Abstract
Ochratoxin A is best known as a potent renal carcinogen in male rats and mice after necessarily protracted ingestion, although valid extrapolation to any human disease has not been verified. The hypothesis that the toxin is a cause of human testicular cancer was proposed a decade ago and has proliferated since, partly through incomplete study of the scientific literature. Archived tumorous rat testes were available from Fischer F344 rats exposed to continuous dietary exposure for half of or the whole life in London in the 2000s. Renal cancer occurred in some of these cases and testicular tumours were observed frequently, as expected, in both treated and untreated animals. Application of clinical immunohistochemistry has for the first time consistently diagnosed the testicular hypertrophy in toxin-treated rats as Leydig cell tumours. Comparison is made with similar analysis of tumorous testes from control (untreated) rats from U.S. National Toxicology Program studies, both of ochratoxin A (1989) and the more recent one on Ginkgo biloba. All have been found to have identical pathology as being of sex cord-stromal origin. Such are rare in humans, most being of germinal cell origin. The absence of experimental evidence of any specific rat testicular cellular pathology attributable to long-term dietary ochratoxin A exposure discredits any experimental animal evidence of testicular tumorigenicity. Thus, no epidemiological connection between ochratoxin A and the incidence of human testicular cancer can be justified scientifically.
Highlights
Comparison is made with similar analysis of tumorous testes from control rats from U.S National Toxicology Program studies, both of ochratoxin A (1989) and the more recent one on Ginkgo biloba
The carcinogenicity of ochratoxin A (OTA) in rats and mice was firmly established for the kidneys, in males, in lifetime gavage exposure studies three decades ago [1,2], and since confirmed via dietary exposure [3,4,5]
In the U.S National Toxicology Program (NTP) toxicity study of OTA [2], the kidney was the only locus for primary cancer attributed to the toxin, from which distant metastasis was observed
Summary
The carcinogenicity of ochratoxin A (OTA) in rats and mice was firmly established for the kidneys, in males, in lifetime gavage exposure studies three decades ago [1,2], and since confirmed via dietary exposure [3,4,5]. In that publication, neither the absence of testicular cancer in mice given lifetime exposure to high-dose OTA (40 mg/Kg b.w.) while a 50% renal tumour incidence occurred [1], nor the ubiquity of tumorous testes in both control and OTA-treated rats of the NTP study [2], were explained. Primary ovary tumours were absent from all control and OTA-treated female rats in the two-year NTP study [2]; in only one case did an ovary tumour occur, and this was attributed to metastasis from a kidney carcinoma, as has since been confirmed immunohistochemically [14]. Comments on the limitations of the testicular cancer hypothesis and its experimental exploration in mice [13] were subsequently made [15], since recognition of OTA/DNA adducts only indicates exposure to the toxin, as was implicit in the mouse embryo kidney by the experimental design. Subsequently have tumorous rat testes of untreated control examples from NTP Archives been included for comparison and for scientific rigour, not to question their previous pathological diagnosis
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