Attachment 1 - SOO.pdf

1 Statement of Objectives

1.1 General Requirements

The Contractor shall provide services, qualified personnel, materials, equipment, and facilities needed to carry out the pathology needs of the NIEHS Divisions of Translational Toxicology (DTT) and Division of Intramural Research (DIR). DTT requires a contractor that can avoid real or perceived conflicts of interest in the diagnosis of pathological lesions; work performed across multiple functional groups (i.e. sections 1.2, 1.3 and 1.4) shall be coordinated in a way that provides independence for pathology evaluation, peer review, and reporting. Several of the capabilities require frequent trips to NIEHS and/or the NTP Archives for purposes of obtaining materials, performing work, or participating in meetings/consultations.

1.2 Pathology Peer Review

Provide ongoing and recurring support for pathology peer review of DTT studies. Peer review of DTT studies requires adherence to the DTT pathology 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 Appendix A for more details on the peer review process. Peer review shall be provided by Veterinary Anatomic Pathologist(s), preferably ACVP-certified, or MD pathologist(s), with expertise in general toxicology and toxicological pathology, developmental and reproductive toxicology, immunopathology, molecular pathology, ultrastructural pathology, carcinogenesis, and neurotoxicology.

1.3 DTT and DIR Pathology Reporting

Provide ongoing and recurring support to DTT for the overview and coordination of the pathology peer review process for DTT toxicity and carcinogenicity studies conducted at toxicology contract laboratories or in-house. This support includes but is not limited to:

coordination of the evaluation of study pathology and toxicology research data, review of data for clarity, accuracy, and identification of target tissues; determination of the most appropriate descriptive terminology based on DTT controlled vocabulary to achieve consistency between and within pathology study evaluations; involvement in the pathology peer reviews;

interpretation and reporting of the data; and identification of special projects that would advance the understanding of various biological endpoints, as directed by the COR. This also includes various areas of scientific investigation including general toxicology and toxicological pathology, developmental and reproductive toxicology, immunopathology, molecular pathology, ultrastructural pathology, carcinogenesis, and neurotoxicology. The Contractor shall provide Veterinary Anatomic Pathologist(s), preferably ACVP-certified, or MD pathologist(s), with expertise in research and investigations relating to pathology, electron microscopy, mechanistic toxicology, and carcinogenesis studies, and translation of animal data to human disease.

1.4 Pathology Evaluations

As directed by the COR, provide ongoing and recurring support for pathology evaluations for the DTT and DIR projects, including but not limited to providing histopathology evaluation, immunohistochemistry evaluations, electron microscopy evaluations for DTT and DIR investigations. Evaluations shall be provided by Veterinary Anatomic Pathologists, preferably ACVP-certified, or MD pathologists with expertise in toxicology and toxicological pathology, developmental and reproductive toxicology, immunopathology, molecular pathology, ultrastructural pathology, carcinogenesis, and neurotoxicology.

1.5 Necropsy

Provide personnel to support conduct of necropsies for approved DIR and DTT protocols at Government-designated laboratories as required. Necropsy procedures shall include blood collection, euthanasia, whole body or organ perfusion, tissue/organ collection and immersion fixation (preservation) and rapid freezing, radiography, and acquisition of digital images of gross lesions. The number of animals necropsied and the extent of the necropsies for individual projects will vary. The average necropsy may involve 30-60 animals with collection of approximately 50 tissues per animal (as described in the DTT Specifications March 2023 -https://ntp.niehs.nih.gov/go/DTT_toxicologyspecs). Necropsy assistance may also entail post-fixation trimming of collected tissue samples, tissue processing, paraffin embedding and preparation of histological slides. It is anticipated that support will be required for 15 - 30 projects per year for DTT and DIR.

1.6 Histology

Provide personnel, facilities, and equipment to conduct a variety of histological services.

including but not limited to the following: tissue trimming, processing (dehydration, clearing, and infiltration); embedding of processed tissue samples in paraffin wax to produce tissue blocks; microtomy (sectioning) of paraffin blocks; and histological/histochemical staining of tissues to produce high-quality tissue sections mounted on glass histology slides. The extent of the histology project assignments will vary to include: the preparation of paraffin or plastic tissue blocks, the preparation of stained (Hematoxylin and Eosin or special stains) and/or unstained tissue sections from wet tissue, trimmed tissues in cassettes or paraffin-embedded tissue blocks.

It is anticipated that histology support will be required for approximately 100 investigative projects per year for DTT and DIR.

1.7 Optical and Digital Imaging

The Contractor shall provide the following services and support as required: Assist pathologists to identify and capture high quality/resolution images of microscopic lesions in rodent tissue from DTT and DIR studies for use in various technical reports, project reports, presentations, and scientific publications.

Adjust digital images for inclusion in presentations, publications, posters, or other purposes using government furnished image editing graphics software. This task 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 posters 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.

1.8 Electron Microscopy

Provide support for Transmission and Scanning Electron Microscopy including but not limited to performing the major tasks (fixation, dehydration, embedding, microtomy, and staining) involved in the routine preparation of rodent tissues and cells for ultrastructural microscopy and evaluation, assisting NIEHS research scientists to identify components of interest in tissue and cells and generating high quality digital electron micrograph images. This support will be provided at NIEHS.

1.9 Publication Support and Outreach

Scientific publications support for technical writing, publication support, online content updates including but not limited to include:

1.9.1 Scientific Manuscripts, Online Content

Assist with the preparation of manuscripts, scientific posters, and educational materials such as atlases including the Non-Neoplastic Lesion Atlas 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. Anticipate 5-10 such projects per year.

1.9.2 Global Toxicologic Pathology Training Program

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 PPT 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 determined by the COR in consultation with pathologists of the DTT.

1.9.3 Scientific Presentations

Have qualified personnel make presentations at various DTT-sponsored symposia, workshops, etc. as requested by the DTT COR. These workshops are held sporadically, with exception to the Satellite Symposium which is held annually.

1.9.4 Scientific Symposia, Meeting, and Workshop Support

On behalf of and under the direction of the DTT COR, coordinate continuing education mini symposia for DTT. Activities may include booking a facility selected by the DTT, arranging AV equipment and support, preparing written materials, preparing, and disseminating promotional materials, and inviting speakers and arranging their travel, lodging, and honoraria. This will be done on an as-needed basis (approximately 1-2 mini symposia every other year) as requested by

DTT COR.

1.10 Clinical Pathology

Provide ongoing or recurring support to DTT and DIR 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 to assess a variety of analytes (e.g., biomarkers of inflammation, lipid and carbohydrate metabolism, and liver, kidney, and cardiac function or injury). Support shall be provided by a Medical Technologist or Veterinary Technologist. This support will be provided at NIEHS.

1.11 Investigative/Mechanistic Studies

Provide expertise and support, as required, for the conduct of investigative/mechanistic evaluations that may involve in vitro or in vivo exposures and the use of molecular biology techniques. In vitro evaluations may include the use of 2D and 3D cell culture systems, primary cell cultures, and established cell lines, and cell manipulation using lentiviral and/CRISPR technologies. In vivo evaluations may involve the validation and use of animal models to study corresponding human diseases, such as colon cancer, with endpoints that 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. Molecular biology evaluations may include extraction of nuclei acids from fresh and archival samples including formalin fixed paraffin embedded tissues, perform PCR/RTPCR, Western blots, and generate sequencing libraries for next generation sequencing projects. As required by the COR, the contractor may summarize the results and present at scientific conferences and in manuscripts. This support will be provided at

NIEHS.

1.12 Preferred Capability: Whole slide scanning

The contractor shall provide facilities, equipment and/or expertise as required for state-of the-art, high-speed, high-precision, high resolution, high throughput, whole-slide scanners and associated computer equipment and software. 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.

1.13 Preferred Capability: Imaging Science Technologies

The contractor shall provide facilities, equipment and/or expertise as required for DTT and DIR programs to utilize new imaging sciences technologies including but not limited to: Image Analysis and Artificial Intelligence (Machine Learning, Deep Learning and Neural network) to develop protocols for development of algorithm associated methodologies for pathological diagnosis, research applications, and data analysis and quantification.

Appendix A: Pathology Peer Review Process Summary

In the conduct of NTP/DTT studies Pathology Peer Review is an essential component of generating pathology data. It is important to review the data and lesions to ensure accuracy and consistency in pathology evaluations. This improves the quality and defensibility of the pathology data. There are several steps in the DTT Pathology Peer Review process described below. Because DTT currently has 2 processes it is utilizing for peer review, and because the process differs slightly for different study types, some of these steps may not be utilized for some studies.

Pathology Data Review (PDR) – In the PDR, a contract pathologist (PDR pathologist) reviews all study data (not limited to pathology data) and makes recommendations on which lesions are to be reviewed during the peer review process. The data is also reviewed to determine whether the study was conducted, and specimens collected according to the study protocol and the DTT specifications. These recommendations are captured in a PDR report. A meeting is held that includes DTT pathology staff (including the DTT pathologist assigned to the study), the study scientist, and the PDR pathologist, during which the report is reviewed, and additions or deletions are discussed and decided upon. The PDR pathologist updates the report based on these deliberations and the final PDR report is submitted to the DTT Data Coordination Unit (DCU).

For some short-term studies, a target organ letter (TOL), a shortened version of the PDR, may be done in lieu of the PDR.

Audit of Pathology Specimens (APS) – In the APS, the records and study materials (including the wet tissues, blocks, and slides) are reviewed for quality. There reviews are to confirm that the correct tissues are on the correct slides (conducted by technical personnel), that the quality of the materials would not adversely affect interpretation of the tissue sections or data (conducted by pathology staff), and that lesions were not missed during necropsy (conducted by pathology staff). Missed lesions are trimmed in and added to the study set. A report is prepared to reflect these findings.

Quality Assessment Review (QA) – During the QA, a contract pathologist [QA pathologist, (note that the QA pathologist also conducts the Pathology Working Group PWG)review, see below] reviews the slides as directed by the PDR. The QA pathologists who also serves as the PWG (QA/PWG) pathologist, records their diagnoses in the Slide Review Module (SRM). The QA/PWG pathologist also assesses the quality of the slides. The QA/PWG pathologist prepares a report of the findings of the QA review which includes tables comparing the Study Pathologist (SP) diagnoses to the QA/PWG pathologist’s diagnoses and an explanation for disagreements between the SP and QA/PWG pathologists. The report should also include thorough descriptions and diagnostic criteria for all lesions reviewed, a conclusion statement, and a comment on the histological quality of the slides.

Reconciliation – Reconciliation occurs in a subset of studies. During reconciliation, the QA/PWG pathologist meets with the SP to reconcile differences between their diagnoses. This entails the QA/PWG pathologist scanning all the slides to be reviewed (those in which the SP’s and QA/PWG pathologist’s diagnoses differed) so that the reconciliation meeting can be conducted virtually. A draft of the QA report must be sent to the SP, so that the SP is aware of the slides/diagnoses to be discussed. The QA/PWG pathologist records the decisions in the SRM.

Following the reconciliation meeting, the QA/PWG pathologist documents the proceedings of meeting, adds to the QA report, finalizes the report, and submits the QA report to the DCU.

Pathology Working Group (PWG) – During the PWG, a panel of invited pathologists convene to review selected lesions from the study to confirm diagnoses, to confirm the consistency of diagnoses including thresholds, resolve outstanding discrepancies, and address other issues as needed. One (1) or two (2) of the PWG panelists are often external pathologists external to the DTT or DDT contractor, considered to have expertise is specific organ systems . The QA/PWG pathologist selects the slides for PWG review (in conjunction with the DTT pathologist), has all the slides scanned, annotates the slides (so that the PWG panelists can locate the lesion(s) to review/evaluate), prepares PWG worksheets listing all the slides to be reviewed and the question(s) the QA/PWG pathologist wants answered, and prepares a PowerPoint presentation to be given at the beginning of the PWG. The PowerPoint presentation introduces the study (including why the chemical was studied, its relevant properties, results of other relevant studies, etc.) and provides the SP’s and QA/PWG pathologist’s diagnoses and diagnostic criteria. The QA/PWG pathologist then conducts the PWG and records the votes and important comments of the PWG members. If the PWG recommends any post-PWG action items, these are conducted by the QA/PWG pathologist overseen by the DTT pathologist for the study. The results, comments of the PWG members, thorough descriptions of all lesions reviewed, results of post-PWG action items, and conclusions are captured in the PWG report written by the QA/PWG pathologist.

Special Reviews – In some studies, there may be outstanding questions or issues following PWG meeting. In such cases, there may be special reviews of specific slides or lesions to clarify or confirm the data (i.e., slide reading). Special reviews may also involve special techniques (e.g., image analysis, special stains or immunohistochemistry, electron microscopy). Such reviews are typically performed at the discretion of the DTT pathologist and/or the discipline leader for DTT pathology, but occasionally may be recommended by the PWG and conducted as a post-PWG action item. When not associated with the PWG, a separate report must be prepared.

Summary - The steps described are typically conducted in the order listed and are directed by the discipline leader for DTT pathology. Throughout the peer review process, the contract pathologists conducting the peer review will be required to organize and attending meetings with the DTT pathologist (at the DTT pathologist’s discretion) either in person, by phone, or virtually.

The contract pathologists assigned to the peer review will be expected to be familiar with the lesions in a study or with special stains or techniques to further evaluate the lesions. This may require the contract pathologist(s) to conduct research or spend time reading books or journal articles to ensure such familiarity.