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1.
Mutagenesis ; 39(2): 96-118, 2024 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-38183622

RESUMEN

The N-nitrosamine, N-nitrosodimethylamine (NDMA), is an environmental mutagen and rodent carcinogen. Small levels of NDMA have been identified as an impurity in some commonly used drugs, resulting in several product recalls. In this study, NDMA was evaluated in an OECD TG-488 compliant Muta™Mouse gene mutation assay (28-day oral dosing across seven daily doses of 0.02-4 mg/kg/day) using an integrated design that assessed mutation at the transgenic lacZ locus in various tissues and at the endogenous Pig-a gene-locus, along with micronucleus frequencies in peripheral blood. Liver pathology was determined together with NDMA exposure in blood and liver. The additivity of mutation induction was assessed by including two acute single-dose treatment groups (i.e. 5 and 10 mg/kg dose on Day 1), which represented the same total dose as two of the repeat dose treatment groups. NDMA did not induce statistically significant increases in mean lacZ mutant frequency (MF) in bone marrow, spleen, bladder, or stomach, nor in peripheral blood (Pig-a mutation or micronucleus induction) when tested up to 4 mg/kg/day. There were dose-dependent increases in mean lacZ MF in the liver, lung, and kidney following 28-day repeat dosing or in the liver and kidney after a single dose (10 mg/kg). No observed genotoxic effect levels (NOGEL) were determined for the positive repeat dose-response relationships. Mutagenicity did not exhibit simple additivity in the liver since there was a reduction in MF following NDMA repeat dosing compared with acute dosing for the same total dose. Benchmark dose modelling was used to estimate point of departure doses for NDMA mutagenicity in Muta™Mouse and rank order target organ tissue sensitivity (liver > kidney or lung). The BMD50 value for liver was 0.32 mg/kg/day following repeat dosing (confidence interval 0.21-0.46 mg/kg/day). In addition, liver toxicity was observed at doses of ≥ 1.1 mg/kg/day NDMA and correlated with systemic and target organ exposure. The integration of these results and their implications for risk assessment are discussed.


Asunto(s)
Dimetilnitrosamina , Mutágenos , Dimetilnitrosamina/toxicidad , Mutación , Mutágenos/toxicidad , Daño del ADN , Mutagénesis
2.
Toxicol Pathol ; 50(6): 793-807, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35950710

RESUMEN

Digital toxicologic histopathology has been broadly adopted in preclinical compound development for informal consultation and peer review. There is now increased interest in implementing the technology for good laboratory practice-regulated study evaluations. However, the implementation is not straightforward because systems and work processes require qualification and validation, with consideration also given to security. As a result of the high-throughput, high-volume nature of safety evaluations, computer performance, ergonomics, efficiency, and integration with laboratory information management systems are further key considerations. The European Society of Toxicologic Pathology organized an international expert workshop with participation by toxicologic pathologists, quality assurance/regulatory experts, and information technology experts to discuss qualification and validation of digital histopathology systems in a good laboratory practice environment, and to share the resulting conclusions broadly in the toxicologic pathology community.


Asunto(s)
Patología , Revisión por Pares , Humanos , Laboratorios , Patólogos
3.
Toxicol Pathol ; 49(4): 720-737, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33297858

RESUMEN

With advancements in whole slide imaging technology and improved understanding of the features of pathologist workstations required for digital slide evaluation, many institutions are investigating broad digital pathology adoption. The benefits of digital pathology evaluation include remote access to study or diagnostic case materials and integration of analysis and reporting tools. Diagnosis based on whole slide images is established in human medical pathology, and the use of digital pathology in toxicologic pathology is increasing. However, there has not been broad adoption in toxicologic pathology, particularly in the context of regulatory studies, due to lack of precedence. To address this topic, as well as practical aspects, the European Society of Toxicologic Pathology coordinated an expert international workshop to assess current applications and challenges and outline a set of minimal requirements needed to gain future regulatory acceptance for the use of digital toxicologic pathology workflows in research and development, so that toxicologic pathologists can benefit from digital slide technology.

4.
Sci Rep ; 13(1): 21759, 2023 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-38066073

RESUMEN

Over the past decade, automation of digital image analysis has become commonplace in both research and clinical settings. Spurred by recent advances in artificial intelligence and machine learning (AI/ML), tissue sub-compartments and cellular phenotypes within those compartments can be identified with higher throughput and accuracy than ever before. Recently, immune checkpoints have emerged as potential targets for auto-immune diseases. As such, spatial identification of these proteins along with immune cell markers (e.g., CD3+/LAG3+ T-cells) is a crucial step in understanding the potential and/or efficacy of such treatments. Here, we describe a semi-automated imaging and analysis pipeline that identifies CD3+/LAG3+ cells in colorectal tissue sub-compartments. While chromogenic staining has been a clinical mainstay and the resulting brightfield images have been utilized in AI/ML approaches in the past, there are associated drawbacks in phenotyping algorithms that can be overcome by fluorescence imaging. To address these tradeoffs, we developed an analysis pipeline combining the strengths of brightfield and fluorescence images. In this assay, immunofluorescence imaging was conducted to identify phenotypes followed by coverslip removal and hematoxylin and eosin staining of the same section to inform an AI/ML tissue segmentation algorithm. This assay proved to be robust in both tissue segmentation and phenotyping, was compatible with automated workflows, and revealed presence of LAG3+ T-cells in ulcerative colitis biopsies with spatial context preserved.


Asunto(s)
Inteligencia Artificial , Colitis Ulcerosa , Humanos , Algoritmos , Técnica del Anticuerpo Fluorescente , Aprendizaje Automático , Biomarcadores
5.
Adv Drug Deliv Rev ; 71: 15-33, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24530633

RESUMEN

Alveolar macrophage (AM) responses are commonly induced in inhalation toxicology studies, typically being observed as an increase in number or a vacuolated 'foamy' morphology. Discriminating between adaptive AM responses and adverse events during nonclinical and clinical development is a major scientific challenge. When measuring and interpreting induced AM responses, an understanding of macrophage biology is essential; this includes 'sub-types' of AMs with different roles in health and disease and mechanisms of induction/resolution of AM responses to inhalation of pharmaceutical aerosols. In this context, emerging assay techniques, the utility of toxicokinetics and the requirement for new biomarkers are considered. Risk assessment for nonclinical toxicology findings and their translation to effects in humans is discussed from a scientific and regulatory perspective. At present, when apparently adaptive macrophage-only responses to inhaled investigational products are observed in nonclinical studies, this poses a challenge for risk assessment and an improved understanding of induced AM responses to inhaled pharmaceuticals is required.


Asunto(s)
Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Macrófagos Alveolares/metabolismo , Administración por Inhalación , Aerosoles , Animales , Biomarcadores/metabolismo , Descubrimiento de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Medición de Riesgo/métodos , Pruebas de Toxicidad/métodos
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