||5R21CA094709-03 Interpret this number
||University Of Calif-Lawrnc Lvrmr Nat Lab
||Quantifying the Impact of Diet on Carcinogen Exposure
DESCRIPTION (provided by applicant):
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.
Environmental and chemical carcinogenesis.
, Hecht S.S.
, Felton J.S.
, Conney A.H.
, Loeb L.A.
Seminars in cancer biology, 2004 Dec; 14(6), p. 473-86.
Impact of environmental exposures on the mutagenicity/carcinogenicity of heterocyclic amines.
, Knize M.G.
, Bennett L.M.
, Malfatti M.A.
, Colvin M.E.
, Kulp K.S.
Toxicology, 2004-05-20; 198(1-3), p. 135-45.
An in vitro model system to predict the bioaccessibility of heterocyclic amines from a cooked meat matrix.
, Fortson S.L.
, Knize M.G.
, Felton J.S.
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 2003 Dec; 41(12), p. 1701-10.