Abstract
An experiment to explore renal carcinogenic efficacy of male rat exposure to dietary ochratoxin A (OTA) only in the first year of life has been made in comparison to lifetime exposure. Ten months exposure to OTA at 300 µg/kg b.w. was sufficient to cause high incidence of tumours which became apparent clinically after a latency of up to a year. As a putative model for human kidney cancer, the study shows a silent organ-specific carcinogenic effect through protracted exposure up to middle age and focused probably on very few nephrons. So far, tumourigenesis has not been recognised until in the last quarter of natural rat life, but for OTA, rat renal carcinogenesis requires both long exposure and only during the first year of normal longevity. The present findings offer an experimental framework within which systematic histopathology during tumourigenesis might show whether findings of mechanistic studies in key focal neoplasms can reasonably be applied to OTA as a putative renal carcinogen for idiopathic kidney cancer in humans. Already, the rat tumours mimic those occurring spontaneously in the Eker rat, and there is disparity between the large necessary OTA exposure in the rat and the trace amounts of OTA consumed by humans. In all such complex considerations it is important to adhere rigorously to established principles of disease epidemiology.
Highlights
Ochratoxin A (OTA) is the most potent naturally-occurring nephrotoxin causing experimental kidney cancer in rats [1], and has been recognised as presenting the gold standard for log dose/response relationships as a thresholded carcinogen [2]
The comprehensive design of the National Toxicology Program (NTP) study established that, whereas no renal cancer was evident after 9 months of the gavage dosing regimen, 15 months of gavage 5 days/week caused two cases of renal Journal of Kidney Cancer and VHL 2016; 3(3)
A commentary on OTA pharmacokinetics in the middle of ‘lifetime’ exposure to the contaminated diet is evident in Figure 2, showing steady decline in plasma OTA concentration from the steady state of ~11 μg/ml when the 10month exposure to OTA ceased, corresponding to a plasma half-life of about 10 days
Summary
Ochratoxin A (OTA) is the most potent naturally-occurring nephrotoxin causing experimental kidney cancer in rats [1], and has been recognised as presenting the gold standard for log dose/response relationships as a thresholded carcinogen [2]. The first step was a male rat lifetime study in London on responses to continuous dietary administration of OTA [3], which revealed only a 20 % incidence of kidney cancer at a daily OTA intake similar to that at the high dose of the NTP study, if expressed as the average daily intake through a week [3]. This expression is relevant to a commonly used unit in toxicity risk analysis, namely the tolerable weekly intake (TWI). Continuous dietary delivery avoided the temporary decline in circulating OTA concentration in blood during the two weekly ‘rest days’ in applying the NTP’s 5day gavage regimen [4] that was reflected in ochratoxin B (OTB) excretion [5]
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