13-week oral toxicity study with stanol esters in rats

Plant sterols and their saturated derivatives, known as stanols, reduce ser um cholesterol when consumed in amounts of approximately 2 g per day. Stano l fatty acid esters have been developed as a highly fat-soluble form that m ay lower cholesterol more effectively than stanols. Stanol esters occur nat urally in human diets, but at levels far below those known to lower cholest erol. The present study was conducted to assess the safety of stanol esters upon subchronic ingestion at levels comparable to or exceeding those recom mended for lowering cholesterol. Two stanol fatty acid ester preparations, wood-derived stanol esters and vegetable oil-derived stanol esters, were fe d to groups of 20 male and 20 female Wistar rats for 13 weeks, at dietary c oncentrations of 0, 0.2, 1, and 5% total stanols (equivalent to 0, 0.34, 1. 68, and 8.39% wood-derived stanol esters and 0, 0.36, 1.78, and 8.91% veget able ai l-derived stanol esters), Both preparations were well tolerated as evidenced by the absence of clinical changes or major abnormalities in grow th, food and water consumption, ophthalmoscopic findings, routine hematolog ical and clinical chemistry values, renal concentrating ability, compositio n of the urine, appearance of the feces, estrus cycle length, organ weights , gross necropsy findings, and histopathological findings. Plasma cholester ol and phospholipids were slightly decreased in males fed the stanol esters . In both sexes, plasma levels of plant sterols were decreased whereas thos e of stanols tended to increase. Fecal excretion of sterols, including chol esterol, and stanols was markedly increased in the stanol ester groups. Com pared to controls, male rats fed stanol esters showed somewhat lower liver weights and more pronounced glycogen depletion. These hepatic changes were considered to reflect an altered nutritional condition slid not a pathologi cal condition. Plasma levels of vitamin E, vitamin K-1, and, to a lesser ex tent, vitamin D were decreased in males and females fed the high-dose diets . Hepatic levels of vitamins E and D showed similar changes (vitamin K-1 in the liver was not determined). For both preparations, the mid-dose level ( 1% total stanols in the diet) was a no-observed-adverse-effect level. This dietary level provided approximately 0.5 g total stanols/kg body wt/day. (C ) 1999 Academie Press.