title: Chronic toxicity of an environmentally relevant mixture of pharmaceuticals to three aquatic organisms (alga, daphnid, and fish).
abstract: Principles of concentration addition and independent action have been used as effective tools to predict mixture toxicity based on individual component toxicity. The authors investigated the toxicity of a pharmaceutical mixture composed of the top 10 detected active pharmaceutical ingredients (APIs) in the Tama River (Tokyo, Japan) in a relevant concentration ratio. Both individual and mixture toxicities of the 10 APIs were evaluated by 3 short-term chronic toxicity tests using the alga Pseudokirchneriella subcapitata, the daphnid Ceriodaphnia dubia, and the zebrafish Danio rerio. With the exception of clarithromycin toxicity to alga, the no-observed-effect concentration of individual APIs for each test species was dramatically higher than the highest concentration of APIs found in the environment. The mixture of 10 APIs resulted in toxicity to alga, daphnid, and fish at 6.25 times, 100 times, and 15,000 times higher concentrations, respectively, than the environmental concentrations of individual APIs. Predictions by concentration addition and independent action were nearly identical for alga, as clarithromycin was the predominant toxicant in the mixture. Both predictions described the observed mixture toxicity to alga fairly well, whereas they slightly underestimated the observed mixture toxicity in the daphnid test. In the fish embryo test, the observed toxicity fell between the predicted toxicity by concentration addition and independent action. These results suggested that the toxicity of environmentally relevant pharmaceutical mixtures could be predicted by individual toxicity using either concentration addition or independent action.
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
authors.forename: Haruna
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.|Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamura
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Abe
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Takanobu
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
authors.forename: Ataru
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Environmental Science, Tokyo Metropolitan Institute of Public Health, Tokyo, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Division of Risk Assessment, Biological Safety Research Center, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Hirose
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan.
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Nishimura
authors.affiliation: Center for Environmental Risk Research, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Tatarazako
mesh_terms: D000818:Animals; D059001:Aquatic Organisms; D000460:Chlorophyta / Q000187:drug effects*; D033361:Cladocera / Q000187:drug effects*; D064420:Drug-Related Side Effects and Adverse Reactions; D004625:Embryo, Nonmammalian; D007564:Japan; D019055:No-Observed-Adverse-Effect Level; D018570:Risk Assessment / Q000379:methods; D045483:Rivers / Q000737:chemistry; D036401:Toxicity Tests, Chronic; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D015027:Zebrafish
chemical_list: D014874:Water Pollutants, Chemical
keywords: Concentration addition; Independent action; Mixture toxicity; Pharmaceutical; Short-term chronic toxicity test