Toxicologic Pathology最新文献

Medical devices are a product class encompassing many materials and intended uses. While adversity determination is a key part of nonclinical safety assessments, relatively little has been published about the unique challenges encountered when determining adversity for implantable medical devices. The current paper uses the Society of Toxicologic Pathology (STP)'s "Scientific and Regulatory Policy Committee Recommended ('Best') Practices for Determining, Communicating, and Using Adverse Effect Data from Nonclinical Studies," which were crafted for conventional bio/pharmaceutical products (small and large molecules, cell and gene therapies, etc), as a framework for making adversity decisions for medical devices. Some best principles are directly translatable to medical devices: (1) adversity indicates harm to the animal; (2) effects should be assessed on their merits without speculation regarding future or unmeasured implications; (3) adversity decisions apply only to the test species under the specific conditions of the nonclinical study; and (4) adversity decisions and supporting evidence should be clearly stated in reports. However, unique considerations also apply for evaluating implanted medical devices, including testing of multiple articles in the same animal and the unavoidable tissue trauma during device implantation. This opinion piece offers suggestions for applying previously published STP best practice recommendations for assigning adversity to implantable medical devices.

Nonhuman primates (NHPs) have been and remain a highly valuable animal model with an essential role in translational research and pharmaceutical drug development. Based on current regulatory guidelines, the nonclinical safety of novel therapeutics should be evaluated in relevant nonclinical species, which commonly includes NHPs for biotherapeutics. Given the practical and ethical limitations on availability and/or use of NHPs and in line with the widely accepted guiding "3Rs" (replace, reduce, and refine) principles, many approaches have been considered to optimize toxicity study designs to meaningfully reduce the number of NHPs used. Standard general toxicity studies usually include four groups of equal size, including one group of vehicle control animals. Here, we describe an approach to achieve an overall significant reduction in control animal use, while also resolving many of the issues that may limit application of fully virtual control animals. We propose in Good Laboratory Practice (GLP)-compliant toxicity studies to maintain concurrent control group animals for the in-life phase of the studies, but to limit euthanasia to a subset of control animals. The nonterminated control animals can then be returned to the facility colony for reuse in subsequent studies. The proposed study design could lead to a 15% to 20% reduction in NHP usage. The scientific, logistical, and animal welfare considerations associated with such an approach and suggested solutions are discussed in detail.

Thyroid tissue is sensitive to the effects of endocrine disrupting substances, and this represents a significant health concern. Histopathological analysis of tissue sections of the rat thyroid gland remains the gold standard for the evaluation for agrochemical effects on the thyroid. However, there is a high degree of variability in the appearance of the rat thyroid gland, and toxicologic pathologists often struggle to decide on and consistently apply a threshold for recording low-grade thyroid follicular hypertrophy. This research project developed a deep learning image analysis solution that provides a quantitative score based on the morphological measurements of individual follicles that can be integrated into the standard pathology workflow. To achieve this, a U-Net convolutional deep learning neural network was used that not just identifies the various tissue components but also delineates individual follicles. Further steps to process the raw individual follicle data were developed using empirical models optimized to produce thyroid activity scores that were shown to be superior to the mean epithelial area approach when compared with pathologists' scores. These scores can be used for pathologist decision support using appropriate statistical methods to assess the presence or absence of low-grade thyroid hypertrophy at the group level.

The Golden Syrian hamster is a well-characterized rodent model for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2)-associated pneumonia. We sought to characterize the pulmonary disease course during SARS-CoV-2 infection (strain USA-WA1/2020) in the hamster model using micro-computed tomography (micro-CT) and compare radiologic observations with histopathologic findings. We observed a range of radiologic abnormalities, including ground glass opacities (GGOs), consolidations, air bronchograms, and pneumomediastinum. The appearance, distribution, and progression of these abnormalities in hamsters were similar to those observed in the lungs of coronavirus disease 2019 (COVID-19) patients by clinical CT and chest X-rays, and correlated with clinical signs and weight loss during the course of disease. Histopathological analysis of infected hamsters revealed lung pathology characteristic of COVID-19 pneumonia, and we observed a strong association between CT and histopathologic scorings. We also analyzed accumulation of air in the thoracic cavity by both manual and automated threshold-based segmentation and found that automated analysis significantly decreases the time needed for data analysis. Data presented here demonstrate that micro-CT imaging can be a major tool in preclinical investigative studies using animal models by providing early and detailed assessment of disease severity and outcomes.

Before the COVID-19 pandemic, digital pathology was increasingly used in veterinary education, diagnostics, and research. The pandemic accelerated this adoption as institutions needed to maintain operations amidst lockdowns. It also enabled pharmaceutical companies to conduct peer reviews digitally, circumventing travel restrictions. At the 2023 Society of Toxicologic Pathology Annual Symposium, a Town Hall Meeting highlighted the current use of digital pathology. A majority of the respondents viewed whole slide images (WSI) favorably. Many institutions use digital pathology primarily for non-GLP and GLP conforming primary reads and peer reviews. Takeda has long utilized digital pathology, incorporating scanners and an image management repository, and recently adopted a cloud-based platform tailored for toxicologic pathology, enhancing efficiency and collaboration. Digital pathology not only saves time but also reduces travel needs and environmental impact. Technological advancements and wider adoption are expected to further enhance the field, promising significant benefits for the overall digital pathology infrastructure.

Recent trends in toxicological pathology include implementation of digital platforms that have gained rapid momentum in the field. Are we ready to fully implement this new modality? This opinion piece provides some practical perspectives on digital pathology such as its cost limitations, relative time requirements, and a few technical issues, some of which are encountered for specific lesions, that warrant caution. Although the potential for digital pathology assessment with whole slide images has made great strides, we are of the opinion that it is not yet ready for complete replacement of glass slides in toxicologic pathology safety assessments.

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.

Sharing pathology data is critical for educational and scientific purposes. Since most pharmaceutical or (agro)chemical companies outsource nonclinical safety assessment studies to contract research organizations (CROs), the pathology data of those studies are not owned by the investigator but is the legal property of the respective company sponsoring the work. Although some companies have installed policies that govern sharing of pathology data, many companies generally do not allow the external use of data by either the CRO-based study pathologist or the sponsor pathologist. Policies for governing the external use of data vary significantly. In this article, we present an overview of the different approaches taken across different companies (CROs, pharmaceutical/chemical companies, or other institutes) for sharing pathology material for educational and/or scientific purposes. The results of a survey and interviews with legal departments of different companies will be presented (anonymously) and discussed. In addition, the importance of sharing pathology data is addressed, as well as the challenges and opportunities this presents. Suggestions will be provided regarding what material should be made available and what will be needed to achieve agreement for this to happen.

One of the emerging concepts on the reduction of animal use in non-clinical studies is the use of virtual control group (VCG) to replace concurrent control group (CCG). The VCG involves the generation of a control data from historical control data to match a specific study design. This review focuses on two recently published proof-of-concept (POC) studies conducted in rats. One major issue that was consistently seen across these POC studies was the non-reproducibility of some quantitative endpoints between the CCG and the VCG, with clinical pathology parameters being the most affected. The inconsistencies observed with the clinical pathology parameters when using VCGs may lead to: (1) misconception about the accuracy and sensitivity of traditional clinical pathology biomarkers and its implications on safety monitoring in the clinic; (2) inability to correctly identify and characterize organ dysfunctions; (3) interference with the weight-of-evidence approach used in identifying hazards in toxicologic clinical pathology and toxicology studies at large; and (4) wrong interpretations and data reproducibility issues. Other alternatives to reduce animal use in toxicology studies are also discussed including blood microsampling for toxicokinetics, scientifically justified use of recovery animals, and appropriate use and continuous investments in new alternative methods.