Some chemicals contained in foods originating from a variety of sources including natural plants, food additives, residual pesticides, mycotoxins and by-products created during food processing and/or cooking have previously been demonstrated to be carcinogenic at various sites in rodents. This review focuses on reported renal carcinogens in natural products such as d-limonene and aristolochic acid (AA), food additives such as potassium bromate (KBrO3) and madder color (MC), as well as mycotoxins such as ochratoxin A (OTA) and citrinin (CTN) and discusses data from reporter gene mutation assays. In addition to in vivo genotoxicity, recent information on several factors related to chemical carcinogenesis, such as DNA modifications and cell proliferation, gave insight into possible modes of action that underlie renal carcinogenesis. Given that neither d-limonene nor CTN induced increases in mutant frequencies (MFs) in some reporter genes, cell proliferation at target sites arising from compensatory and/or direct mitogenic action may play a key role in the carcinogenic mechanism of these compounds. Clear positive results from reporter gene mutation assays for AA, MC and OTA strongly suggest that genotoxic mechanisms are involved in carcinogenesis induced by these agents. While KBrO3 elevated MFs in the red/gam gene (Spi−), it did so to a lower extent than did potent genotoxic carcinogens. Accordingly, the participation of genotoxic mechanisms in KBrO3-induced renal carcinogenesis may be limited.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment for methyl pyruvate (CAS No. 600–22-6) and Marinedip, an ectozoon parasiticide containing methyl pyruvate as an active ingredient for Tetraodontiformes, based on documents including a written application for marketing approval of a new veterinary medicinal product. Methyl pyruvate, a designated additive, is approved for use in fragrances in Japan. In pharmacokinetic studies, methyl pyruvate is gradually decomposed into pyruvic acid in sea water during bath treatment of fish. The concentration of methyl pyruvate in each tissue of skin, muscles and others was already below the detection limit soon after the bath treatment. Therefore, an amount of methyl pyruvate absorbed, if any, was minimal and/or rapidly metabolized in Japanese pufferfish (Takifugu rubripes). It is thus unnecessary to specify an acceptable daily intake (ADI) for methyl pyruvate. Methyl lactate, a metabolite of methyl pyruvate, is also approved as a food additive in Japan and methyl lactate is found in food such as raw sardine. It was suggested that methyl lactate is derived from a feed or an endogenous compound produced in the body of Japanese pufferfish. A Japanese pufferfish was dipped in excess amount (2 × 300 ppm) of methyl pyruvate for 15 minutes. Muscle levels of methyl lactate of non-treated wild Japanese pufferfish did not differ from those of fish treated with methyl pyruvate measured at one to five days after the treatment. Based on these findings, it was unnecessary to specify an ADI for methyl lactate. Consequently, FSCJ concludes that the risk to human health through consumption of aquatic foods from the parameters assessed is negligible as long as Marinedip is appropriately used.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of quinoclamine (CAS No. 2797–51-5), a herbicide having the structural feature of naphthoquinone, based on summary reports submitted by the applicant. Major adverse effects of quinoclamine observed are decreased body weight gain and epithelial hyperplasia of the urinary tract. Quinoclamine did not show any clear reproductive toxicity, developmental toxicity, and genotoxicity relevant to human health. Although increased incidences of transitional cell papillomas were observed in the urinary bladder of both sexes at 676 ppm in a chronic toxicity study and a carcinogenicity study in rats, a genotoxic mechanism was not likely to participate in the tumor development. It was thus considered possible to establish a threshold in the assessment. Based on the above results, only quinoclamine (parent compound) was identified as a residue definition for dietary risk assessment in agricultural products and fishery products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all the tests was 0.21 mg/kg bw/day in a two-year carcinogenicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 0.0021 mg/kg bw/day by applying a safety factor of 100 to the NOAEL.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of orbifloxacin (CAS No.113617–63-3), a family of synthetic antimicrobial agents of fluoroquinolones, based on a written application for the marketing approval of new veterinary medicinal products and its attached documents. All the in vivo data were negative in studies on genotoxicity of orbifloxacin, although some in vitro data were positive. Therefore, FSCJ concludes that orbifloxacin has no genotoxicity relevant to human health. Orbifloxacin showed photogenotoxicity in vitro and in vivo through the indirect action to DNA, suggesting that orbifloxacin has no photogenotoxicity relevant to human health. No carcinogenicity was observed in a 2 year carcinogenicity study in rats. From the results of toxicity studies, FSCJ judged it appropriate to use a lowest-observed-adverse-effect level (LOAEL) of 12.5 mg/kg bw/day observed in a 30-day subacute toxicity study in dogs, and to specify the toxicological ADI as 0.013 mg/kg bw/day, applying a safety factor of 1000 to this LOAEL. Microbiological ADI was estimated to be 0.012 mg/kg bw/day based on the VICH (the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products) guideline 36. FSCJ specified the ADI of orbifloxacin as 0.012 mg/kg bw/day which is smaller than the toxicological ADI.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of ethoxysulfuron (CAS No. 126801–58-9), a sulfonylurea herbicide, based on summary reports submitted by the applicant and documents from the Australian Government. Major adverse effects of ethoxysulfuron observed were decreased body weight gain, chronic septal hepatitis of dogs, and decreased serum T3 and T4 levels. Ethoxysulfuron did not show any clear reproductive toxicity, developmental toxicity, and genotoxicity. Although increased incidences of uterine adenocarcinomas were observed in rats in a two-year combined chronic toxicity/carcinogenicity study of ethoxysulfuron, a genotoxic mechanism was unlikely to participate in the tumor development. It was thus considered possible to establish a threshold in the assessment. Based on the above results, only ethoxysulfuron (parent compound) was identified as the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all the tests was 5.60 mg/kg bw/day in a 90-day subacute toxicity study in dogs. FSCJ specified an acceptable daily intake (ADI) of 0.056 mg/kg bw/day by applying a safety factor of 100 to the NOAEL.