title: Toxicokinetic model describing bioconcentration and biotransformation of diazinon in Daphnia magna.
abstract: A toxicokinetic model for Daphnia magna , which simulates the internal concentration of the insecticide diazinon, its detoxification product 2-isopropyl-6-methyl-4-pyrimidinol, and its active metabolite diazoxon, is presented. During in vivo exposure to diazinon with and without inhibition of cytochrome P450 by piperonyl butoxide, the parent compound as well as its metabolites were quantified with high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) in extracts of D. magna . Rate constants of all relevant toxicokinetic steps were obtained by modeling the time course of the internal concentrations with a multicomponent first-order kinetics model. When cytochrome P450 was inhibited, the kinetic bioconcentration factor (BCF) of diazinon increased from 17.8 to 51.0 mL·g(ww)(-1). This clearly indicates that diazinon is biotransformed to a high degree by cytochrome P450 in D. magna . The dominant elimination step of diazinon was shown to be its oxidative dearylation to pyrimidinol (62% of total elimination) with a corresponding rate constant of 0.16 h(-1). In contrast, oxidative activation to diazoxon with a rate constant of 0.02 h(-1) amounted to only 8% of the total elimination. During exposure to diazinon, the active metabolite diazoxon could be detected only in very low concentrations (approximately 0.5% of the parent compound), presumably due to a very fast reaction with the target site acetylcholinesterase. During the exposure experiments (no feeding of daphnids), an exponential decline of the lipid content in D. magna with a first-order rate constant of 0.013 h(-1) was observed. For short exposure times (≤ 24 h), this had only a minor influence on the determined TK parameters. Such a TK model containing detailed biotransformation processes is an important tool for estimation of the toxic potential of chemicals, particularly, when active metabolites are formed inside an organism.
authors.affiliation: Eawag, Swiss Federal Institute of Aquatic Science and Technology, 8600 Dübendorf, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kretschmann
authors.forename: Roman
authors.initials: R
authors.lastname: Ashauer
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Preuss
authors.forename: Piet
authors.initials: P
authors.lastname: Spaak
authors.forename: Beate I
authors.initials: BI
authors.lastname: Escher
authors.forename: Juliane
authors.initials: J
authors.lastname: Hollender
mesh_terms: D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003621:Daphnia / Q000378:metabolism*; D003976:Diazinon / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D007306:Insecticides / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D050356:Lipid Metabolism; D008954:Models, Biological; D009943:Organophosphorus Compounds / Q000032:analysis; D011743:Pyrimidines / Q000032:analysis; D018570:Risk Assessment
chemical_list: C561419:2-isopropyl-6-methyl-4-pyrimidinol; D007306:Insecticides; D009943:Organophosphorus Compounds; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; C000912:diazoxon; D003976:Diazinon