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Raleigh, NC, United States

Hall A.P.,Astrazeneca | Elcombe C.R.,CXR Biosciences | Foster J.R.,Astrazeneca | Harada T.,Institute of Environmental Toxicology | And 10 more authors.
Toxicologic Pathology

Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPARα. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach. © 2012 by The Author(s). Source

Maronpot R.R.,Maronpot Consulting LLC | Yoshizawa K.,Kansai Medical University | Nyska A.,Tel Aviv University | Harada T.,Institute of Environmental Toxicology | And 4 more authors.
Toxicologic Pathology

Hepatic enzyme induction is generally an adaptive response associated with increases in liver weight, induction of gene expression, and morphological changes in hepatocytes. The additive growth and functional demands that initiated the response to hepatic enzyme induction cover a wide range of stimuli including pregnancy and lactation, hormonal fluctuations, dietary constituents, infections associated with acute-phase proteins, as well as responses to exposure to xenobiotics. Common xenobiotic enzyme inducers trigger pathways involving the constitutive androstane receptor (CAR), the peroxisome proliferator-activated receptor (PPAR), the aryl hydrocarbon receptor (AhR), and the pregnane-X-receptor (PXR). Liver enlargement in response to hepatic enzyme induction is typically associated with hepatocellular hypertrophy and often, transient hepatocyte hyperplasia. The hypertrophy may show a lobular distribution, with the pattern of lobular zonation and severity reflecting species, strain, and sex differences in addition to effects from specific xenobiotics. Toxicity and hepatocarcinogenicity may occur when liver responses exceed adaptive changes or induced enzymes generate toxic metabolites. These undesirable consequences are influenced by the type and dose of xenobiotic and show considerable species differences in susceptibility and severity that need to be understood for assessing the potential effects on human health from similar exposures to specific xenobiotics. Copyright © 2010 by The Author(s). Source

Tempel-Brami C.,Aspect Imaging | Schiffenbauer Y.S.,Aspect Imaging | Nyska A.,Tel Aviv University | Ezov N.,Harlan Biotech Israel | And 3 more authors.
Toxicologic Pathology

Magnetic resonance imaging (MRI) is widely used in preclinical research and drug development and is a powerful noninvasive method for assessment of phenotypes and therapeutic efficacy in murine models of disease. In vivo MRI provides an opportunity for longitudinal evaluation of tissue changes and phenotypic expression in experimental animal models. Ex vivo MRI of fixed samples permits a thorough examination of multiple digital slices while leaving the specimen intact for subsequent conventional hematoxylin and eosin (H&E) histology. With the advent of new compact MRI systems that are designed to operate in most conventional labs without the cost, complexity, and infrastructure needs of conventional MRI systems, the possibility of MRI becoming a practical modality is now viable. The purpose of this study was to investigate the capabilities of a new compact, high-performance MRI platform (M2™; Aspect Imaging, Israel) as it relates to preclinical toxicology studies. This overview will provide examples of major organ system pathologies with an emphasis on how compact MRI can serve as an important adjunct to conventional pathology by nondestructively providing 3-dimensional (3-D) digital data sets, detailed morphological insights, and quantitative information. Comparative data using compact MRI for both in vivo and ex vivo are provided as well as validation using conventional H&E. Copyright © 2015 by The Author(s). Source

Maronpot R.R.,Maronpot Consulting LLC
Food and Chemical Toxicology

Known as ashitaba in Japan, powder from the sap is widely consumed for its medicinal properties in Asia as a dietary supplement. Limited previously reported mammalian studies were without evidence of toxicity. GLP studies reported here, including a bacterial reverse mutation assay, a chromosome aberration assay, and an in vivo micronucleus assay are negative for genotoxicity. A GLP- compliant 90-day repeated oral gavage study of ashitaba yellow sap powder containing 8.45% chalcones in Sprague Dawley rats resulted in expected known physiological effects on coagulation parameters and plasma lipids at 300 and 1000 mg/kg/day. Ashitaba-related pathology included a dose-related male rat-specific alpha 2-urinary globulin nephropathy at 100, 300, and 1000 mg/kg/day and jejunal lymphangiectasia in both sexes at 1000 mg/kg/day. All other study parameters and histopathological changes were incidental or not of toxicological concern. Based on these studies ashitaba chalcone powder is not genotoxic with a NOAEL of 300 mg/kg in male and female rats. © 2014 Elsevier Ltd. Source

The "omics," high-throughput screening, computational modeling, and database mining revolutions have each arrived with euphoric expectations, considerable hand waving, and promises to set toxicity testing priorities and reduce reliance on conventional animal toxicity and carcinogenicity testing. Reflecting back on prior experience with other predictive approaches and alternatives, what follows the rush to endorse a promising new technology or different approach to toxicity/carcinogenicity testing is years of grinding out data for validation and optimization. Much of what has driven the enthusiasm for each new emerging technology and approach is the costly, labor-intensive, and sometimes irrelevant and inefficient rodent bioassay-testing paradigm. However, no one should expect abandonment of all animal testing for the foreseeable future, especially for agrochemicals and environmental xenobiotic exposures. It is reasonable to anticipate the future will bring still new approaches to safety testing and human risk assessment. In the past, each new approach has not achieved the inflated expectations for safety testing and human risk assessment but often has become a useful research tool with tangible contributions to basic biology and clinical medicine. The toxicologic pathologist is embedded in the matrix of a mixed disciplinary milieu and is faced with some critical challenges and important opportunities in the postgenomic decades ahead. So what advice do we give to the journeyman toxicologic pathologist who will hopefully function effectively in the postgenomic decades ahead? And what advice do we also give to the experienced bench pathologist confronted with emerging technologies each accompanied by a bewildering array of techno-jargon so that he or she can remain effective as a toxicologic pathology practitioner? © 2012 by The Author(s). Source

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