br Pickled vegetables and nitrosamines br Commonly
2.2. Pickled vegetables and nitrosamines
Commonly consumed in the high-risk areas of China, pickled ve-getables were once suspected to be contributing to the esophageal cancer epidemic. But epidemiological studies did not find consistent association between cancer risk and intake of pickled vegetables (Kamangar et al., 2009; Li et al., 1989). Nitroso compounds, particu-larly nitrosamine detected in drinking water and pickled vegetables, were once suspected to be the most likely causative agents for eso-phageal cancer in the Taihang Mountains region, but the researchers failed to detect nitrosamine-DNA adducts in human esophagus tissues. Extracts of the pickled vegetables were found to be mutagenic ac-cording to the Ames test and contain N-nitroso compounds, but the International Agency for Research on Cancer (IARC) Working Group failed to find adequate evidence from experimental animals to support the carcinogenicity of pickled vegetables (International Agency for Research on Cancer (IARC), 1993).
2.3. Thermally hot food
It was once thought that consumption of thermally hot meals might contribute to the development of esophageal cancer. However, com-parative surveys in high- and low-incidence areas and laboratory in-vestigations did not support this hypothesis. For example, food at a temperature of 75 °C causes only minor scalds whereas corn meal or millet gruel usually has a temperature of 51 °C (Li and Cheng, 1984). In an African study, ESCC patients were found to have higher oral heat tolerance (69–75 °C) than the general community (53–62 °C) (McCormack et al., 2017); preference for hot food might be the eﬀect of ESCC development rather than a cause of it. Hot food intake was not associated with increased risk of ESCC and precursor lesions according to a population-based endoscopic survey in Anyang, China (He et al., 2010).
2.4. Vitamin and mineral deficiencies
Vitamin and micronutrient deficiencies were considered important risk factors for ESCC because low intake of fruit and vegetables were inversely associated with ESCC risk in most studies conducted by the early 1980s. In the high risk area of Linxian county, the residents were found to have deficiencies in certain vitamins and minerals. However, the micronutrient hypothesis of the ESCC etiology was not supported by the two large chemoprevention trials: the Linxian Dysplasia Trial on a Ecotoxicology and Environmental Safety 178 (2019) 79–85
combination of 26 vitamins and minerals and the Linxian General Population Trial on four nutrient groups: 1) retinol and zinc, 2) ribo-flavin and niacin), 3) ascorbic Geneticin and molybdenum, and 4) selenium,
α -tocopherol, and β -carotene. After 6 years of intervention, neither of the two trials demonstrated any risk reduction for ESCC using any of these nutrient supplements (Kamangar et al., 2009). Overall mortality or cancer incidence was not reduced by the nutritional intervention, either (Wang et al., 2013).
2.5. Silica fibers from millet bran
Dr. C. H. O'Neill (Imperial Cancer Research Fund, London, UK) first reported the linkage between biogenic silica fibers in millet bran and ESCC development in Linxian, China (O'Neill et al., 1982). Sharply pointed silica fragments was detected in the esophagus of the ESCC patients. These silica fibers lodged in the esophageal tumors and throughout the depth of the mucosa. Esophagus of domestic chickens in Linxian, which also had a high incidence of ESCC, contained similarly high content of silica. These silica fibers can cause repeated local injury as they pass down the esophagus and stimulate proliferation by pro-viding anchorage (O'Neill et al., 1986). The findings of O'Neill was challenged by van Rensburg (1982) for at least two reasons: 1) high contents of silica in esophagus tissue in Linxian cases was based on the comparison with England controls, which was not considered an ap-propriate comparison; 2) in the regions of China with the highest in-cidence of esophageal cancer, maize and wheat, instead of millet, were the major staple. This research area on silica fiber and cancer lost an important drive with the retirement of Dr. O'Neill in the late 1980s (Sangster et al., 2001). This hypothesis of millet bran derived silica has since been largely ignored in later etiologic studies of ESCC in China.
Silica fibers from wheat husks and esophageal cancer: a renewed hypothesis.
Integrating the previous multidisciplinary findings, we hypothesize that silica fiber from wheat husks is an important risk factor for the ESCC epidemic in north China. This hypothesis is supported by the following observations: 1) Wheat, silica, and ESCC. By genotype, wheat (Triticum aestivum) is a silica accumulator (Hodson et al., 2005; Rodrigues and Datnoﬀ, 2015); wheat consumption is linked to an ele-vated ESCC risk in human population studies (Chen et al., 1993; Li et al., 1989; Rensburg, 1981). As seen in Fig. 1, siliceous prickles are abundant on the surface of wheat husks (Hodson and Sangster, 1989, 1988; Sangster et al., 2001); these silica prickles can contaminate wheat flour, lodge in the esophagus tissue, and enhance cell proliferation by providing anchorage stimulation (O'Neill et al., 1986). Silicified prickles broken from the wheat husks during the wheat threshing process cannot be easily removed from the subsequent winnowing process because of their siliceous nature and high density. As seen in Fig. 1F, these prickles occur with a high frequency in wheat dust (Martin, 1981). Only in wheat and rye, these silica prickles occur on both inner and outer surfaces of inflorescence bracts while they occur only on the outer surfaces of the bracts in other genera (Hodson and Sangster, 1989). Wheat is a C3 plant. Silicified prickles occur more frequently on C3 leaves than on C4 grass leaves (Sangster and Hodson, 1986). 2) Aridity, silica, and ESCC. By climate conditions, aridity enhances silica deposit in plants (Cooke and Leishman, 2011; Coskun et al., 2016; Morgan-Edel et al., 2015; Sangster and Hodson, 1986); aridity is linked to an elevated ESCC risk (Rensburg, 1981; Wu and Li, 2007). 3) Siallitic soil, silica, and ESCC. The soil in the ESCC epidemic area of north China is siallitic soil (Wei et al., 1991), a soil type with high silica content. Biogenic silica formation in plants depends on not only genotype and climate, but also silicon availability in soil. 4) Chicken, silica, and ESCC. Chicken in the ESCC epidemic area had a similarly high incidence of ESCC (Liu and Li, 1984); the esophagus of domestic chickens in Linxian contained a similarly high content of silica as in the human esophageal tumors (O'Neill et al., 1982); wheat husks, an unintentional food source shared by men and chicken, have much