Pub Date : 2022-06-13DOI: 10.1177/01926233221101314
D. Bangari, L. Lanigan, F. Goulet, S. Sisó, B. Bolon
The increasing specificity of novel druggable targets coupled with the complexity of emerging therapeutic modalities for treating human diseases has created a growing need for nonhuman primates (NHPs) as models for translational drug discovery and nonclinical safety assessment. In particular, NHPs are critical for investigating potential unexpected/undesired on-target and off-target liabilities associated with administration of candidate biotherapeutics (nucleic acids, proteins, viral gene therapy vectors, etc.) to treat nervous system disorders. Nervous system findings unique to or overrepresented in NHPs administered biomolecule-based (“biologic”) test articles include mononuclear cell infiltration in most neural tissues for all biomolecule classes as well as neuronal necrosis with glial cell proliferation in sensory ganglia for certain viral vectors. Such test article-related findings in NHPs often must be differentiated from procedural effects (e.g., local parenchymal or meningeal reactions associated with an injection site or implanted catheter to administer a test article directly into the central nervous system) or spontaneous background findings (e.g., neuronal autophagy in sensory ganglia).
{"title":"Society of Toxicologic Pathology Neuropathology Interest Group Article: Neuropathologic Findings in Nonhuman Primates Associated With Administration of Biomolecule-Based Test Articles","authors":"D. Bangari, L. Lanigan, F. Goulet, S. Sisó, B. Bolon","doi":"10.1177/01926233221101314","DOIUrl":"https://doi.org/10.1177/01926233221101314","url":null,"abstract":"The increasing specificity of novel druggable targets coupled with the complexity of emerging therapeutic modalities for treating human diseases has created a growing need for nonhuman primates (NHPs) as models for translational drug discovery and nonclinical safety assessment. In particular, NHPs are critical for investigating potential unexpected/undesired on-target and off-target liabilities associated with administration of candidate biotherapeutics (nucleic acids, proteins, viral gene therapy vectors, etc.) to treat nervous system disorders. Nervous system findings unique to or overrepresented in NHPs administered biomolecule-based (“biologic”) test articles include mononuclear cell infiltration in most neural tissues for all biomolecule classes as well as neuronal necrosis with glial cell proliferation in sensory ganglia for certain viral vectors. Such test article-related findings in NHPs often must be differentiated from procedural effects (e.g., local parenchymal or meningeal reactions associated with an injection site or implanted catheter to administer a test article directly into the central nervous system) or spontaneous background findings (e.g., neuronal autophagy in sensory ganglia).","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"94 1","pages":"693 - 711"},"PeriodicalIF":1.5,"publicationDate":"2022-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78704210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-01DOI: 10.1177/01926233221099273
T. Forest, F. Aeffner, D. Bangari, B. Bawa, Jonathan Carter, J. Fikes, Wanda High, S. Hayashi, M. Jacobsen, LuAnn Mckinney, D. Rudmann, T. Steinbach, V. Schumacher, Oliver C. Turner, J. Ward, C. Willson
The Society of Toxicologic Pathology’s Scientific and Regulatory Policy Committee formed a working group to consider the present and future use of digital pathology in toxicologic pathology in general and specifically its use in primary evaluation and peer review in Good Laboratory Practice (GLP) environments. Digital histopathology systems can save costs by reducing travel, enhancing organizational flexibility, decreasing slide handling, improving collaboration, increasing access to historical images, and improving quality and efficiency through integration with laboratory information management systems. However, the resources to implement and operate a digital pathology system can be significant. Given the magnitude and risks involved in the decision to adopt digital histopathology, this working group used pertinent previously published survey results and its members’ expertise to create a Points-to-Consider article to assist organizations with building and implementing digital pathology workflows. With the aim of providing a comprehensive perspective, the current publication summarizes aspects of digital whole-slide imaging relevant to nonclinical histopathology evaluations, and then presents points to consider applicable to both primary digital histopathology evaluation and digital peer review in GLP toxicology studies. The Supplemental Appendices provide additional tabulated resources.
{"title":"Scientific and Regulatory Policy Committee Points to Consider: Primary Digital Histopathology Evaluation and Peer Review for Good Laboratory Practice (GLP) Nonclinical Toxicology Studies","authors":"T. Forest, F. Aeffner, D. Bangari, B. Bawa, Jonathan Carter, J. Fikes, Wanda High, S. Hayashi, M. Jacobsen, LuAnn Mckinney, D. Rudmann, T. Steinbach, V. Schumacher, Oliver C. Turner, J. Ward, C. Willson","doi":"10.1177/01926233221099273","DOIUrl":"https://doi.org/10.1177/01926233221099273","url":null,"abstract":"The Society of Toxicologic Pathology’s Scientific and Regulatory Policy Committee formed a working group to consider the present and future use of digital pathology in toxicologic pathology in general and specifically its use in primary evaluation and peer review in Good Laboratory Practice (GLP) environments. Digital histopathology systems can save costs by reducing travel, enhancing organizational flexibility, decreasing slide handling, improving collaboration, increasing access to historical images, and improving quality and efficiency through integration with laboratory information management systems. However, the resources to implement and operate a digital pathology system can be significant. Given the magnitude and risks involved in the decision to adopt digital histopathology, this working group used pertinent previously published survey results and its members’ expertise to create a Points-to-Consider article to assist organizations with building and implementing digital pathology workflows. With the aim of providing a comprehensive perspective, the current publication summarizes aspects of digital whole-slide imaging relevant to nonclinical histopathology evaluations, and then presents points to consider applicable to both primary digital histopathology evaluation and digital peer review in GLP toxicology studies. The Supplemental Appendices provide additional tabulated resources.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"52 1","pages":"531 - 543"},"PeriodicalIF":1.5,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81771882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-24DOI: 10.1177/01926233221095443
G. Weinbauer, L. Mecklenburg
Long-tailed macaques are the predominant nonhuman primate species for the nonclinical safety testing of biopharmaceuticals. This species comprises 9 subspecies with Macaca fascicularis fascicularis naturally occurring in Southeast Asia. Since the 17th century, M. f. fascicularis also occurs on Mauritius. Cynomolgus macaques do not naturally occur in China, but are bred in many farms across the country. The current shortage in animal supply raises the question whether geographical animal origin matters and if animals from different geographical regions can be combined on a drug development program or even a single experiment. This article reviews geographical animal origin in relation to selected endpoints that are relevant in nonclinical drug safety testing. Animals from different countries within Asia mainland do not appear to show any meaningful difference. Very little data are available for animals from Asia island. Mauritian animals show consistent differences from Asian animals in several clinical and anatomical pathology parameters. For developmental parameters, animals from Mauritius and Asia are comparable with the exception that Mauritian animals mature faster. In the authors’ view, differences between the geographical clusters can be accounted for as long as baseline and reference data are available.
{"title":"Does Geographical Origin of Long-Tailed Macaques (Macaca fascicularis) Matter in Drug Safety Assessment?: A Literature Review and Proposed Conclusion","authors":"G. Weinbauer, L. Mecklenburg","doi":"10.1177/01926233221095443","DOIUrl":"https://doi.org/10.1177/01926233221095443","url":null,"abstract":"Long-tailed macaques are the predominant nonhuman primate species for the nonclinical safety testing of biopharmaceuticals. This species comprises 9 subspecies with Macaca fascicularis fascicularis naturally occurring in Southeast Asia. Since the 17th century, M. f. fascicularis also occurs on Mauritius. Cynomolgus macaques do not naturally occur in China, but are bred in many farms across the country. The current shortage in animal supply raises the question whether geographical animal origin matters and if animals from different geographical regions can be combined on a drug development program or even a single experiment. This article reviews geographical animal origin in relation to selected endpoints that are relevant in nonclinical drug safety testing. Animals from different countries within Asia mainland do not appear to show any meaningful difference. Very little data are available for animals from Asia island. Mauritian animals show consistent differences from Asian animals in several clinical and anatomical pathology parameters. For developmental parameters, animals from Mauritius and Asia are comparable with the exception that Mauritian animals mature faster. In the authors’ view, differences between the geographical clusters can be accounted for as long as baseline and reference data are available.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"93 1","pages":"552 - 559"},"PeriodicalIF":1.5,"publicationDate":"2022-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90371410","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-24DOI: 10.1177/01926233221097970
Kevin Agostinucci, T. Manfredi, A. Cosmas, F. J. Vetter, S. Engle
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones located in atria granules. Both peptides respond to cardiac pressure and volume dynamics and accordingly serve as translation biomarkers for the clinical treatment of heart failure. Serum ANP and BNP play central secretary roles in blood pressure and cardiac output regulation and have proven utility as differential biomarkers of cardiovascular proficiency and drug-induced maladaptation, yet both peptides are impervious to exercise-induced hypertrophy. We employed immunoelectron microscopy to examine the effects of 28 days of chronic swim exercise or administration of a PPARγ agonist on atrial granules and their stored natriuretic peptides in Sprague Dawley rats. Chronic swimming and drug treatment both resulted in a 15% increase in heart weight compared with controls, with no treatment effects on perinuclear granule area in the left atria (LAs). Drug treatment resulted in larger size granules with greater BNP density in the right atria. Comparing swimming and PPARγ agonist treatment effects on ANP:BNP granule density ratios between atrial chambers revealed a shift toward a greater proportion of ANP than BNP in LAs of swim-trained rats. These data suggest a distinction in the population of ANP and BNP after chronic swim or PPARγ that makes it a novel metric for the differentiation of pathological and physiological hypertrophy.
{"title":"Comparison of ANP and BNP Granular Density in Atria of Rats After Physiological and Pathological Hypertrophy","authors":"Kevin Agostinucci, T. Manfredi, A. Cosmas, F. J. Vetter, S. Engle","doi":"10.1177/01926233221097970","DOIUrl":"https://doi.org/10.1177/01926233221097970","url":null,"abstract":"Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones located in atria granules. Both peptides respond to cardiac pressure and volume dynamics and accordingly serve as translation biomarkers for the clinical treatment of heart failure. Serum ANP and BNP play central secretary roles in blood pressure and cardiac output regulation and have proven utility as differential biomarkers of cardiovascular proficiency and drug-induced maladaptation, yet both peptides are impervious to exercise-induced hypertrophy. We employed immunoelectron microscopy to examine the effects of 28 days of chronic swim exercise or administration of a PPARγ agonist on atrial granules and their stored natriuretic peptides in Sprague Dawley rats. Chronic swimming and drug treatment both resulted in a 15% increase in heart weight compared with controls, with no treatment effects on perinuclear granule area in the left atria (LAs). Drug treatment resulted in larger size granules with greater BNP density in the right atria. Comparing swimming and PPARγ agonist treatment effects on ANP:BNP granule density ratios between atrial chambers revealed a shift toward a greater proportion of ANP than BNP in LAs of swim-trained rats. These data suggest a distinction in the population of ANP and BNP after chronic swim or PPARγ that makes it a novel metric for the differentiation of pathological and physiological hypertrophy.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"10 1","pages":"497 - 506"},"PeriodicalIF":1.5,"publicationDate":"2022-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85293561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-24DOI: 10.1177/01926233221100414
Kendall S. Frazier
Drug-induced kidney injury has historically been associated with renal tubule injury related to small molecule pharmaceuticals such as nonsteroidal anti-inflammatory drugs, antineoplastic agents, or antibiotics, but as a greater number of alternative classes of medicines such as biotherapeutics, molecular-targeted antineoplastic drugs, chimeric antigen receptor T-cell therapies, antibody-drug conjugates, oligonucleotide therapies, or other immunomodulatory drugs come to market, the presentation of drug-induced nephrotoxicity is changing. This review article describes the potential rare clinical events in drug-induced kidney injury that might be noted with these new therapies and their potential impact on patients. Potential pathogenic mechanisms related to immunogenicity, immune complex formation, and stimulation of downstream proinflammatory pathways with some of these alternative medicine classes have resulted in the potential for glomerulonephritis, acute interstitial nephritis, renal vasculitis, and other immune-mediated renal disorders in humans. This contrasts with nonclinical toxicity studies, where biologic therapies more often result in vasculitis and glomerulonephritis associated with antidrug antibodies and immunomodulatory pharmacology, and which are not always predictive of clinical effects. While nonclinical antidrug antibody-related renal disease is generally not clinically relevant, other immune-mediated nephrotoxicities associated with immunomodulatory drugs may be predictive of clinical adverse events. Fortunately, these conditions are still rare and account for a small percentage of serious adverse events in kidneys of patients.
{"title":"Kidney Effects by Alternative Classes of Medicines in Patients and Relationship to Effects in Nonclinical Toxicity Studies","authors":"Kendall S. Frazier","doi":"10.1177/01926233221100414","DOIUrl":"https://doi.org/10.1177/01926233221100414","url":null,"abstract":"Drug-induced kidney injury has historically been associated with renal tubule injury related to small molecule pharmaceuticals such as nonsteroidal anti-inflammatory drugs, antineoplastic agents, or antibiotics, but as a greater number of alternative classes of medicines such as biotherapeutics, molecular-targeted antineoplastic drugs, chimeric antigen receptor T-cell therapies, antibody-drug conjugates, oligonucleotide therapies, or other immunomodulatory drugs come to market, the presentation of drug-induced nephrotoxicity is changing. This review article describes the potential rare clinical events in drug-induced kidney injury that might be noted with these new therapies and their potential impact on patients. Potential pathogenic mechanisms related to immunogenicity, immune complex formation, and stimulation of downstream proinflammatory pathways with some of these alternative medicine classes have resulted in the potential for glomerulonephritis, acute interstitial nephritis, renal vasculitis, and other immune-mediated renal disorders in humans. This contrasts with nonclinical toxicity studies, where biologic therapies more often result in vasculitis and glomerulonephritis associated with antidrug antibodies and immunomodulatory pharmacology, and which are not always predictive of clinical effects. While nonclinical antidrug antibody-related renal disease is generally not clinically relevant, other immune-mediated nephrotoxicities associated with immunomodulatory drugs may be predictive of clinical adverse events. Fortunately, these conditions are still rare and account for a small percentage of serious adverse events in kidneys of patients.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"7 1","pages":"408 - 414"},"PeriodicalIF":1.5,"publicationDate":"2022-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83337754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-10DOI: 10.1177/01926233221096424
R. Chamanza, S. Naylor, M. Gregori, M. Boyle, Marcia E Pereira Bacares, E. Drevon-Gaillot, Annette Romeike, Cynthia Courtney, Kelsey Johnson, Julie Turner, Nadine Swierzawski, Alok K. Sharma
To investigate the influence of geographical origin, age, and sex on toxicologically relevant spontaneous histopathology findings in cynomolgus macaques (Macaca fascicularis), 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. Developmental and degenerative findings were more common in Mauritian macaques, while lymphoid hyperplasia and lung pigment showed higher incidences in Asian macaques. Various sex and age-related differences were also present. Despite origin-related differences, the similarities in the nature and distribution of background lesions indicate that macaques from all geographical regions are suitable for toxicity testing and show comparable lesion spectrum. However, in a toxicity study, it is strongly recommended to use animals from a single geographical origin and to follow published guidelines when using HCD to evaluate and interpretate commonly diagnosed spontaneous lesions.
{"title":"The Influence of Geographical Origin, Age, Sex, and Animal Husbandry on the Spontaneous Histopathology of Laboratory Cynomolgus Macaques (Macaca Fascicularis): A Contemporary Global and Multisite Review of Historical Control Data","authors":"R. Chamanza, S. Naylor, M. Gregori, M. Boyle, Marcia E Pereira Bacares, E. Drevon-Gaillot, Annette Romeike, Cynthia Courtney, Kelsey Johnson, Julie Turner, Nadine Swierzawski, Alok K. Sharma","doi":"10.1177/01926233221096424","DOIUrl":"https://doi.org/10.1177/01926233221096424","url":null,"abstract":"To investigate the influence of geographical origin, age, and sex on toxicologically relevant spontaneous histopathology findings in cynomolgus macaques (Macaca fascicularis), 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. Developmental and degenerative findings were more common in Mauritian macaques, while lymphoid hyperplasia and lung pigment showed higher incidences in Asian macaques. Various sex and age-related differences were also present. Despite origin-related differences, the similarities in the nature and distribution of background lesions indicate that macaques from all geographical regions are suitable for toxicity testing and show comparable lesion spectrum. However, in a toxicity study, it is strongly recommended to use animals from a single geographical origin and to follow published guidelines when using HCD to evaluate and interpretate commonly diagnosed spontaneous lesions.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"94 1","pages":"607 - 627"},"PeriodicalIF":1.5,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81530294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-05DOI: 10.1177/01926233221095445
N. Shirai, S. Choudhary, C. Houle
Malignant neuroendocrine tumors were diagnosed in the stomach of two out of sixty female Sprague-Dawley rats treated for 89 weeks with a high dose of a novel, small molecule, cannabinoid-1 antagonist. The tumors were associated with parietal cell atrophy accompanied by foveolar hyperplasia of the glandular stomach mucosa. Parietal cell atrophy/foveolar hyperplasia was considered test article related at the high dose, given the higher incidence and severity relative to untreated controls, although the precise mechanism of the parietal cell atrophy was undetermined. Spontaneous gastric neuroendocrine tumors are very rare in rats, and the current cases were considered secondary to parietal cell atrophy causing reduced gastric acid secretion and subsequent overstimulation of gastrin release through a feedback loop.
{"title":"Gastric Neuroendocrine Tumors With Parietal Cell Atrophy in a Long-term Carcinogenicity Study in Rats","authors":"N. Shirai, S. Choudhary, C. Houle","doi":"10.1177/01926233221095445","DOIUrl":"https://doi.org/10.1177/01926233221095445","url":null,"abstract":"Malignant neuroendocrine tumors were diagnosed in the stomach of two out of sixty female Sprague-Dawley rats treated for 89 weeks with a high dose of a novel, small molecule, cannabinoid-1 antagonist. The tumors were associated with parietal cell atrophy accompanied by foveolar hyperplasia of the glandular stomach mucosa. Parietal cell atrophy/foveolar hyperplasia was considered test article related at the high dose, given the higher incidence and severity relative to untreated controls, although the precise mechanism of the parietal cell atrophy was undetermined. Spontaneous gastric neuroendocrine tumors are very rare in rats, and the current cases were considered secondary to parietal cell atrophy causing reduced gastric acid secretion and subsequent overstimulation of gastrin release through a feedback loop.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"1 1","pages":"507 - 511"},"PeriodicalIF":1.5,"publicationDate":"2022-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87696129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-28DOI: 10.1177/01926233221091763
B. Bolon, J. Everitt
Humans and nonhuman primates (NHPs) share numerous anatomical and physiological characteristics, thereby explaining the importance of NHPs as essential animal models for translational medicine and nonclinical toxicity testing. Researchers, toxicologic pathologists, toxicologists, and regulatory reviewers must be familiar with normal and abnormal NHP biological traits when designing, performing, and interpreting data sets from NHP studies. The current compilation presents a list of essential books, journal articles, and websites that provide context to safety assessment and research scientists working with NHP models. The resources used most frequently by the authors have been briefly annotated to permit readers to rapidly ascertain their applicability to particular research endeavors. The references are aimed primarily for toxicologic pathologists working with cynomolgus and rhesus macaques and common marmosets in efficacy and safety assessment studies.
{"title":"Selected Resources for Pathology Evaluation of Nonhuman Primates in Nonclinical Safety Assessment","authors":"B. Bolon, J. Everitt","doi":"10.1177/01926233221091763","DOIUrl":"https://doi.org/10.1177/01926233221091763","url":null,"abstract":"Humans and nonhuman primates (NHPs) share numerous anatomical and physiological characteristics, thereby explaining the importance of NHPs as essential animal models for translational medicine and nonclinical toxicity testing. Researchers, toxicologic pathologists, toxicologists, and regulatory reviewers must be familiar with normal and abnormal NHP biological traits when designing, performing, and interpreting data sets from NHP studies. The current compilation presents a list of essential books, journal articles, and websites that provide context to safety assessment and research scientists working with NHP models. The resources used most frequently by the authors have been briefly annotated to permit readers to rapidly ascertain their applicability to particular research endeavors. The references are aimed primarily for toxicologic pathologists working with cynomolgus and rhesus macaques and common marmosets in efficacy and safety assessment studies.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"83 1","pages":"725 - 732"},"PeriodicalIF":1.5,"publicationDate":"2022-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84025692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-25DOI: 10.1177/01926233221089843
Tara Arndt, Mandy J. Meindel, Joseph Clarke, Amanda Shaw, M. Gregori
Cynomolgus macaques (Macaca fascicularis) are commonly used in safety assessment and as translational models for drug development. Recent supply chain pressures, exportation bans, and increased demand for drug safety assessment studies exacerbated by the COVID-19 pandemic have prompted the investigation of utilizing macaques of different geographic origin in preclinical toxicity studies. This study compares routine hematology, coagulation, and clinical chemistry endpoints of 3 distinct subpopulations of mainland Asia origin (Cambodia, China, and Vietnam) with Mauritius origin macaques compiling results of 3,225 animals from 123 regulatory toxicology studies conducted at North American and European Union contract research organization facilities between 2016 and 2019. Results were generally similar amongst the subpopulations compared in this study. Few notable differences in hematology test results and several minor differences in serum biochemistry and coagulation test results were identified when 3 distinct subpopulations of mainland Asia origin macaques were compared with Mauritius origin macaques. Our findings support the use of different origin macaques in drug development programs; however, emphasizes the importance of maintaining consistency in geographic origin of animals within a study.
{"title":"Comparison of Routine Hematology, Coagulation, and Clinical Chemistry Parameters of Cynomolgus Macaques of Mauritius Origin With Cynomolgus Macaques of Cambodia, China, and Vietnam Origin","authors":"Tara Arndt, Mandy J. Meindel, Joseph Clarke, Amanda Shaw, M. Gregori","doi":"10.1177/01926233221089843","DOIUrl":"https://doi.org/10.1177/01926233221089843","url":null,"abstract":"Cynomolgus macaques (Macaca fascicularis) are commonly used in safety assessment and as translational models for drug development. Recent supply chain pressures, exportation bans, and increased demand for drug safety assessment studies exacerbated by the COVID-19 pandemic have prompted the investigation of utilizing macaques of different geographic origin in preclinical toxicity studies. This study compares routine hematology, coagulation, and clinical chemistry endpoints of 3 distinct subpopulations of mainland Asia origin (Cambodia, China, and Vietnam) with Mauritius origin macaques compiling results of 3,225 animals from 123 regulatory toxicology studies conducted at North American and European Union contract research organization facilities between 2016 and 2019. Results were generally similar amongst the subpopulations compared in this study. Few notable differences in hematology test results and several minor differences in serum biochemistry and coagulation test results were identified when 3 distinct subpopulations of mainland Asia origin macaques were compared with Mauritius origin macaques. Our findings support the use of different origin macaques in drug development programs; however, emphasizes the importance of maintaining consistency in geographic origin of animals within a study.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"40 1","pages":"591 - 606"},"PeriodicalIF":1.5,"publicationDate":"2022-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87337552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-06DOI: 10.1177/01926233221088283
Rachel Amato, J. F. Gardin, J. Tooze, J. Cline
Laboratory animal research is an important contributor to both human and animal medicine. Currently, there is extensive use of cynomolgus monkeys (Macaca fascicularis) in pathology and toxicology research. The purpose of this study was to define reference values for absolute and percentage organ weights in M fascicularis of different ages and sex. Organ weights were obtained from necropsies of 1022 cynomolgus monkeys at the Wake Forest School of Medicine from 1997 to 2018. Distributions of absolute and percentage weights for each organ were described; sex and age groups were compared using analysis of variance. Age effects on percentage of body weights for each organ were analyzed within each sex. Diet effects were also analyzed. This evaluation showed that male body weights and absolute organ weights were greater for all age groups; however, female organ to body weight percentages were greater for most organs. Percentage of organ weight to body weight declined for the adrenals, brain, lung, thyroid and thymus during maturation, whereas percentage weight of pancreas, prostate, testes, and uterus increased. Animals consuming a high-fat, Western-type diet had a lower body weight than animals consuming a carbohydrate-rich chow diet. This information will be useful for further toxicology and pathology studies concerning cynomolgus monkeys.
{"title":"Organ Weights in Relation to Age and Sex in Cynomolgus Monkeys (Macaca fascicularis)","authors":"Rachel Amato, J. F. Gardin, J. Tooze, J. Cline","doi":"10.1177/01926233221088283","DOIUrl":"https://doi.org/10.1177/01926233221088283","url":null,"abstract":"Laboratory animal research is an important contributor to both human and animal medicine. Currently, there is extensive use of cynomolgus monkeys (Macaca fascicularis) in pathology and toxicology research. The purpose of this study was to define reference values for absolute and percentage organ weights in M fascicularis of different ages and sex. Organ weights were obtained from necropsies of 1022 cynomolgus monkeys at the Wake Forest School of Medicine from 1997 to 2018. Distributions of absolute and percentage weights for each organ were described; sex and age groups were compared using analysis of variance. Age effects on percentage of body weights for each organ were analyzed within each sex. Diet effects were also analyzed. This evaluation showed that male body weights and absolute organ weights were greater for all age groups; however, female organ to body weight percentages were greater for most organs. Percentage of organ weight to body weight declined for the adrenals, brain, lung, thyroid and thymus during maturation, whereas percentage weight of pancreas, prostate, testes, and uterus increased. Animals consuming a high-fat, Western-type diet had a lower body weight than animals consuming a carbohydrate-rich chow diet. This information will be useful for further toxicology and pathology studies concerning cynomolgus monkeys.","PeriodicalId":23113,"journal":{"name":"Toxicologic Pathology","volume":"140 1","pages":"574 - 590"},"PeriodicalIF":1.5,"publicationDate":"2022-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77025843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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