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) 710-0267, 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 An 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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