Cadmium (Cd) intake via diet (Cd-D) has been a long-standing focus of administrative as well as public concern in Japan after the endemic of Itai-itai disease (chronic cadmium poisoning). The aim of this report was to review cadmium exposure in Japan by introducing publications from our study group and related articles. Literature survey disclosed that Cd-D was high (up to 100 µg/day) in 1960s even in non-polluted areas. Such high Cd-D levels were followed by gradual decreases in 1970s-1980s to current level of well below 20 µg/day. Once, a very high Cd-D (600 µg/day) was reported for a Cd-polluted area. Replacement of Cd-polluted rice paddy soil with clean soil resulted in substantial reduction in rice-associated Cd-D. In large-scale surveys in 10 prefectures all over Japan conducted early in 2000s, the geometric mean (GM) of Cd-U_cr (Cd in urine as corrected for creatinine concentration) was 1.26 µg/g cr, but was higher in one north-west sea coast prefecture in Honshu Island (>3 µg/g cr). Supplemental survey in 6 neighboring prefectures on the sea coast disclosed that Cd-U_cr in some prefectures were higher as compared with the national average. It was reported that Cd in brown rice was also high. However no clear-cut indication was detected to suggest renal tubular dysfunctions. Surveys in major cities in East and South-East Asia in 1980s-1990s made it clear that Cd-D was substantially lower there than in Japanese cities; Cd exposure of general populations was almost exclusively from foods. Statistical analysis revealed that tubular dysfunction markers increased sharply when Cd-U_cr exceeded 10–12 µg/g cr. The Cd-U_cr level of 11 µg/g cr corresponded to Cd-D level of 59 µg/day. This level was in agreement with the tolerable weekly intake of 7 µg/kg body weight/week, the value recommended by the Food Safety Commission of Japan.

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There are increasing concerns about the influence of branched chain amino acid (BCAA) supplementation on the risk of cancer. However, there is no epidemiological data relevant to an association of dietary BCAA and the risk of cancer. Experimental studies evaluating the effects of leucine and isoleucine on urinary bladder carcinogenesis using a two-stage (initiation-promotion) carcinogenesis protocol with male F344 rats found that supplementation of CE2 and AIN-93G diets, but not an MF diet, with leucine or isoleucine has tumor-promoting activity on bladder carcinogenesis in rats. These findings indicate that the effects of dietary leucine and isoleucine on rat bladder carcinogenesis are dependent on the type of basal diet used. Importantly, leucine and isoleucine increased expression of amino acid transporters in bladder carcinogen-initiated urothelial cells; but in hyperplasias and bladder tumors, increased expression of these transporters became independent of leucine and isoleucine. Furthermore, leucine or isoleucine themselves do not induce toxicity; therefore, regenerative proliferation is not likely to be involved in their tumor-promoting activity. Leucine and isoleucine are essential amino acids that cannot be synthesized in the body, making optimum intake of these BCAAs essential for health. However, given the results of the above animal experiments, the long-term use of unnecessarily high dose of leucine and isoleucine should be avoided until more is known about their effects on carcinogenesis; this is particularly applicable to patients with bladder cancer.

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of oxathiapiprolin (CAS No. 1003318–67–9), a fungicide of piperidinyl thiazole isoxazoline-type, based on results from various studies. Major adverse effects of oxathiapiprolin observed are reduced gain of body weight and delayed preputial separation in rat offsprings in a two-generation reproductive toxicity study. No neurotoxicity, carcinogenicity, reproductive toxicity, teratogenicity or genotoxicity was observed. Oxathiapiprolin (parent compound only) was identified as a chemical for the residue definition for dietary risk assessment in agricultural products. The lowest no-observed-adverse-effect level (NOAEL) obtained in all the studies was 346 mg/kg bw/day in a two-generation reproductive toxicity study in rats. FSCJ specified an acceptable daily intake (ADI) of 3.4 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. FSCJ considered it unnecessary to specify an acute reference dose (ARfD), since no adverse effects would be likely to be elicited by a single oral administration.

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The Food Safety of Commission (FSCJ) conducted a risk assessment of fluazifop (fluazifop-butyl (racemate): CAS No. 69806–50–4 and fluazifop-P-butyl (R-selective): CAS No. 79241–46–6), aryloxy phenoxypropionic acid herbicides, based on results from various studies. Fluazifop-butyl and fluazifop-P-butyl show bioequivalence in pharmacokinetics in the following animal experiments, and thus data on both the chemicals were used for the assessment irrespective of the chemical forms. The lowest no-observed-adverse-effect level (NOAEL) obtained in all the studies was 0.44 mg/kg bw/day in a two-year combined chronic toxicity/carcinogenicity study of fluazifop-butyl in rats. FSCJ specified the acceptable daily intake (ADI) of 0.0044 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for adverse effects that would be likely to be elicited by a single oral administration of fluazifop-butyl or fluazifop-P-butyl was 2 mg/kg bw/day obtained in developmental toxicity studies of fluazifop-P-butyl in rats and rabbits. Applying a safety factor of 100 to the NOAEL, FSCJ specified the acute reference dose (ARfD) of 0.02 mg/kg bw for women of child-bearing ages. For general population, the lowest NOAEL of a single oral administration of fluazifop was 948 mg/kg bw obtained in an acute toxicity study of fluazifop-P-butyl in rats. FSCJ, thus, considered it unnecessary to specify ARfD due to the NOAEL above the cut-off level (500 mg/kg bw).

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The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of albendazole (CAS No. 54965–21–8), a parasiticide, based on the documents including assessment reports from the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the European Medicines Agency (EMEA), and the Australian Pesticides and Veterinary Medicines Authority (APVMA). Albendazole is considered to be of no concern for genotoxicity relevant to human health as long as used appropriately as a veterinary medicinal product, though this compound may have a genotoxic potential. The combined chronic toxicity/carcinogenicity study and carcinogenicity study in mice and rats showed no carcinogenicity. Therefore, a threshold level as acceptable daily intake (ADI) is possible to be established for the toxicity. FSCJ compared the no-observed-adverse-effect levels (NOAELs) from various toxicity studies, and adopted the NOAEL of 5 mg/kg bw/day obtained in a 6-month subacute toxicity study in dogs, and also in developmental toxicity studies in rats and in rabbits for ADI estimation. FSCJ concluded it appropriate to apply an additional safety factor of 5, and specified the ADI of 0.01 mg/kg bw/day, applying a safety factor of 500 to the NOAEL of 5 mg/kg bw/day. It has been evident that albendazole is metabolized to albendazole sulphoxide in vivo, and veterinary medicinal products containing albendazole sulphoxide as a main ingredient are used overseas. Therefore, FSCJ specified the group ADI of 0.01 mg/kg bw/day for the combined level of albendazole and albendazole sulphoxide (as albendazole eq.) considering the effect of albendazole sulphoxide.

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