Induction of forestomach lesions by butylhydroxyanisole and structurally related substances

Butylated hydroxyanisole (BHA) is widely used as an antioxidant in foodstuffs, in materials which come into contact with food and also in cosmetic products. The safety of BHA was questioned, however, when it was reported that in a recent Japanese carcinogenicity study 2% BHA in a pelleted diet caused hyperplasia, papillomas and squamous cell carcinomas in the forestomach of rats. In order to clarify whether substances with a similar chemical structure would also induce forestomach lesions, BHA was compared with some related chemicals in 28 day feeding studies. For this purpose groups of 5 to 10 Wistar rats were fed diets containing 2% BHA, 2% tert.-butylhydroquinone (TBHQ), 2% 4-methoxyphenol, 2% 1,4-dimethoxybenzene, 2% hydroquinone or 1% butylated hydroxytoluene (BHT), respectively, for periods of 4 weeks. BHA treatment caused severe diffuse hyperplasia, acanthosis and hyperkeratosis in the forestomach mucosa which was most pronounced in the vicinity of the limiting ridge. In TBHQ treated animals brownish discolorations of the mucosa and mild hyperplasia with focally increased hyperplasia of basal cells were observed. In the case of p-hydroxyanisole a circular deep ulceration parallel to the limiting ridge occurred with hyperplasia and mild hyperkeratosis in the adjoining mucosa. Hydroquinone caused only mild hyperplastic and hyperkeratotic areas near the oesophageal entry in a few cases. The feeding of BHT induced no visible forestomach lesions. The strong effects of BHA and 4-methoxyphenol and the more or less inactivity of BHT and hydroquinone indicate that the methoxy group of the tested anisoles might be involved in their hyperplasiogenic activity.