Search

To investigate the toxicity and carcinogenic potential of indole-3-carbinol (I3C), the National Toxicology Program has conducted 13-week subchronic studies in Fisher 344 rats and B6C3F1 mice, and chronic 2-year bioassays in Sprague-Dawley rats and B6C3F1 mice. While the chronic study results are not yet available, subchronic study results and short-term special evaluations of interim sacrifices in the 2-year rat bioassay are presented. F344 rats were orally gavaged ≤300 mg I3C/kg body weight 5 days a week for 13 weeks. Rats treated with ≥150 mg/kg demonstrated a dose-related dilation of lymphatics (lymphangiectasis) of the duodenum, jejunum, and mesenteric lymph nodes. Material within dilated lacteals stained positively for Oil Red O and Sudan Black, consistent with lipid. Electron microscopic evaluation confirmed extracellular lipid accumulation within the villar lamina propria, lacteals, and within villar macrophages. Analyses of hepatic and pulmonary CYP1A enzymes demonstrated dose-dependent I3C induction of CYP1A1 and 1A2. B6C3F1 mice orally gavaged ≤250 mg I3C/kg body weight did not demonstrate histopathological changes; however, hepatic CYP induction was similar to that in rats. The histopathologic changes of intestinal lymphangiectasis and lipidosis in this study share similarities with intestinal lymphangiectasia as observed in humans and dogs. However, the resultant clinical spectrum of protein-losing enteropathy was not present. [ABSTRACT FROM PUBLISHER]

The heart is increasingly recognized as a target for toxicity. As studies in laboratory rodents are commonly used to investigate the potential toxicity of various agents, the identification and characterization of lesions of cardiotoxicity is of utmost importance. Although morphologic criteria have been established for degenerative myocardial lesions in rats and mice, differentiation of spontaneously occurring lesions from toxin-induced or toxin-related lesions remains difficult. A retrospective light microscopic evaluation was performed on the hearts of F344 rats and B6C3F1 mice from National Toxicology Program (NTP) studies of six chemicals identified in the NTP database in which treatment-induced myocardial toxicity was present. Two previously defined myocardial lesions were observed: “cardiomyopathy” that occurred spontaneously or as a treatment-related effect and “myocardial degeneration” that occurred as a treatment-related effect. Both lesions consisted of the same basic elements, beginning with myofiber degeneration and necrosis, with varying amounts of inflammation, interstitial cell proliferation, and eventual fibrosis. This observation is indicative of the heart’s limited repertoire of responses to myocardial injury, regardless of the nature of the inciting agent. A prominent differentiating factor between spontaneous and treatment-induced lesions was distribution and lesion onset. Once the respective lesions had undergone fibrosis, however, they generally appeared morphologically indistinguishable. [ABSTRACT FROM PUBLISHER]