Recently, a long-term (1-year) dog toxicity study has not been a mandatory toxicity study for application of agricultural chemical in the United States (US) and the European Union (EU). This study was conducted to propose a guide for making science-based judgement on the necessity of long-term dog toxicity study, which is one of required toxicity studies at toxicological evaluation in Japanese pesticide regulation system. In order to carry out the proposal we analyzed the results of toxicity studies including subacute (3-month) toxicity study in dogs or toxicity studies in other species in the pesticide evaluation reports published by the Food Safety Commission of Japan (FSCJ), the responsible regulatory body for toxicological evaluation of pesticides in food. In the analysis of evaluation reports of 286 pesticides ADI (acceptable daily intake) of 93 pesticides (32.5%) were established based on dog studies. The ADIs of 74 pesticides among them, however were not considered to have a big influence if the long-term dog toxicity study was omitted. With regard to the other four agents the possibility that the long-term dog study becomes unnecessary was considered by adding detailed examination. With respect to the remaining 15 agents, we could not judge that long-term dog study were unnecessary. The analysis indicated that the dog long term test could be omitted in most cases. On the other hand, it should be considered carefully necessity of the long-term dog study when the toxicological profiles observed in dogs and rats were different, when the toxicity susceptibility in dogs was considered high, when no no-observed-adverse-effect level (NOAEL) is specified in subacute toxicity study in dogs or when bioaccumulation in dogs is concerned. We also noted that the studies already conducted for pesticide registered previously should be used for their hazard evaluation.
The Listerial flora and Listeria monocytogenes bio-load associated with 411 ready-to-eat (RTE) foods sold at several locations in southern Nigeria was evaluated using phenotypic procedures which included serial dilution and pour plate techniques. Selected L. monocytogenes strains phenotypically identified from the RTE foods were further identified using virulence gene markers and 16srRNA amplification procedures. All the 90 L. monocytogenes strains cultured from the RTE foods were subjected to antibiogram analysis using disc diffusion. Some of the antibiotics employed included; Ceftazidine, cefuroxime, gentamicin, ofloxacin, augumentin, tetracycline and erythromycin. L. monocytogenes L. ivanovii, L. grayi, L.welshimeri, L. seeligeri and L. innocua were detected in the RTE foods. Haemolysin (hlyA) gene, Internalin gene (inlA) and invasive gene (iap) were detected in all L. monocytogenes isolates. L. monocytogenes LMEW70 with accession number KY053295 was 93% similar to L. monocytogenes L1846. All the L. monocytogenes isolates were resistant to amoxicillin, cloxacillin, augumentin and ceftazidime.
The prevalence and antimicrobial susceptibility of Salmonella in 512 poultry meat samples collected from retail stores and poultry-processing plants in Japan between 2015 and 2016 were investigated. The results showed that 55.9% of poultry meat samples were contaminated with Salmonella, with nine different serotypes represented. The most frequent serovar was Salmonella enterica serovar Infantis, followed by S. Schwarzengrund, together accounting for 78.2% of the isolates. High antimicrobial resistance rates were observed against tetracycline (80.9% S. Infantis and 83.9% S. Schwarzengrund), streptomycin (53.4% S. Infantis and 76.8% S. Schwarzengrund), and kanamycin (33.6% S. Infantis and 82.1% S. Schwarzengrund). All tested isolates were susceptible to colistin and ciprofloxacin. In addition, a high proportion (65.6% of S. Infantis, 85.7% of S. Schwarzengrund) of Salmonella isolates were resistant to two or more antimicrobials, and 22 and 17 different resistance patterns were observed in the two strains, respectively. The predominant antibiotic resistance patterns were streptomycin-tetracycline (32/131, 24.4% of S. Infantis) and streptomycin-kanamycin-tetracycline-sulfamethoxazole/trimethoprim (43/112, 38.4% of S. Schwarzengrund). These data indicate that multidrug-resistant S. Infantis and S. Schwarzengrund have spread among poultry meat in Japan.
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of desmedipham (CAS No. 13684-56-5), a carbanilate herbicides, based on results from various studies. Major adverse effects of desmedipham were suppressed body weight, hemolytic anemia, methemoglobinemia and follicular cell hypertrophy in thyroid. Neither carcinogenicity, reproductive toxicity, nor genotoxicity relevant to human health was observed on desmedipham. Desmedipham, at the dose with maternal toxicity, caused external anomalies such as mandibular malformation and cleft palate, visceral anomalies such as ventricular septum defect, and skeletal anomalies such as defect of sternum and asymmetric alignment of seternebral hemicentres in developmental toxicity studies in rats. No teratogenetic effects were observed in rabbits. The lowest no-observed-effect level (NOAEL) obtained in all studies was 3.2 mg/kg bw/day in a two-year combined chronic toxicity/carcinogenicity in rats. FSCJ specified an acceptable (ADI) of 0.032 mg/kg bw/day, applying a safety factor of 100 to the NOAEL. The lowest NOAEL for adverse effects elicited by a single oral administration of desmedipham was 90 mg/kg bw/day obtained from the developmental toxicity study in rabbits (the 2nd study in the Table 2). Consequently, FSCJ specified an acute reference dose (ARfD) of 0.9 mg/kg bw applying a safety factor of 100 to the NOAEL.
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of dicycranil (CAS No. 112636-83-6), a pyrimidine-derived insect growth regulator, using the evaluation reports from the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the European Medicines Agency (EMEA), and also the Australian government. In an 18-month chronic toxicity/carcinogenicity study in mice, increased incidences of hepatocellular adenomas and carcinomas were observed in females in the 500 ppm group. In spite of a recent experiment implying the possible indirect genotoxicity of dicyclanil on the carcinogenicity, dicyclanil is unlikely to exert the carcinogenicity in vivo through the genotoxic mechanism judging from other studies. FSCJ recognized it as feasible to set the threshold value. Adverse effects detected at the lowest dose in various toxicological studies were the increased plasma levels of cholesterol and phospholipid at 100 ppm (equivalent to 2.7 mg/kg bw/day in males and 3.5 mg/kg bw/day in females) in a 90-day subacute toxicity study in dogs. No-observed-adverse-effect level (NOAEL) of this study was 20 ppm (equivalent to 0.61 mg/kg bw/day in males and 0.71 mg/kg bw/day in females). On the other hand, the NOAEL in a long term study, a 12-month chronic toxicity study in dogs was 25 ppm (equivalent to 0.71 mg/kg bw/day in males) based on increased level of plasma cholesterol observed only in males at 150 ppm (equivalent to 4.4 mg/kg bw/day in males and 5.1 mg/kg bw/day in females). The increased cholesterol levels in plasma were common in both studies in dogs. It was appropriate to choose the NOAEL for the effect on cholesterol in the longer term treatment, and thus FSCJ adopted the NOAEL of 0.71 mg/kg bw/day. Consequently, FSCJ specified the ADI of 0.0071 mg/kg bw/day for dicyclanil based on the NOAEL of 0.71 mg/kg bw/day in the 12-month chronic toxicity study in dogs, by applying a safety factor of 100.
Food Safety Commission of Japan (FSCJ) conducted a risk assessment of dexamethasone (CAS No. 50-02-2), a synthetic adrenocortical hormone, using mainly the evaluation reports from the Joint FAO/WHO Expert Committee on Food Additives (JECFA), and the European Medicines Agency (EMEA). Major adverse effects of dexamethasone were observed in the decrease in white blood cell count (WBC), atrophy of thymus and spleen as well as the decrease in adrenal weights, which were found in various toxicity studies. These effects are attributable to the glucocorticoid action. FSCJ supported the EMEA’s judgment “dexamethasone lacks structural similarity with known carcinogens”, and concluded that this drug is unlikely to be carcinogenic. Teratogenicity was observed in rats developmental toxicity studies and the no-observed-adverse-effect level (NOAEL) for fetus was 10 μg/kg bw/day. The effect observed at the lowest dose in various toxicological studies was decreased WBC in rats in an endocrinological study. The NOAEL in this study was 1μg/kg bw/day. JECFA and EMEA specified an acceptable daily intake (ADI) based on the pharmacological action, the induction of tyrosine aminotransferase activity (TAT), in rat liver. However FSCJ judged this endpoint is not appropriate to establish an ADI, because the increase of TAT in response to glucocorticoid was a physiological response, and the relationship of changes in TAT with the toxicological findings was obscure. Consequently, FSCJ specified the ADI for dexamethasone at 0.01μg/kg bw/day, based on NOAEL of 1μg/kg bw/day, which was obtained in rats in an endocrinological study, applying a safety factor of 100.