We read with great interest the article by Bravi et al.,1 who reported results of one of the largest case-control investigations on renal cell carcinoma (RCC) aimed at investigating the role of diet in determining the risk of RCC in Italy. Interestingly, the authors observed a direct association of RCC risk for cereals, mainly bread, explaining that, as for other common cancers, the increased risk of RCC for elevated cereals intake may be due to the high glycemic index of these foods, and their possible involvement in insulin-like growth factors. The association of RCC with cereals is certainly a warning but is also very intriguing. Indeed, cereals grains and related by-products have a unique importance as they are consumed by millions of people and are the primary source of carbohydrates for humans. We do not want to be critical about the article by Bravi et al.1 However, we believe that, as for other diet-related tumours, mycotoxins should be considered as a dietary co-factor in determining RCC for the reasons that we propose in the present comment.
Mycotoxins are a very vast family of fungal moulds' secondary metabolites that occur in almost the totality of foods.2 They are highly undesired substances that should not be present in food and for which a zero tolerance should be adopted. However, so far, it has been impossible to achieve a truly mycotoxin-free food chain, because even good agricultural, storing and processing practices cannot completely avoid contamination.2 The Food and Agricultural Organization (FAO) estimates that about 25% of the world's food crops are affected by mycotoxins.2
Cereals are an optimal substrate for colonisation by phytopathogenic moulds as they provide excellent growth conditions for fungi in the field, after harvest and during storage.2 Two mycotoxins frequently occurring on cereals in mild climates and proved to be renal carcinogen in experimental animals are ochratoxin A (OTA) and fumonisins (i.e. FB1 and FB2). The carcinogenic potential of OTA and FB1 is firmly established on experimental animals, but the International Agency for the Research on Cancer (IARC) has classified them as Group 2B (possibly carcinogenic to humans), due to the lack of epidemiological studies on humans.3
OTA can enter the human food chain by almost the totality of foods, i.e. cereals, wine, coffee, spices, beer, cocoa, dried fruits and pork meats. Cereals are the major contributors to human exposure to OTA, accounting for 50% of the mean European dietary intake and over 70% in France.2 OTA has been identified as the causal agent in the development of renal diseases in pigs.4 According to the authors, because of the similarity of the renal anatomy and morphology of porcine and human kidney, it is plausible that humans would also be susceptible to mycotoxins known to have renal effects in pigs. Both OTA and FB1 were proved to be renal carcinogens in male Fisher rats.5, 6 These 2-year studies raised the question on the carcinogenicity of low OTA and FB1 doses in humans and whether life-long exposure could be the cause of RCC in humans. Low concentrations of OTA are frequently found in blood samples of healthy humans all round the world, which is the proof of the widespread exposure to this mycotoxin.7, 8 Besides, in humans, OTA has been suspected to be the causative agent of urothelial tumours extremely frequent in the areas with endemic nephropathy.9
Cereals are very often co-contaminated by OTA and citrinin, a mycotoxin which has marked nephrotoxic properties and is able to act synergistically with OTA.10, 11, 12, 13 Although corn surely represents the grain most susceptible to fumonisins contamination, there are some literature reports of wheat contamination by fumonisins.14 However, there is no overall consensus about the true occurrence of fumonisins in wheat as doubts have been raised on possible analytical faults leading to false positives.14 We reported in Italy the occurrence of fumonisins in wheat products, such as pasta and bread, analysed by HPLC and confirmed by LC-MS15; thus no doubt exists on the fumonisins' molecules identification. More in detail, FB1 and FB2 were detected in 29 and 33 % of bread samples, whereas FB2 was detected in all of the pasta samples. Additional data are obviously needed to confirm that in Italy bread and pasta are significant dietary sources of fumonisins, but the risk exists.
There are not available data on the occurrence of OTA in pasta and bread consumed in Italy. However, it is reasonable to believe that wheat products are important sources of OTA dietary intake, for the following reasons: (i) there are numerous data reporting the occurrence OTA in unprocessed wheat flour and wheat bread from European countries other than Italy15, 16; (ii) no significant destruction of OTA from wheat flours occurs during their processing to bread and pasta; (iii) an important amount of pasta and bread produced in Italy are obtained by wheat imported from countries known to be burdened from serious mycotoxins' contamination issues (i.e. Canada); (iv) in Italy pasta and bread are staple foods, much more than in any other country. For all the above reasons Italian researchers are called to perform monitoring and epidemiological studies. However, we believe that the fundamental limit of toxicological and epidemiological studies on mycotoxins, which form the scientific basis on which health public health authorities establish legal limits and tolerable intake, is the single mycotoxin approach. The typical pharmacological single molecule approach likely leads to an undervaluation of the real toxicological risk. Indeed, very frequently diverse mycotoxins simultaneously occur in a food and, in any case, diverse mycotoxins are ingested by means of the whole diet. Regrettably, there is growing scientific evidence demonstrating that mycotoxins, particularly OTA and other nephrotoxic mycotoxins, act in an interactive or synergistic way10, 11, 12, 17, 18 sharing the same bioactivation/detoxification metabolic pathways.
A very animated debate is still in progress in the scientific community regarding the real risk posed by mycotoxins and, in this sense, OTA is exemplary. Undeniably, many aspects of OTA, i.e. the mechanism of genotoxicity, the total dietary burden, the efficacy of the legal limit and the reliability of proposed tolerable dietary intake still remain open questions.2 The uncertainties on this very singular mycotoxin have been efficaciously resumed by O'Brien and Dietrich,19 whose study defined OTA as the continuing enigma. Obviously, by the present letter we do not pretend to solve such an enigma, neither definitively clarify whether OTA, as well as other mycotoxins, are associated with the risk of RCC and other human cancers. We just hope that, in the meanwhile, mycotoxins could be considered in future studies aimed to establish the role of dietary factors in determining human cancers and the elegant study by Bravi et al.1 gave us the opportunity to emphasise it.