National Institutes of Environmental Health Sciences, Research Contracts Branch, DERT, P.O. Box 12874, Building 4401, Research Commons, 79 T.W. Alexander Drive, Research Triangle Park, NC 27709

A -- RESEARCH AND DEVELOPMENT SOURCES SOUGHT FOR EVALUATING HEALTH EFFECTS OF CHEMICALS IN DEVELOPING AND ADULT ANIMALS SOL SS-NIEHS-00-25 POC Marilyn B. Whaley, Contracting Officer, 919/541-0416 or e-mail: whaley@niehs.nih.gov Research and development sources are sought who are capable of conducting toxicology and special studies, which will assist the National Toxicology Program (NTP) in evaluating the health effects of chemicals in developing and adult laboratory animals, primarily in rats and mice. Test chemicals shall be administered to animals via various routes (i.e., gavage, dosed feed, dosed water, parenteral and/or dermal), and a variety of toxicologic endpoints will be evaluated which will require sophisticated facilities and equipment and specialized expertise. Because of the urgent nature of these studies in providing information prior to design of chronic studies and to regulatory and research agencies, studies shall be completed as quickly as possible. Therefore, multiple studies shall be conducted concurrently which will require rigorous planning and scheduling of the contractor's staff and facilities in order to meet all study requirements within the overall project time frame. SCOPE OF WORK: It is anticipated that the following toxicology studies will be conducted: Toxicology Studies in Adult Animals: Four to six 14-day toxicity studies per year (Gavage, Dosed Feed, Dosed Water, parenteral and/or Dermal) in rats and mice, body weights, clinical observations, pathology on selected tissues. Two to six 90-day toxicity studies per year, (Gavage, Dosed Feed, Dosed Water, parenteral and/or Dermal) in rats and mice, clinical observations, food and water consumption where applicable, sperm morphology and vaginal cytology evaluation (SMVCE), micronuclei in mice, hematology and clinical chemistry in rats at days 4, 21, 90, hematology in mice at day 90 only, histopathologic evaluation of tissues. Two to six 26/39-week toxicity studies per year (Gavage, Dosed Feed, Dosed Water, parenteral and/or Dermal) in transgenic mice to include body weights, clinical observations and histopathologic evaluation of tissues. Toxicology Studies in Developing Animals: Two to three studies per year to evaluate the Health Effects of Chemicals in Developing and Adult Animals, to include reproductive, immunotoxicity, and developmental neurotoxicity parameters. The general approach will be to initiate exposure in pregnant rat dams, take measurements on their newborns, and then directly dose offspring beginning on postnatal day (PND) 7. The pups for the immunotoxicity and reproductive toxicity groups will be dosed until puberty (PND42), at which point exposure will cease. Animals destined for developmental neurotoxicity studies will be dosed until PND 12. A detailed sample study design with a time line will be provided upon request. Special Studies: The following special studies may be included with any of the above studies as options: hematology and clinical chemistry evaluations, urinalysis, urinary enzyme determinations, toxicokinetics, preparation of blood smears for micronuclei determination, and performance of sperm morphology/vaginal cytology assessments. Occasionally, the study protocols will call for additional toxicologic endpoints to be evaluated such as biochemical analyses of tissues for cytochrome P 450 activities, marker enzymes for peroxisomes, or protein kinase activities; cell proliferation analyses following bromodeoxyuridine incorporation; and neurobehavioral studies (as described in Federal Register 40: 942-963, 1988). All studies (i.e., toxicology and special studies) shall be performed in accordance with the Good Laboratory Practice Regulations established by the FDA for Non-clinical Laboratory Studies (FDA Good Laboratory Practice Regulations for Non-clinical Laboratory Studies; Final Report (Fed. Register, Vol 52, # 172, Friday September 4, 1987, pp 33768-33782; 21 CFR Part 58) and the "Specifications for the Conduct of Studies to Evaluate the Toxic and Carcinogenic Potential of Chemical, Biological and Physical Agents in Laboratory Animals for the National Toxicology Program (NTP)" dated August 1992 with subsequent revisions. The Government will provide: (1) the test chemical and methods for bulk chemical reanalysisand dose formulation analysis, (2) animals (in most cases), and, (3) computer terminals, software and user manuals for collection of data into the Toxicology Data Management System. An NTP contractor will provide serology testing as part of an infectious disease surveillance program. REQUIRED IN-HOUSE CAPABILITIES: Contractors submitting capability statements must have a working laboratory in place. The Principal Investigator, Toxicologist, Pathologist, Chemist, Health and Safety Officer and Quality Assurance Unit Officer must be employees of the firm. The daily interaction and constant coordination of efforts needed amongst these discipline areas throughout the in-life portion of the studies makes it critical that they be physically and organizationally together. Specifically, in-house requirements include: General Toxicology: Principal Investigator who is experienced in conducting toxicologic studies and in the management and coordination of multidisciplinary projects; toxicologist and toxicology technicians, who are experienced in rodent studies by routes of exposure identified above; pathologist(s), prosectors, histology technicians, and special study technicians, who are experienced in rodent studies; veterinarian and animal care technicians; chemist and chemistry technicians, who can perform bulk chemical reanalysis, dose formulation and dose analysis; and. adequate facilities and equipment for lab animal management and to perform routine histopathology. Reproductive Toxicology: The ability to: (1) breed animals, permanently mark individual neonates, gavage PND7 rats, (2) identify sperm in vaginal smears and measure anogenital distance, (3) identify hypospadias in males and nipples on PND14 male, and (4) detect open vaginae in females and separated preputial glands in males. Immunotoxicity Endpoints: The ability to: (1) flush femurs of hematopoietic cells, (2) perform aseptic removal and shipping of spleens, i.v. injection, urinalysis for protein and glucose, and hemanalysis for Rheumatic factor, and (3) aseptically and repetitively wash sheep erythrocytes in preparation for injection into animals. Neurotoxicity Endpoints: Demonstrated proficiency in: (1) detecting eye-opening and pinna detachment and conduct standardized functional observational battery (FOB) for clinical signs, auditory startle and learning and memory using the specified apparatus, (2) collecting motor activity data on juveniles and adult rats by automated apparatus, and (3) detecting subtle changes in baseline functioning. REQUIRED IN-HOUSE OR SUBCONTRACT CAPABILITIES: The breadth of measures in these studies is expected to require subcontracting some of the work. The contractor shall have the necessary facilities, personnel, equipment, and capability in-house or through subcontract to perform the following parameters: General Toxicology: The ability to perform specific toxicologic parameters such as urinalysis, or Toxicokinetics which may require separate groups of special study animals treated at the same time and in the same manner as the core study animals; collection and evaluation of blood for clinical pathology parameters, and the evaluation of additional toxicologic endpoints including biochemical analyses of tissues for cytochrome P 450 activities, marker enzymes for peroxisomes, or protein kinase activities, assessment of enzyme activities in urine and other urine analyses, and cell proliferation analyses following bromodeoxyuridine incorporation. Reproductive Toxicology: The ability to perform vaginal cytology, sperm motility and count, and other necropsy-based measures of the reproductive system and demonstrated expertise in morphology of testis and ovary/uterus. Immunotoxicity Endpoints: Demonstrated expertise in: (1) histopathology of immune organs and (2) analysis of blood for antibodies to nuclear proteins, laminin, glomerular basement membrane, and thyroglobulin. Neurotoxicity Endpoints: Demonstrated expertise in CNS histopathology, immunohistochemistry, morphological measurements in both adult and young animals.This is a request for submission of capability statements only at this time (and NOT specific proposals) so that we may evaluate your R&D capabilities. Firms should request and review a copy of the detailed sample study design for toxicology studies in developing animals (with time line) and "Specifications for the Conduct of Studies to Evaluate the Toxic and Carcinogenic Potential of Chemical, Biological and Physical Agents in Laboratory Animals for the National Toxicology Program (NTP)" dated August 1992 with subsequent revisions before submitting a capability statement. Firms having the toxicologic research and development capabilities identified above and facilities for the performance of this work are invited to submit a capability statement (as defined below) to the procuring office listed in this notice within 30 calendar days from the date of this notice. Capability statements should include: (1) the professional qualifications of scientific and technical personnel who would be assigned to perform the proposed studies, (2) a description of the general and specific facilities (to include a floor plan) and equipment for the proposed studies, (3) a general description of the firm's ability to perform the general toxicology and special studies identified in this synopsis, (4) an outline of previous multidisciplinary projects similar to this that have been conducted by your firm to include a synopsis identifying the work that was performed, the time period (dates) during which it was performed, the name and address of the client, and the point of contact (name and telephone number) at the client, (5) more detailed, separate, distinct sections that address the firm's ability in each area of toxicology as well as identifying relevant projects performed in each area of toxicology identifying the work that was performed, the time period (dates) during which it was performed, the name and address of the client, and the point of contact (name and telephone number) at the client, (6) a description of proposed subcontractors to include qualifications of their staff, a description of their facilities, and a list of projects performed for the prime contractor in each area of toxicology, and (7) other pertinent information. Qualifications of staff should be furnished in the form of a curriculum vitae. This synopsis is for planning purposes only and does not commit the Government to pay for the information requested, issue a solicitation, or award a contract. The concept for this project (as presented in this synopsis) has not been reviewed by the Board of Scientific Counselors. Cancellation of the requirement due to disapproval by the Board of Scientific Counselors or revision of the requirement is a possibility. No solicitation documents exist at this time. Any subsequent solicitation for an R&D contract will be synopsized. It is anticipated that any subsequent solicitation would be for one (1) task order level of effort type contract with a term of three years and options to renew for an additional five years. Firms who respond to this advance notice will be added to the solicitation mailing list for any subsequent solicitation. An original and five (5) copies of the requested information should be submitted and should reference Sources Sought Announcement No. SS-NIEHS-00-25. Posted 02/16/00 (W-SN426227). (0047)

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