NON-MOUSE MODELS OF DIABETES COMPLICATIONS IN CARDIOVASCULAR AND MICROVASCULAR DISEASES Release Date: November 20, 2000 RFA: HL-01-010 National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov/ National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov Letter of Intent Receipt Date: February 26, 2001 Application Receipt Date: March 21, 2001 PURPOSE The purpose of this solicitation is to support efforts to develop non-mouse animal models of diabetic complications. The animal models are expected to mimic vascular diseases in patients with type 1 or type 2 diabetes mellitus with an emphasis on, but not limited to, cardiovascular disorders of coronary heart disease, stroke, peripheral arterial disease, cardiomyopathy, and congestive heart failure. Improved animal models of microvascular complications are also needed. The goal of this initiative is to obtain these non-mouse animal models, through the use of selective breeding, dietary manipulation, or molecular genetic approaches. Applicants to this initiative are also expected to characterize and validate the models for use in various aspects of basic, developmental, or translational research including testing prevention, early detection, therapeutic, or diagnostic imaging strategies. Applicants should also propose plans to make these models available to other research investigators for studies to advance our understanding of the etiology, pathobiology, clinical progression, management and prevention of diabetic vascular diseases. A companion RFA (DK-01-009, Mouse Models of Diabetic Complications: Consortium) solicits applications to develop mouse models of diabetic complications in order to take advantage of unique genetic technologies that are applicable in the mouse. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2010", a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Non-Mouse Models Of Diabetes Complications In Cardiovascular And Microvascular Diseases, is related to the priority areas, "Heart Disease and Stroke", and "Chronic Disabling Conditions". Potential applicants may obtain a copy of AHealthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Awards under this RFA to foreign institutions will be made only for research of very unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. Cell biology, molecular biology, nutrition, biochemistry, physiology, pathology, genetics, and imaging modalities are among the disciplines and expertise that may be appropriate for this research program. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01) award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed 5 years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator- initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2001. FUNDS AVAILABLE The NHLBI and NIDDK intend to commit approximately $1,500,000 in FY 2001 to fund three to five new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $350,000 per year. The Facilities and Administrative costs for collaborating institutions are excluded from this ceiling and a maximum increase of no more than three percent is allowed in each additional year requested in the application. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of both Institutes provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. Equipment is included in the budget limitation. However, requests for major equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires in- depth justification. Final decisions will depend on the nature of the justification and the Institute"s fiscal situation. Because we expect that there will not be any applications requesting less that $250,000 in first year direct costs, applications should be in the standard (non-modular) format with a detailed budget. Consortium Arrangements When a grant application includes research activities that involve institutions other than the grantee institution, it is considered a consortium effort. Such activities may be included in a grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. Facilities and administrative costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in-aid. Consult the latest published policy governing consortia before developing the application. RESEARCH OBJECTIVES Background Prevention and treatment of long-term micro- and macro-vascular complications remain a critical problem in the management of patients with type 1 or type 2 diabetes mellitus. In the United States, diabetes is the leading cause of new blindness in adults, of new cases of end stage renal disease and of non- traumatic lower leg amputations. In addition, cardiovascular complications are now the leading cause of diabetes-related morbidity and mortality particularly among women and the elderly. In adult patients with diabetes, the risk of cardiovascular disease (CVD)is three to five fold greater than in nondiabetics, up to three fourths of all deaths among diabetics can be directly attributed to accelerated atherosclerosis and CVD. A number of known risk factors for CVD, such as hypertension, central obesity, and dyslipidemia, are more common in diabetics than in the general population. However, no more than 25% of the excess coronary artery disease (CAD) risk in diabetics can be accounted for by known risk factors such as high plasma cholesterol, low plasma HDL, high plasma triglycerides, and hypertension, suggesting the presence of other factors contributing to the development of CVD in patients with diabetes. The 1998 Diabetes Research Working Group report noted that a lack of good animal models has been a major impediment to research on the long-term micro- and macrovascular complications of diabetes. Improved animal models are critical for understanding the pathogenesis of complications and for testing potential new prevention and treatment modalities. Animal models can be used to conduct studies at the molecular, cellular and tissue level not feasible in humans. Thus, there is an urgent need to derive, thoroughly characterize, and validate animal models for their relevance to human biology, and to use these models for testing therapeutic, prevention, early detection or diagnostic imaging strategies. Clinical studies have repeatedly shown a strong correlation between susceptibility to micro- and macrovascular complications, especially in patients with diabetic nephropathy. Cardiovascular events are much more frequent in patients with diabetic nephropathy. In addition, renal artery atherosclerosis may contribute to renal disease, likewise, accelerated lower extremity arterial disease interacts with neuropathy, resulting in the high rate of lower extremity amputations in patients with diabetes. In addition, it is becoming increasingly clear that the pathogenesis of microvascular complications, as well as of macrovascular disease, includes disordered function of endothelial cells. There is a growing recognition that diabetes may be increasing the risk of CVD partly due to its association with a variety of metabolic abnormalities. Hyperglycemia, the defining metabolic change in diabetes, may accelerate the development of atherosclerosis. However, the specific contribution of hyperglycemia has been difficult to demonstrate in either population studies or animal models. Moreover, hyperglycemia alone is unlikely to play a role in the development of atherosclerosis that is seen in individuals with impaired glucose tolerance (IGT) who usually demonstrate only modest postprandial hyperglycemia. Therefore, it has been suggested that, in addition to glucose levels, other factors associated with IGT are likely to contribute to the development of atherosclerosis and CVD in type 2 diabetes. Thus, it is clear that the pathogenesis of diabetes-related CVD, and the mechanisms by which known risk factors may enhance atherosclerosis and CAD are poorly understood. In addition, factors contributing to type 1 and type 2 diabetes, such as autoimmune inflammatory and immunological responses, insulin resistance and clustering of CVD risk factors need to be better understood. Experimental verification of these potential mechanisms has been greatly hindered by a lack of appropriate animal models. Existing animal models of diabetes, CVD and atherosclerosis, although providing useful information, have suffered from serious problems. A separate RFA (DK-01-009) has been issued which focuses on the development of mouse models of diabetic complications. This initiative solicits applications to generate animal models in other species. There is a sizable body of work that establishes a number of features in other species which are relevant to diabetes-associated vascular disease. Nonhuman primates fed atherogenic diets have been used to model human atherosclerosis for many years. However, in some instances, as in the squirrel monkey, the plasma cholesterol elevation that develops following increased dietary cholesterol results from increases in -VLDL rather than in LDL. Glucose intolerance and insulin resistance do develop spontaneously in some nonhuman primates, although the development of diabetes is much more rare than in humans. Therefore, diabetes is most often induced artificially which has been problematic as the degree of beta cell damage and the need for insulin vary greatly. Moreover, maintaining stable hyperglycemia and healthy animals is costly and requires intensive monitoring and care. Pigs have been frequently favored as an animal model because of their close cardiovascular and metabolic similarities to humans. Natural mutations have been identified for the development of hypercholesterolemia. These animals developed advanced atherosclerotic lesions, morphologically similar to humans, that resulted in their deaths. However, no attempts were made to selectively breed these animals for diabetic states. Another pig model, the Yucatan miniature swine, was developed by genetic selection for altered glucose clearance during a glucose tolerance test. These animals display insulin resistance and a diabetic-like state. On a high fat diet, these animals become more glucose intolerant and diabetic. The cardiovascular and metabolic abnormalities in this model have yet to be explored. There are currently several animal models of insulin resistance induced by high fructose diets. Although this approach has been used in dogs and hamsters, fructose enriched diets are most frequently used to induce a hyperinsulinemic, euglycemic insulin resistant condition in rats. These diets also induce enhanced hepatic secretion of VLDL, frequently resulting in moderate hypertriglyceridemia. Although all of these animal models have proven useful for studies of insulin resistance, they do not develop extensive atherosclerosis or CVD. The New Zealand White rabbit has also been widely used as a model for atherosclerosis. When fed high cholesterol diets, these rabbits develop marked hypercholesterolemia and extensive atherosclerosis. However, surprisingly, cholesterol fed rabbits made diabetic by alloxan treatment developed less atherosclerosis compared to their nondiabetic controls. This apparent paradox has not been explained. Rabbits lacking functional LDL receptors (WHHL rabbits) also develop marked hypercholesterolemia and extensive aortic lesions. However, the WHHL rabbit has not been used for studies of diabetes and atherosclerosis. Given the absence of spontaneously diabetic rabbits and the high mortality of alloxan treated rabbits, rabbits have not proven as yet to be a useful model of diabetic atherosclerosis. Another animal model commonly used for atherosclerosis studies is the hamster. However, attempts to chemically induce diabetes have produced variable results, with some animals showing marked hyperglycemia, weight loss and poor survival, while others develop only moderate hyperglycemia and demonstrate prolonged survival. Diabetic hamsters fed standard or cholesterol enriched diets showed ultrastructural changes in the aorta consistent with atherosclerosis development. However, the extent of atherosclerosis that develops in the diabetic hamster model is modest, and more information is needed on the changes in lipoprotein levels and composition that occur. Several different strains of rats have been proposed as models of type 2 diabetes. These models were the result of naturally occurring mutations in laboratory animals and the recognition that some rats are uniquely susceptible to develop insulin resistance and diabetes on special diets. Rats homozygous for the "fatty"(fa) or "corpulent"(cp) genes are typically obese, hyperlipidemic, hyperinsulinemic and insulin resistant. The "fatty" (Zucker) rat has been used primarily as a model of obesity. However, because of the accompanying hyperglycemia and insulin resistance it is also useful as a model of type 2 diabetes. As in most animal models of insulin resistance, there is no evidence of advanced arterial lesion formation in the Zucker rat model. The corpulent (JCR:LA-cp) rat has marked hyperinsulinemia that develops shortly after birth and persists throughout life. This strain develops spontaneous arterial lesions that resemble fatty streaks in humans. However, these fatty streaks do not progress to fully developed atherosclerotic lesions. This suggests that different etiologies for lesion formation may exist in humans and the JCR:LA-cp rat. Another rat model of type 2 diabetes and atherosclerosis is the sand rat. When fed standard rat chow, the sand rat becomes obese, hyperglycemic, hyperinsulinemic and insulin resistant. When made hypothyroid and fed a cholesterol-enriched diet, they develop cardiovascular lesions. However, it remains unknown whether factors other than lipid levels contribute to the development of atherosclerosis in this strain. Models of type I diabetes are usually generated by administration of chemicals toxic to the pancreas, these animals require insulin to avoid developing marked hyperglycemia, dehydration and ketosis. Using low doses of insulin to avoid wasting and death while maintaining hyperglycemia to induce complications is difficult and time consuming. Therefore, mortality rates are frequently high and the possibility that poor health may influence metabolic parameters and development of atherosclerosis always remains a concern. As noted above, a common limitation of many of the existing animal models of diabetes is that they develop only very modest atherosclerosis. Some species, particularly the rat and the dog are naturally resistant to developing atherosclerosis. In addition, lipoprotein patterns and metabolism in some animal models are sufficiently different from those in humans to raise concerns about the relevance of risk factors identified in studies using these animal models. To date, available animal models of microvascular complications have also shared these limitations. Most of these models have not been fully validated, or they reproduce only a small portion of the full human disease. For example, there are several rodent models of diabetes associated with renal damage. However, these animals generally lack a number of the key pathological features seen in human disease. Thus, no animal model consistently exhibits the vascular abnormalities, basement membrane thickening and nodule formation characteristic of human diabetic nephropathy. Objectives The objective of this initiative is to accelerate the pace at which accurate and reproducible non-mouse animal models of diabetic vascular complications are developed. The animal models are expected to mimic disease in patients with type 1 or type 2 diabetes mellitus. The major focus of this RFA is on diabetes-associated cardiovascular disorders, including coronary heart disease, stroke, peripheral arterial disease, cardiomyopathy, and congestive heart failure. However, animals models of microvascular disease are also acceptable. The goal of the program is to obtain these non-mouse animal models, through selective breeding, dietary or molecular genetic approaches. Once the models are developed, characterized and validated, it will be important to disseminate the models and information related to them to the research community, for studies to advance our understanding of the etiology, pathobiology, clinical progression, management and prevention of diabetes related cardiovascular and microvascular diseases. Specific areas of interest would include identification of 1) genes which confer protection or induce initiation and progression of diabetic vascular disease, 2) environmental components that contribute to disease progression and 3) new therapeutic strategies to block or retard progression of vascular disease. It is hoped that rapid progress in creating animal models will be stimulated by attracting investigators to integrate approaches involving animal breeding and nutrition, vascular physiology, tissue-specific pathology, vascular cell biology, molecular analysis of gene expression, clinical investigations, and genetics. More careful characterization and creative utilization of tissue and animal resources would expedite this effort. In addition, cross-breeding experiments to explore the interactions of specific genes with various genetic backgrounds could be useful. Proposed Research Appropriate investigations under this RFA would include, but not be limited to, the generation and characterization of non-mouse animal model(s) of insulin resistance or diabetes, which develop vascular disease which resembles that seen in humans with type 1 or type 2 diabetes. Applicants must also outline their proposed plans to make these animals available to the research community. It is envisaged that the most appropriate animal models of type I diabetes would have low insulin levels, while models of type 2 diabetes would have normal or slightly elevated plasma insulin. The models should also have moderate to severe hyperglycemia and lipoprotein patterns typical of those present in human diabetes. Atherosclerotic lesions in these models should have many of the morphologic and cellular features characteristic of early and advanced human lesions. Finally, the models should fulfill several practical criteria for in vivo studies of atherosclerosis such as development of atherosclerotic lesions and/or kidney dysfunction within a relatively short time to allow the detection of differences between experimental and control groups. Similarly, new models of diabetic microvascular disease must demonstrate pathology analogous to human disease. EXCLUSIONS This RFA is intended to support R01 research programs to create, characterize, evaluate, and disseminate non-mouse animal models to study diabetes complications of accelerated atherosclerosis, and other cardiovascular diseases, as well as microvascular disease cardiovascular and kidney diseases. Applications that propose mouse models will be considered unresponsive to this initiative. Investigators proposing mouse models may wish to consider RFA : DK -01-009 entitled "Mouse Models of Diabetic Complications Consortium" or consult with the NHLBI and NIDDK staff at the address listed under INQUIRIES. SPECIAL REQUIREMENTS Upon initiation of the program, the NHLBI and the NIDDK will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. Applicants should request travel funds for a 1 day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should include a statement in their applications indicating their willingness to participate in these meetings. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit, by February 26, 2001 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 and 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 a subsequent application, the information that it contains allows staff to estimate the potential review workload and to plan the review. The letter of intent is to be mailed, or faxed, to: Dr. Deborah Beebe at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. These forms are available at most institutional offices of sponsored research, and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. Because we expect that there will not be any applications requesting less that $250,000 in first year direct costs, applications should be in the standard (non-modular) format with a detailed budget. The RFA label found in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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. In addition, the RFA title (Non-Mouse Models of Diabetes Complications in Cardiovascular and Kidney Diseases) and number (HL -01-010) must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label available at: email: 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 and three signed, 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 submission, two additional copies of the application must be sent to Dr. Deborah Beebe, Chief, Review Branch at the address listed under INQUIRIES. It is important to send these two copies at the same time as the original and three copies are sent to the Center for Scientific Review (CSR), otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by March 21, 2001. 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 Upon receipt, applications will be reviewed for completeness by the CSR, and responsiveness by NHLBI and NIDDK. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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 NHLBI in accordance with the review criteria stated below. 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, assigned a priority score, and receive a second level review by the advisory councils of NHLBI and NIDDK. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1) Significance Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2) Approach Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? Once the models are developed, characterized and validated, does the applicant propose plans for the efficient dissemination of the models and information related to them to the research community? 3) Innovation Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4) Investigator Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if an)? 5) Environment Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for animals or the environment, to the extent they may be adversely affected by the project proposed in the application. o The adequacy of the proposed plan to share and disseminate the animal models. SCHEDULE Letter of Intent Receipt Date: February 26, 2001 Application Receipt Date: March 21, 2001 Review by NHLBI Advisory Council: September 6-7, 2001 Anticipated Award Date: September 30, 2001 AWARD CRITERIA Applications will receive a secondary level of review by advisory councils of NHLBI and NIDDK in September, 2001. The earliest anticipated date of award is September 2001. Applicants should be aware that, in addition to scientific merit, program priorities and program balance, the total costs of the proposed project and the availability of funds will be considered by NHLBI staff as well as NHLBAC in making funding recommendations. In addition, NHLBI appreciates the value of complementary funding from other public and private sources including foundations and industrial concerns. In circumstances in which applications have similar scientific merit, but vary in cost competitiveness, NHLBI is likely to select the more cost competitive application for funding. INQUIRIES Inquiries concerning this RFA are encouraged. Potential applicants should request a copy of the full RFA, which will include sample budget pages. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Momtaz Wassef, Ph.D. Leader, Atherosclerosis Research Group Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10186 Bethesda, MD 20892-7956 Telephone: (301) 435-0550 FAX: (301) 480-2848 E-mail: WASSEFM@NIH.GOV Barbara Linder, M.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Blvd Bethesda, MD 20892-5460 Telephone: (301) 594-0021 Fax: (301) 480-3503 E-mail: LINDERB@NIH.GOV Direct inquiries regarding review issues, send letter of intent and two copies of the application to: Dr. Deborah Beebe Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301)435-0270 FAX: (301) 480-3541 E-mail: Beebeb@NIH.GOV Direct inquiries regarding fiscal matters to: Mr. Owen Bobbitt Grants Operations Branch National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 7156 Bethesda, MD 20892-7926 Telephone: (301)435-0177, FAX: (301)480-3310 E-mail: BobbittO@NIH.GOV AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, and 93.121. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) 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 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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