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Harmonization of diagnostic terminology used during the histopathologic analysis of rodent tissue sections from nonclinical toxicity studies will improve the consistency of data sets produced by laboratories located around the world. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a cooperative enterprise of 4 major societies of toxicologic pathology to develop a globally accepted standard vocabulary for proliferative and nonproliferative lesions in rodents. A prior manuscript (Toxicol Pathol 2012;40[4 Suppl]:87S-157S) defined multiple diagnostic terms for toxicant-induced lesions, common spontaneous and age-related changes, and principal confounding artifacts in the rat and mouse central nervous system (CNS) and peripheral nervous system (PNS). The current article defines 9 new diagnostic terms and updates 2 previous terms for findings in the rodent CNS and PNS, the need for which has become evident in the years since the publication of the initial INHAND nomenclature for findings in rodent neural tissues. The nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/).
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Sistema Nervioso Periférico , Animales , Ratones , RatasRESUMEN
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. The workshop panel was comprised of representatives from the European Union, Japan, and the United States. Participants shared case examples illustrating issues related to adversity assessments of thyroid changes. Provided here are summary discussions, key case presentations, and panel recommendations. This information should increase consistency in the interpretation of adverse changes in the thyroid based on pathology findings in nonclinical toxicity studies, help integrate new types of biomarker data into the review process, and facilitate a more systematic approach to communicating adversity determinations in toxicology reports.
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Células Epiteliales Tiroideas , Biomarcadores , Humanos , Hiperplasia , Hipertrofia , Medición de Riesgo , Estados UnidosRESUMEN
Neuropathology methods in rodent developmental neurotoxicity (DNT) studies have evolved with experience and changing regulatory guidance. This article emphasizes principles and methods to promote more standardized DNT neuropathology evaluation, particularly procurement of highly homologous brain sections and collection of the most reproducible morphometric measurements. To minimize bias, brains from all animals at all dose levels should be processed from brain weighing through paraffin embedding at one time using a counterbalanced design. Morphometric measurements should be anchored by distinct neuroanatomic landmarks that can be identified reliably on the faced block or in unstained sections and which address the region-specific circuitry of the measured area. Common test article-related qualitative changes in the developing brain include abnormal cell numbers (yielding altered regional size), displaced cells (ectopia and heterotopia), and/or aberrant differentiation (indicated by defective myelination or synaptogenesis), but rarely glial or inflammatory reactions. Inclusion of digital images in the DNT pathology raw data provides confidence that the quantitative analysis was done on anatomically matched (i.e., highly homologous) sections. Interpreting DNT neuropathology data and their presumptive correlation with neurobehavioral data requires an integrative weight-of-evidence approach including consideration of maternal toxicity, body weight, brain weight, and the pattern of findings across brain regions, doses, sexes, and ages.
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Encéfalo , Técnicas Histológicas , Neuroanatomía , Síndromes de Neurotoxicidad , Animales , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/fisiología , Química Encefálica , Ratones , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/fisiopatología , RatasRESUMEN
The identification of adverse health effects has a central role in the development and risk/safety assessment of chemical entities and pharmaceuticals. There is currently a need for better alignment regarding how nonclinical adversity is determined and characterized. The European Society of Toxicologic Pathology (ESTP) therefore coordinated a workshop to review available definitions of adversity, weigh determining and qualifying factors of adversity based on case examples, and recommend a practical approach to define and characterize adversity in toxicology reports, to serve as a valuable prerequisite for future organ- or lesion-specific workshops planned by the ESTP.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Toxicología/normas , Animales , Guías como Asunto , Humanos , Medición de Riesgo , Fenómenos ToxicológicosRESUMEN
A half-day Society of Toxicologic Pathology continuing education course on "Fundamentals of Translational Neuroscience in Toxicologic Pathology" presented some current major issues faced when extrapolating animal data regarding potential neurological consequences to assess potential human outcomes. Two talks reviewed functional-structural correlates in rodent and nonrodent mammalian brains needed to predict behavioral consequences of morphologic changes in discrete neural cell populations. The third lecture described practical steps for ensuring that specimens from rodent developmental neurotoxicity tests will be processed correctly to produce highly homologous sections. The fourth talk detailed demographic factors (e.g., species, strain, sex, and age); physiological traits (body composition, brain circulation, pharmacokinetic/pharmacodynamic patterns, etc.); and husbandry influences (e.g., group housing) known to alter the effects of neuroactive agents. The last presentation discussed the appearance, unknown functional effects, and potential relevance to humans of polyethylene glycol (PEG)-associated vacuoles within the choroid plexus epithelium of animals. Speakers provided real-world examples of challenges with data extrapolation among species or with study design considerations that may impact the interpretability of results. Translational neuroscience will be bolstered in the future as less invasive and/or more quantitative techniques are devised for linking overt functional deficits to subtle anatomic and chemical lesions.
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Modelos Animales de Enfermedad , Síndromes de Neurotoxicidad/patología , Investigación Biomédica Traslacional , Animales , Humanos , Neurociencias , Medición de Riesgo , Pruebas de ToxicidadRESUMEN
The INHAND Proposal (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) has been operational since 2005. A Global Editorial Steering Committee (GESC) manages the overall objectives of the project and the development of harmonized terminology for each organ system is the responsibility of the Organ Working Groups (OWG), drawing upon experts from North America, Europe and Japan.Great progress has been made with 9 systems published to date - Respiratory, Hepatobiliary, Urinary, Central/Peripheral Nervous Systems, Male Reproductive and Mammary, Zymbals, Clitoral and Preputial Glands in Toxicologic Pathology and the Integument and Soft Tissue and Female Reproductive System in the Journal of Toxicologic Pathology as supplements and on a web site - www.goreni.org. INHAND nomenclature guides offer diagnostic criteria and guidelines for recording lesions observed in rodent toxicity and carcinogenicity studies. The guides provide representative photo-micrographs of morphologic changes, information regarding pathogenesis, and key references. During 2012, INHAND GESC representatives attended meetings with representatives of the FDA Center for Drug Evaluation and Research (CDER), Clinical Data Interchange Standards Consortium (CDISC), and the National Cancer Institute (NCI) Enterprise Vocabulary Services (EVS) to begin incorporation of INHAND terminology as preferred terminology for SEND (Standard for Exchange of Nonclinical Data) submissions to the FDA. The interest in utilizing the INHAND nomenclature, based on input from industry and government toxicologists as well as information technology specialists, suggests that there will be wide acceptance of this nomenclature. The purpose of this publication is to provide an update on the progress of INHAND.
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The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) project is a joint initiative of the societies of toxicological pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP). Its aim is to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory rodents. A widely accepted international harmonization of nomenclature in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and will provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. The purpose of this publication is to provide a standardized nomenclature for classifying microscopical lesions observed in the integument of laboratory rats and mice. Example colour images are provided for most lesions. The standardized nomenclature presented in this document and additional colour images are also available electronically at http://www.goreni.org. The nomenclature presented herein is based on histopathology databases from government, academia, and industrial laboratories throughout the world, and covers lesions that develop spontaneously as well as those induced by exposure to various test materials. (DOI: 10.1293/tox.26.27S; J Toxicol Pathol 2013; 26: 27S-57S).
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Harmonization of diagnostic nomenclature used in the pathology analysis of tissues from rodent toxicity studies will enhance the comparability and consistency of data sets from different laboratories worldwide. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of four major societies of toxicologic pathology to develop a globally recognized nomenclature for proliferative and nonproliferative lesions in rodents. This article recommends standardized terms for classifying changes observed in tissues of the mouse and rat central (CNS) and peripheral (PNS) nervous systems. Sources of material include academic, government, and industrial histopathology databases from around the world. Covered lesions include frequent, spontaneous, and aging-related changes as well as principal toxicant-induced findings. Common artifacts that might be confused with genuine lesions are also illustrated. The neural nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/).
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Enfermedades del Sistema Nervioso Central/patología , Enfermedades del Sistema Nervioso Periférico/patología , Terminología como Asunto , Animales , Enfermedades del Sistema Nervioso Central/clasificación , Ratones , Enfermedades del Sistema Nervioso Periférico/clasificación , Ratas , Pruebas de ToxicidadRESUMEN
The International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice is a global project that is publishing criteria for both proliferative and nonproliferative changes in laboratory animals. This paper presents a set of general suggestions for terminology across systems. These suggestions include the use of diagnostic versus descriptive terms, modifiers, combination terms, and grading systems; and the use of thresholds, synonyms, and terminology for some processes that are common to several organ systems. The purpose of this paper is to help the reader understand some of the basic principles underlying the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice process.
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Patología/normas , Terminología como Asunto , Toxicología/normas , Animales , Internacionalidad , Ratones , Neoplasias , Ratas , Pruebas de ToxicidadRESUMEN
The continuing education course on Developmental Neurotoxicity Testing (DNT) was designed to communicate current practices for DNT neuropathology, describe promising innovations in quantitative analysis and noninvasive imaging, and facilitate a discussion among experienced neuropathologists and regulatory scientists regarding suitable DNT practices. Conventional DNT neuropathology endpoints are qualitative histopathology and morphometric endpoints of particularly vulnerable sites (e.g., cerebral, cerebellar, or hippocampal thickness). Novel imaging and stereology measurements hold promise for automated analysis of factors that cannot be effectively examined in routinely processed specimens (e.g., cell numbers, fiber tract integrity). The panel recommended that dedicated DNT neuropathology data sets be acquired on a minimum of 8 sections (for qualitative assessment) or 3 sections (for quantitative linear and stereological analyses) using a small battery of stains to examine neurons and myelin. Where guidelines permit discretion, immersion fixation is acceptable for younger animals (postnatal day 22 or earlier), and peripheral nerves may be embedded in paraffin. Frequent concerns regarding DNT data sets include false-negative outcomes due to processing difficulties (e.g., lack of concordance among sections from different animals) and insensitive analytical endpoints (e.g., qualitative evaluation) as well as false-positive results arising from overinterpretation or misreading by inexperienced pathologists.
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Educación Continua , Enfermedades del Sistema Nervioso/patología , Neurociencias/tendencias , Pruebas de Toxicidad/métodos , Animales , Cerebelo/patología , Guías como Asunto , Técnicas Histológicas/métodos , Humanos , Neuronas/patología , Síndromes de Neurotoxicidad/patología , Patología/educación , Medición de Riesgo , Toxicología/educaciónRESUMEN
The frequencies of micronuclei (MN), histopathological changes and cell proliferation were determined in the nasal epithelium of male Fischer-344 rats after exposure to formaldehyde (FA) by whole-body inhalation for four weeks (6h/day, 5 days/week). Groups of 12 rats each were exposed to the target concentrations of 0, 0.5, 1, 2, 6, 10 and 15ppm. The micronucleus test (MNT) was performed with nasal epithelial cells prepared from six animals per group. Two thousand cells per animal were analysed for the presence of MN. The other six rats per group were subcutaneously implanted with osmotic pumps containing 5-bromo-2'-deoxyuridine (BrdUrd), three days prior to necropsy. Paraffin sections were made from the nasal cavity (four levels) of these animals for histopathology and cell-proliferation measurements. The frequency of cells with MN was not increased in any of the groups. However, there was also no induction of MN in nasal cells of rats exposed to a single dose of cyclophosphamide (CP, 20mg/kg) by gavage and analysed 3, 7, 14 or 28 days after the treatment. In contrast, nasal epithelial cells from rats exposed to 10 or 15ppm FA vapour showed clear site-specific pathological changes (focal epithelial degeneration, inflammation and squamous metaplasia) in a decreasing gradient (anterior to posterior). Analysis of slides after anti-BrdUrd antibody staining clearly indicated increased cell proliferation (unit length labelling indices, ULLI) after exposure to 6ppm and higher. No treatment-related effects were measured after exposure to 0.5, 1 and 2ppm. When comparing the cell-proliferation rate of normal epithelium with that of directly adjacent metaplastic epithelium, no consistent pattern was found: depending on the location, cell proliferation of normal epithelia was either higher or lower. Our results support previous findings demonstrating local cytotoxic effects in the nose of rats after inhalation of FA. However, induction of MN in the nasal epithelium as an indicator of a mutagenic effect was not seen. Because only limited experience exists for the MNT with rat nasal epithelial cells, this result has to be interpreted with great care. The contribution of mutagenicity to FA's carcinogenicity in rat nasal epithelium remains unclear.
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Proliferación Celular/efectos de los fármacos , Formaldehído/toxicidad , Micronúcleos con Defecto Cromosómico/inducido químicamente , Mutágenos/toxicidad , Mucosa Nasal/efectos de los fármacos , Administración por Inhalación , Animales , Relación Dosis-Respuesta a Droga , Masculino , Mucosa Nasal/patología , Ratas , Ratas Endogámicas F344RESUMEN
Feasibility of the ILSI-HESI (ACSA) extended one-generation protocol was tested with vinclozolin (dietary 0, 4, 20, 100mg/kg/day). Parental Wistar rats (n=25/sex/dose) were dosed pre-mating (males 4, females 2 weeks) through F1 offspring weaning (postnatal day PND21); F1 dosing continued through PND70. At PND21, 3 subsets (each 1 pup/sex/litter) were selected for neurotoxicology (functional observational battery, motor activity, neuropathology), clinical pathology (hematology, clinical chemistry, urinalysis, thyroid hormone assay) (subsets 1a, 1b; each n=10/sex/dose), immunotoxicology (IgM) SRBC antibody response and natural killer cell assays (subset 2; n=25/sex/dose), and estrus cycle (subset 3; n=25/dose). Vinclozolin reduced parental and offspring bodyweight and prostate, seminal vesicles and epididymides weight, and increased adrenal weight/induced adrenal cortical hypertrophy at 100mg/kg. Mating, fertility, gestation and lactation were unaffected. At 20 and 100mg/kg, F1 males had reduced anogenital distance and retained areolae; at 100mg/kg only, there was hypospadias, purulent prostatitis and seminal vesicle inflammation with atrophy, and Leydig cell hyperplasia, and in F1 females accelerated vaginal opening. These effects are consistent with vinclozolin's known anti-androgenic developmental effects. Neuro- and immunotoxicology tests were unaffected. F1 Only T4 was reduced at 20 and 100mg/kg. The overall sensitivity of the extended one-generation protocol is comparable to or even greater than the current two-generation study. Thus it reduces animal use while maintaining or enhancing information for risk assessment.
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Antagonistas de Andrógenos/toxicidad , Disruptores Endocrinos/toxicidad , Fungicidas Industriales/toxicidad , Oxazoles/toxicidad , Reproducción/efectos de los fármacos , Pruebas de Toxicidad , Factores de Edad , Antagonistas de Andrógenos/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Disruptores Endocrinos/administración & dosificación , Estudios de Factibilidad , Femenino , Fungicidas Industriales/administración & dosificación , Edad Gestacional , Sistema Inmunológico/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Nivel sin Efectos Adversos Observados , Oxazoles/administración & dosificación , Embarazo , Ratas , Ratas Wistar , Maduración Sexual/efectos de los fármacos , Hormonas Tiroideas/sangre , Factores de TiempoRESUMEN
The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the hepatobiliary system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the hepatobiliary system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
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Enfermedades de las Vías Biliares/diagnóstico , Enfermedades de las Vías Biliares/patología , Hepatopatías/diagnóstico , Hepatopatías/patología , Hígado/patología , Terminología como Asunto , Animales , Animales de Laboratorio , Enfermedades de las Vías Biliares/clasificación , Europa (Continente) , Agencias Internacionales , Japón , Hepatopatías/clasificación , Ratones , América del Norte , Ratas , Enfermedades de los Roedores/clasificación , Enfermedades de los Roedores/patología , Pruebas de Toxicidad , Reino UnidoRESUMEN
The National Toxicology Program (NTP) Satellite Symposium is a one-day meeting that is held in conjunction with the annual Society of Toxicologic Pathology (STP) meeting. The topic of the 2009 Symposium was "Tumor Pathology and INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) Nomenclature." The goal of this article is to provide summaries of each speaker's presentation, including the diagnostic or nomenclature issues that were presented, along with a few select images that were used for voting. The results of the voting process and interesting points of discussion that were raised during the presentation are also provided. A supplemental file with voting choices and voting results for each case presented at the symposium is available at http://tpx.sagepub.com/supplemental.
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Neoplasias/patología , Médula Suprarrenal/patología , Animales , Proliferación Celular , Colangiocarcinoma/patología , Inmunohistoquímica , Neoplasias Hepáticas/patología , Meningioma/patología , Ratones , Ratas , Terminología como AsuntoRESUMEN
Specific regions in the rat larynx exhibit cellular changes in response to inhaled xenobiotics. These regions include the base of the epiglottis, ventral pouch, and medial surfaces of the vocal processes of the arytenoid cartilages. 1 , 2 In order to collect information on the usefulness of trimming techniques, the influence of different vehicles, the impact of different application routes in toxicity studies, and differences between induced vs. spontaneous lesions, the data obtained from a large number of inhalation and non-inhalation studies performed in Wistar RCCHan(TM): Wist rats at Harlan Laboratories Ltd Switzerland, all evaluated or reviewed by the same pathologist, were compiled for a detailed review. The value of different trimming techniques was deemed to be greatest for transverse and sagittolongitudinal section techniques, as compared to horizontolongitudinally section techniques. The comparison of lesions encountered in control rats of inhalation studies treated with different vehicles did not reveal differences in the type, distribution pattern, incidence and/or severity of spontaneous lesions. The types of lesions were also independent of different application routes in non-inhalation studies compared to inhalation studies. The pattern of spontaneous lesions in the rodent larynx was determined by degenerative and inflammatory lesions starting most often in the submucosal glands by desiccated secretion followed by mineralization and local inflammation or were induced by impacted foreign bodies. Squamous metaplasia was recorded in the respiratory epithelium overlaying the ventral gland as a spontaneous lesion in male Wistar rats from inhalation studies with a maxim of 20.0% in an inhalation oncogenicity study. Induced metaplastic changes recorded in the larynx were reversible. Other induced lesions in inhalation studies consisted of submucosal edema, necrosis, inflammation and/or granuloma. Induced lesions in non-inhalation studies were found to be exclusively related to reflux laryngitis or food impaction. It is concluded, that in rodents induced lesions of the larynx differ in type, distribution pattern, severity and incidence from spontaneous lesions.
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The purpose of the study was to investigate a possible transgenerational effect of the fungicide vinclozolin on the male reproductive system following oral exposure since this effect was reported by Anway et al. [Anway MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 2005;308(5727 (June 3)):1466-9] after intraperitoneal administration. Pregnant Wistar rats were dosed by oral gavage with vinclozolin 0, 4 or 100mg/(kg bw day) on days 6-15 post coitum (p.c.). F1 male offspring was mated with untreated females to produce F2, which were then similarly mated to produce F3 offspring. F0 maternal treatment had no effect on mating and fertility indices or male offspring sexual development, mean sperm parameters, or histopathology of the sexual organs in F1, F2 or F3 males (at age 127-134 days). Apoptotic germ cell counts were statistically significantly lower in F1, F2 and F3 generations, however, control values showed a pronounced variance over time. Also, as anti-androgenic compounds are more likely to induce the opposite effect (increased apoptosis), this observation is not considered to be treatment related. Consequently, spermatogenesis was not affected by vinclozolin exposure in utero. As vinclozolin has been shown to induce clear anti-androgenic effects in offspring following treatment with 100mg/(kg bw day) during entire gestation, the lack of effects in this study indicates that the window of sensitivity for anti-androgenic effects is from days 16-20 p.c. No transgenerational effect on the male reproductive system was found. The NOAEL was >100mg/(kg bw day) for fertility and reproductive performance, for systemic parental and developmental toxicity in F1, F2 and F3 males.
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Feto/efectos de los fármacos , Fungicidas Industriales/toxicidad , Oxazoles/toxicidad , Reproducción/efectos de los fármacos , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Femenino , Masculino , Embarazo , Ratas , Ratas Wistar , Maduración Sexual/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacosRESUMEN
The revision of the OECD TG 407 test guideline (repeated dose 28-day oral toxicity study in rodents) focuses on endpoints to detect endocrine activities of chemicals. The new endpoints are likely to influence other previously established core endpoints of this study type. An expert group of pathologists and toxicologists within the European Society of Toxicologic Pathologists (ESTP) has contributed to the scientific discussion of the draft guideline. The advantages and disadvantages of methodical changes as necropsy of all females in dioestrus, blood collection for clinical chemistry and haematology at the same cycle stage, weighing of the thyroid gland and separate weighing of ventral and dorsolateral lobes of the prostate are considered. Possible alternatives are pointed out covering scientific as well as practical aspects.
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Sistema Endocrino/efectos de los fármacos , Guías como Asunto , Proyectos de Investigación , Pruebas de Toxicidad/métodos , Animales , Femenino , Masculino , RatasRESUMEN
The potential for developmental neurotoxicity (DNT) of environmental chemicals may be evaluated using specific test guidelines from the US Environmental Protection Agency or the Organisation for Economic Cooperation and Development (OECD). These guidelines generate neurobehavioral, neuropathological, and morphometric data that are evaluated by regulatory agencies globally. Data from these DNT guideline studies, or the more recent OECD extended one-generation reproductive toxicity guideline, play a pivotal role in children's health risk assessment in different world areas. Data from the same study may be interpreted differently by regulatory authorities in different countries resulting in inconsistent evaluations that may lead to inconsistencies in risk assessment decisions internationally, resulting in regional differences in public health protection or in commercial trade barriers. These issues of data interpretation and reporting are also relevant to juvenile and pre-postnatal studies conducted more routinely for pharmaceuticals and veterinary medicines. There is a need for development of recommendations geared toward the operational needs of the regulatory scientific reviewers who apply these studies in risk assessments, as well as the scientists who generate DNT data sets. The workshops summarized here draw upon the experience of the authors representing government, industry, contract research organizations, and academia to discuss the scientific issues that have emerged from diverse regulatory evaluations. Although various regulatory bodies have different risk management decisions and labeling requirements that are difficult to harmonize, the workshops provided an opportunity to work toward more harmonized scientific approaches for evaluating DNT data within the context of different regulatory frameworks. Five speakers and their coauthors with neurotoxicology, neuropathology, and regulatory toxicology expertise discussed issues of variability, data reporting and analysis, and expectations in DNT data that are encountered by regulatory authorities. In addition, principles for harmonized evaluation of data were suggested using guideline DNT data as case studies.
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Guías como Asunto , Síndromes de Neurotoxicidad , Pruebas de Toxicidad , Animales , Congresos como Asunto , Humanos , Proyectos de Investigación , Sociedades Científicas , Teratología , Pruebas de Toxicidad/métodos , Estados Unidos , United States Environmental Protection AgencyRESUMEN
Developmental neurotoxicity (DNT-) studies are the first reproduction toxicity studies for which an extended histopathological examination of developing structures is required by the current EPA and OECD guidelines. The morphological screening includes a macroscopic evaluation of the brain and nervous tissue, brain weight parameters, gross morphometry of the brain, neurohistological examinations and a quantitative analysis of major brain areas. This review is intended to give an overview about the needs according to guideline requirements, practical approaches for a successful developmental neuropathology and its preconditions and does include examples of background data on the value and functional meaning of morphological data. A selection of experimental data from literature is also presented in the light of their contribution for the understanding of important, neurodevelopmental disorders in humans.
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Enfermedades del Sistema Nervioso/patología , Efectos Tardíos de la Exposición Prenatal , Pruebas de Toxicidad/métodos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/embriología , Encéfalo/patología , Femenino , Sustancias Peligrosas/toxicidad , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/embriología , EmbarazoRESUMEN
Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors.