SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Today's stringent requirements for new drugs make it necessary to prove their safety by the use of ever more refined techniques, in particular methods to quantify morphologic findings to determine accurately, for example, the highest non-toxic dose in animal studies or to correlate morphological effects with other parameters. Increased cell proliferation due to subtle cytotoxicity can lead to epigenetic tumorigenicity, which can be recognized early by cytokinetic investigations using bromodeoxyuridine (BrdU) incorporation and/or proliferating cell nuclear antigen (PCNA) expression, or by malignancy-associated nuclear texture changes. Morphometric criteria are also used to increase diagnostic accuracy in experimental animal pathology. The various applications of morphometry in toxicopathology are reviewed, and examples illustrating these applications are presented, most of them unpublished.
Explore the source record for details and available documents.
The emergence of the biotechnology industry and introduction of drugs derived from recombinant DNA technology has generated many new issues in approaches to preclinical safety evaluation and extrapolation of results to risk assessment in humans. Products or therapeutic approaches for consideration include hormones, growth factors, cytokines, monoclonal antibodies, vaccines, blood products, antisense, and gene therapy. In many instances the application of standard safety tests conventionally used for small molecules are of limited value or are inappropriate. Studies should be designed to answer specific scientific questions rather than simply to fulfill regulatory requirements. Special consideration must be given to study design and species selection in terms of biological activity and species specificity, implications of immunological responses in the animal studies, and effects of systemic administration of molecules at clinically relevant doses. A full understanding of the clinical relevance of toxicological and pathologic findings associated with administration of these molecules to laboratory animals requires definition of the pathogenic mechanism of lesion induction.
Macroscopic and histologic evaluation of animal studies for general toxicity and carcinogenicity are cornerstones of the risk assessment of new chemical entities. Standard toxicopathologic evaluation is mainly based on the study of paraffin sections stained with hematoxylin and eosin. There are, however, a number of new approaches and techniques which have improved the objectivity of evaluation and the accuracy of cell identification, and provided deeper insight into the molecular biological mechanisms of toxicity and carcinogenicity. Such approaches include the standardization of the nomenclature, the creation of data banks for morphological alterations, the use of computers to register pathological findings in toxicity studies and to statistically evaluate incidences, and the use of morphometry. Other modern techniques are immunohistochemistry, in situ hybridization, and the assessment of cell kinetics.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Microscopic examination of the incisors of rats and mice may reveal toxicologically significant changes. First, the incisor morphology reflects the nutritional status of the animal: fluctuations of mineral metabolism and vitamin availability are disclosed by the rodent incisors, because the incisors continue to grow during life. Similarly, direct or indirect changes of mineral metabolism by a test substance are reflected in the morphological appearance of the incisor dentin. In addition, hormonal disturbances may give rise to typical structural alterations of the incisor in the test animal. Certain chemicals may have deleterious effects upon the odontogenic tissues, resulting in tooth malformation and malocclusion and eventually in odontomas. Apparent nasal tumors may turn out to be of dental origin. Nasal luminal masses that are discussed within this scope are dental malformation, dental callus, and true odontogenic tumors. According to our experience, odontogenic tumors might possibly develop within the scope of a reaction to mechanical tooth trauma as well. In carcinogenicity studies, this consideration deserves attention when evaluating treatment-related putative odontogenic tumors.
Understanding the pathology of the female reproductive system with respect to toxicology requires a basic understanding of morphology and function of the system over time because the nature of the female reproductive system is cyclical. Thus, the morphology and the endocrinology is dependent on age and time, as form follows function and function follows form. The life span of the rodent is used as an outline to present an overview of key morphological and endocrinological events important for toxicologic pathologists to consider in study evaluations. Environmental and pharmaceutical compounds differentially impact the organs individually and/or the system in its entirety in a time- and dose-dependent way. Examples are used to illustrate the consequences of exposures at different times and with different outcomes.
A general outline of the risk assessment process at the Center for Food Safety and Applied Nutrition (CFSAN) of the Food and Drug Administration based on the toxicologic evaluation of data is described. Examples of recent pathology evaluations are presented to illustrate primarily the pathology review process at the CFSAN. These examples include the review of data from rodent studies from proposed indirect food additives and data from dog studies submitted in support of an investigational new drug, a short-acting opioid, proposed as an anesthetic in humans.
Risk assessment of a pesticide includes the identification of hazard, dose-response, exposure assessment, and risk characterization. Toxicology study reports undergo several levels of scientific and regulatory review in the Environmental Protection Agency's (EPA's) Office of Pesticide Programs. A Health Effects Division (HED) scientist reviews the reports. The resulting Data Evaluation Records are presented to several internal HED Peer Review committees to ensure consistency across chemicals in establishing which hazard end points to use when determining the reference dose and carcinogenicity potential for use in dietary and nondietary risk assessments. There may also be external reviews. The toxicologic pathologist can impact many steps in this process. The noncancer end points are just as important as the cancer end points when evaluating the hazard component of a pesticide. The toxicologic pathologist can assist in the hazard and risk characterization by being clear and concise, carefully defining terms and relating individual lesions to the animal, study, and database as a whole. The preceding will assist the HED in fulfilling EPA Administrator Carol Browner's guidance for risk characterizations that are transparent, clear, concise, and reasonable.
The zebrafish (Danio rerio) is now the pre-eminent vertebrate model system for clarification of the roles of specific genes and signaling pathways in development. The zebrafish genome will be completely sequenced within the next 1-2 years. Together with the substantial historical database regarding basic developmental biology, toxicology, and gene transfer, the rich foundation of molecular genetic and genomic data makes zebrafish a powerful model system for clarifying mechanisms in toxicity. In contrast to the highly advanced knowledge base on molecular developmental genetics in zebrafish, our database regarding infectious and noninfectious diseases and pathologic lesions in zebrafish lags far behind the information available on most other domestic mammalian and avian species, particularly rodents. Currently, minimal data are available regarding spontaneous neoplasm rates or spontaneous aging lesions in any of the commonly used wild-type or mutant lines of zebrafish. Therefore, to fully utilize the potential of zebrafish as an animal model for understanding human development, disease, and toxicology we must greatly advance our knowledge on zebrafish diseases and pathology.
Magnetic Resonance Imaging (MRI) is a noninvasive imaging technique that provides multidimensional images of the soft tissues of the body. This imaging technique has proven to be an excellent diagnostic and experimental tool for the detection of pathologic alterations in soft tissues, as well as an adjunct screening method for following the genesis, progression, or regression of chemically induced lesions in the same live animal. Future applications of MRI technology in small animals include MRI microscopy, mapping of vascular or circulatory alterations, measurement of perfusion and diffusion rates of body fluids, and acquisition of cell metabolic states in combination with Nuclear Magnetic Resonance (NMR) spectroscopy, all of which will contribute immensely to the advancement of toxicologic and biomolecular research.
The new ICH S8 guideline on Immunotoxicology Studies for Human Pharmaceuticals indicates that additional, functional testing of pharmaceuticals is not mandatory to screen for unintended immunotoxicity. The usefulness of conventional parameters like clinical pathology, organ weights and histopathology as measured in Standard Toxicity Studies (STS) to screen for potential unintended immunotoxicity was investigated in an ICH survey. Data of this survey appear to support the notion that properly evaluated STS endpoints would be sufficient for the detection of the majority of unintended immunosuppression by investigational pharmaceutical compounds. Thus the ICH S8 guideline was based on a cause for concern approach using a weight of evidence review of various factors like: findings from STS, pharmacological properties of the drug, intended patient population, structural similarities to known immunomodulators, drug disposition and/or clinical information. Overall the S8 guideline allows for more flexible approaches, and requires a weight of evidence review for which there is no given set of rules. For a proper use this asks for a sensible, realistic and above all a responsible approach both from Industry and Regulators. Some examples regarding the use of clinical pathology parameters like immunoglobulin levels and lymphocyte phenotyping have been included to illustrate this. In conclusion, to detect and evaluate potential immunotoxic effects of human pharmaceuticals the ICH S8 guideline allows for a more flexible, scientifically sound approach. For a proper evaluation of potential immunotoxic effects integration of data from standard toxicological parameters like clinical pathology, histopathology and functional assays are important.
Recent advances in immunocytochemical techniques allow the localization of specific antigens in tissue sections. The work reported here attempts to evaluate the application of antibody-labeled, disease-related protein, followed by microscopy and computerized image analysis. Using an experimental anti-tumor, polyclonal antibody (anti-oncomodulin) as a model, various tissues were prepared for light microscope immunocytochemistry. Sections were incubated with primary antibody, then biotinylated secondary antibody. This was followed by incubation with avidin-biotin-peroxidase (ABC method). Marker was visualized by the presence of precipitated diaminobenzidine. Samples were evaluated using a Zeiss/Kontron IBAS I & II semi-automatic digital image analysis system. Statistical analyses were performed on output data. Results demonstrated the localization and determined optical density of immunolabel. Statistical comparisons showed significant differences between control and experimental sections. The practical application of these combined techniques provides the toxicologic pathologist with a powerful tool for accurate and objective determination of the location and relative amount of selected proteins in normal and abnormal tissues.