To find out whether ochratoxin A (OTA), citrinin (CIT), aristolochic acids (AA) are etiologic agents of Balkan endemic nephropathy (BEN) or Chinese herbal nephrotoxicity, and associated urinary tract tumor (UTT), we have compared (i) in human kidney cell culture, the DNA adduct formation and persistence of OTA/CIT and AA adducts (ii) analyzed DNA adduct in several tumors from human kidney suspected to be exposed to either OTA and CIT, or AAs (iii) analyzed OTA, CIT, and AA in food. In kidney cell cultures, formation of specific OTA-DNA adduct and AA-DNA adduct were detected in the same range (around 10 adducts/10(9) nucleotides) and were time- and dose-dependent. After 2 days all disappeared. DNA adduct related to OTA and CIT are found in human kidney tissues from Balkans, France, and Belgium whereas no DNA adducts related to AA could be found in any tumors of BEN patients from Croatia, Bulgaria, or Serbia. No DNA adduct was found in kidney biopsy or necropsy of the French women suspected to be exposed to AA. OTA and CIT are more frequently found in rural area. AA was never detected. All these plead for implication of mycotoxins, especially OTA, in BEN and UTT.

The combined toxic effect of ochratoxin A (OTA) and penicillic acid (PA) on the body mass, the weight and pathomorphology of some internal organs was studied in 85 broiler chickens fed a mouldy diet containing 130, 300 or 800 ppb OTA and 1000-2000 ppb PA. The main pathomorphological changes were cloudy swelling and granular degeneration in the epithelium and mononuclear cell proliferation and activation of capillary endothelium in the kidney and liver; degenerative changes and depletion of lymphoid cells in lymphoid organs (bursa of Fabricius, thymus and spleen) were also seen. Protective effects of 5% total water extract of artichoke and a new natural phytosubstance Rosallsat against these pathomorphological changes were observed. A significant decrease in body mass and relative weight of lymphoid organs was found after 6 weeks of exposure and a greater decrease after 10 weeks of exposure to OTA and PA, and a protective effect of artichoke extract and a slight effect of Rosallsat against that decrease was observed. A significant increase in relative weight of liver and kidneys was also observed as well as a protective effect of artichoke extract against that increase. The quantity of OTA and the percentage of positive samples were significantly lower in tissues of chickens treated with artichoke extract or Rosallsat in addition to OTA than in those treated with only OTA.

Citrinin (CTN) is a nephrotoxic mycotoxin produced by several fungal strains belonging to the genera Penicillium, Aspergillus, and Monascus. It contaminates various commodities of plant origin, cereals in particular, and is usually found together with another nephrotoxic mycotoxin, ochratoxin A (OTA). These two mycotoxins are believed to be involved in the aetiology of endemic nephropathy. In addition to nephrotoxicity, CTN is also embryocidal and fetotoxic. The genotoxic properties of CTN have been demonstrated with the micronuleus test (MN), but not with single-cell gel electrophoresis. The mechanism of CTN toxicity is not fully understood, especially not whether CTN toxicity and genotoxicity are the consequence of oxidative stress or of increased permeability of mitochondrial membranes. CTN requires complex cellular biotransformation to exert mutagenicity. Compared with other mycotoxins, CTN contamination of food and feed is rather scarce. However, it is reasonable to believe that humans are much more frequently exposed to CTN than generally accepted, because it is produced by the same moulds as OTA, which is a common contaminant of human food all over the world. At present, there are no specifi c regulations either in Croatia or in the European Union concerning CTN in any kind of commodity.

-Histopathological, biochemical and toxicological investigations of tissues and blood of normally slaughtered chickens exhibiting different frequencies (1-2%, 40-50% and above 80%) of nephropathy changes (congested or pale and enlarged kidneys) at the slaughtering meat inspection were carried out to elucidate the aetiology of nephropathies of chickens encountered in Bulgaria. A close relationship was observed between the frequency of this nephropathy and the rate of nephrotoxic mycotoxin ochratoxin A in muscles, kidneys and livers of chickens, but the levels of ochratoxin A in corresponding feed samples (0.1-0.3 ppm) were significantly lower than the levels (2-4 ppm) required to reproduce such nephropathy. Clinicomorphological changes such as nervous symptoms, vascular and oedematous changes in various internal organs and the brain, and subcutaneous or liver and kidney haemorrhages in addition to known degenerative changes in the kidneys, liver and lymphoid organs differed from the classical description of the nephropathy made in Scandinavia. The conclusion is that the Bulgarian chicken nephropathy may have a multitoxic aetiology because it cannot be explained by the concentration of ochratoxin A alone. mycotoxic nephropathy / ochratoxicosis / mycotoxin / ochratoxin A / pathology Résumé -Néphropathie mycotoxique spontanée sans étiologie mycotoxique déterminée chez des poulets bulgares. Des études histopathologiques, biochimiques et toxicologiques des tissus et du sang de poulets montrant des fréquences variées (1-2 %, 40-50 % et supérieures à 80 %) de changements néphropathiques (reins congestionnés ou pâles et hypertrophiés) lors de l'inspection des viandes à l'abattoir, ont été entreprises afin de déterminer l'étiologie des néphropathies du poulet en Bulgarie. Une relation étroite a été observée entre la fréquence de cette néphropathie et le taux de la

Ochratoxin A (OTA) is a nephrotoxic mycotoxin with carcinogenic properties. Its presence was detected in various foodstuffs all over the world but with significantly higher frequency and concentrations in areas with endemic nephropathy (EN). Even though food is often contaminated with more than one mycotoxin, earlier studies focused on the occurrence and toxicology of only OTA. Only a limited number of surveys showed that OTA co-occurs in food with mycotoxins (citrinin-CIT, penicilic acid, fumonisin B1-FB1, aflatoxins-AF) which exert nephrotoxic, carcinogenic or carcinogen-promoting activity. This review summarises the findings on OTA and its co-occurrence with the mentioned mycotoxins in food as well as experimental data on their combined toxicity. Most of the tested mycotoxin mixtures involving OTA produced additive or synergistic effects in experimental models suggesting that these combinations represent a significant health hazard. Special attention should be given to mixtures that include carcinogenic and cancer-promoting mycotoxins.

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