Trans-zearalenone, a resorcylic acid lactone, also known as F-2 toxin, is a nonsteroidal estrogenic mycotoxin produced by numerous species of Fusarium. As a result zearalenone is found in a number of cereal crops and their derived food products. A closely related substance “zeranol” (zearalanol) is at present being used in the United States and Canada as an anabolic agent in beef cattle. Zearalenone has been implicated in numerous incidences of mycotoxicosis in farm animals, especially pigs.
In this report the health risks to Canadians due to the presence of zearalenone in food products have been evaluated. The first part of the report deals with the physicochemical aspects, mycology, laboratory production, and natural occurrence in plant products and animal products of zearalenone. The stability of zearalenone in foods and feeds, the effects of food processing, and the removal from foods and feeds by physicochemical means are also discussed. From these data the daily exposure of Canadians to zearalenone from food consumption has been estimated to be in the range of 0.05–0.10 μg/kg b.w./day (mean and 90th percentile of eaters, respectfully) for young children, the highest consumption group on a body weight basis.
The second part of the report deals with the metabolic disposition of zearalenone as well as the available toxicity data base of zearalenone in laboratory animals, farm animals, and humans. Studies in various species (rodents, rabbits, pigs, monkeys) including man have shown that zearalenone has estrogenic and anabolic activity. Its major effects are on reproduction, including reproductive organs and their function, leading to hyperestrogenism. Zearalenone has been implicated in numerous incidences of hyperestrogenism in farm animals, especially pigs. For reproductive effects a no adverse effect level (NOAEL) of 0.06 mg/kg b.w./day was estimated for the pubertal pig, the most sensitive species tested.
Important differences in the biotransformation of zearalenone were noted, with greater amounts of α-zearalenol, the more estrogenic metabolite, formed in man and the pig compared to rodents. In addition, the biological half-life of these substances was longer in man than in other species tested.
The binding of zearalenone to estrogen receptors was approximately 20-fold lower than that seen with 17β-estradiol in several assays. The estrogenic potency of zearalenone in most uterotropic and vaginal cornification assays was approximately 1000-fold lower than that seen with 17β-estradiol; lower potency differences were apparent in the neonate and in vitro. The nonhormonal effect level (NHEL) for zearalenone was estimated to be 0.05 mg/kg b.w./day, based on a 90-day vaginal cornification study in ovariectomized monkeys with the closely related α-zearalanol. This value compares closely to the NOAEL of 0.06 mg/kg b.w./day for reproductive effects caused by zearalenone in pubertal pigs. In extrapolating to humans the significance of the NHEL obtained in studies with monkeys, we have used a safety factor of 500, which takes into account factors for interspecies (10) and intraspecies (10) differences as well as problems regarding suitability of the model (5). Thus, the safe intake estimate based on the NHEL is 0.10 μg/kg b.w./day.
The results of carcinogenicity bioassays conducted in rats and mice were considered by NCI/NTP as “positive evidence of carcinogenicity”; IARC placed zearalenone in the category of “limited evidence of carcinogenicity.” Further studies will be required to confirm whether zearalenone should be considered as a potential human carcinogen. The genotoxicity of zearalenone has not yet been adequately studied. Based on the NTP study with zearalenone in mice, the virtual safe dose (VSD) at a risk level of 1:106 was estimated as 0.05 μg/kg b.w./day.
The safe intake estimates based on the NHEL and the tumorigenicity data were similar, indicating that these are probably reasonable approaches for risk assessment of hormonal substances. The risk assessment approach used for the extrapolation of the tumorgenicity data is a very conservative one. The overall weight of evidence suggests that an intake of less than 0.10 μg/kg b.w./day would provide an adequate margin of safety to the consumer. Nevertheless, this should only be considered as a tentative tolerable daily intake, open to continual review.
Comparison of the current Canadian exposure to zearalenone with the above estimated tentative tolerable daily intake indicates that no adverse health effects are anticipated from zearalenone exposure from corn cereals. However, it is possible that exposure to zearalenone from other food sources such as wheat, flour, or milk could increase the exposure estimates. Furthermore, exposure to estrogens from other sources would add to the estrogenic burden.
Recommendations for risk management and further research needs are included.
