DBP risk assessments that support
drinking water regulatory decisions.

Applications must be directly related to the potential carcinogenicity of
bromodichloromethane, sodium chlorate, 3-chloro-4-(dichloromethyl)-5-
hydroxy-2(5H)-furanone (MX), or dibromoacetic acid. Other endpoints such as
reproductive toxicity, neurotoxicity or immunotoxicity or the carcinogenicity of
other chemicals are not considered responsive to the RFA and will not be
accepted.

Study Design Considerations

A detailed statement of work including test doses and tissues that will be
analyzed by the NTP as well as special groups of animals available to
investigator-initiated studies under this RFA, may be obtained from the NIEHS
home page at the following address: http://www.niehs.nih.gov/dert/dbp.htm

The following information is intended to complement the information found on the
web site.

1.  The NTP studies include cell proliferation analysis at 4 and 21 days,
clinical chemistry evaluations, and toxicokinetic studies of the parent compound
and major metabolites in the expected target tissues.

2.  All short-term studies include five doses and controls with the DBP given in
the drinking water to male and female F344/N rats and B6C3F1 for 14 and 90 days
or 21 days. The two year studies include three doses and controls in groups of
50 male and female F344/N rats and B6C3F1 mice, except for the
bromodchloromethane study which is carried out only in male rats and female mice.

3.  Since the NTP is conducting drinking water studies, investigator-initiated
studies should be focused on utilization of tissues that can be made available
from these studies. In vitro studies can be proposed to extend the experimental
findings resulting from the use of tissues from the NTP studies and to
investigate lower concentrations of the DBPs. DBPs for use in the in vitro
studies may be requested from the NTP.

4.  Tissues will be shared (especially those from the two year sacrifice) by the
successful applicants of this RFA.  Applicants should contact the NTP (see
INQUIRIES section) for tissue availability before finalizing the application.

5.  It is expected that some studies will use tissues from rats and mice, in some
cases to compare species differences (for example, rats but not mice appear to
have thyroid follicular cell hyperplasia following sodium chlorate exposure). In
some cases, carcinogenicity is predicted but not known (for example both
dichloroacetic acid (rats and mice) and trichloroacetic acid (mice) cause liver
tumors suggesting that liver tumors will also occur with dibromoacetic acid). 
Investigators must, in their applications, be specific and justify the tissues
needed, preparation of tissues needed, concentrations to be studied, shipping
requirements, sex and species to be studied and time points.

6. If it is essential that the principal investigator be present at tissue
collection, the proposal must include funding for trips to Southern Research
Institute, Birmingham AL.

7.  Applicants need not address all 4 DBPs under study since
bromodichloromethane, sodium chlorate, 3-chloro-4-(dichloromethyl)-5-
hydroxy-2(5H)-furanone (MX), or dibromoacetic acid may act by very different
mechanisms. An applicant may focus on a single DBP or more than one DBP, if
common mechanisms are suspected.

8.  Applicants should include the highest concentration for the two year study
in the proposed application, a concentration which is most likely to produce a
carcinogenic response. Selected tissues will be available from the two year study
at the three highest concentrations tested.

9.  The contract laboratory will also dose animals for periods of up to 4 weeks
at the concentrations used in the two year study plus at 1/2, 1/4 and 1/10 of the
lowest concentration for the long-term studies and make tissues available to
investigators. Liver and kidney tissues will also be available from the two year
study, but sections for slides for the NTP study will take priority. Lobes of the
liver and sections of kidney not used in the NTP study will be made available on
a competitive basis for investigators for their studies. Tissues from the larger
tumors found grossly at necropsy can also be made available for investigators.
There will be an effort to harmonize studies and collection of tissues among
investigators.

10. Applicants are requested to set aside funds for two trips to NIEHS. The first
trip will be to meet other successful applications, meet with the U.S. EPA
officials responsible for using the mechanistic data, discuss means for sharing
tissues, discuss the goals of the program with NIEHS program managers and EPA
staff scientists, to discuss procedures for meeting the needs of the
investigators and coordinating the studies. A second trip to NIEHS will be to
discuss the results and be prepared to integrate the findings into the final NTP
technical reports on bromodichloromethane, sodium chlorate, 3-chloro-4-
(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), and dibromoacetic acid.

11. Inclusion of data in the NTP Technical Reports does not preclude independent
publication. The investigators are encouraged to publish their work independently
in the scientific literature at their discretion. Investigators may also have
access to NTP data on, for example, blood and tissue levels of parent compound
or major metabolites which may be needed for analysis and interpretation of their
own data.

LETTER OF INTENT

Prospective applicants are asked to submit, by August 16, 1999, a letter of
intent that includes a descriptive title of the proposed research, the name,
address and telephone number of the Principal Investigator, the identities of
other key personnel, participating institutions, and the number and title of the
RFA in response to which the application may be submitted. Although a letter of
intent is not required, is not binding and does not enter into the review of the
subsequent application, the information that it contains is helpful in planning
for the review of the applications. It allows NIEHS staff to estimate the
potential review workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

J. Patrick Mastin, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-24
111 T. W. Alexander Drive, Building 4401, Room 3455
Research Triangle Park, NC 27709
Telephone:  (919) 541-1446
FAX:  (919) 541-2503
EMAIL: mastin@niehs.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev 4/98) is to be used in applying
for these grants.  These forms are available at most institutional offices of
sponsored research and may be obtained from the Division of Extramural Outreach
and Information Resources, National Institute of Health, 6701 Rockledge Drive,
MSC 7910, Bethesda, MD 20892-7910, telephone (301) 435-0714, EMAIL:
GrantsInfo@nih.gov and may be obtained on the Web:
http://grants.nih.gov/grants/forms.htm

The modular grant concept establishes specific modules in which direct costs may
be requested as well as a maximum level for requested budgets.  Only limited
budgetary information is required under this approach.  The just-in-time concept
allows applicant to submit certain information only when there is a possibility
for an award.  It is anticipated that these changes will reduce the
administrative burden for the applicants, reviewers and Institute staff.  The
research grant application form PHS 398 (rev. 4/98) to be used in applying for
these grants, with the modifications noted below.

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $50,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative (F&A) costs] for the initial budget
period.  Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398.  It is not required and will not be accepted with the
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398.  It is not required and
will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Use a Modular Grant Budget Narrative page.
(See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At
the top of the page, enter the total direct costs requested for each year.  This
is not a form page.

o  Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should be
provided.  However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing the
budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct plus
facilities and administrative) for each year, each rounded to the nearest $1,000.
List the individuals/organizations with whom consortium or contractual
arrangements have been made, the percent effort of key personnel, and the role
on the project.  Indicate whether the collaborating institution is foreign or
domestic.  The total cost for a consortium/contractual arrangement is included
in the overall requested modular direct cost amount.  Include the letter of
intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall qualifications
of the research team.  A biographical sketch is required for all key personnel,
following the instructions below. No more than three pages may be used for each
person.  A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page
- List current position(s) and honors
- Provide information, including overall goals and responsibilities, on research
projects ongoing or completed during the last three years
- List selected peer-reviewed publications, with full citations

OTHER SUPPORT - Do not submit the "other support" pages. Selected other support
relevant to the proposed research may be included in the Biographical Sketch as
indicated above.  Complete other support information will be requested by the
staff of NIEHS or collaborating Institutes if there is a possibility for an
award.

CHECKLIST - This page should be completed and submitted with the application. If
the F&A rate agreement has been established, indicate the type of agreement and
the date. It is important to identify all exclusions that were used in the
calculation of the F&A costs for the initial budget and all future budget years.

APPENDIX þAn appendix or additional supporting materials will not be accepted
with the exception of originals of photos used in the application.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information is
necessary following the initial review.

THE FOLLOWING ARE SUPPLEMENTAL INSTRUCTIONS

1.  The applicant must be explicit in describing the proposed interface between
the NTP study design and the proposed project.

2.  Preliminary data are not required except to indicate the expertise of the
Principal Investigator to carry out the proposed studies.

3. The Research Plan (Specific Aims, Background and Significance, Preliminary
Studies, Research Design and Methods sections) is not to exceed Ten (10) pages. 
Tables and figures are included in the ten page limitation. Applications that
exceed page limitations or PHS 398 requirements for font size (height or
letters), type density (characters per inch), and margins (see PHS 398
directions) will be returned to the investigator.

The RFA label and line 2 of the application should both indicate the RFA number. 
The RFA label must be affixed to the bottom of the face page.  Failure to use
this label could result in delayed processing of the application such that it may
not reach the review committee in time for review.  The sample RFA label
available at:  http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been
modified to allow for this change.  Please note this is in pdf format.

Submit a signed, typewritten original of the application, including the
checklist, and three signed, clear, and single-sided photocopies in one package
to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of the application, two additional copies of the application must be
sent to Dr. J. Patrick Mastin at the address listed under LETTERS OF INTENT.

Applications must be received by September 13, 1999. If an application is
received after that date, it will be returned to the applicant without review.

The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application. The CSR
will not accept any application that is essentially the same as one already
reviewed. This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
the NIEHS in accordance with NIH peer review procedures. As part of the initial
merit review, all applications will receive a written critique and undergo a
process in which only those applications deemed to have the highest scientific
merit, generally the top half of the applications under review, will be discussed
and assigned a priority score.

Review Criteria

(1) Significance: If the study is completed, how will the scientific knowledge
on the mechanisms of carcinogenesis of the DBPs be advanced and how will it help
policy makers in setting scientifically-based DBP drinking water standards?

(2) Approach: Are the designs, methods and analysis adequately developed and
appropriate to meet the aims of the project? Does the applicant acknowledge
potential problems and consider alternative tactics? Is there an explanation of
how the data obtained will be integrated with the NTP study data to provide a
more comprehensive analysis of the potential mechanisms of carcinogenicity of
bromodichloromethane, sodium chlorate, 3-chloro-4-(dichloromethyl)-5-
hydroxy-2(5H)-furanone (MX), or dibromoacetic acid? Will the study provide
information on whether these mechanisms are likely to act at concentrations at
or near the concentrations found in the drinking water? Is the study focused on
the relationship between exposure, endpoint, sex and species, especially when
different results are found with different sex species combination?

(3) Innovation: Is their justification as to how the tissues unique to the
proposed study and how the study will make the best use of the tissues?

(4) Investigator: Is the investigator appropriately trained and well suited to
carry out the proposed project? Is the work proposed appropriate to the
experience level of the principal investigators and other researches (if any)?

(5) Environment: Does the scientific environment in which the work will be done
contribute to the probability of success? Is there evidence of institutional
support?

NOTE: If the project can be completed without the aid of the NTP studies, the
proposal will not quality under this RFA.

Schedule

Letter of Intent Receipt Date:       August 16, 1999
Application Receipt Date:            September 13, 1999
Peer Review Date:                    December 1999
Earliest Anticipated Date of Award:  February 2000

AWARD CRITERIA

The anticipated date of award is February 1999 pending availability of funds. 
The following will be considered in making funding decisions: Quality of the
proposed project as determined by peer review, availability of funds; and program
balance among research areas of the RFA.

INQUIRIES

Written, telephone or e-mail inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or questions from potential applicants is
welcomed.

Direct inquiries regarding programmatic issues to:

Jerrold J. Heindel, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC - 23
111 T.W. Alexander Drive, Building 4401, Room 3413 (courier address)
Research Triangle Park, NC 27709-2233
Telephone: (919) 541-0781
FAX: (919) 541-5064
EMAIL: heindelj@niehs.nih.gov

Direct inquiries regarding fiscal matters to:

Mr. David L. Mineo
Grants Management Branch
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-22
111 T.W. Alexander Drive, Building 4401, Room 3403 (courier address)
Research Triangle Park, NC 27709-2233
Telephone: (919) 541-7628
FAX: (919) 541-2860
EMAIL: mineo@niehs.nih.gov

For clarification of NTP Study design or for information on tissue availability
contact:

Gary A Boorman, DVM, Ph. D.
Office of Special Programs
National Institute of Environmental Health Sciences
P.O. Box 12233, MD B3-08
111 T.W. Alexander Drive, Rm. B350 (courier address)
Research Triangle Park, NC 27709-2233
Telephone: (919) 541-3440
FAX: (919) 541-4714
EMAIL: boorman@niehs.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.113 and 93.115. Awards are made under the authorization of the Public Health
Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law
99-158, 43 USC 241 and 385) and administered under PHS grants policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.

The Public Health Services (PHS) strongly encourages all grant and contract
recipients to provide a smoke-free workplace and promote the non-use of all
tobacco products. In addition, Public Law 103-227, the Pro Children Act of 1994,
prohibits smoking in certain facilities (or in some cases, any portion of a
facility) in which regular or routine education, library, day care, health care,
or early childhood development services are provided to children. This is
consistent with the PHS mission to protect and advance the physical and mental
health of the American people.


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