RESUMO
In the constantly evolving field of toxicologic pathology, a pathologist's career is often characterized by multiple career transitions. However, these transitions can be challenging and/or overwhelming and may require a shift in focus, strategic approach, and acquisition of new skills and expertise. In order to provide a forum to discuss challenges associated with career transitions and skill set/competencies required to navigate career changes effectively and successfully, the Career Development and Outreach Committee of the Society of Toxicologic Pathology (STP) sponsored a career development workshop entitled "Transitions in a Pathologist's Career" in conjunction with the STP 36th annual symposium. The presentations at this workshop provided perspectives of managers from pharmaceutical companies and Contract Research Organizations as well as consultants. This article is designed to provide brief summaries of their talks in this well-received career development workshop.
Assuntos
Mobilidade Ocupacional , Patologia , Toxicologia , Humanos , Patologia Clínica/educação , Sociedades Científicas , Pesquisa Translacional BiomédicaRESUMO
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.
Assuntos
Cardiomiopatias/patologia , Diagnóstico por Imagem/métodos , Ventrículos do Coração/patologia , Ratos Sprague-Dawley , Doenças dos Roedores/patologia , Testes de Toxicidade/métodos , Animais , Cardiomiopatias/veterinária , Cardiotoxicidade/patologia , Cardiotoxicidade/veterinária , Simulação por Computador , Diagnóstico por Imagem/normas , Diagnóstico por Imagem/veterinária , Progressão da Doença , Masculino , Testes de Toxicidade/veterináriaRESUMO
Spontaneous rodent progressive cardiomyopathy (PCM) in the Sprague Dawley rat may confound identification and/or interpretation of potential test article (TA)-related cardiotoxicity. Pathologists apply diagnostic term(s) and thresholds for diagnosing and assigning severity grades for PCM and/or PCM-like (PCM/like) lesions consistently within a study, which is necessary to identify and interpret TA-related findings. Due to differences in training and/or experiences, diagnostic terms and thresholds may vary between pathologists. Harmonized terminology and thresholds across studies will generate better historical control data, will likely enhance interpretation of study data, and may further enhance our understanding of the spontaneous change. An assessment of the diagnostic approaches of a group of 37 pathologists identified an approach that is relatively easily applied; and if adopted, it could enhance diagnostic consistency across studies. This approach uses the single "slash" term "necrosis/inflammatory cell infiltrate (NICI)" as the diagnosis for the spectrum of lesions seen in younger rats, uses no threshold for diagnosis (e.g., diagnose all lesions clearly identifiable as PCM/like), and uses aggregate lesion size of approximately ≥45% of the field of view (FOV) using a 10×/22 eyepiece and the 40× objective or approximately ≥100% of the FOV using the 60× objective as the criterion separating minimal from mild severities.
Assuntos
Cardiomiopatias/patologia , Diagnóstico por Imagem/métodos , Ratos Sprague-Dawley , Doenças dos Roedores/patologia , Testes de Toxicidade/veterinária , Animais , Cardiomiopatias/veterinária , Cardiotoxicidade/patologia , Cardiotoxicidade/veterinária , Simulação por Computador , Diagnóstico por Imagem/normas , Diagnóstico por Imagem/veterinária , Progressão da Doença , Masculino , Necrose , Índice de Gravidade de DoençaRESUMO
The field of dermal toxicity continues to evolve in order to accurately predict dermal (and systemic) responses in humans to topically applied chemicals. Although the testing methods have undergone extensive refinements, idiosyncrasies and unexpected issues during the conduct of these studies are not unusual due to the plethora of new vehicles available for formulating test substances, changing regulatory requirements, and introducting new strain and/or species of laboratory animals as no single species or method seems to suffice for evaluating skin toxicity. The objective of this article is to illustrate some pragmatic issues that should be considered during the conduct as well as interpretation of dermal toxicity studies. Routine procedure-related issues such as hair clipping, tape stripping, and wrapping the animal's torso to prevent oral ingestion can influence the interpretation. Excipients used in dermal toxicity studies may be nontoxic when used alone but complex dermal formulations can result in unexpected irritation and toxicity. In conclusion, interpretation and risk assessment of dermal toxicity studies should be done in a comprehensive manner, taking into account procedure-related impact on study results, unique species susceptibility, limitation of gross visual (naked eye) observation for evidence of toxicity, and normal anatomical variation.
Assuntos
Dermatopatias/induzido quimicamente , Testes Cutâneos/métodos , Pele/efeitos dos fármacos , Testes de Toxicidade/métodos , Administração Tópica , Animais , Testes Cutâneos/normas , Testes de Toxicidade/normasRESUMO
Interpretation of chemical-induced effects on the female beagle mammary gland can be difficult owing to the wide variation of normal glandular morphology. In this retrospective study, morphological features of the gland in four (proestrus, estrus, diestrus, and anestrus) phases of the cycle are described. The gland was quiescent (inactive) in proestrus and estrus. In diestrus, with the rise of progesterone, four (I-IV) distinct morphological changes were evident. In phase I, there was exuberant stromal and ductal proliferation. In phase II, there was early lobular development with branching ducts and alveolar proliferation. In phase III, there was an abundance of glandular tissue with large lobules containing secretory material, whereas phase IV had features of early regression, increased interlobular connective tissue, and eosinophilic secretions in distended ducts and acini. In early anestrus, ducts were distended, with eosinophilic secretions with alveolar regression, whereas regression was complete in late anestrus. Glandular morphology was slightly variable in the mammary chain within the same dog. Progesterone receptor expression was prominent in estrus and early diestrus, and peak estrogen receptor expression was noted in diestrus II. Expression of proliferation marker ki-67 was highest in diestrus I, followed by diestrus II. There was excellent concordance between the estrous stage and the glandular morphology.
Assuntos
Ciclo Estral/fisiologia , Glândulas Mamárias Animais/anatomia & histologia , Animais , Biomarcadores/metabolismo , Cães , Feminino , Imuno-Histoquímica , Glândulas Mamárias Animais/fisiologia , Estudos RetrospectivosRESUMO
Drug effects on mitochondrial function are frequently characterized in vitro. Whether these findings are relevant pharmacologically or toxicologically is generally unclear. Methods for in vivo assessment of mitochondrial function would help establish biological significance, but none is widely accepted or readily available. Ideally, these methods would be sensitive and specific, noninvasive, predictive of efficacy or toxicity, translatable from preclinical to clinical studies and localizable to the target organ. Although not fully developed or validated, several approaches to in vivo mitochondrial assessment show promise. Collaboration between scientists from academia, the pharmaceutical industry, and regulatory agencies will be required to develop and apply these methods.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Mitocôndrias/efeitos dos fármacos , Animais , Biomarcadores , Líquidos Corporais/química , Líquidos Corporais/metabolismo , Testes Respiratórios , Humanos , Espectroscopia de Ressonância Magnética , Mitocôndrias/química , Mitocôndrias/fisiologia , Tomografia por Emissão de PósitronsRESUMO
The beagle is a monoestric, nonseasonal breeder with a long estrous cycle. Owing to lengthy stages in individual phases of the estrous cycle, limited group size, and typical group assignment focused on homogenized body weight, dogs in the same stage of the cycle can be inadvertently assigned to one treatment group in toxicity studies potentially leading to erroneous interpretation. This study was conducted to better understand the frequency of the different stages of the cycle and review the associated histological features. Histologic sections of reproductive tissues were reviewed from 102 control dogs from thirty-two GLP studies. The average age of dogs at necropsy was 14.38 months, and the mean terminal body weight was 6.87 kg. Based on histological classification, fifty-five dogs were in anestrus, twenty-eight in diestrus, nine in estrus, five in proestrus, and five were classified as immature. Mean ovarian weights were higher in the estrus stage. This review indicates that more than 80% of the dogs in this study were in the anestrus-diestrus stage, and a small percentage of dogs were immature. Interpretation of drug-induced effects on the morphologic changes in the reproductive tract should be performed with due consideration given to the stage of the cycle and the potential for nonuniform assignment to drug treatment groups.
Assuntos
Cães/fisiologia , Ciclo Estral , Ovário/anatomia & histologia , Vagina/anatomia & histologia , Animais , Cruzamento , Cães/anatomia & histologia , Feminino , Histocitoquímica , Glândulas Mamárias Animais/anatomia & histologia , Estudos Retrospectivos , Maturidade Sexual/fisiologia , Útero/anatomia & histologiaRESUMO
The Executive Committee of the Society of Toxicologic Pathology (STP) appointed an ad hoc task force to devise and recommend a standard list of tissues to be evaluated histopathologically in repeat-dose toxicity and carcinogenicity studies that are used to support the registration of new pharmaceutical products. The recommended tissue list is intended to be a minimum core list that can be used for all types of repeat-dose toxicity and carcinogenicity studies, regardless of route of administration, species or strain of mammalian laboratory animal, duration, or class of drug to be tested. The resulting recommendations of the task force, presented here, were subsequently reviewed by the STP membership and endorsed by the STP Executive Committee.