Kretschmann_2012_Environ.Toxicol.Chem_31_2014

A mechanistic toxicokinetic and toxicodynamic model for acute toxic effects immobilization mortality of the organothiophosphate insecticide diazinon in Daphnia magna is presented The model was parameterized using measured external and internal whole-body concentrations of diazinon its toxic metabolite diazoxon and the inactive metabolite 2-isopropyl-6-methyl-4-pyrimidinol plus acetylcholinesterase AChE activity measured during exposure to diazinon in vivo The toxicokinetic and toxicodynamic model provides a coherent picture from exposure to the resulting toxic effect on an organism level through internally formed metabolites and the effect on a molecular scale A very fast reaction of diazoxon with AChE pseudo first-order inhibition rate constant k(i 3.3 h(-1 compared with a slow formation of diazoxon activation rate constant k(act 0.014 h(-1 was responsible for the high sensitivity of D magna toward diazinon Recovery of AChE activity from inhibition was slow and rate-determining 99 recovery within 16 d compared with a fast elimination of diazinon 99 elimination within 17 h The obtained model parameters were compared with toxicokinetic and toxicodynamic parameters of Gammarus pulex exposed to diazinon from previous work This comparison revealed that G pulex is less sensitive because of a six times faster detoxification of diazinon and diazoxon and an approximately 400 times lower rate for damage accrual These differences overcompensate the two times faster activation of diazinon to diazoxon in G pulex compared to D magna The present study substantiates theoretical considerations that mechanistically based effect models are helpful to explain sensitivity differences among different aquatic invertebrates.