Colistin is a critically important antibiotic for humans. The Japanese government withdrew colistin growth promoter and shifted therapeutic colistin to a second-choice drug for pigs in 2017. A quantitative release assessment of mcr-mediated colistin-resistant Escherichia coli (E. coli) in Japanese finisher pigs was conducted under the World Organisation for Animal Health (OIE) risk assessment framework. Input data included colistin resistance and mcr-1-5 test results for E. coli isolates in the Japan Veterinary Resistance Monitoring System (JVARM), postal survey results regarding indication disease occurrence and colistin use by swine veterinarians in 2017 and 2018, and colistin resistance and mcr monitoring experiments at four pig farms in 2017-2018. An individual-based model was developed to assess the risk: the proportion of Japanese finisher pigs with mcr-1-5-mediated colistin-resistant E. coli dominant in the gut on an arbitrary day. Before implementing risk management measures, the risk was estimated to be 5.5% (95% CI: 4.2%-10.1%). At 12 months after stopping colistin growth promoter, the proportion of pigs with plasmid-mediated colistin-resistant E. coli declined by 52.5% on the experiment farms (95% CI: 8.7%-80.8%). The probability of therapeutic colistin use at the occurrence of bacterial diarrhea declined from 37.3% (95% CI: 30.3%-42.5%) in 2017 to 31.4% (95% CI: 26.1%-36.9%), and that of edema disease declined from 55.0% (95% CI: 46.0%-63.7%) to 44.4% (95% CI: 36.9%-52.0%). After risk management implementation, the risk was estimated to have declined to 2.3% (95% CI: 1.8%-4.3%; 58.2% reduction). Scenario analyses showed that pen-level colistin treatment effectively reduces the risk from 5.5% to 4.7% (14.5% reduction), an effect similar to stoppage of therapeutic colistin (16.4% reduction to 4.6%).
Human CYP3A4 is involved in metabolisms of diverse hydrophobic chemicals. Using the data of therapeutic azole fungicides known to interact with CYP3A4, applicability of CYP3A4 Template system was first confirmed to reconstitute faithfully the interaction on Template. More than twenty numbers of pesticide azoles were then applied to the Template system. All the azole stereo-isomers applied, except for talarozole, interacted through nitrogen atoms of triazole or imidazole parts and sat stably for inhibitions through fulfilling three-essential interactions. For their CYP3A4-mediated oxidations, clear distinctions were suggested among the enantiomers and diastereomers of azole pesticides on Templates. Thus, the stereoisomers would have their-own regio- and stereo-selective profiles of the metabolisms. A combined metabolic profile of each azole obtained with CYP3A4 Template system, however, resembled with the reported profile of the in vivo metabolism in rats. These results suggest the major roles of CYP3A forms on the metabolisms of most of azole pesticides in both rats and humans. Free triazole is a metabolite of azole fungicides having a methylene-spacer between triazole and the rest of the main structures in experimental animals and humans. During the simulation experiments, a placement for the oxidation of a methylene spacer between the triazole and main carbon-skeleton was found to be available throughout the azole fungicides tested on Template. The occurrence of this reaction to lead to triazole-release is thus discussed in relation to the possible involvement of CYP3A forms.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment of betamethasone (CAS No. 37-44-9), a synthetic adrenocortical hormone, based on the documents including assessment reports from the European Medicines Evaluation Agency (EMEA). Among results of various studies, a no-observed-adverse-effect level (NOAEL) of betamethasone (as betamethasone dipropionate) was shown as 0.02 mg/kg bw per day in a fertility and early embryonic development study in rats. FSCJ concluded that it is appropriate to set an acceptable daily intake (ADI) of betamethasone by applying the same ADI as dexamethasone. The ADI for dexamethasone at 0.01 μg/kg bw per day (0.00001 mg/kg bw/day) was specified based on the NOAEL of 0.001 mg/kg bw per day of the endocrine toxicity study in rats1). Consequently, FSCJ specified the ADI for betamethasone at 0.01 μg/kg bw per day.