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Biochemical changes during ochratoxin A-induced renal tumorigenesis

Radiolabeled ochratoxin A for AC/MS studies have been provided and large amounts of ochratoxin a produced. In this part of the project, groups of male Fischer rats were exposed to OTA in the diet. After 11 months at 0.2mg/kg OTA daily with feed, OTA did not influence body weight gain and no gross abnormalities were seen.

Microscopically, there was only a more prominent karyocytomegaly in renal proximal tubule epithelia than was seen at earlier stages.

Giving OTA for up to 2 years induced a dose-dependent increase in the incidence of renal tumors, all tumors were discovered in the last quarter of life of the treated rats. The regime was well tolerated; only at the highest dose there was slight impairment of renal function. Aging Fischer rats have a confounding factor of a particular leukaemia, which complicated assessment of tumour incidence.

When comparing the present data with that of the NTP (gavage) study of 1989, OTA is app. 5 times less potent when given in diet as compared to oral gavage 5 times a week. Consequently, the threshold dose of the NTP study may be adjusted higher for a dietary exposure regime. Rats given the highest dose of OTA for only the first 10 months developed renal tumours after a further one-year latency, during which circulating ochratoxin A had disappeared with a half-life of about 11 days.

Consequently, any mechanism for carcinogenesis in the rat will have to be in place by within at most 10 months’ exposure, and must then be able to endure long absence of OTA during which many or all of the mild general toxicologic influences will have probably long been resolved. That mechanism must be shown to apply to the human since OTA has never been shown to cause human morbidity.

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Reported by

Imperial College London
Department of Environmental Science and Engineering, Imperial College London
SW7 2AZ London
United Kingdom
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