title: Application of biotic ligand and toxicokinetic-toxicodynamic modeling to predict the accumulation and toxicity of metal mixtures to zebrafish larvae.
abstract: Predicting the accumulation and toxicity of mixtures of metals to aquatic organisms is a key challenge in ecotoxicological studies. In this study, the accumulation and toxicity of mixed essential (Cu) and nonessential (Cd and Pb) metals in zebrafish larvae exposed to a binary mixture of these elements at environmentally relevant concentrations were predicted using a refined toxicokinetic (TK)-toxicodynamic (TD) model aided with biotic ligand model (BLM) and toxic equivalent factor (TEF) approach. Competitive inhibition and non-competitive interaction/inhibition were observed in bio-uptake. Both Pb and Cd behaved as competitive inhibitors of Cu uptake at high Cu concentrations (>0.1 μM). By contrast, Cu uptake was independent of Cd or Pb when the Cu concentrations were below 10(-7) M. Furthermore, low concentrations of Cu had an adiaphorous effect on Cd or Pb uptake. Cd uptake was inhibited by Pb, and the Pb uptake rates consistently decreased in the presence of Cd. The accumulation processes of Cd-Pb, Cu-Cd, and Cu-Pb were accurately predicted by the BLM-aided TK models. The traditional TD model could successfully predict the toxicity of Cd-Pb mixtures, but not those of Cu-Cd or Cu-Pb mixtures. The revised TD model, which considered the possible different killing rates (Kk) above or below the threshold, offered better prediction for the toxicity of Cu-Cd or Cu-Pb mixtures. The overall findings may be of key significance in understanding and predicting metal uptake, accumulation, and toxicity in binary or multiple metal exposure scenarios.
authors.affiliation: Key Laboratory of Pollution Process and Environmental Criteria of Ministry of Education and Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering, Nankai University, Tianjin 300071, China.
authors.forename: Yongfei
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Key Laboratory of Pollution Process and Environmental Criteria of Ministry of Education and Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering, Nankai University, Tianjin 300071, China. Electronic address: fengjf@nankai.edu.cn.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Feng
authors.affiliation: Bureau of Hydrology and Water Resources of Henan Province, Zhenzhou, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Han
authors.affiliation: Key Laboratory of Pollution Process and Environmental Criteria of Ministry of Education and Tianjin Key Laboratory of Environmental Remediation and Pollution Control, College of Environmental Science and Engineering, Nankai University, Tianjin 300071, China. Electronic address: zhulin@nankai.edu.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002104:Cadmium / Q000493:pharmacokinetics / Q000633:toxicity*; D003300:Copper / Q000493:pharmacokinetics / Q000633:toxicity*; D054750:Ecotoxicology; D017136:Ion Transport / Q000502:physiology; D007814:Larva / Q000187:drug effects*; D007854:Lead / Q000493:pharmacokinetics / Q000633:toxicity*; D008024:Ligands; D008954:Models, Biological; D066007:Toxicokinetics; D015027:Zebrafish / Q000196:embryology*
chemical_list: D008024:Ligands; D002104:Cadmium; D007854:Lead; D003300:Copper
keywords: Acute toxicity; BL; BLM; Bioaccumulation; Biotic ligand; CBR; Metal mixtures; TD model; TEF; TEQ; TK model; TK-TD model; TK1; TK2; Toxicokinetic–toxicodynamic (TK-TD) model; biotic ligand; biotic ligand model; the dynamic Critical Body Residue; the toxic equivalent quantity; toxic equivalent factor; toxicodynamic model; toxicokinetic model; toxicokinetic model 1; toxicokinetic model 2; toxicokinetic–toxicodynamic model