Spontaneous primary pleural mesotheliomas in Fischer 344 (F344) or other rat strains have rarely been reported. The objectives of this retrospective study were to develop historical incidence data and better characterize the light-microscopic morphology of these naturally occurring neoplasms in a large cohort of rats of several strains. A retrospective review was performed of National Toxicology Program (NTP) studies in rats conducted between 1980 and 2019 and comprising a total of 104,029 rats (51,326 males, 52,703 females), predominantly (90%) of the F344 strain. Of the 94,062 F344 rats surveyed, there were 30 cases of primary pleural mesotheliomas (22 males, 8 females). Of the 2998 Wistar Han rats surveyed, primary pleural mesotheliomas were present in 2 male rats. No primary pleural mesotheliomas were noted in male and female rats of other strains (6669 Sprague Dawley; 300 Osborne-Mendel). All primary pleural mesotheliomas in control and treated F344 and Wistar Han rats were considered spontaneous and unrelated to treatment. Based on light-microscopic evaluation of paraffin-embedded hematoxylin and eosin stained sections, only epithelioid and biphasic histologic subtypes were observed: 18 and 12 in F344 rats, respectively, and one each in Wistar Han rats. No sarcomatoid subtype cases were noted in any strain of rat.

Although generally not required in the global Good Laboratory Practice regulations, the practice of Pathology Peer Review serves as an important quality control procedure to increase confidence in the accuracy of the pathology diagnoses and report interpretations. Pathology peer review entails a second pathologist (the Peer Review Pathologist) or a group of pathologists (the Pathology Working Group) evaluating a subset of the pathology postmortem findings originally identified by the Study Pathologist (gross and microscopic evaluation and terminology), in addition to the overall study diagnostic interpretation in the report. This chapter will review current pathology peer review practices for the various toxicity studies conducted by industry and government research institutes, describe appropriate documentation and reporting practices, and present the current state of government regulatory guidance for peer review.

In 2019 California's Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. In parallel with this review, herein we evaluated the mechanistic data related to the steps and timing of cellular events following therapeutic recommended (<= 4 g/day) and higher doses of acetaminophen that may cause hepatotoxicity to evaluate whether these changes indicate that acetaminophen is a carcinogenic hazard. At therapeutic recommended doses, acetaminophen forms limited amounts of N-acetyl-p-benzoquinone-imine (NAPQI) without adverse cellular effects. Following overdoses of acetaminophen, there is potential for more extensive formation of NAPQI and depletion of glutathione, which may result in mitochondrial dysfunction and DNA damage, but only at doses that result in cell death - thus making it implausible for acetaminophen to induce the kind of stable, genetic damage in the nucleus indicative of a genotoxic or carcinogenic hazard in humans. The collective data demonstrate a lack of a plausible mechanism related to carcinogenicity and are consistent with rodent cancer bioassays, epidemiological results reviewed in companion manuscripts in this issue, as well as conclusions of multiple international health authorities.

Two young cynomolgus macaques (Macaca fascicularis) given a small molecule kinase inhibitor ((S)-4-((2-(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-N-(2-hydroxypropyl)nicotinamide [SCIO-120]) via nasogastric intubation gavage, once-daily for 21 days at 400 mg/kg/day, developed an unusual epithelial proliferative process in the renal parenchyma. Morphological and immunohistochemical characterization of the lesions confirmed an invasive malignant epithelial neoplasm (carcinoma). A similar renal neoplasm was seen in a third macaque after a 14-day exposure to a second kinase inhibitor in the same chemical series ((S) 4-((2-(5-chloro-2-fluorophenyl)-5-methoxypyrimidin-4-yl)amino)-N-cyclopropylnicotinamide [SCIO-974]). Despite remarkably short latency periods, exposure to these kinase inhibitors was likely causally associated with the induction of the renal tumors, as renal carcinomas are exceedingly rare spontaneously in macaques. Both SCIO-120 and SCIO-974 were designed as potent TGF beta R1 inhibitors (IC(50)s 37 and 39nM, respectively). SCIO-120 and SCIO-974 inhibited additional kinases, most notably closely related ALK4 (IC50 = 34 and 20 nM, respectively), c-Jun n-Terminal kinase 3 (JNK3, IC50 = 10 and 20 nM, respectively), and Fms-related tyrosine kinase 1 (29 and 76 nM, respectively). TGF beta R1 has been specifically implicated in epithelial proliferative disorders, including neoplasia. Neither SCIO-120 nor SCIO-974 was genotoxic based on bacterial reverse mutation and/or clastogenicity screening assays. The rapid appearance of renal carcinomas in primates following short-term treatment with nongenotoxic kinase inhibitors is remarkable and suggests that the compounds had noteworthy tumor-enhancing effects, hypothetically linked to their TGF beta R1 inhibition activity. These observations have implications for mechanisms of carcinogenesis and TGF beta R1 biology.

In 2016 one person died and others had neurological sequelae during a clinical trial with BIA 10-2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-lH-imidazol-4-yl)pyridine 1-oxide), a novel fatty acid amide hydrolase (FAAH) inhibitor being developed for the treatment of medical conditions such as pain. Prior to the clinical trial a full battery of regulatory toxicology tests were carried out and this paper describes the genotoxicity/mutagenicity tests undertaken with BIA 10-2474 using the Ames (Salmonella typhimurium) reverse mutation test, the Escherichia coli WP2uvrA forward mutation test, an in vitro chromosome damage assay in human lymphocytes, and an in vivo micronucleus test in mice. All tests were conducted with and without a rat liver S9 metabolic activation system. None of the test results were judged to be positive with regards to the mutagenicity/genotoxicity of BIA 10-2474 making it unlikely that any such effect was involved in the toxicity observed in the clinic.

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard.

BIA 10-2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide) is a novel fatty acid amide hydrolase (FAAH) inhibitor developed by BIAL for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10-2474 and others displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial we report here the nonclinical toxicology studies performed in cynomolgus monkeys. Maximum Tolerated Dose (MTD) studies and a preliminary 14-day study by oral (capsule) administration of BIA 10-2474 established a dose between 90 and 120 mg/kg/day as a suitable high dose for a subsequent regulatory toxicity studies. An up-titration scheme was used to achieve these doses. The dose-limiting effect was the early sacrifice for ethical reasons of monkeys at doses from 125 mg/kg/day upwards. Thereafter, regulatory 4- and 13-week oral gavage toxicity studies followed by a 2- or a 4-week recovery period, respectively, were performed. In both cases a 3-4-week up-titration period was used prior to repeat dosing with the target doses. One female was euthanized during the up-titration period after receiving 9 administrations of 75 mg/kg as a result of bleeding erosion on the feet and hands and ulceration on the tongue. These signs were not seen in any other monkeys during these studies. Doses of 10, 50 or 100 mg/kg/day were administered during the 4-week study and clinical signs related to the pharmacological action of BIA 10-2474 (e.g., tremors and weakness, incoordination and loss of balance, reduction in food intake and reduced body weight) were observed in several monkeys from the intermediate and high dose. Histological alterations consisted of axonal dystrophy in the fasciculus cuneatus (dorsal medulla oblongata) characterized by swollen axons and myelin sheath edema, edema in the pars nervosa of the pituitary gland and vacuolation of Meissner's plexus ganglia in all gastrointestinal segments. All lesions recovered and a dose of 100 mg/kg/day was considered to be the NOAEL. In the 13-week oral study the monkeys received BIA 10-2474 daily by gavage at a dose of 6.25, 37.5 or 75 mg/kg/day. Similar clinical signs and histological alterations as noted in monkeys of the 28-day study were observed in monkeys at 37.5 or 75 mg/kg/day. All findings recovered, and the dose of 75 mg/kg/day was considered the NOAEL.

Thymomas from 277 Fischer 344/N (F344/N), 10 Sprague Dawley (HSD:Sprague Dawley SD) (SD), 129 Wistar Han [Crl:WI(Han)] (WH), and 4 Wistar Outbred (WO) rats were reviewed from long-term studies in the National Toxicology Program (NTP) database. The incidence of thymomas in F344/N rats was slightly higher in males than in females, while the incidences in SD and WH rats were higher in females than in males. Only male WO rats were used in NTP studies. Of the 277 thymomas in F344/N rats, 235 (84.8%) were benign and 42 (15.2%) malignant, 14 of which exhibited metastasis. Of the 10 thymomas in SD rats, 5 (50%) were benign and 5 (50%) were malignant, one of which exhibited metastasis. Of the 129 thymomas in WH rats, 126 (98%) were benign and 3 (2%) were malignant, 1 with metastasis. Of the 4 thymomas in WO rats, 3 (75%) were benign and 1 (25%) was malignant, with no metastases. Malignant thymomas in F344/N and WH rats showed a propensity to be the cause of death and to result in early mortality, whereas the benign thymomas were associated less often with decreased survival. No occurrences of this neoplasm were reported to be related to exposure to any test articles.

BIA 10-2474 is a novel fatty acid amide hydrolase (FAAH) inhibitor developed for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10-2474 and four other subjects displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial, we report here the preclinical toxicology studies examining once-a-day oral administration of BIA 10-2474 to male and female Wistar rats. These included a 14-day dose range finding (150, 200 and 250 mg/kg/day), a 4-week study (30, 90 and 150 mg/kg/day) and 13- and 26-week studies (both at 10, 30 and 90 mg/kg/day). The 13- and 26-week studies also included a 4-week recovery arm and a toxicokinetic arm for the parent compound, BIA 10-2474, and the two major metabolites (BIA 10-2445 and BIA 10-2583) were also measured in the 26-week study. At 150 mg/kg and below, all animals survived the scheduled treatment periods although neurological side-effects (abnormal or stiff gait, dragging of fore- or hind-limbs) were seen at 150 mg/kg in both the dose-range finding and 4-week studies. At 90 mg/kg/day, even up to 26-weeks treatment, no clinical signs were seen apart from some decreases in body weight gain. A number of consistent hematological and biochemical changes were noted which were considered related to treatment with BIA 10-2474. Morphologically, in the 4-week study, except for a slight gliosis in the hippocampus of one female at 150 mg/kg, no CNS histopathology was observed; hippocampus gliosis was not observed in subsequent studies. In the 13-week study axonal swelling was present in the medulla oblongata in about half the animals at 90 mg/kg/day and this increased to nearly all the rats at 90 mg/kg/day in the 26-week study. Additional signs seen only in the 26-week study at 90 mg/kg/day included axonal swelling of the fasiculus gracilis and vacuolar changes in the medulla oblongata and ventral commissure of the 3rd ventricle. Other findings included vacuolar degeneration in the ganglia of the GI tract, salivary glands, prostate gland, uterus, and parathyroid glands. The pituitary gland showed edema and mitotic figures in the pars nervosa. These observations outside the CNS were seen in most rats at 90 and 150 mg/kg/day independent of study duration. At 30 mg/kg/day, most of these observations were only seen in isolated cases except for the vacuolar degeneration in GI tract ganglia, which was absent at this dose after 4 weeks treatment but was present in almost all rats at 13 and 26 weeks. Hepatocellular hypertrophy and nephropathy were seen across all studies and the extent of these changes was similar in the 13- and 26-week studies. Most findings resolved after the 4-week recovery periods except for the axonal swelling seen in the medulla oblongata and spinal cord. BIA 10-2474 exposure was markedly higher than the exposure to either metabolite, BIA 10-2445 (19- to 192-fold) and BIA 10-2583 (63- to 526-fold). Exposure to metabolites differed between sexes with higher concentrations of BIA 10-2445 in females compared to males, but the inverse for BIA 10-2583. Although a No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day was concluded following the 4-week study, the histopathological findings at that dose in the 13- and 26-week studies resulted in the NOAEL being determined to be 10 mg/kg/day.

We independently and retrospectively reviewed three studies that evaluated the toxicity of BIA 10-2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-lH-imidazol-4-yl)pyridine 1-oxide), a novel fatty acid amide hydrolase (FAAH) inhibitor in male and female CD-1 mice based upon raw data obtained from Bial Portela & Companhia S.A. (São Mamede do Coronado, Portugal). These studies were carried out prior to the clinical trial with BIA 10-2474 and formed part of the regulatory submission. An initial oral dose range-finding study with BIA 10-2474 showed that doses from 600 mg/kg/day were poorly tolerated with a high mortality rate and signs of weakness, prostration, labored breathing, clear lacrimation, tachypnea/bradypnea and decreased activity. At lower doses (100 and 300 mg/kg/day) there were few signs but post-mortem analysis showed increased liver weight. In a 28-day study a third of the animals receiving 500 mg/kg/day died or required euthanasia, with similar signs to those seen in the dose-range finding study. At lower doses (i.e. 100 and 300 mg/kg/day) there were few clinical signs although there were dose-related decreases in erythrocyte count and hemoglobin. Histopathology was seen in the 300 and 500 mg/kg/day groups and included hepatocellular hypertrophy (with increased liver weight), nephropathy and enterocyte vacuolation. Finally, in the 13-week oral gavage study, BIA 10-2474 was administered to CD-1 mice of both sexes at dose levels of 25, 75 and 150 mg/kg/day. Under these conditions, there were almost no clinical signs apart from a tendency to increase body-weight. Cholesterol was increased at 75 and 150 mg/kg and remained high after recovery. Liver and spleen weights increased at 75 and 150 mg/kg/day. Histopathologically, there was a dose-dependent increase in sciatic nerve and myofiber degeneration, hepatocellular hypertrophy, nephropathy and inflammatory loci in the bladder. The nerve damage and nephropathy seen at 150 mg/kg/day persisted after a 4-week recovery period. Toxicokinetic analysis in the 4- and 13-week studies showed that exposure was broadly dose-proportional with no evidence of accumulation. On the basis of the changes seen during the 13-week study, the NOAEL was established at 75 mg/kg/day.

A series of regulatory studies were carried out to investigate the effects of the FAAH inhibitor BIA 10-2474 on fertility, embryo-fetal toxicity and pre- and post-natal development in rats and rabbits. Despite some reductions in sperm count in rats from 50 mg/kg, there were no major changes in male fertility up to 100 mg/kg. In female rats administered up to GD6, there were increases in pre-implantation loss at 50 and 100 mg/kg but neither post-implantation loss nor early embryonic development was affected. In contrast, when administered to female rats during pregnancy (GD6-GD17), BIA 10-2474 at 75 mg/kg/day reduced food consumption resulting in weight loss, increased post-implantation loss and reduced mean fetal body weight. In rabbits, the same maternal toxicity was seen but there were no effects in this species on post-implantation loss or fetal body weights. There were no teratological effects clearly due to BIA 10-2474 and developmental milestones and behavior of offspring were not affected. When administered during pregnancy and lactation (GD6-PND20), some post-implantation loss was seen from 20 mg/kg/day, but developmental milestones and behavior of the offspring were not affected, although males tended to have lower body weight. Based on these data the NOAEL for parental fertility was established as 50 mg/kg/day, the maternal NOAEL during pregnancy was 25 mg/kg/day in rats and developmental NOAEL was 25 and 75 mg/kg/day in rats and rabbits, respectively. When administered during post-natal development to rats the maternal NOAEL was 6 mg/kg/day. The parental reproductive NOAEL, the NOAEL for viability and growth of the F1 offspring, the F1 parental NOAEL and the F1 reproductive NOAEL were all considered to be 20 mg/kg/day.

BIA 10-2474 is a novel fatty acid amide hydrolase inhibitor developed for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10-2474 and others displayed neurological signs. We describe here the toxicology studies in beagle dogs that supported phase I testing of BIA 10-2474 in humans. A Maximum Tolerated Dose (MTD) study using once-a-day oral (capsule) application of BIA 10-2474 was first conducted to establish suitable dose levels for subsequent studies. Based on these results, 100 mg/kg/day was considered to be the MTD. The 4-week oral (capsule) toxicity study with a 3-week recovery period for BIA 10-2474 was therefore carried out at 20, 50 or 100 mg/kg/day. There were no changes recorded at 50 mg/kg/day and this was considered the oral No Observed Effect Level (NOEL) for four-week once-a-day capsule administration to Beagle dogs. At 100 mg/kg/day, the dose-limiting findings consisted of clinical symptoms including tremor, loss of balance, abnormal gait, decreased motor activity, weakness, vomits, salivation increase and miosis, increased severity of thymic atrophy/involution, and moderate acute, focal/multifocal bronchopneumonia in lungs of three animals. In a 13-week oral (capsule) toxicity study in the Beagle dog with a 6-week recovery period, using the same dose levels, clinical signs were recorded during treatment with BIA 10-274 at 50 and 100 mg/kg/day. The most frequent signs included difficulty breathing, respiratory sounds (with or without auscultation) and cough. Incoordination of the hind limbs with absence of correction reflex were also observed on some occasions. As a result, the 50 and 100 mg/kg/day doses were reduced to 35 and 50 mg/kg/day respectively on day 37. Because of the continued signs, the doses in both groups were further reduced to 20 mg/kg/day from day 77. Under the conditions of this study and given the severe signs recorded in groups treated at 100-50-20 and 50-35-20 mg/kg/day and only very occasional presence of signs in the group treated for the 13-week period at 20 mg/kg/day (abnormal respiratory sounds once in two animals), the dose of 20 mg/kg/day was considered the No Observed Adverse Effect Level (NOAEL).

In a subchronic (13-week) inhalation toxicity study with a terminal sacrifice (after 13 weeks inhalation) and several recovery period sacrifices (13, 26, 39, and 52 weeks), the effects of AEROSIL® 200 (pyrogenic synthetic amorphous silica (SAS)), AEROSIL® R 974 (surface-treated pyrogenic SAS), and SIPERNAT® 22 S (precipitated SAS) were tested in rats at multiple dose levels. The aforementioned materials are all SAS products. A comparative group of animals was exposed to quartz dust. This study attempts to reexamine the lung tissues originally evaluated in a study published by Reuzel et al. using the current standards. To reach a high level of credibility, the results of the reevaluation were subsequently examined by a pathology working group (PWG). In particular, the reevaluating pathologist and the PWG concluded that, even though quartz (crystalline silica) persisted, induced alterations in the lungs following 13 weeks of exposure to amorphous silicas were reversible following 52 weeks of recovery. A long-term adversity has not been established with SAS products. However, quartz dust damages lungs significantly by causing pulmonary fibrosis.

A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines. The PWG results indicate that permethrin induced a significant dose-dependent increase in the incidence of hepatocellular neoplasms in treated female mice (p < .01) as well as a nonstatistically significant increase in the incidence of hepatocellular tumors in treated male mice. Given the continuum of the diagnoses of adenoma and carcinoma, and the difficulty in distinguishing some of the lesions, it is appropriate to consider only the combined incidences of hepatocellular tumors (adenoma and/or carcinoma) for biological significance and risk assessment.

To test the diagnostic approach described in part 1 of this article, 2 exercises were completed by pathologists from multiple companies/agencies. Pathologist's examination of whole slide image (WSI) heart sections from rats using personal diagnostic approaches (exercise #1) corroborated conclusions from study #1. Using the diagnostic approach described in part 1, these pathologists examined the same WSI heart sections (exercise #2) to determine whether that approach increased consistency of diagnosis of rodent progressive cardiomyopathy (PCM) lesions. In exercise #2, there was improved consistency of categorization of small borderline morphologies and mild lesions, but a decrement in consistency of categorizing minimal lesions. Exercises 1 and 2 suggest the described diagnostic approach is representative of that in use by the majority of toxicologic pathologists across companies/agencies and that application by all may improve diagnostic consistency of PCM/like lesions. Additionally, a criterion of approximately 5% heart section involvement is suggested for separating mild from moderate or greater severity. While evidence is not absolute, until further investigation shows otherwise, microscopic changes resembling PCM, but located in the epicardial and subepicardial region of the right ventricle, may be considered as part of the spectrum of PCM.

Regulatory authorities worldwide have found the nonnutritive sweetener, sucralose, to be noncarcinogenic, based on a range of studies. A review of these and other studies found through a comprehensive search of electronic databases, using appropriate key terms, was conducted and results of that review are reported here. An overview of the types of studies relied upon by regulatory agencies to assess carcinogenicity potential is also provided as context. Physiochemical and pharmacokinetic/toxicokinetic studies confirm stability under conditions of use and reveal no metabolites of carcinogenic potential. In vitro and in vivo assays reveal no confirmed genotoxic activity. Long-term carcinogenicity studies in animal models provide no evidence of carcinogenic potential for sucralose. In studies in healthy adults, sucralose was well-tolerated and without evidence of toxicity or other changes that might suggest a potential for carcinogenic effects. In summary, sucralose does not demonstrate carcinogenic activity even when exposure levels are several orders of magnitude greater than the range of anticipated daily ingestion levels.

This article describes the results of comparisons of digitally scanned whole slide images (WSIs) and glass microscope slides for diagnosis of tissues under peer review by the National Toxicology Program. Findings in this article were developed as a result of the data collected from 6 pathology working groups (PWGs), 1 pathology peer review, and survey comments from over 25 participating pathologists. For each PWG, 6–14 pathologists examined 10–143 tissues per study from 6- and 9-month perinatal studies and 2-year carcinogenicity studies. Overall it was found that evaluation of WSIs is generally equivalent to using glass slides. Concordance of PWG consensus diagnoses based upon review of WSIs versus glass slides ranged from 74% to 100% (median 86%). The intra- and interobserver diagnostic variation did not appear to influence the conclusions of any study. Based upon user opinions collected from surveys, WSIs may be less optimal than glass slides for evaluation of subtle lesions, large complex lesions, small lesions in a large section of tissue, and foci of altered hepatocytes. These results indicate that, although there may be some limitations, the use of WSIs can effectively accomplish the objectives of a conventional glass slide review and definitely serves as a useful adjunct to the conduct of PWGs.

Chapter 109 Human Relevance of Rodent Leydig Cell Tumors Thomas J. Steinbach, Thomas J. SteinbachSearch for more papers by this authorRobert. R. Maronpot, Robert. R. MaronpotSearch for more papers by this authorJerry F. Hardisty, Jerry F. HardistySearch for more papers by this author Thomas J. Steinbach, Thomas J. SteinbachSearch for more papers by this authorRobert. R. Maronpot, Robert. R. MaronpotSearch for more papers by this authorJerry F. Hardisty, Jerry F. HardistySearch for more papers by this author Book Editor(s):Raymond D. Harbison, Raymond D. HarbisonSearch for more papers by this authorMarie M. Bourgeois, Marie M. BourgeoisSearch for more papers by this authorGiffe T. Johnson, Giffe T. JohnsonSearch for more papers by this author First published: 20 March 2015 https://doi.org/10.1002/9781118834015.ch109Citations: 2 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onFacebookTwitterLinked InRedditWechat Summary This chapter reviews the human relevance of Leydig cell tumors (LCTs), which have been induced in rodents by a number of compounds. It considers the similarities and differences between humans and rats in the physiology of the LC and the pathology of LCTs. Most importantly, the chapter examines the mechanisms of action that induce LCTs in rats and humans and presents data on incidence, physiology, human endocrine disease, and comparative epidemiological studies that strongly indicate LCTs in rodents, in particular the rat, are of little relevance to human health. The adult LC forms mostly during puberty and produces the testosterone responsible for spermatogenesis, along with differentiation of other secondary sex characteristics. The primary signaling method for steroidogenesis is initiated when luteinizing hormone (LH) binds to a G protein-coupled receptor. Testicular tumors are more common in individuals with androgen insensitivity syndrome. Citing Literature Hamilton & Hardy's Industrial Toxicology RelatedInformation