Effects of BHA and related phenols on the forestomach of rats.

To determine the pathogenesis of BHA-induced forestomach lesions, the nature and time course of the early lesions in the forestomach of Wistar rats were studied. The rats were given BHA at a dose level of 2% in a powdered diet or by oral intubation of 1 g BHA/kg body weight/day in arachis oil. The hyperplastic changes in the mucosa were visible 1 day after the second application. The localization was dependent on the mode of application. Dietary exposure yielded changes in the area of the limiting ridge; oral intubation of BHA produced lesions in the apex of the forestomach. In a subchronic 90-day feeding study in rats, no recognizable effect was observed when 0.125% BHA was incorporated into the diet as a solution in arachis oil. In reversibility studies, severe forestomach lesions observed after feeding 2% BHA for 6, 12 or 15 months regressed almost completely following withdrawal of the BHA for a period of 7 months. BHA induced similar forestomach damage in NMRI mice and Syrian golden hamsters, whereas guinea-pigs, a species having no forestomach, did not show comparable lesions. Substances with similar chemical structure were tested in short-term feeding studies (tert-butylhydroquinone, 4-methoxyphenol, 1,4-dimethoxybenzene, hydroquinone, 3-methoxyphenol, 2-methoxyphenol, anisole, p-cresol, phenol and BHT). Only 4-methoxyphenol strongly affected the forestomach mucosa in a manner similar to that associated with BHA. The methoxy group in the para position seems to be important for the hyperplasiogenic activity.