The International Academy of Toxicologic Pathology (IATP) Satellite Symposium on Pathology Working Groups (PWGs) in Toxicologic Pathology, organized in the United Kingdom, addressed the value and importance of PWGs and expert working groups in assuring the accurate evaluation of chronic/carcinogenicity studies. These specialized panels of expert pathologists play a crucial role in confirming data quality and accurate interpretation in support of human safety and risk decisions of xenobiotics. While not every carcinogenicity bioassay may require a PWG to evaluate the quality and accuracy of study interpretation, it was the consensus of the workshop that it can be a highly valuable addition to traditional peer review. Performing a PWG should be given serious consideration, especially when it is anticipated that the chronic/carcinogenicity study will be used for making significant regulatory or business decisions.

The 2025 joint British Society of Toxicologic Pathology (BSTP) and European Society of Toxicologic Pathology (ESTP) Congress included a session on data interpretation, which can be complex and is a critical aspect of carcinogenicity studies. In addition to statistical analysis, consistency in nomenclature, high-quality peer review, the appropriate use of historical control data, knowledge on compound- and target-related information, and literature can contribute to high-quality data, optimal interpretation of biological relevance, and safety assessment. The speakers covered several of these aspects which are critical in data interpretation of carcinogenicity studies. Based on experience and case examples, recommendations for updating International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) terminology for some proliferative findings in exocrine pancreas, liver, and ovaries were presented, including a case example of human relevance and risk assessment of endocrine and reproductive system tumors.

A retrospective study was performed to determine the incidences of spontaneous findings in control laboratory New Zealand White (NZW) and Dutch Belted (DB) rabbits. Terminal body and organ weights data were also collected. A total of 2170 NZW (526 males/1644 females), 100 DB rabbits (50 animals per sex), aged 4- to 7-month-old were obtained from 158 non-clinical studies evaluated between 2013 and 2022. The NZW rabbits had greater mean terminal body weights than DB strain. Mixed cell infiltration in the lung was the most recorded finding in both strains, followed by pulmonary inflammation/mononuclear cell infiltration. Differentiation between pulmonary “infiltration”/“inflammation” remained challenging as interpretation of guidelines for diagnostic terminology may vary amongst pathologists. Other common findings included mineralization and basophilia of the renal tubules; hepatic/renal mononuclear cell infiltration, all more common in females. Cysts were commonly recorded, with high prevalence in the oviduct, thyroid gland, ovary in NZW strain, while uterine, pituitary gland, and thyroid gland cysts were the most identified in DB rabbits. Neoplasms and infectious etiologies were absent. Most of the animals were sexually mature. To our knowledge, this is the most recent comprehensive study of spontaneous lesions and organ weights in both rabbit strains and should facilitate the differentiation of spontaneous and induced lesions in safety studies.

Digital pathology (DP) for the purpose of primary reads has emerged as a transformative tool in the practice of histopathology and has already proved to be suitable, bringing numerous advantages over traditional light microscopy (LM). This position paper promotes the adoption of DP, particularly whole slide imaging (WSI), within toxicologic pathology, emphasizing its applicability in Good Laboratory Practice (GLP)-compliant nonclinical safety assessments. With established benefits such as efficiency, remote collaboration, data security, and compatibility with artificial intelligence AI-based tools, DP represents a reliable and advanced alternative. This paper offers a counterpoint to recent skepticism expressed in the literature on the readiness of DP including discussion of implementation strategies, technical requirements, and the growing body of validation evidence supporting DP's utility in toxicologic pathology.

The Tumor Combination Guide was created at the request of the U. S. Food and Drug Administration (FDA) by a Working Group of biopharmaceutical experts from international societies of toxicologic pathology, the Food and Drug Administration (FDA), and members of the Standard for Exchange of Nonclinical Data (SEND) initiative, to assist pharmacology/toxicology reviewers and biostatisticians in statistical analysis of nonclinical tumor data. The guide will also be useful to study and peer review pathologists in interpreting the tumor data. This guide provides a higher-level hierarchy of tumor types or categories correlating the tumor names from the International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) publications with those available in the NEOPLASM controlled terminology (CT) code list in SEND. The version of CT used in a study should be referenced in the nonclinical study data reviewer’s guide (SDRG) (section 3.1) of electronic submissions to the FDA. The tumor combination guide instructions and examples are in a tabular format to make informed decisions for combining tumor data for statistical analysis. The strategy for combining tumor types for statistical analysis is based on scientific criteria gleaned from the current scientific literature; as SEND and INHAND terminology and information evolve, this guide will be updated.

Gliosis, including microgliosis and astrocytosis, can be challenging to interpret in nonclinical studies. Incidences of glial foci in brains and spinal cords of control rats and nonhuman primates (NHPs) were reviewed in the historical control databases from two contract research organizations, including one specializing in neuropathology. In the brain, minimal to mild (grades 1-2) microgliosis was the most common diagnosis, especially in NHPs, although occasional moderate or marked microgliosis (grades 3 and 4) was encountered in both species. Microgliosis was more common in the cerebral cortex, cerebellum, and medulla oblongata in both species and was frequent in the white matter (brain), thalamus, and basal nuclei of NHPs. Gliosis (“not otherwise specified”) of minimal severity was diagnosed in similar brain sub-sites for both species and was more common in NHPs compared with rats. Astrocytosis was most prominent in the cerebellum (molecular layer) of NHPs but was otherwise uncommon. In the spinal cord, microgliosis was most common in the lateral white matter tracts in rats and NHPs, and in the dorsal white matter tracts in NHPs. These data indicate that low-grade spontaneous glial responses occur with some frequency in control animals of two common nonclinical species.

As biotechnology companies continue to develop immunomodulatory compounds, more often than not, the only relevant species for preclinical safety assessment is the non-human primate (NHP). Toxicology pathologists are increasingly evaluating tissues from preclinical safety assessment studies conducted in the NHP, mainly the cynomolgus monkey but occasionally the rhesus monkey and common marmoset. A basic understanding of the spontaneous infections and opportunistic pathogens that can arise in NHPs is important when evaluating compounds that ultimately can affect the integrity and function of the immune system. This chapter provides a brief overview on the pathological characteristics of the most common infections and pathogens that can occur in NHP in the research settings.

From a neuropathology standpoint, the close phylogenetic relationship between cynomolgus monkeys and humans makes them a highly useful animal model for preclinical studies. This is especially true for studies with a neuroscience focus and/or those using large molecule studies (biologics) because cynomolgus monkeys and humans share similar biochemical responses, pharmacological distribution and behavior of the target proteins, and comparable absorption, metabolic, pharmacokinetic, and distribution profiles for some chemicals. In addition, the brains and spinal cords of non-human primates (NHP) such as cynomolgus monkeys have multiple structural, functional, and molecular similarities with humans. Therefore, in general, NHP species are good models to study human neurodegenerative diseases and neurological injury. This chapter focuses on evaluation of the nervous system of cynomolgus macaques and other NHPs commonly used in toxicology studies. Sections include a general overview of the nervous system with discussion of embryology and sampling. Disease states are covered, including congenital, spontaneous, aging, and neoplastic diseases. Infectious diseases are covered in the chapter dedicated to such conditions and only briefly mentioned here. The chapter ends with a brief discussion of common xenobiotic-related effects seen in nervous system tissues.

The functional anatomy and physiology of muscle, bone, and joints provide a basis for understanding the spontaneous and induced lesions that occur in these tissues in non-human primates (NHPs) commonly utilized in toxicology studies (cynomolgus macaques, rhesus macaques, and marmosets). To be able to interpret induced changes when evaluating the musculoskeletal system in toxicology studies, it is important to have a good understanding of gross and microscopic spontaneous lesions within the context of these studies. Spontaneous and induced lesions in these tissues include changes that are degenerative, congenital, inflammatory, proliferative, and neoplastic, all of which are discussed in the chapter, with associated illustrative images.

Toxicologic/veterinary pathologists are working remotely from Good Laboratory Practice (GLP) test facilities (TFs) in increasing numbers, most commonly in home-office settings. A study pathologist (SP) generating data on GLP-compliant nonclinical studies must be keenly aware of applicable national GLP regulations and comply with TF and protocol requirements. This Toxicological Pathology Forum Opinion Piece will summarize primary areas of emphasis for the SP generating GLP data using glass slides. Peer review and digital review of whole slide images are out of scope for this opinion piece. Key GLP considerations for primary pathology on glass slides are discussed with respect to SP location and employment status, including pathologist qualifications, specimen management, facilities, equipment, archive, and quality assurance. Notable differences between national GLP regulations of the United States, the United Kingdom, Germany, the Netherlands, France, Ireland, Switzerland, Italy, and Israel are presented. With the understanding that each combination of location and employment is unique, the authors provide a general overview of considerations for successful remote GLP work.

The age of digitalization has arrived in light microscopy. While the current practice of toxicologic pathology remains largely based on the light microscopic evaluation of stained tissue sections, it is no longer limited to it. Thanks to the availability of whole-slide imaging (WSI), histopathologic evaluation can now be accomplished via a computer screen. Substituting a computer monitor for a traditional microscope may at first seem to be a minor change. However, the digitization of glass slides has opened up a host of new options to interrogate tissue sections. These include geographically remote viewing of slides for more convenient and expedient pathology peer review, simplification of obtaining rapid and even real-time consultations with specific subject matter experts, formation of pathology working groups with global membership, building digital workflows that link WSI to associated metadata stored in laboratory information management systems, integrating other relevant data (e.g., in vivo data), enhancing teaching and training capabilities, and applying image analysis algorithms to whole-slide images to extract data previously not easily accessible or quantified. While WSI has been commercially available for over 20 years and is being rapidly adopted by the global pathology community, regulatory guidance on the use of digital pathology and related topics in toxicologic pathology is still evolving and currently incomplete. This chapter introduces digital pathology, including WSI and tissue image analysis, and explores potential future use in nonclinical toxicology. Additional related topics such as stereology and alternative imaging modalities are briefly introduced. General principles for consideration in use of WSI in regulated studies are included. A list of relevant references provides additional scope for the interested reader.

With their close phylogeny to Homo sapiens, Nonhuman Primates (NHPs) stand at the forefront of the wave of new medical and scientific breakthroughs. Currently, most toxicologic research conducted in NHPs occurs in three species—cynomolgus macaques, rhesus macaques, and common marmosets—with the baboon closely following. In this chapter, the origins of these NHPs commonly utilized in toxicologic research, along with those less commonly utilized, are described, and their essential nature to scientific advancement, key toxicology considerations, application as animal models, and background pathology findings are reviewed.

Aneurysms of the ascending aorta, unrelated to xenobiotic administration, are described in 5 rats and 2 mice in nonclinical safety studies conducted at Charles River Laboratories (CRL) sites over the past 10 years. The most prominent microscopic finding was focal dilation with disruption of the wall of the ascending aorta with chronic adventitial inflammation or fibroplasia. The pathogenesis of this finding is unknown. There were no associated macroscopic findings, clinical abnormalities, or vascular lesions elsewhere. The results of a search of historical control data from toxicology studies of 1 day to 72 weeks' duration performed at CRL for aortic findings from 5900 mice and 23,662 rats are also reported. Aortic lesions are uncommon in mice and rats used in nonclinical safety studies, but toxicologic pathologists should be aware that aneurysms of the ascending aorta with fibroplasia and inflammation in the aortic wall and adventitia may occur spontaneously or iatrogenically, as they have the potential to impact interpretation in toxicology studies.

The rabbit has been and continues to be a vital resource for biomedical research. This chapter focuses on the role of rabbits in toxicologic research and related biomedical studies. First, the rabbit is placed in context compared to other animal models; aspects where rabbits closely match human physiology and/or anatomy are highlighted. Basic rabbit physiological and anatomic features are discussed. This is followed by a review of the different classes of studies in which rabbits are a commonly used species (e.g., medical device, regenerative medicine, development and reproductive toxicity studies). Finally, key species-specific microscopic findings will be highlighted for the rabbit, as well as unique tissues/structures that could be misidentified.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the laboratory rabbit used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

This Proof of Concept (POC) study was to assess whether assessment of whole slide images (WSI) of the 2 target tissues for a contemporaneous peer review can elicit concordant results to the findings generated by the Study Pathologist from the glass slides. Well-focused WSI of liver and spleen from 4 groups of mice, that had previously been diagnosed to be the target tissues by an experienced veterinary toxicologic pathologist examining glass slides, were independently reviewed by 3 veterinary pathologists with varying experience in assessment of WSIs. Diagnostic discrepancies were then reviewed by an experienced adjudicating pathologist. Assessment of microscopic findings using WSI showed concordance with the glass slides, with only slight discrepancy in severity grades noted. None of the lesions recorded by the Study pathologist were "missed" and no lesions were added by the pathologists evaluating WSIs, thus demonstrating equivalence of the WSI to glass slides for this study.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the nonhuman primate used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

Although manuscripts for multiple species recommending nervous system sampling for histopathology evaluation in safety assessment have been published in the past 15 years, none have addressed the laboratory rabbit. Here, we describe 2 trimming schemes for evaluating the rabbit brain in nonclinical toxicity studies. In both schemes, the intact brain is cut in the coronal plane to permit bilateral assessment. The first scheme is recommended for general toxicity studies (tier 1) in screening agents where there is no anticipated neurotoxic potential; this 6-section approach is consistent with the Society of Toxicologic Pathology (STP) “best practice” recommendations for brain sampling in nonrodents ( Toxicol Pathol 41: 1028-1048, 2013 1 ). The second trimming scheme is intended for dedicated neurotoxicity studies (tier 2) to characterize known or suspected neurotoxicants where the nervous system is a key target organ. This tier 2 strategy relies on coronal trimming of the whole brain into 3-mm-thick slices and then evaluating 12 sections. Collection of spinal cord, ganglia, and nerve specimens for rabbits during nonclinical studies should follow published STP “best practice” recommendations for sampling the central nervous system 1 and peripheral nervous system ( Toxicol Pathol 46: 372-402, 2018 2 ).