Complex In Vitro Model Characterization for Context of Use in Toxicologic Pathology: Use Cases by Collaborative Teams of Biologists, Bioengineers, and Pathologists.

Complex in vitro models (CIVMs) offer the potential to increase the clinical relevance of preclinical efficacy and toxicity assessments and reduce the reliance on animals in drug development. The European Society of Toxicologic Pathology (ESTP) and Society for Toxicologic Pathology (STP) are collaborating to highlight the role of pathologists in the development and use of CIVM. Pathologists are trained in comparative animal medicine which enhances their understanding of mechanisms of human and animal diseases, thus allowing them to bridge between animal models and humans.

Proceedings of the 2023 Division of Translational Toxicology Satellite Symposium.

The 2023 annual Division of Translational Toxicology (DTT) Satellite Symposium, entitled "Pathology Potpourri," was held in Summerlin, Nevada, at the Society of Toxicologic Pathology's 41st annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion.

Intravenous Administration of Ad26.COV2.S Does Not Induce Thrombocytopenia or Thrombotic Events or Affect SARS-CoV-2 Spike Protein Bioavailability in Blood Compared with Intramuscular Vaccination in Rabbits.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a very rare but serious adverse reaction that can occur after Ad26.COV2.S vaccination in humans, leading to thrombosis at unusual anatomic sites.

Chemistry-Based Modeling on Phenotype-Based Drug-Induced Liver Injury Annotation: From Public to Proprietary Data.

Drug-induced liver injury (DILI) is an important safety concern and a major reason to remove a drug from the market. Advancements in recent machine learning methods have led to a wide range of in silico models for DILI predictive methods based on molecule chemical structures (fingerprints). Existing publicly available DILI data sets used for model building are based on the interpretation of drug labels or patient case reports, resulting in a typical binary clinical DILI annotation.

Booster with Ad26.COV2.S or Omicron-adapted vaccine enhanced immunity and efficacy against SARS-CoV-2 Omicron in macaques.

Omicron spike (S) encoding vaccines as boosters, are a potential strategy to improve COVID-19 vaccine efficacy against Omicron. Here, macaques (mostly females) previously immunized with Ad26.COV2.

Special Issue on the Pathobiology of Laboratory Nonhuman Primates: A Review of Species, Substrain, Geographical Origin, Age, and Modality-Related Factors.

Nonhuman primates (NHPs) are utilized in nonclinical safety testing due to their phylogenetic proximity to humans and similarity in physiology and anatomy. However, ethical considerations and the increased demand for NHPs, coupled with the current shortage in their supply, have increased the calls to minimize their use. In addition, the increased demand and supply shortage of NHPs have increased the use of animals sourced from different geographical origins, and animals of different ages, which can complicate the interpretation of study results.

The Influence of Geographical Origin, Age, Sex, and Animal Husbandry on the Spontaneous Histopathology of Laboratory Cynomolgus Macaques (): A Contemporary Global and Multisite Review of Historical Control Data.

To investigate the influence of geographical origin, age, and sex on toxicologically relevant spontaneous histopathology findings in cynomolgus macaques (), we performed a comparative analysis of historical control data (HCD) from 13 test sites that included 3351 animals (1645 females and 1706 males) sourced from Mauritius, China, Vietnam, and Cambodia, aged from 2 to 9.5 years, and from 446 toxicology studies evaluated between 2016 and 2021. The most common findings were mononuclear infiltrates in the kidney, liver, brain, and lung, which showed highest incidences in Mauritian macaques, and heart, salivary glands, and gastrointestinal tract (GIT), which showed highest incidences of mononuclear infiltrates in mainland Asian macaques.

Low-dose Ad26.COV2.S protection against SARS-CoV-2 challenge in rhesus macaques.

We previously reported that a single immunization with an adenovirus serotype 26 (Ad26)-vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge.

Application of solid lipid nanoparticles as a long-term drug delivery platform for intramuscular and subcutaneous administration: In vitro and in vivo evaluation.

The purpose of this work was to evaluate solid lipid nanoparticles (SLNs) as a long acting injectable drug delivery platform for intramuscular and subcutaneous administration. SLNs were developed with a low (unsaturated) and high (supersaturated) drug concentration at equivalent lipid doses. The impact of the drug loading as well as the administration route for the SLNs using two model compounds with different physicochemical properties were explored for their in vitro and in vivo performance.

Low-Dose Ad26.COV2.S Protection Against SARS-CoV-2 Challenge in Rhesus Macaques.

We previously reported that a single immunization with an adenovirus serotype 26 (Ad26) vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge.

Adversity Considerations for Thyroid Follicular Cell Hypertrophy and Hyperplasia in Nonclinical Toxicity Studies: Results From the 6th ESTP International Expert Workshop.

The European Society of Toxicologic Pathology organized an expert workshop in May 2018 to address adversity considerations related to thyroid follicular cell hypertrophy and/or hyperplasia (FCHH), which is a common finding in nonclinical toxicity studies that can have important implications for risk assessment of pharmaceuticals, food additives, and environmental chemicals. The broad goal of the workshop was to facilitate better alignment in toxicologic pathology and regulatory sciences on how to determine adversity of FCHH. Key objectives were to describe common mechanisms leading to thyroid FCHH and potential functional consequences; provide working criteria to assess adversity of FCHH in context of associated findings; and describe additional methods and experimental data that may influence adversity determinations.

An Angiomyomatous Hamartoma With Features of Vascular Transformation of Sinuses in the Mediastinal Lymph Node of a Beagle Dog.

Two similar benign, nonneoplastic vascular lesions have been described in the lymph nodes of humans and animals: angiomyomatous hamartoma (AMH), which is characterized by the replacement of lymphoid tissue by blood vessels, smooth muscle, and fibrous tissue, and vascular transformation of sinuses (VTS), which is considered a reactive transformation of lymph node sinuses into capillary-like vascular channels. We hereby report a lesion with features common to both lesions in the mediastinal lymph nodes of a 1-year-old beagle dog in a 1-month toxicity study. Grossly, enlargement and red discoloration were observed, while microscopically, the lesion was characterized by effacement of the lymph node parenchyma with replacement by mature blood vessels, smooth muscle, and fibrous tissue, associated with lymphoid atrophy, which is consistent with AMH.

Multisite Analysis of Lesions in the Respiratory Tract of the Rat and Nonhuman Primate (Cynomolgus Monkey) Exposed to Air, Vehicle, and Inhaled Small Molecule Compounds.

This paper presents a review of the nature, range, and incidences of background pathology findings in the respiratory tract of cynomolgus monkeys and rats. Data were collected from 81 inhalation studies and 133 non-inhalation studies evaluated at 3 geographically distinct contract research organization facilities. The inhalation studies were comprised of 44 different small molecule pharmaceuticals or chemicals which were also analyzed in order to understand the patterns of induced changes within the respiratory tract.

Scientific and Regulatory Policy Committee Points to Consider*: Approaches to the Conduct and Interpretation of Vaccine Safety Studies for Clinical and Anatomic Pathologists.

The design and execution of toxicology studies supporting vaccine development have some unique considerations relative to those supporting traditional small molecules and biologics. A working group of the Society of Toxicologic Pathology Scientific and Regulatory Policy Committee conducted a review of the scientific, technical, and regulatory considerations for veterinary pathologists and toxicologists related to the design and evaluation of regulatory toxicology studies supporting vaccine clinical trials. Much of the information in this document focuses on the development of prophylactic vaccines for infectious agents.

Normal Anatomy, Histology, and Spontaneous Pathology of the Kidney, and Selected Renal Biomarker Reference Ranges in the Cynomolgus Monkey.

To further our understanding of the nonhuman primate kidney anatomy, histology, and incidences of spontaneous pathology, we retrospectively examined kidneys from a total of 505 control Cynomolgus monkeys (; 264 male and 241 females) aged 2 to 6 years, from toxicity studies. Kidney weights, urinalysis, and kidney-related clinical biochemistry parameters were also evaluated. Although the functional anatomy of the monkey kidney is relatively similar to that of other laboratory animals and humans, a few differences and species-specific peculiarities exist.

Comparison of the Local Tolerability to 5 Long-acting Drug Nanosuspensions with Different Stabilizing Excipients, Following a Single Intramuscular Administration in the Rat.

To investigate the effects of common nanosuspension-stabilizing excipients on the nature and temporal evolution of histopathological changes at intramuscular (i.m.) administration sites, 5 groups of 39 male rats per group received a single injection of 1 of the 5 analogous crystalline drug nanosuspensions containing 200 mg/ml of an antiviral compound with particle sizes of ±200 nm and identical vehicle compositions, except for the type of nanosuspension stabilizer.

Normal Anatomy, Histology, and Spontaneous Pathology of the Nasal Cavity of the Cynomolgus Monkey (Macaca fascicularis).

The evaluation of inhalation studies in monkeys is often hampered by the scarcity of published information on the relevant nasal anatomy and pathology. We examined nasal cavities of 114 control cynomolgus monkeys from 11 inhalation studies evaluated 2008 to 2013, in order to characterize and document the anatomic features and spontaneous pathology. Compared to other laboratory animals, the cynomolgus monkey has a relatively simple nose with 2 unbranched, dorsoventrally stacked turbinates, large maxillary sinuses, and a nasal septum that continues into the nasopharynx.

A Review of the Comparative Anatomy, Histology, Physiology and Pathology of the Nasal Cavity of Rats, Mice, Dogs and Non-human Primates. Relevance to Inhalation Toxicology and Human Health Risk Assessment.

There are many significant differences in the structural and functional anatomy of the nasal cavity of man and laboratory animals. Some of the differences may be responsible for the species-specific nasal lesions that are often observed in response to inhaled toxicants. This paper reviews the comparative anatomy, physiology and pathology of the nasal cavity of the rat, mouse, dog, monkey and man, highlighting factors that may influence the distribution of nasal lesions.

Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies.

The authors performed a retrospective study to determine the incidences and range of spontaneous pathology findings in control cynomolgus monkeys. Data were collected from 570 monkeys (285 animals per sex), aged twelve to thirty-six months, from sixty regulatory studies evaluated at our laboratory between 2003 and 2009. The most common finding overall was lymphoplasmacytic infiltrates observed in the following incidence: liver (60.

Spontaneous lesions of the cardiovascular system in purpose-bred laboratory nonhuman primates.

This retrospective study was performed to determine the range, occurrence and incidence of spontaneously arising histopathological findings of the cardiovascular system in purpose-bred laboratory nonhuman primates. Data were collected from 84 controlled toxicological studies with equal numbers of male and female animals and full tissue lists. Attempts were also made to standardize pathological terms used by various original pathologists.

Arthropathic and amyloidogenic Enterococcus faecalis infections in brown layers: A study on infection routes.

Intravenous, intra-articular and intraperitoneal inoculation of 6-week-old brown-layer pullets with an arthropathic and amyloidogenic strain of Enterococcus faecalis resulted in amyloid arthropathy, while intramuscular, oral and intratracheal inoculation did not. Oral inoculation of 1-day-old chickens did not cause any pathology. However, intramuscular inoculation with 10 colony forming units resulted in severe growth retardation and arthritis in 60% of the birds, and amyloid arthropathy in approximately 40%.

Serum amyloid A and transferrin in chicken. A preliminary investigation of using acute-phase variables to assess diseases in chickens.

The concentrations of serum amyloid A protein (SAA) and transferrin in blood samples from broilers in various stages of natural Staphylococcus aureus infection, from healthy counterparts, and from turpentine- or saline-injected pullets were measured using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, and densitometry. SAA was not detected in healthy chickens but was detected in turpentine-injected pullets and in S. aureus-infected broilers.