Abstract
The toxicity and possible carcinogenicity of lactitol, a lactose-derived reduced calorie sugar substitute, were examined in Wistar Cpb:WU rats. In a first 13-week study, groups of 10 weanling rats of each sex were fed diets containing 0, 5, 10, or 20% lactitol, or 25% lactose. In a second 13-week study, groups of 20 rats of each sex received diets with 0, 10, or 20% lactitol, or 25% lactose starting from an age of 3 months. In a lifetime toxicity/cancerogenicity study with in utero exposure, groups of 50 rats of each sex consumed diets with 0, 2, 5, or 10% lactitol, or 20% lactose for 130 weeks. Satellite groups of 10 rats/group received the same diet but were sacrificed after 53 weeks. Subchronic and chronic ingestion of lactitol and lactose was generally well tolerated and an effect on mortality rate was not seen. Body weight gains were slightly decreased in a dose-related manner in all experiments. Dose-related cecal enlargement was observed consistently with lactitol and lactose. Examinations for hematological parameters and urine composition did not reveal any treatment-related abnormalities. The clinical chemistry examinations revealed increased plasma alkaline phosphatase (AP) levels in rats fed 5 or 10% lactitol, or 20% lactose. Slight (microscopic) cytoplasmic alterations in the staining pattern of hepatocytes were observed in the first but not the second 13-week study in a number of male rats of the 10 and 20% lactitol groups. In the chronic study, a statistically significant increase in bile duct hyperplasia was noted in female rats fed 5 or 10% lactitol, or 20% lactose. Measurement of femur calcium content in terminated female rats revealed a dose-related, yet statistically nonsignificant decrease in the lactitol groups and lowest levels in the 20% lactose group. The histopathological examination of rats treated with lactitol and lactose for their lifetime showed an increased incidence of (1) pelvic nephrocalcinosis (5% lactitol females, and 10% lactitol and 20% lactose males and females), (2) adrenomedullary proliferative changes (10% lactitol and 20% lactose males), and (3) hyperplastic and neoplastic changes of Leydig cells (10% lactitol and 20% lactose males). Results from other studies suggest that nephrocalcinosis and adrenal medullary proliferative disease represent sequelae of a chronic, treatment-related hyperabsorption of calcium which does not occur in man. The mechanism of the testicular effect is not yet identified. However, lactitol gave completely negative results in standard tests for mutagenicity and clastogenicity, and no testicular effects or other neoplastic response was observed in lactitol-fed mice. Since Leydig cell tumors occur in humans at an extremely low rate despite the ingestion of substantial amounts of lactose with ordinary meals, the observation made in rats lacks apparent relevance for man.