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Molecular Dosimetry of Urinary Aflatoxin-DNA Adducts in People Living in Guangxi Autonomous Region, People's Republic of China¹

Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland 21205 [J. D. G., A. P.]; Institute of Nutrition and Food Hygiene, Chinese Academy of Preventive Medicine, Beijing, China [Z. J., C. J-s.]; Massachusetts Institute of Technology, Division of Toxicology, Cambridge, Massachusetts 02139 [P. R. D., G. N. W.]; and Guangxi Regional Institute for Cancer Research, Nanning, Guangxi, China [Z. L.]

Hepatocellular carcinoma is one of the five leading human cancers causing at least 250,000 deaths each year. One of the major risk factors for this disease is exposure to dietary aflatoxins, and the development of appropriate molecular dosimetry biomarkers would facilitate the identification of individuals at risk. This study was undertaken to explore the relationship between dietary intake of aflatoxins and the excretion of the major aflatoxin-DNA adduct and other metabolites into the urine of chronically exposed people. The following protocol was developed for this investigation in Guangxi Autonomous Region, People's Republic of China, where the diets of 30 males and 12 females (ages, 25–64 years) were monitored for 1 week and aflatoxin intake levels determined each day. Starting on the fourth day, total urine volumes were obtained in consecutive 12-h fractions for 3 or 4 days. High performance liquid chromatography and competitive radioimmunoassay analyses were done on each of the urine samples, and the relationships between excretion of total aflatoxin metabolites, aflatoxin-N⁷-guanine, aflatoxin M₁, aflatoxin P₁, and aflatoxin B₁, and aflatoxin B₁ intake values were determined. The average intake of aflatoxin B₁ by men was 48.4 µg/day, giving a total mean exposure during the study period of 276.8 µg. The average daily intake by women was 77.4 µg/day, resulting in a total average exposure during the 7-day period of 542.6 µg aflatoxin B₁. Initial efforts to characterize aflatoxin metabolites in urine samples were with an analysis by competitive radioimmunoassay. The analysis by linear regression of the association between aflatoxin B₁ intake/day and total aflatoxin metabolite excretion/day showed a correlation coefficient of only 0.26. These findings stimulated the immunoaffinity/analytical high performance liquid chromatography analysis for individual metabolites. When the data were analyzed by linear regression analysis, the aflatoxin N⁷-guanine excretion and aflatoxin B₁ intake from the previous day showed a correlation coefficient of 0.65 and P< 0.000001. Similar analysis for aflatoxin M₁ resulted in a correlation coefficient of 0.55 and P < 0.00001, whereas there was no positive statistical association between exposure in the diet and aflatoxin P₁ excretion, despite aflatoxin P₁ being quantitatively a major metabolite. Analysis of the total aflatoxin-N⁷-guanine excretion in the urine during the complete collection period plotted against the total aflatoxin B₁ exposure in the diet for each of the individuals, smoothing the day to day variations, revealed a correlation coefficient of 0.80 and P < 0.0000001. Given this analysis, it is clear that a summation of excretion and exposure status provides a stronger association between exposure and a molecular dosimetry marker than was seen in prior statistical analyses. These findings support the concept that quantitation of the aflatoxin-N⁷-guanine adduct in urine is a good biomarker for aflatoxin B₁ exposures.

¹ This research was supported by grants U01 CA48409, ES00597, and CA54114 from the USPHS. J.D.G. is a recipient of USPHS Research Career Development Award K04 CA01517. Preliminary results of these data were reported at the American Association of Cancer Research Annual Meetings in 1987 and 1989.

² To whom requests for reprints should be addressed, at Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, 615 North Wolfe Street, Baltimore, MD 21205.

Received 7/24/91. Accepted 10/17/91.

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