Human epidemiologic and animal studies have shown that diet has a role in the etiology of human cancer. Cooked muscle meats contain potent mutagens and rodent carcinogens belonging to the heterocyclic amine (HA) class of compounds. Based on analyses of cooked meats, humans are exposed to HAs at levels that may exceed a hundred parts-per-billion. Although we can reliably measure the amount of HAs present in cooked meats, quantifying the biologically effective dose of these compounds is currently limited by our imperfect understanding of the effects of individual physiology and the interactions of these carcinogens with other foods in the diet. The objective of this study is to develop an exposure assessment method that will predict the effect of digestion parameters, intestinal transport and diet upon the low dose exposure to commonly ingested food carcinogens.
The specific aims of the proposal are: 1) develop an in vitro digestion procedure to estimate the bioavailability of the four most commonly occurring HAs, 2) determine the absorption of the carcinogens from the digestates using the human colon carcinoma cell line Caco2, a commonly used model for intestinal absorption, 3) determine the effects of single and multiple food interactions on carcinogen bioavailability in a controlled environment and 4) determine the biologically effective dose of these compounds in humans and validate the in vitro method. Cooked meats will be digested in the laboratory and HAs made available from the meat matrix will be measured using HPLC. The laboratory digestates will then be coupled to Caco-2 intestinal cells to measure transport across the intestinal cell wall. Using this method the effect of other foods on HA bioavailability will be determined by digesting the meat concurrently with vegetables, fruits, liquids, carbohydrates, and fats. Finally, the results of the laboratory study will be compared to two human studies to validate the method. At present there is no accurate way to determine bioavailability of HAs. The in vitro method proposed here could provide valuable insight into the dietary interactions that modulate the bioavailability of these compounds. These experiments will also provide a basis for more accurate exposure measurements for epidemiological investigations of diet and cancer. Better estimates of the bioavailable dose of these food carcinogens and an understanding of how other foods affect bioavailability will make it possible to devise strategies that could potentially reduce exposure levels. Because the results will be based upon interactions of common foods, these results can be easily translated to the public. Once the impact of dietary factors is understood, then it will be possible to emphasize prevention strategies that will eliminate or modify the risk.
| Wogan, Gerald N; Hecht, Stephen S; Felton, James S et al. (2004) Environmental and chemical carcinogenesis. Semin Cancer Biol 14:473-86 |
| Felton, James S; Knize, Mark G; Bennett, L Michelle et al. (2004) Impact of environmental exposures on the mutagenicity/carcinogenicity of heterocyclic amines. Toxicology 198:135-45 |
| Kulp, Kristen S; Fortson, Susan L; Knize, Mark G et al. (2003) An in vitro model system to predict the bioaccessibility of heterocyclic amines from a cooked meat matrix. Food Chem Toxicol 41:1701-10 |
