ToxSci Advance Access originally published online on March 31, 2004
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Toxicological Sciences 79, 242-247 (2004)
Toxicological Sciences vol. 79 no. 2 © Society of Toxicology; all rights reserved.
Evaluation of the Potential of Triethanolamine to Alter Hepatic Choline Levels in Female B6C3F1 Mice
* Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 84674; and Department of Nutrition, School of Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599–7641
Received January 9, 2004; accepted February 14, 2004
Triethanolamine (TEA), a widely used nongenotoxic alcohol-amine, has recently been reported to cause an increased incidence of liver tumors in female B6C3F1 mice, but not in males nor in Fischer 344 rats. Choline deficiency induces liver cancer in rodents, and TEA could compete with choline uptake into tissues. The potential of TEA to cause choline deficiency in the liver of these mice as a mode of tumorigenesis was investigated. Groups of female B6C3F1 mice were administered 0 (vehicle) or a maximum tolerated dosage (MTD) of 1000 mg/kg/day TEA (Trial I) and 0, 10, 100, 300, or 1000 mg/kg/day TEA (Trial II) in acetone vehicle via skin painting 5 days/week for 3 weeks. Female CDF® rats were also administered 0 or an MTD dosage of 250 mg/kg/day TEA (Trial II) in a similar manner. No clinical signs of toxicity were noted, and upon sacrifice, levels of hepatic choline, its primary storage form, phosphocholine (PCho), and its primary oxidation product, betaine, were determined. A statistically significant decrease in PCho and betaine, was observed at the high dosage (26–42%) relative to controls and a dose-related, albeit variable, decrease was noted in PCho levels. Choline levels were also decreased 13–35% at the high dose level in mice. No changes in levels of choline or metabolites were noted in treated rats. A subsequent evaluation of the potential of TEA to inhibit the uptake of 3H-choline by cultured Chinese Hamster Ovary Cells revealed a dose-related effect upon uptake. It was concluded that TEA may cause liver tumors in mice via a choline-depletion mode of action and that this effect is likely caused by the inhibition of choline uptake by cells.
Key Words: triethanolamine; mechanism; choline deficiency.
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