Abstract
Experimental renal cancer caused by ochratoxin A (OTA) in rats was first defined in the US National Toxicology Program (1989) and raised questions about any aetiological role in human urinary tract tumours. A review of histopathology in several rat kidney tumours from dietary OTA in recently described London studies, augmented by clinical immunohistochemistry for the first time for this mycotoxin, establishes their renal tubular cell origin. It had been assumed that the toxin might cause the human urothelial tumours associated with Balkan endemic nephropathy, but the present study could not support this. Comparison with a similar review of a metastasising renal tumour from a female rat of the NTP study consistently shows the kidney as the primary carcinogenic site for OTA. Morphological heterogeneity of these kidney tumours as epithelioid and/or sarcomatoid is revealed. Leiomyosarcoma was also diagnosed, and rhabdomyosarcoma differentiation was observed in the exceptionally aggressive NTP female tumour. The present pilot study involving immunohistochemistry indicates need for wider review of archived tumours for experimental evidence before formulating any epidemiological basis from a rat model for OTA’s relevance to idiopathic human renal cell carcinoma. Although the NTP study concluded that females are less sensitive to OTA than males, some female tumours still had heterogeneous morphology.
Highlights
Ochratoxin A (OTA) was first characterised in South Africa [1] but found application as a significant mycotoxin in epidemics of nephropathy in the Danish bacon industry, first noted by Larsen [2] and seasonally prevalent in the 1960s and 1970s
A major study followed in the US National Toxicology Program [4,5], notably demonstrating renal carcinomas, in male rats
A focus on the mechanisms of carcinogenicity was made in a European Commission project in the 2000s, confirming male rat sensitivity to continuous dietary OTA during most of the first half of life [7,8]
Summary
Ochratoxin A (OTA) was first characterised in South Africa [1] but found application as a significant mycotoxin in epidemics of nephropathy in the Danish bacon industry, first noted by Larsen [2] and seasonally prevalent in the 1960s and 1970s. Renal carcinogenicity was demonstrated experimentally in male mice after protracted exposure to OTA [3]. A major study followed in the US National Toxicology Program [4,5], notably demonstrating renal carcinomas, in male rats. The latter generated precautionary concern for natural OTA occurrence in some foodstuffs such as cereals, coffee and wine caused by fungal spoilage of agricultural products, and precipitated current human food safety regulations for the toxin in several parts of the world [6]. The International Agency for Research on Cancer considered
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