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Cell proliferation and apoptosis during chloroform-induced hepatocarcinogenesis in male F-344/N rats.
Citation:
Deddens, J. A., J. H. Carter, W. H. Carter, R. Richmond, AND A. B. DEANGELO. Cell proliferation and apoptosis during chloroform-induced hepatocarcinogenesis in male F-344/N rats. . Presented at American Association of Cancer Research (AACR), Washington, DC, April 17 - 21, 2010.
Impact/Purpose:
Time/dose analysis of chloroform-induced liver cancer in rats. Quantification of lesion sequence, cell birth and cell death within the lesion. May be useds as basis of a BBDRM for chloroform
Description:
The carcinogenic potential of chlorinated organics is of direct importance in human risk assessment. Most drinking water chlorinated organics are disinfection by products (DBPs) of water chlorination and many test positive in rodent bioassays. Trihalomethanes (THMs) are the most prevalent DBPs generated in chlorinated drinking water and chloroform (TCM) is the THM in highest concentration in finished drinking water. Human exposure to TCM occurs through ingestion ofdrinking water, inhalation and dermal exposure. TCM is carcinogenic to the liver and kidney of rodents including male and female B6C3Fl mice and male F-344/N and Osborne-Mendel rats. The carcinogenic mechanism ofTCM in the rodent is not completely understood. Four mechanisms have been proposed: 1) mutagenicity; 2) reparative hyperplasia; 3) altered gene expression; and 4) secondary genotoxicity. Here, histopathology, immunohistochemistry, and quantitative image analysis were used to examine reparative cell proliferation and altered gene expression as potential mechanisms of TCM-induced hepatocellular carcinogenesis in male F-344/N rats. Animals were exposed to concentrations of 803 ± 5 or 1592 ± 21 mg/L in the drinking water for 78 or 100 weeks. Distilled water was the vehicle control. The high TCM dose increased the prevalence (% of animals with a lesion) ofhepatocellular neoplasia (carcinoma and adenoma) 17.5% vs. 5.1% (p<0.05) and marginally enhanced the prevalence of combined preneoplastic and neoplastic tumors (20.5% vs 7.7%; 0.05