The liver is the most important organ that metabolizes and detoxifies chemicals taken into the body. Therefore, there is always a risk of liver damage owing to the toxic effects of chemicals. The mechanisms of hepatotoxicity have been studied extensively and deeply based on toxic effects of chemicals themselves. However, it is important to note that liver damage is variously modified by the patho-biological reactions evoked mainly via macrophages. Macrophages appearing in hepatotoxicity are evaluated by the M1/M2 polarization; M1 macrophages promote tissue injury/inflammation, whereas M2 macrophages show anti-inflammatory action including reparative fibrosis. The “portal vein-liver barrier” regulated by Kupffer cells and dendritic cells in and around the Glisson’s sheath may be related to the initiation of hepatotoxicity. In addition, Kupffer cells exhibit the two-sides of functions (that is, M1 or M2 macrophage-like functions), depending on microenvironmental conditions which may be raised in part by gut microbiota-derived lipopolysaccharide. Furthermore, damage-associated molecular patterns (DAMPs) (in particular, HMGB1) and autophagy (which degrades DAMPs) also play roles in the polarity of M1/M2 macrophages. The mutual relation of “DAMPs (HMGB-1)–autophagy–M1/M2 macrophage polarization” as the patho-biological reaction should be taken into consideration in hepatotoxicity evaluation.

In this review, we focus on the rat pulmonary carcinogenicity of two solid substances, fibrous multi-walled carbon nanotube (MWCNT) and particulate indium tin oxide (ITO). Inhalation exposure to MWNT-7, a type of MWCNTs, and ITO induced lung carcinogenicity in both male and female rats. Toxicity to the alveolar epithelium is induced by macrophages undergoing frustrated phagocytosis or frustrated degradation of engulfed particles (referred to as frustrated macrophages). Melted macrophage contents contribute significantly to development of hyperplasia of the alveolar epithelium, which eventually results in the induction of lung carcinoma. MWNT-7 and ITO induce secondary genotoxicity; consequently, a no-observed-adverse-effect level can be applied to these materials rather than benchmark doses that are used for non-threshold carcinogens. Thus, establishing occupational exposure limit values for MWNT-7 and ITO based on the existence of a carcinogenic threshold is reasonable.

In this review, the histological structures of the skin are summarized for fundamental knowledge for toxicological assessment. The skin is composed of epidermis, dermis, subcutaneous tissue, and associated adnexa. In the epidermis, keratinocytes comprise four layers, and three other cell types, besides keratinocytes, play various roles. Epidermal thickness varies with species and body site. In addition, it can be affected by tissue preparation procedures, which can render toxicity assessments difficult. Bulge stem cells are the origin of sebaceous glands, epidermal basal layer, and hair follicle formation, and they play an important role in the maintenance of the basic structure of the skin. Stem cells and appendages formed from stem cells sometimes become toxic targets, and it is useful to study the origins of the hair follicle/hair cycle to interpret their toxicity. Irritant contact dermatitis and allergic contact dermatitis are the main adverse reactions in topical application studies. The mechanism involves direct chemical irritation of the skin, and histologically, epidermal necrosis and accompanying inflammatory cell infiltration. In allergic contact dermatitis, an inflammatory reaction and intercellular or intracellular edema, histologically represented by lymphocytic infiltration of the epidermis and dermis, are observed. Regional and species differences exist in the dermal absorption of compounds, and differences in the thickness of the stratum corneum substantially contribute to these differences. Learning the basic structures, functions, and possible artifacts will contribute to the evaluation of skin toxicity by topical and systemic applications.

Nonhuman primates (NHPs), which have many advantages in scientific research and are often the only relevant animals to use in assessing the safety profiles and biological or pharmacological effects of drug candidates, including biologics. In scientific or developmental experiments, the immune systems of animals can be spontaneously compromised possibly due to background infection, experimental procedure-associated stress, poor physical condition, or intended or unintended mechanisms of action of test articles. Under these circumstances, background, incidental, or opportunistic infections can seriously can significantly complicate the interpretation of research results and findings and consequently affect experimental conclusions. Pathologists and toxicologists must understand the clinical manifestations and pathologic features of infectious diseases and the effects of these diseases on animal physiology and experimental results in addition to the spectrum of infectious diseases in healthy NHP colonies. This review provides an overview of the clinical and pathologic characteristics of common viral, bacterial, fungal, and parasitic infectious diseases in NHPs, especially macaque monkeys, as well as methods for definitive diagnosis of these diseases. Opportunistic infections that can occur in the laboratory setting have also been addressed in this review with examples of cases of infection disease manifestation that was observed or influenced during safety assessment studies or under experimental conditions.

Diphenylarsinic acid (DPAA), a neurotoxic organic arsenical, is present in groundwater and soil in some regions of Japan owing to illegal dumping. The present study evaluated the potential carcinogenicity of DPAA, including investigating whether bile duct hyperplasia in the liver that was observed in a chronic study on 52 week mouse, develops into a tumor when administered to mice in their drinking water for 78 weeks. DPAA was administered to 4 groups of male and female C57BL/6J mice at concentrations of 0, 6.25, 12.5, and 25 ppm in drinking water for 78 weeks. A significant decrease in the survival rate was found for females in the 25 ppm DPAA group. Body weights of males in the 25 ppm and females in the 12.5 and 25 ppm DPAA groups were significantly lower than those of the controls. Histopathological evaluation of neoplasms in all tissues showed no significant increase in tumor incidence in any organ or tissue of 6.25, 12.5, or 25 ppm DPAA-treated male or female mice. In conclusion, the present study demonstrated that DPAA is not carcinogenic to male or female C57BL/6J mice. Taken together with the fact that the toxic effect of DPAA is predominantly restricted to the central nervous system in humans, and the finding that DPAA was not carcinogenic in a previous 104-week rat carcinogenicity study, our results suggest that DPAA is unlikely to be carcinogenic in humans.

We report a case of mammary fibroadenoma in a 7-week-old male SD rat. This case showed rapid growth within one week from the time when the nodule was detected. Histologically, the nodule was a well-circumscribed subcutaneous mass. The tumor consisted of an epithelial component with island-like proliferation (cribriform to tubular patterns) and an abundant mesenchymal component. Alpha-SMA-positive cells were arranged at the periphery of the epithelial component and showed cribriform and tubular patterns. Discontinuous basement membranes and high cell proliferative activities were observed in the cribriform area. These features resembled those of normal terminal end buds (TEBs). Since the mesenchymal component had abundant fine fibers and a mucinous matrix, its stroma was regarded as neoplastic growth of fibroblasts; thus, this tumor was diagnosed as a fibroadenoma. This case is an extremely rare fibroadenoma in that it occurred in a young male SD rat and was composed of an epithelial component showing multifocal proliferation of TEB-like structures and a mucinous mesenchymal component consisting of fibroblasts with fine collagen fibers.

Ectopic pancreatic tissue can occasionally cause inflammation, hemorrhage, stenosis, and invagination, similar to normal pancreatic tissue; however, tumorigenesis is rare. This case report describes an ectopically observed pancreatic acinar cell carcinoma in the thoracic cavity of a female Fischer (F344/DuCrlCrlj) rat. Histopathologically, polygonal tumor cells with periodic acid-Schiff-positive cytoplasmic eosinophilic granules showed solid proliferation and infrequently formed acinus-like structures. Immunohistochemically, the tumor cells were positive for cytokeratin, trypsin, and human B-cell leukemia/lymphoma 10, which specifically reacted with pancreatic acinar cells, and negative for vimentin and human α-smooth muscle actin. Ectopic pancreas develops in the submucosa of the gastrointestinal tract; however, there are few reports of its development and neoplasia in the thoracic cavity. To the best of our knowledge, this is the first report of ectopic pancreatic acinar cell carcinoma in the thoracic cavity of a rat.

Neurofilament light chain (NfL) has recently been used as a biomarker of neurodegeneration. Although cerebrospinal fluid (CSF) NfL levels are hypothesized to affect blood NfL levels, whether blood NfL levels change independently of the CSF during peripheral nerve injury remains unclear. Thus, we evaluated the nervous tissues histopathology and serum and CSF NfL levels in partial sciatic nerve-ligated rats at 6 h and one, three, or seven days after the surgery. Sciatic and tibial nerve fiber damage was observed at 6 h after the surgery, and peaked at three days postoperatively. The serum NfL levels peaked 6 h to one day after ligation, but they tended to return to the normal seven days after ligation. However, the CSF NfL levels were unchanged throughout the study period. In conclusion, the comparative evaluation of serum and CSF NfL levels can provide useful information as biomarkers of nerve tissue damage and its distribution.