Effects of 0.5% and 2.0% Sodium Lauryl Sulfate in Male CD-1 Mice From a 3-Month Oral Gavage Toxicity Study.

The tolerability of single daily gavage doses of 0.5% or 2.0% (wt/vol) sodium lauryl sulfate (SLS) in 11- to 12-week-old male CD-1 mice was evaluated in a study of 3 months in duration.

Reevaluation of Hepatocellular Neoplasms in CD-1 Mice from a 2-year Oral Carcinogenicity Study with Permethrin.

A 24-month oral carcinogenicity study of permethrin was conducted by feeding male and female CD-1 mice diets containing concentrations of 0, 20, 500, and 2,000 ppm of permethrin (males) or 0, 20, 2,500, and 5,000 ppm of permethrin (females). After approximately two years on study, surviving mice were sacrificed for the evaluation of chronic toxicity and/or carcinogenicity. An expert panel of pathologists was convened as a Pathology Working Group (PWG) to review coded liver histology sections from male and female mice and to classify all liver neoplasms according to current nomenclature and diagnostic criteria guidelines.

Regulatory Forum Opinion Piece*: The Value of Publishing Negative Scientific Study Data.

Historically it has been easier to publish positive scientific results than negative data not supporting the research hypothesis. This appears to be increasing, with fewer negative studies appearing in the literature across many disciplines. Failure to recognize the value of negative results has important implications for the toxicology community.

Distinguishing cystic degeneration from other aging lesions in the adrenal cortex of Sprague-Dawley rats.

Cystic degeneration of the adrenal cortex is a common age-related finding in the Sprague-Dawley (SD) rat strain occurring more frequently in females. Compression of the adjacent cortex, a common hallmark of benign adrenal cortical tumors, often accompanies foci of cystic degeneration, creating a diagnostic challenge. Accurately differentiating these relatively common degenerative changes from proliferative lesions is critical in safety assessment studies.

Molecular mechanisms of fibrosis-associated promotion of liver carcinogenesis.

Hepatocellular carcinoma (HCC) mostly develops in patients with advanced fibrosis; however, the mechanisms of interaction between a genotoxic insult and fibrogenesis are not well understood. This study tested a hypothesis that fibrosis promotes HCC via a mechanism that involves activation of liver stem cells. First, B6C3F1 mice were administered diethylnitrosamine (DEN; single ip injection of 1mg/kg at 14 days of age).

Acetaminophen-induced acute liver injury in HCV transgenic mice.

The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects.

A comprehensive review of the carcinogenic and anticarcinogenic potential of capsaicin.

Human exposure to capsaicin, the most abundant pungent chili pepper component, is ubiquitous. Evaluation of capsaicin's carcinogenic potential has produced variable results in in vitro and in vivo genotoxicity and carcinogenicity assays. The capsaicin tested in older studies was often from pepper plant extracts and included other capsaicinoids and diverse impurities.

Proceedings of the 2011 National Toxicology Program Satellite Symposium.

The 2011 annual National Toxicology Program (NTP) Satellite Symposium, entitled "Pathology Potpourri," was held in Denver, Colorado in advance of the Society of Toxicologic Pathology's 30th Annual Meeting. The goal of the NTP Symposium is to present current diagnostic pathology or nomenclature issues to the toxicologic pathology community. This article presents summaries of the speakers' presentations, including diagnostic or nomenclature issues that were presented, along with select images that were used for audience voting or discussion.

Increased incidence of aflatoxin B1-induced liver tumors in hepatitis virus C transgenic mice.

Viral hepatitis and aflatoxin B1 (AFB1) exposure are common risk factors for hepatocellular carcinoma (HCC). The incidence of HCC in individuals coexposed to hepatitis C (HCV) or B virus and AFB1 is greater than could be explained by the additive effect; yet, the mechanisms are poorly understood because of the lack of an animal model. Our study investigated the outcomes and mechanisms of combined exposure to HCV and AFB1.

Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning.

Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 or 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan).

Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans.

Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans.

Gene set enrichment analysis for non-monotone association and multiple experimental categories.

Background: Recently, microarray data analyses using functional pathway information, e.g., gene set enrichment analysis (GSEA) and significance analysis of function and expression (SAFE), have gained recognition as a way to identify biological pathways/processes associated with a phenotypic endpoint.

Evaluation of dichloroacetic acid for carcinogenicity in genetically modified Tg.AC hemizygous and p53 haploinsufficient mice.

There has been considerable interest in the use of genetically modified mice for detecting potential environmental carcinogens. For this reason, the National Toxicology Program has been evaluating Tg.AC hemizygous and p53 haploinsufficient mice as models to detect potential carcinogens.

Gene expression response in target organ and whole blood varies as a function of target organ injury phenotype.

This report details the standardized experimental design and the different data streams that were collected (histopathology, clinical chemistry, hematology and gene expression from the target tissue (liver) and a bio-available tissue (blood)) after treatment with eight known hepatotoxicants (at multiple time points and doses with multiple biological replicates). The results of the study demonstrate the classification of histopathological differences, likely reflecting differences in mechanisms of cell-specific toxicity, using either liver tissue or blood transcriptomic data.

Heat map visualization of high-density clinical chemistry data.

Clinical chemistry data are routinely generated as part of preclinical animal toxicity studies and human clinical studies. With large-scale studies involving hundreds or even thousands of samples in multiple treatment groups, it is currently difficult to interpret the resulting complex, high-density clinical chemistry data. Accordingly, we conducted this study to investigate methods for easy visualization of complex, high-density data.

Gene expression analysis offers unique advantages to histopathology in liver biopsy evaluations.

Liver diseases that induce nonuniform lesions often give rise to greatly varying histopathology results in needle biopsy samples from the same patient. This study examines whether gene expression analysis of such biopsies could provide a more representative picture of the overall condition of the liver. We utilized acetaminophen (APAP) as a model hepatotoxicant that gives a multifocal pattern of necrosis following toxic doses.

Hepatic transcript levels for genes coding for enzymes associated with xenobiotic metabolism are altered with age.

Metabolism studies are crucial for data interpretation from rodent toxicity and carcinogenicity studies. Metabolism studies are usually conducted in 6 to 8 week old rodents. Long-term studies often continue beyond 100 weeks of age.

Application of visualization tools to the analysis of histopathological data enhances biological insight and interpretation.

Gene expression profiling, metabolomic screens, and other high-dimensional methods have become an integral part of many biological investigations. To facilitate interpretation of these data, it is important to have detailed phenotypic data--including histopathology--to which these data can be associated, or anchored. However, as the amount of phenotypic data increases, associations within and across these data can be difficult to visualize and interpret.

Optimal sampling of rat liver tissue for toxicogenomic studies.

Different degrees of a toxic response between and within the various lobes of the liver have been observed in rodents following treatment with acetaminophen. This study was designed to compare 2 sampling methods of the rat liver for gene-expression analysis. Ten male Fischer 344/N rats, 12-14 weeks of age, were treated with vehicle (0.

Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver.

Toxicogenomics provides the ability to examine in greater detail the underlying molecular events that precede and accompany toxicity, thus allowing prediction of adverse events at much earlier times compared to classical toxicological end points. Acetaminophen (APAP) is a pharmaceutical that has similar metabolic and toxic responses in rodents and humans. Recent gene expression profiling studies with APAP found an oxidative stress signature at a subtoxic dose that we hypothesized can be phenotypically anchored to conventional biomarkers of oxidative stress.

Gene interaction network analysis suggests differences between high and low doses of acetaminophen.

Bayesian networks for quantifying linkages between genes were applied to detect differences in gene expression interaction networks between multiple doses of acetaminophen at multiple time points. Seventeen (17) genes were selected from the gene expression profiles from livers of rats orally exposed to 50, 150 and 1500 mg/kg acetaminophen (APAP) at 6, 24 and 48 h after exposure using a variety of statistical and bioinformatics approaches. The selected genes are related to three biological categories: apoptosis, oxidative stress and other.

The utility of the guppy (Poecilia reticulata) and medaka (Oryzias latipes) in evaluation of chemicals for carcinogenicity.

There has been considerable interest in the use of small fish models for detecting potential environmental carcinogens. In this study, both guppies (Poecilia reticulata) and medaka (Oryzias latipes) were exposed in the aquaria water to three known rodent carcinogens for up to 16 months. Nitromethane, which caused mammary gland tumors by inhalation exposure in female rats, harderian gland and lung tumors in male and female mice, and liver tumors in female mice by inhalation, failed to increase tumors in either guppies or medaka.

Standardizing global gene expression analysis between laboratories and across platforms.

To facilitate collaborative research efforts between multi-investigator teams using DNA microarrays, we identified sources of error and data variability between laboratories and across microarray platforms, and methods to accommodate this variability. RNA expression data were generated in seven laboratories, which compared two standard RNA samples using 12 microarray platforms. At least two standard microarray types (one spotted, one commercial) were used by all laboratories.

Hepatic gene expression changes throughout the day in the Fischer rat: implications for toxicogenomic experiments.

There is increasing use of transcriptional profiling in hepatotoxicity studies in the rat. Understanding hepatic gene expression changes over time is critical, since tissue collection may occur throughout the day. Furthermore, when comparing results from different data sets, times of dosing and tissue collection may vary.