Att2_Statement of Work.docx

STATEMENT OF WORK (SOW)

Pathology Support for the National Institute of Environmental Health Sciences October 25, 2024

General Information General This is a non-personal service(s) contract under which the personnel rendering the service(s) are not subject, either by the contract’s terms or by the manner of its administration, to the supervision and control usually prevailing in relationships between the Government and its employees. The purpose of this contract is to provide all services and supplies necessary to provide a variety of pathology support services for the research programs of the National Institute of Environmental Health Sciences (NIEHS).

Description of Services Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, procedures, materials, equipment, and facilities not otherwise provided by the Government as needed to perform the objectives set forth below. In general, all services shall be conducted according to the requirements described as outlined below, which includes the specific professional, technical, and administrative personnel; procedures; and deliverables. Since wet tissues, paraffin blocks, and original histological slides are essentially irreplaceable specimens from studies that often cost several million dollars and require years to complete, ensuring that these materials are not lost or damaged is of utmost concern.

Background and Scope The NIEHS, National Institutes of Health includes two intramural divisions, the Division of Translational Toxicology (DTT; https://www.niehs.nih.gov/research/atniehs/dtt/index.cfm) and the Division of Intramural Research (DIR; https://www.niehs.nih.gov/research/atniehs/dir/index.cfm). NIEHS conducts research in-house and by contract that contributes to the understanding of biological and chemical processes, the role(s) of environmental agents in human disease and dysfunction, underlying mechanisms of environmentally associated diseases, and how intervention and prevention strategies can reduce the effects of exposures to environmental agents.

The contractor shall provide a broad range of pathology support for studies conducted by the DTT Contract Research Organization (CROs) and by in-house investigators at NIEHS. Support includes peer review and assessment of pathology evaluations and technical support of these efforts, histopathological interpretation, histology, specialized procedures and emerging technologies, preparation of material for publication and outreach, and support for NIEHS Core laboratories.

Overview of Required and Elective Capabilities The Contractor shall provide comprehensive pathology support in the following Capability Areas described in more detail in Section 2. Capabilities listed below are divided into Required and Elective.

Required Capability Areas

· Pathology Evaluation and Peer Review

· Necropsy, Histology, Immunohistochemistry

· Publication Support and Outreach

· Global Toxicologic Pathology Training Program Support

· Imaging Sciences Capability Areas to Support Elective Options

· Support for NIEHS Clinical Pathology Core Laboratory

· Support for NIEHS Electron Microscopy Core Laboratory

· Support for NIEHS Mouse Embryo Phenotyping Core Laboratory

· Support for NIEHS Molecular Pathology Laboratory

· Support for Laboratory Animal Medicine Program Policies and Procedures The contractor and applicable subcontractor facilities shall comply with the below regulations and specifications:

· Necropsy and histology for DTT studies shall be conducted in accordance with Chapter 8 of the Specifications for the Conduct of Toxicity Studies by the Division of Translational Toxicology at NIEHS (https://doi.org/10.22427/NIEHS-00) referred to hereafter as the DTT Specifications. When directed by the Contracting Officer’s Representative (COR), pathology evaluations for NIEHS investigator studies shall be conducted in accordance with study-specific goals as defined by the Principal Investigator.

· Society of Toxicologic Pathology INternational HArmonization of Nomenclature and Diagnostic Criteria (INHAND) Guides (https://www.toxpath.org/inhand.asp#pubg).

· The DTT Data Dictionary (see Pathology Terms; https://doi.org/10.22427/NTP-DATA-002-00092-0002-0000-5) provides a DTT controlled vocabulary for pathology diagnoses.

· When required by a specific research outline or by the COR, necropsy, histology, and pathology evaluations shall be performed in accordance with Good Laboratory Practice (GLP) Regulations established by the U.S. Food and Drug Administration (FDA) for Non-clinical Laboratory Studies (21 CFR 58; https://www.ecfr.gov/current/title-21/chapter-I/subchapter-A/part-58) or as most recently updated.

· The Contractor shall have in place a quality management plan. Information on quality management plans can be found at https://www.epa.gov/quality/epa-qar-2-epa-requirements-quality-management-plans.

Reports and Deliverables Information on specific reporting requirements is presented below. All final reports shall be dated and signed by the individual(s) responsible. Electronic deliverables must be compliant with Section 508 regarding accessibility. In some cases, there may be accommodations for which the Government will provide information annually. Formats and additional requirements for monthly reports and pathology reports are described in more detail within this Statement of Work (SOW).

In addition to the reports mentioned herein, any incidence or unforeseeable occurrence not listed here, including issues with materials, personnel changes, equipment, or data issues which may impact study conduct or timelines shall be immediately reported to the Government.

In addition to those documents required by the other terms of this contract, the Contractor shall prepare and submit the following reports to the COR electronically (an electronic copy of the Title Page shall also be sent to the Contracting Officer (CO) as a required deliverable in the manner stated below).

Periodic Reports Monthly Technical Progress Reports The Contractor shall submit a monthly technical progress report designed to help the contractor and CORs document and track recent activities in a timely fashion. The Monthly Technical Progress Report shall include, (1) potential areas of concern; (2) the contractor's analysis of issues affecting personnel, analysis, or performance; (3) a list of all materials received during the month (per NIEHS Investigator and by study); (4) and a list of all evaluations/studies, and number of slides/samples per study, scanned during the month. The Monthly Technical Progress Report shall in most cases be a short descriptive narrative of progress for the preceding month. The report shall include a list of milestones achieved in the preceding month; specific activity, analysis, or goals for the upcoming month; any problems or concerns affecting study/evaluation, analysis, or progress; any personnel performance concerns; and provide a table of submitted samples with details as described in the SOW. All tables and lists shall be provided in sortable MS Excel spreadsheets. The report shall be submitted to the CO and COR in electronic format.

Monthly Budget Summary Report The Contractor shall submit a monthly Budget Summary Report for each activity separately undertaken and monitored (e.g., work per DTT or NIEHS investigator), and for the contract as a whole, and shall include the amounts for each activity: budget, total expenditures on the activity for the month, summaries of current contract year and cumulative expenditures, projected expenses to complete each research outline, and remaining funds, and hours used separated by labor category. Budget Summary Reports shall be submitted as MS Excel spreadsheets (or in other spreadsheet software by agreement), and shall be sortable as required by the COR, and shall include summaries of costs and hours separated.

Annual Fiscal Year Reports: Technical Progress Report and Budget Summary Report For each fiscal year, the Contractor shall prepare and submit an Annual Fiscal Year Technical Progress Report. The Report shall consist of a descriptive summary by separately monitored activities undertaken and planned during the fiscal year immediately preceding. The format shall be the same as the Monthly Technical Progress Report. The Contractor shall also prepare and submit an Annual Fiscal Year Budget Summary Report. This report shall include amounts of each activity budget, total expenditures on the activity for each month, summaries of current contract year and cumulative expenditures, projected expenses to complete each activity in a sortable MS Excel spreadsheet. The Annual Report shall include a sortable spreadsheet of the current Government Furnished Equipment and a summary of current holdings of research materials.

Annual Contract Year Reports: Technical Progress Report and Budget Summary Report For each contract year, the Contractor shall prepare and submit an Annual Contract Year Technical Progress Report. The Report shall be the same format as they Annual Fiscal Year Report, with the time frame shifted to report on the contract year.

Pathology Reports Reports including drafts shall be submitted to the COR and others as indicated in the Research Outline and shall include the details requested for the study. Pathology reports for DTT peer review studies (see Technical Exhibit B) and other pathology evaluations shall follow a format to be reviewed and agreed upon with the COR. Example report templates can be provided upon request.

IT Security Plan and Other IT Deliverables Refer to Appendix A for specific requirements related to IT Security.

HHS Section 508 and Accessibility Standards Refer to Section H of the contract of specific requirements.

Post Award Conference/Periodic Progress Meetings The Contractor shall attend any post award conference convened by the contracting activity or contract administration office in accordance with FAR Subpart 42.5. The CO, COR, and other Government personnel, as appropriate, may meet periodically with the Contractor to review the Contractor's performance. At these meetings the CO will apprise the Contractor of how the Government views the Contractor's performance and the Contractor shall apprise the Government of problems, if any, being experienced. Appropriate action shall be taken to resolve outstanding issues. These meetings shall be at no additional cost to the Government.

Prior to initiating support under the contract, the COR shall review and approve all Contractor standard operating procedures (SOPs) related to DTT Pathology Peer Review. The COR shall be notified of any changes to SOPs and be given opportunity to review updates before being used on a DTT study.

Progress Meetings The Contractor shall attend, participate in, and furnish input to scheduled and unscheduled meetings, conferences, and briefings that relate to the functions and services herein as required by the Government to provide effective communication and impart necessary information. These meetings will include regularly scheduled progress meetings (e.g. biweekly or monthly) and ad hoc, including NIEHS investigators for specific studies. The Principal Investigator or designated representative shall attend meetings as requested by the Government. Meeting attendees shall at times include Contractor managerial, supervisory, and other personnel knowledgeable of the subject matter. Meetings may start or end outside of regular duty hours.

Contracting Officer’s Representative As determined by the CO, a COR shall be appointed and identified by letter of designation, a copy of which shall be provided to the Contractor by the CO. The designation letter states the responsibilities and limitations of the COR.

Professional and Technical Personnel Key personnel and Toxicologic Pathologists (1.9.2.1.1) must be employees of the prime contractor. Other personnel positions may be supported by subcontractors or consultants. Pathologists supporting histopathology evaluation and peer review, and other staff providing support for on-site capabilities must be located near NIEHS; other staff may be remote.

Key Personnel Principal Investigator The Principal Investigator (PI) shall have a D.V.M., or equivalent degree, or M.D., and board certification preferred by one of the following: American College of Veterinary Pathologists (ACVP), American College of Pathologists, Fellow of the International Academy of Toxicologic Pathologists (FIATP), European College of Veterinary Pathologists (ECVP). The PI shall have a minimum of 10 years of experience in rodent toxicologic pathology and have experience managing the diversity and complexity of pathology peer review and other required capabilities. The experience shall include both evaluation of short-term and long-term toxicity and carcinogenicity studies in rats and mice, as well as experience in the evaluation of pathology generated through the conduct of rodent toxicology studies. The PI is expected to be an active participant in the daily management of the contract and in the communication between NIEHS personnel and the contract personnel.

Program Manager The Program Manager (PM) shall have a B.S. or higher degree and/or a minimum of 7 years of experience in this role. The PM shall have demonstrated capability for effective written and oral communication. The PM is expected to be an active participant in the daily management of the contract and in the communication between NIEHS personnel and the contract personnel.

Personnel to Support Required Capabilities Professional Personnel Toxicologic Pathologist(s) Toxicologic Pathologists shall have a D.V.M. or M.D. and a minimum of 3 years of experience in toxicologic pathology post-residency. Pathologists would preferably be ACVP- or ECVP-certified or eligible, with experience in evaluating toxicology study data and toxicologic pathology. Experience in developmental and reproductive toxicology, immunopathology, molecular pathology, ultrastructural pathology, carcinogenesis, neurotoxicology, or organ specific pathology is desirable. Pathologists meeting some but not all criteria may be acceptable with approval from the COR. These personnel would support capabilities outlined in Section 2.1.1, 2.1.3, and 2.1.4.

For capabilities described in Section 2.1.1, pathologists are required to review materials provided by NIEHS that are specific for each proposed role (e.g. peer review vs. Lead Pathologist). Prior to supporting capabilities outlined in Section 2.1.1, the Contractor must certify the pathologist has completed a review of materials specific to their proposed role, and then the COR must approve the pathologist to serve in a given role. See Technical Exhibit C for an outline of materials required for this process.

Toxicologic Pathologist(s) for the Global Toxicologic Pathology Training Program Toxicologic Pathologists shall have a D.V.M. or M.D. and a minimum of 5 years of experience in toxicologic pathology post-residency. Pathologists would preferably be ACVP- or ECVP-certified or eligible, with experience in evaluating toxicology study data and toxicologic pathology. Experience in developmental and reproductive toxicology, immunopathology, molecular pathology, ultrastructural pathology, carcinogenesis, neurotoxicology, or organ specific pathology is desirable. Pathologists meeting some but not all criteria may be acceptable with approval from the COR. These personnel would support capabilities outlined in Section 2.1.4.

Immunohistochemistry Pathologist(s) Immunohistochemistry Pathologists shall have a D.V.M. or M.D. and a minimum of 3 years of experience in toxicologic pathology post residency. D.V.M. pathologists would preferably be ACVP- or ECVP-certified or eligible, and experience is required in the fundamentals and practice of immunohistochemistry (IHC), immunofluorescence, and in situ hybridization (RNAscope), including all technical aspects related to performing IHC. Experience is also required in digital pathology and imaging. These personnel would support capabilities outlined in Section 2.1.2.3.

Imaging Sciences Research Associate Imaging Sciences Research Associate(s) shall have a Ph.D. (in a relevant scientific discipline), or D.V.M., and with a minimum of 3 years of experience. Experience is required in performing image analysis and artificial intelligence (AI) for diagnostics and research, including but not limited to theoretical, technical, and operational aspects of deep and machine learning, and be well-versed in applying these techniques to research in biological sciences, toxicology, and toxicologic pathology. These personnel would support capabilities outlined in Section 2.1.5.2.

Technical Personnel Histologists/Histotechnologists Histologists/histotechnologists shall have a minimum of 3 years of experience and demonstrated proficiencies, to provide technical expertise including being able to recognize gross and histologic rodent anatomy, and to perform the capabilities as outlined in Section 2.1.2.2. As required, these personnel may also be required to perform rodent necropsy in support of Section 2.1.2.1.

Immunohistochemistry Technicians Immunohistochemistry technicians shall have a minimum of 3 years of experience and demonstrated proficiencies, to provide technical expertise able to perform the capabilities as outlined in Section 2.1.2.3. As required, these personnel may also be required to perform rodent necropsy in support of Section 2.1.2.1.

Personnel to Support Elective Options Professional Personnel Electron Microscopist Electron Microscopist(s) shall have a Ph.D. (in a relevant scientific discipline; e.g. biological sciences) and a minimum of 3 years of relevant experience in electron microscopy (EM) and ultrastructural evaluations. These personnel would support capabilities outlined in Section 2.2.2.

Veterinary Anatomic Pathologist- Mouse Embryology Mouse Embryology Veterinary Anatomic Pathologist(s), shall have a Ph.D. (in a relevant scientific discipline, e.g., biological sciences) or M.D., and a minimum of 3 years of experience in mouse embryology. These personnel are preferably ACVP- or ECVP-certified and would support capabilities outlined in Section 2.2.3.

Biology Research Associate Biology Research Associate(s) shall have a M.S. or higher degree in biology (or related scientific discipline) with a minimum of 3 years of relevant experience. A Biology Research Associate shall have experience in basic cellular and molecular biology techniques. These personnel would support (at a minimum) capabilities outlined in Section 2.2.4.

Laboratory Animal Veterinarian Laboratory Animal Veterinarian(s) shall meet the following requirements: have a D.V.M. from an American Veterinary Medical Association (AVMA)-accredited College of Veterinary Medicine, be licensed to practice veterinary medicine in at least one state, and be board certified by the American College of Laboratory Animal Medicine. They shall also have a minimum of 3 years of relevant experience in managing all aspects of large rodent colonies for research. These personnel would support capabilities outlined in Section 2.2.5.

Technical Personnel Medical or Veterinary Technologist Medical or Veterinary Technologist(s) shall have a minimum of 3 years of experience and demonstrated proficiencies, to provide technical expertise able to perform the capabilities as outlined in Section 2.2.1, or others as appropriate.

Laboratory Animal Medicine Technical Support Specialist Laboratory Animal Medicine Technical Support Specialist(s) shall have a minimum of 3 years of experience and demonstrated proficiencies, to provide technical expertise to perform the capabilities as outlined in Section 2.2.5.

Data Rights, Patents, and Copyrights The Government has unlimited rights to all documents and materials produced under this contract. All documents and materials, to include the source codes of software, produced under this contract shall be Government owned and are the property of the Government with all rights and privileges of ownership and copyright belonging exclusively to the Government. These documents and materials may not be used or sold by the Contractor without written permission from the CO. All materials supplied to the Government shall be the sole property of the Government and may not be used for any other purpose. This right does not abrogate any other Government rights.

Source Documentation All original source documentation is the property of NIEHS. Data summaries and other relevant information generated during the performance of this contract shall be submitted to the COR in the form of status reports and project specific reports as specified in the Deliverables section above. In addition, annual reports shall be submitted for all activities as specified in the Deliverables section below. To the extent possible, the Government will retain unrestricted access and rights to all materials (e.g., formalin-fixed tissues, tissue samples embedded in paraffin, histology glass slides) data, and technical information generated under the contract. In accordance with the DTT Specifications, the Contractor shall arrange for delivery of all project materials and raw data to the NTP Archives upon completion of each individual project.

Non-Disclosure Requirements Performance under this contract may require the Contractor to access data and information proprietary to a Government agency, another Government Contractor, or of such nature that its dissemination or use other than as specified in this work statement would be adverse to the interests of the Government or others. The Contractor and Contractor’s employees (including Subcontractors), shall not divulge, or release data or information developed, or obtained under performance of this contract, except to authorized Government personnel or upon written approval of the CO. The Contractor shall not use, disclose, or reproduce proprietary data, which bears a restrictive legend, other than as specified in this contract. All documentation showing individual names or other personal information shall be controlled and protected under the provisions of the Privacy Act of 1974, Public Law 93-579, 5 United States Code (U.S.C.) Section 552a.

Replication, Dissemination, or use of the Results It is anticipated that the results of the research and/or evaluations conducted under the Contract shall be published in the open, peer-reviewed scientific literature and/or in a NTP or NIEHS technical report series. Specific details concerning authorship and technical issues surrounding the publication of the research shall be discussed and agreed upon by the PI and the DTT COR on a case-by-case basis.

Because premature release of information developed under the contract could be harmful to the public, the Contractor and the Government agree that it is important to consider issues related to the timing of the release of research results when submitting information for publication. With regard to public disclosures of the research and/or the results of evaluations to be carried out pursuant to this contract, the Contractor agrees to submit all proposed articles to the COR at least thirty (30) days in advance of submission for publication. Within this thirty-day period the COR shall inform the Contractor if there are serious concerns raised by the timing of said publication. Upon receipt of a notification that the Government objects to the publication of said information the Contractor agrees to withhold submission of said publication while the author and the COR discuss the issues of concern. The Contractor agrees to give good faith consideration to all such issues and further agrees that it will not knowingly submit for publication any article, abstract or other item that would be harmful to the public welfare. The final decision on whether to submit an article for publication shall rest with the DTT COR after the procedures set forth above are followed. Similar procedures shall apply for scientific presentations and meeting abstracts.

Protection of Government and Contract Information The Contractor shall not cite any information (e.g., contract information, pictures, locations, etc.) obtained through this contract on any hard copy or digital marketing tools to include its company website.

Non-Disclosure Statements The Contractor shall provide signed non-disclosure agreements to the Government no later than five (5) days prior to commencement of work under the contract. Disclosure of information by Contractor personnel may result in removal of Contractor personnel from performance under this contract.

Safety Laws and Regulations The Contractor shall comply with all Federal and State requirements governing safety and health protection.

The Contractor shall indicate its plan for compliance considering conditions of the work described by the design, technical proposal, operational activities of the Government or others in the area of the work, identification of the coordinator, and implementation of all other accident prevention provisions of this contract.

The Contractor shall complete and provide safety notifications as required by national, state, and local regulatory bodies, and will provide documented proof to the CO via the COR, no later than 10 days that such notifications were made.

Capability Areas The Contractor shall provide services, qualified personnel, materials, equipment, and facilities needed to carry out the pathology needs of NIEHS DTT and DIR in all capabilities unless otherwise specified. Notable exceptions include capabilities to support elective options in which support is provided onsite at NIEHS, with all equipment and facilities to be provided by the Government.

Required Capability Areas Pathology Evaluation and Peer Review DTT requires the contractor to avoid real or perceived conflicts of interest (COI) in the diagnosis of pathological lesions: the pathologists performing the original evaluation (study pathologist), the pathologist(s) performing any of the peer review steps, and the Lead Pathologist must be three independent pathologists. Within pathology peer review (see Technical Exhibit B) specific steps may or may not be performed by the same pathologist. In addition, work performed across these functional areas shall be coordinated in a way that provides independence for original evaluation, peer review, and Lead Pathologist duties.

Several of the capabilities require frequent (e.g., daily) discussions, consultations, and the exchange of materials (e.g., formalin-fixed wet tissues, frozen tissues, paraffin embedded tissue blocks, histology glass slides) with the NIEHS and/or NTP Archives, both currently located in Research Triangle Park, North Carolina, 27709. These shall be accomplished by either in person or remote means, e.g., in person meetings, teleconference, video conference, transport or shipment of materials, generation and/or viewing of scanned slides, etc.); the method of interaction/exchange of materials shall be approved by the COR. Contractor shall develop and maintain detailed plans to ensure the integrity of materials while located at the contractor’s facility and during transport or shipment. Shipment of pathology specimens shall follow the NTP Toxicology specifications for anatomic pathology.

Expertise needed for these capabilities are described in Section 1.9.2.1.1.

Pathology Evaluations The Contractor shall provide support for pathology evaluations for the DTT and DIR projects. Pathology evaluation shall be conducted in accordance with the diagnostic terminology and criteria outlined in the DTT Data Dictionary (see Pathology Terms; https://doi.org/10.22427/NTP-DATA-002-00092-0002-0000-5), the Non-Neoplastic Lesion Atlas (NNLA; https://ntp.niehs.nih.gov/atlas/nnl), and the Society of Toxicologic Pathology INternational HArmonization of Nomenclature and Diagnostic Criteria (INHAND) Guides (https://www.toxpath.org/inhand.asp#pubg).

Pathology Peer Review of DTT Studies The Contractor shall provide support for pathology peer review of DTT studies. Peer review of DTT studies requires adherence to the DTT pathology peer review process and includes but is not limited to: audit of pathology specimens, pathology data review, quality assessment review, reconciliation of pathology diagnoses, pathology working group review, and special reviews as determined necessary. See Technical Exhibit B for more details on the peer review process.

It is essential for DTT to have consistency throughout the duration of a pathology peer review for a study. The Contractor shall minimize to the greatest extent feasible, turn-over of personnel supporting a specific study. In addition, related studies, as identified by the COR, shall be a higher priority to be accommodated for support by the same personnel.

Lead Pathologist The Contractor shall provide support to DTT for the overview and coordination of the Pathology Peer Review process for DTT toxicity and carcinogenicity studies conducted at toxicology CROs or in-house at NIEHS. This capability includes research in various areas of systems toxicology including developmental and reproductive toxicology, immunopathology, molecular pathology, ultrastructural pathology, carcinogenesis, and neurotoxicology. Support for this capability may be provided on-site or remote as needed.

This support includes but is not limited to:

· Coordination of the evaluation of pathology and related toxicology research data

· Review of data for accuracy, clarity, and identification of target tissues

· In accordance with the NNLA and DTT Data Dictionary (Pathology Terms; as referenced in Section 2.1.1.1 above), determine the most appropriate descriptive terminology to achieve consistency between and within pathology study evaluations. When guidance is not provided in the above, also consult INHAND

· Involvement in pathology peer reviews (in vivo and in vitro, as needed)

· Interpretation, including mechanistic and translational relevance

· Reporting of the data through NTP/DTT toxicity reports

It is essential for DTT to have consistency throughout the duration of a Pathology Peer Review and publication for a study. When possible, the Contractor shall minimize to the greatest extent feasible, turn-over of personnel supporting a specific study. In addition, related studies, as identified by the COR, shall be a higher priority to be accommodated for support by the same personnel.

The Lead Pathologist, in consultation with the Government and as approved by the COR, shall help identify projects that would advance the understanding of various biological endpoints.

Necropsy, Histology, and Immunohistochemistry Support for the NIEHS Necropsy Core Laboratory The Contractor shall provide support for the conduct of complete necropsies at designated laboratories or at Government facilities as the need arises. This includes necropsy support for DIR and DTT investigators on IACUC-approved protocols. All work will be performed according to the DTT Specifications, specific laboratory SOPs, or project specific protocols provided by individual NIEHS investigators. Expertise needed for these capabilities are described in Section 1.9.2.2.

The Contractor shall be capable of performing the following necropsy procedures including but not limited to the following:

· Blood collection

· Euthanasia

· Whole body or organ perfusion

· Identification and collection of gross lesions

· Tissue/organ collection and immersion fixation (preservation)

· Rapid freezing

· Radiography

· Acquisition of digital images of gross lesions

· Tissue trimming

Support for the NIEHS Histology Core Laboratory NIEHS requires support for the NIEHS Histology Core Laboratory. This support shall be provided on-site at NIEHS using Government facilities and equipment, and following NIEHS SOPs, the DTT Specifications, and/or study-specific requirements provided by individual NIEHS investigators. As needed for overflow support, histotechnology services will also be required to be performed at the Contractor’s facility in which case the facilities, equipment, and all required materials shall be provided by the contractor (see section 2.1.1). Expertise needed for these capabilities are described in Section 1.9.2.2.1.

The Contractor shall provide support for histotechnology services including the ability to perform all tasks essential for preparation of high-quality histological tissue sections mounted on glass slides from surgical/biopsy or necropsy tissue specimens collected from laboratory rodents. These services include but are not limited to:

· Tissue processing (fixation, dehydration, clearing, infiltration)

· Embedding of processed tissue in paraffin wax or plastic to produce blocks

· Microtomy

· Tissue staining (H&E and specialized histochemical staining) or unstained tissue

· Specialized tissue fixation, embedding, and sectioning

· Receiving and organizing individual projects for the work to be performed

· Performing quality control checks on finished histological slides.

Support for the NIEHS Immunohistochemistry Core Laboratory NIEHS requires support for the NIEHS Immunohistochemistry (IHC) Core Laboratory. This support shall be provided on-site at NIEHS using Government facilities and equipment. The Contractor shall provide support to evaluate stained samples and provide detailed reports, provide guidance to technical IHC laboratory personnel, and provide consultations with NIEHS investigators to advise on techniques for specific studies and interpretation of results. Studies will encompass digital pathology and imaging. Expertise needed for these capabilities are described in Section 1.9.2.2.2.

The Contractor shall provide support for the conduct of a variety of services including but not limited to the following:

· Determination of antibody concentrations

· Antigen retrieval

· Antibody preparation

· Primary and secondary antibody application

· Blocking

· Chromagen application

· Counterstaining

· Developing, optimizing, and troubleshooting staining protocols

The Contractor shall perform all activities required for RNAscope in situ hybridization assays to spatially visualize, localize and quantify RNA molecular biomarkers/expression in intact tissues and cells including:

· Fixation

· Permeabilization

· Hybridization

· Signal amplification

· Visualization - Chromogen detection

· Signal quantification

· Probe design and use

· Developing, optimizing, and troubleshooting staining protocols

Publication Support and Scientific Outreach The Contractor shall provide support for technical writing, publications, online content updates, and scientific outreach, including, but not limited to, the activities described below.

Scientific Manuscripts, Online Content The Contractor shall assist with the preparation of manuscripts, scientific posters, and educational materials such as atlases including the NNLA and the Electron Microscopy (Ultrastructural) Atlas, informational videos, or documents on the DTT peer review process. Activities may include identifying or preparing images, writing portions of the text, or performing literature searches or reviews.

Scientific Presentations The Contractor shall have qualified personnel make presentations at various symposia, workshops, etc. as requested by the DTT COR.

Scientific Symposia, Meeting, and Workshop Support On behalf of and under the direction of the DTT COR, the Contractor shall coordinate continuing education mini symposia and workshops for DTT. Workshops are held based on DTT needs, with exception to the DTT Satellite Symposium which is held annually at various venues based on the location of the Annual Society of Toxicologic Pathology Symposium.

Scientific symposia, meetings, and workshops may require internal and/or external meetings or events that are remote (web-based, e.g., webcast, Zoom, or similar), in-person, or a hybrid of the two, and can vary in size (e.g., 4-6 in-person or up to 200 attendees at a webinar). The events will vary in length, generally from one-half to two days. The number of experts required for an event will vary, ranging, for example, from 3-4 speakers for a webinar or symposium.

The Contractor shall provide administrative, technical, and logistical support for the planning and execution of these meetings including identification of an appropriate venue, although use of Government space is priority. The Contractor shall handle travel arrangements for participants, subject to applicable Government regulations. Prior to confirming any arrangements for meetings, the Contractor shall consult with and receive approval from the COR. The Contractor shall provide support for managing or preparing materials for the meeting and drafting any needed documents, minutes/reports, notes, or summaries. The Contractor shall also provide support for preparing information for meeting website(s), distributing promotional materials, and handling communications with targeted individuals. Upon approval from the COR, the Contractor shall obtain and manage subcontracts with identified participants and pay them for their services.

Global Toxicologic Pathology Training Program The Contractor shall provide professional and technical pathology support for the development and generation of DTT Global Toxicologic Pathology Training Program educational modules to address current issues, directives, findings, educational needs, and methods of importance to the DTT. This may include, but is not limited to: creating, editing, and reviewing training module PowerPoint presentations; capturing gross and histologic images; annotating images and whole slide scans to illustrate structural and diagnostic features; and identifying and including additional relevant information to the module, with a focus towards a trainee audience. These materials may also be used to prepare pathology atlases, knowledge assessments, and the development of workshops and symposia. The scope for these modules shall be specified by the COR in consultation with pathologists of the DTT.

Support for the NIEHS Imaging Sciences and Artificial Intelligence Core Laboratory Optical and Digital Imaging The Contractor shall provide the following services and support on-site: Assist DTT/NIEHS or Contractor pathologists with identifying microscopic lesions in rodent tissue from DTT and DIR studies. Capture digital images of lesions and other areas of interest in tissue sections mounted on glass slides for use in various technical reports, and scientific publications using state-of-the-art photomicroscopes.

The Contractor shall adjust digital images for inclusion in presentations, publications, posters, or other purposes using Government furnished image editing graphics software. Adjustment of digital images as described here shall be restricted to adjusting the quality (contrast, brightness, sharpness, size) (https://www.nature.com/nature-portfolio/editorial-policies/image-integrity) of images as appropriate for publication of selected areas of interest in Government technical reports or scientific journals; for presentation in PowerPoint or poster at internal and external scientific meetings; and review of selected lesions or areas of interest by pathologists in preparation for and presentation at Pathology Working Group meetings.

Artificial Intelligence (AI) Image Analysis Expertise needed for these capabilities are described in Section 1.9.2.1.3. The Contractor shall provide support for DTT and DIR programs to utilize new imaging sciences technologies including but not limited to: image analysis with AI (machine learning, deep learning, generative neural networks, and large language models) to develop methodologies which include algorithm development and associated methodologies for pathological diagnosis, research applications, data analysis, quantification, lesion severity scoring, and automated generation of text to summarize results. The Contractor shall provide training to Government staff or other groups, as required by the COR, on how to use any associated software, and how to obtain results from long-term storage (per NIEHS data management plans). NIEHS will provide the infrastructure and software licenses that are required to support these capabilities. In the future, the Contractor may be required to provide infrastructure to support these capabilities.

Whole Slide Scanning The Contractor shall have the capability to perform state-of the-art, high-speed, high-precision, high resolution, high throughput, whole-slide scanning. The Contractor shall provide all equipment such as scanners and associated computer equipment and software to perform these requirements. This function shall include establishing the appropriate metadata and annotations for identification of each scan to facilitate archiving and storage in an image database. Typically, lesions shall be captured to demonstrate morphologic features at low, medium, and high magnifications and at varying orientations.

Capability Areas to Support Elective Options Support for the NIEHS Clinical Pathology Core Laboratory NIEHS requires support for the NIEHS Clinical Pathology Core Laboratory. This support shall be provided on-site at NIEHS using Government facilities and equipment. The Contractor shall provide support to conduct a variety of hematology, clinical chemistry, and/or immunoassay test evaluations, including but not limited to the following: whole blood hematology testing, bone marrow total cell counts, blood or bone marrow smear preparation and staining, microscopic blood or bone marrow smear valuation and cell differential counting, tissue imprint and/or direct fluid smear or cytocentrifugation cytology sample preparation and staining, microscopic cytology slide evaluation and cell differential counting, photomicroscopy of blood, bone marrow or cytology slides for inclusion in presentations, publications, posters, or other purposes, the analysis of serum, plasma, urine, biological fluids and/or cell culture media performed on a variety of manual or automated analyzers or method platforms utilizing spectrophotometry, immunoassay, or other methods (e.g., metabolomics) to assess a variety of analytes (e.g., biomarkers of inflammation, lipid and carbohydrate metabolism, and liver, kidney, and cardiac function or injury). Expertise needed for these capabilities are described in Section 1.9.3.2.1.

Support for the NIEHS Electron Microscopy Core Laboratory NIEHS requires support for the NIEHS Electron Microscopy Core Laboratory. This support shall be provided on-site at NIEHS using Government facilities and equipment. The Contractor shall provide support for transmission and scanning electron microscopy including but not limited to providing technical guidance in performing the major activities (e.g., fixation, dehydration, trimming, embedding, microtomy, and staining) involved in the routine preparation of rodent tissues and cells for ultrastructural microscopy and evaluation, collaborating with NIEHS research scientists to identify components of interest in tissue and cells and generating high quality digital electron micrograph images. At the direction of the COR, assist with the development or optimization of new techniques and protocols. Expertise needed for these capabilities are described in Section 1.9.3.1.1.

Support for the NIEHS Mouse Embryo Phenotyping Core Laboratory NIEHS requires support for the NIEHS Mouse Embryo Phenotyping Core Laboratory. The Contractor shall provide support and guidance in designing plans in collaboration with NIEHS research scientists, including: embryo ages, postnatal ages, organs and tissues to evaluate, types of sections [coronal, sagittal, transverse, frontal], number of slides, if step sections are needed, if special stains or IHC could be of value, etc., to include any issues anticipated. Perform the histopathology review on stained slides, submit select slides for scanning, prepare pathology report and include figures with legends, provide report to investigators and meet to explain and resolve questions about report and/or images/slides. Expertise needed for these capabilities are described in Section 1.9.3.1.2.

Support for the NIEHS Molecular Pathology Laboratory NIEHS requires support for the NIEHS Molecular Pathology Laboratory. This support shall be provided on-site at NIEHS using Government facilities and equipment. The Contractor shall provide support for the conduct of investigative/mechanistic evaluations that may involve in vitro or in vivo exposures and the use of molecular biology techniques. Expertise needed for these capabilities are described in Section 1.9.3.1.3.

Techniques may include, but are not limited to:

· Nucleic acid extraction from fresh, or archival samples frozen or formalin-fixed paraffin-embedded tissues

· PCR/RTPCR/qPCR

· Western blots

· Sequencing library construction for next generation sequencing studies

· Necropsy, sample collection, and processing for downstream molecular/mechanistic studies

· 2D and 3D cell cultures from induced pleuripotent stem cells (iPSC), adult stem cells, primary cell cultures and cell lines

· Manipulation of cells using viral transduction (e.g., lentiviral) and/or CRISPR technologies for mechanistic studies to model toxicity and chemical carcinogenesis in vitro is required.

· Preparation of histologic sections from optimal cutting temperature (OCT) compound embedded tissue blocks and formalin fixed paraffin embedded sections, in performing histochemical, immunohistochemical and immunofluorescence staining

In vitro and in vivo evaluations may be designed to validate the use of experimental models to study corresponding human diseases (e.g. colon cancer). For in vivo evaluations, endpoints may include, but are not limited to animal husbandry, in life (e.g., colonoscopy, body fat, blood pressure), necropsy and collection of blood and tissue specimens.

As required by the COR, the Contractor may summarize the results and present at scientific conferences and in manuscripts.

Laboratory Animal Medicine Program NIEHS requires support for the Laboratory Animal Medicine Program to assist in supporting the DTT animal care and use. The support shall be provided on-site at NIEHS, including scientific review of animal models and in managing all aspects of large rodent colonies used for research. The Contractor shall provide support for NIEHS animal research programs performed in-house at NIEHS and under contract. The Contractor shall maintain a working knowledge of the DTT health monitoring program and environmental enrichment guidelines as described in the DTT Specifications, Chapter 6, and maintain knowledge of the animal models used in DTT studies. Technical support shall include but not limited to the following: prepare and review documents, including feed analysis and sentinel animal reports, and tracking animal use. The expertise needed for this capability is described in Section 1.9.3.1.4 and Section 1.9.3.2.2.

Operating Procedures Project Management The Contractor shall provide project management for the contract to include, but not be limited to:

· Transitioning into and out of the contract with minimal disruption

· Invoicing accurately and on-time

· Submitting deliverables and reports and otherwise complying with contractual commitments

· Providing transparency into operations for carrying out tasks

· Managing personnel and staffing

· Coordinating and scheduling human and other resources

· Providing project management and product tracking

· Providing timely communication with COR The Contractor shall have in place an organizational structure, policies, procedures, processes, and resources to plan and coordinate preparation of the work carried out under this contract. The Contractor shall provide the COR a plan for maintaining the accuracy and integrity of data, information, and work products at all levels in a project including version control of documents, extraction of information, and management and organization of project files. The Contractor shall establish internal procedures to evaluate the quality of the work and shall take actions and communicate to the Government plans to ensure the production of high-quality products. This plan shall also include management strategies to maintain talented staff through the period of performance of this contract. This plan shall be approved by the COR. Work performed across multiple functional groups shall be coordinated in a way that provides independence for peer reviews.

The Principal Investigator and Program Manager shall be responsible for the daily management of the contract and serve as points of contact for communication with the Government officials. The Principal Investigator and Program Manager are expected to be knowledgeable and involved in all aspects of the contract, including project status, record keeping, reporting, and detailed analysis of budget for all contract functions.

Although the contract, as a whole, shall be for the ongoing and recurring pathology support for NIEHS research programs, a Research Outline shall be prepared and issued by the Government for each study to be supported under the contract. Each Research Outline will include a detailed description of the activities to be performed, or an outline of objectives and the deliverables. The Contractor shall submit a technical work plan outlining the proposed technical approach and a budget proposal describing the proposed budget and level of effort.