Lactitol is a disaccharide sugar alcohol (polyol) which is derived from lactose by catalytic hydrogenation and which may be used as a noncariogenic, reduced calorie sugar substitute in different foods. In the context of the safety evaluation of lactitol, a chronic carcinogenicity/toxicity study was conducted in a Wistar-derived strain of rats. In addition to effects that occur commonly in rats fed high doses of polyols, an increased incidence of Leydig cell tumors was observed in rats fed a diet with 10% lactitol for their lifetime. A comparison group receiving a diet with 20% lactose exhibited the same effect. At the 5% dose level of lactitol, no testicular changes were seen. Although lactitol is not genotoxic in standard in vitro tests and was also not associated with tumor formation in female rats and mice of either sex, it was necessary to assess the relevance of the testicular neoplastic growth for human safety. A comparative evaluation of the spontaneous and chemically induced formation of Leydig cell tumors in rats and humans demonstrates that the spontaneous occurrence is extremely low in humans but rather high in rats. Chemical agents or experimental conditions that in rats are associated with interstitial cell hyperplasia or neoplasia have not been associated with similar effects in humans. This is also true for lactose which, in Western countries, is consumed regularly and in substantial amounts with dairy products. Since lactitol is essentially not hydrolyzed in the small intestine, it gains access to the metabolism only after fermentation by the intestinal flora. It is therefore reasonable to assume that the testicular effects of lactitol and lactose were mediated by changes in the digestive tract such as by the known increase of calcium absorption which occurs in lactitol- and lactose-fed rats but not in humans or by effects of these compounds on the enterohepatic cycling of steroid hormones. Although these mechanisms are not yet elucidated, the available data on Leydig cell tumors indicate that the effects seen in male rats are not relevant to humans. The major lines of evidence supporting the human safety of lactitol and lactose are: (1) the lack of genotoxicity of lactitol, (2) the rat specificity of the testicular effects of lactose and lactitol, (3) the long history of safe consumption of lactose in humans, (4) the insensitivity of the human Leydig cells to agents and conditions that are known to cause neoplastic growth of Leydig cells in rats, (5) the generally very low spontaneous incidence of Leydig cell tumors in the human population, and (6) the absence of any epidemiological evidence establishing a link between nutritional factors and the occurrence of Leydig cell tumors in humans.
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