Effects of Butylated Hydroxyanisole, Butylated Hydroxytoluene, and NaCl on Gastric Carcinogenesis Initiated With N-Methyl-N'-nitro-N-nitrosoguanidine in F344 Rats2

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Abstract
Promoting activities of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and NaCI and of combinations of these antioxidants with NaCI on gastric carcinogenesis initiated by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) (CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine] were investigated in male inbred F344 rats. Animals, 6-week old, were given an intragastric administration of MNNG at 150 mg/kg body weight by gastric tube and 1 week later were placed on a diet containing BHA (0.5%), BHT (1.0%), NaCI (5.0%), BHA (0.5%) plus NaCI (5%), or BHT (1.0%) plus NaCI (5.0%) for 51 weeks. Control rats received no further treatment after MNNG administration. A single intragastric application of MNNG to rats induced multiple epithelial tumors of the forestomach and a few epithelial tumors of the glandular stomach after 52 weeks. Squamous cell carcinomas of the forestomach were seen in 2 of 18 effective rats (11.1%) in the control groups, and the incidences in the groups receiving the subsequent treatment were 45.0% with BHA, 15.8% with BHT, 30% with NaCI, 70% with BHA plus NaCI, and 52.9% with BHT plus NaCI. Differences in the incidences of squamous cell carcinoma between the controls and groups given BHA, BHA plus NaCI, and BHT plus NaCI were statistically significant. NaCI given alone after MNNG administration also significantly increased the incidence of papillomas in the forestomach. Incidences of glandular stomach tumors, adenomas, and carcinomas were not affected by any of the subsequent treatments. No tumors of the stomach developed in the groups given BHA, BHT, and NaCI without MNNG pretreatment. Thus the present experiment revealed that BHA and NaCI but not BHT exert promoting activity on MNNG-induced forestomach carcinogenesis in rats and that, when BHA and BHT were given with NaCI, promotion was more marked, suggesting a synergistic effect on tumor promotion.