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Oesophageal cancer occurs at a very high frequency in certain areas of China, especially in Linxian county, Henan province. Previous studies suggested that N-nitroso compounds play a causative role. In order to study further the exposure of Linxian inhabitants, the intake of N-nitrosamines in the diet was determined. The total daily intake of volatile nitrosamines and of N-nitroso-N-methylbenzylamine (NMBzA) was higher in Linxian than in two other counties. NMBzA can induce cancer in animal and human oesophageal epithelium. Human fetal oesophageal epithelia were cultured with NMBzA for 4 h, and eight monkeys were treated with NMBzA. High-molecular-weight DNA extracted from explants and from the oesophageal epithelia of monkeys induced malignant transformation of NIH 3T3 cells. Alu and monkey-specific repeat sequences were present in transformed cells, and H-ras was found in the transforming DNA. Human fetal oesophageal epithelium cultured with NMBzA was transplanted into the mesentery of BALB/c nude mice. Tumours were found after eight months; and the Alu sequence was present in DNA extracted from tumours induced by NMBzA, showing that the tumours were of human origin. The results provide direct evidence that NMBzA is carcinogenic in human oesophageal epithelium and that N-nitrosamines are one of the causative factors of oesophageal cancer in Linxian county.

Studies on the relevance of the N-nitrosamines to esophageal cancer in China are reviewed. Esophageal cancer is a complex and multifactorial problem. Although a causal association between nitrosamines exposure and esophageal cancer in China has not yet been rigorously established, exposure of Lin-Xian subjects to nitrosamines either directly or as a result of their in vivo formation has been detected in our study. Several N-nitrosamines (NDMA, NDEA, NMBzA, NPyr, NPip, and NSAR) in gastric juice collected from Lin-Xian inhabitants have been detected. A correlation was found between the lesions of esophageal epithelium and the amount of nitrosamines present. In addition, the amounts of N-nitrosamino acids (N-nitrosoproline, N-nitrosothiazolidine 4-carboxylic acid, NSAR, and nitrates) excreted in 24-hr urine of subjects in Lin-Xian were significantly higher than those in Fan-Xian, indicating a higher exposure to N-nitroso compound and their precursors of the inhabitants in the high-risk area. The effect of nitrosamines on human esophagus has been investigated at the cellular levels. The amounts of O6-MedG in DNA of esophageal or stomach mucosa of patients from Lin-Xian were higher than that from Europe (Lyon and Essen). The presence of O6-MedG in the human fetal esophagus cultured with NMBzA was also detected. These findings indicate that the elevated levels of O6-MedG in esophageal DNA could be the result of a recent exposure to N-nitroso compounds or a genetically determined reduced cellular capacity for repair of O6-MedG from DNA. The hyperplasia was induced in the esophagus of human fetus that cultured with NMBzA for 2 weeks to 2 months. The intervention studies of esophageal cancer in Lin-Xian have been pursued. Intake of moderate doses of ascorbic acids by Lin-Xian subjects effectively reduced the urinary levels of N-nitrosamino acids to those found in un-dosed subjects in the low-risk area. If N-nitroso compounds are formed in vivo and are among the causative factors of esophageal cancer in Lin-Xian, ascorbic acid appears to be effective in lowering the body burden of these carcinogenic compounds. Thus, the plan of chemoprevention is carried out in Lin-Xian.