Environmental Risk Assessment of Active Human Pharmaceutical Ingredients in Urban Rivers in Japan.

Active pharmaceutical ingredients (APIs) have become a public concern owing to their possible adverse effects on aquatic organisms. Ministry of Health, Labor and Welfare in Japan (MHLW) issued "Guidance on the Environmental Risk Assessment (ERA) in new pharmaceutical development" in 2016. To evaluate the validity of phase 1 in the MHLW's ERA guidance, we monitored the measured environmental concentrations (MECs) of approved APIs in urban rivers and sewage treatment plants (STPs) in Japan and compared these MECs with the predicted environmental concentration (PEC). We collected water samples from urban seven rivers and three STPs during each season. Fifty-one APIs for human and veterinary use and the artificial sweetener sucralose were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Forty-four APIs were observed in the rivers and 42 were found in the influent and effluent of STPs, with levels ranging from nanograms to micrograms per liter. The action limit in phase I of the MHLW's guidance was set to 10 ng/L, and there was no API except for ketoprofen, for which PEC of the MHLW's guidance (PECjapan) was lower than 10 ng/L and the maximum MEC (MECmax) was 10 ng/L or greater. Almost all APIs also had median MECs that were lower than those of the respective PECjapan. These results indicate that the PECjapan values in phase I of the MHLW's guidance were appropriate. However, some APIs had MECmax values that were greater than those of the respective PECjapan due to overestimation of the dilution factor of river water and/or underestimation of API production.

Comparative study for carcinogenicity of 7 different multi-wall carbon nanotubes with different physicochemical characteristics by a single intraperitoneal injection in male Fischer 344 rats.

The present study comparatively examined carcinogenicity of 7 different multi-wall carbon nanotubes (MWCNTs) with different physicochemical characteristics. Physicochemical characteristics of MWCNTs (referred to as M-, N-, WL-, SD1-, WS-, SD2- and T-CNTs in the present study) were determined using scanning electron and light microscopes and a collision type inductively coupled plasma mass spectrometer. Male Fischer 344 rats (10 weeks old, 15 animals per group) were administered MWCNTs at a single intraperitoneal dose of 1 mg/kg body weight, and sacrificed up to 52 weeks after the commencement. Fibers of M-, N-, WL- and SD1-CNTs were straight and acicular in shape, and contained few agglomerates. They were relatively long (38-59% of fibers were longer than 5 µm) and thick (33% to more than 70% of fibers were thicker than 60 nm). All of these 4 MWCNTs induced mesotheliomas at absolute incidences of 100%. Fibers of WS-, SD2- and T-CNTs were curled and tightly tangled to form frequent agglomerates. They were relatively short and thin (more than 90% of measured fibers were thinner than 50 nm). WS- CNT did not induce mesothelioma, and only one of 15 rat given SD2- or T-CNT developed tumor. Any correlations existed between the metal content and neither the size or form of fibers, nor the carcinogenicity. It is thus indicated that the physicochemical characteristics of MWCNTs are critical for their carcinogenicity. The straight and acicular shape without frequent agglomerates, and the relatively long and thick size, but not the iron content, may be critical factors. The present data can contribute to the risk management, practical use and social acceptance of MWCNTs.