Human bioaccumulative potential is an important element in the risk assessment of chemicals. Due to the high number of synthetic chemicals, there exists the need to develop prioritisation strategies. The purpose of this study was to develop a predictive tool for human bioaccumulation risk assessment that incorporates not only the chemical properties of the compounds, but also the processes that tend to decrease the concentration of the compound such as metabolisation. We used a generic physiologically based toxicokinetic model that based on in vitro human liver metabolism data, minimal renal excretion and a constant exposure was able to assess the bioaccumulative potential of a chemical. The approach has been analysed using literature data on well-known bioaccumulative compounds and liver metabolism data from the ECVAM database and a subset of the ToxCast phase I chemical library—in total 94 compounds covering pharmaceuticals, plant protection products and industrial chemicals. Our results provide further evidence that partitioning properties do not allow for a reliable screening criteria for human chemical hazard. Our model, based on a 100% intestinal absorption assumption, suggests that metabolic clearance, plasma protein-binding properties and renal excretion are the main factors in determining whether bioaccumulation will occur and its amount. It is essential that in vitro metabolic clearance tests with metabolic competent cell lines as well as plasma protein-binding assays be performed for suspected bioaccumulative compounds.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-011-0768-0) contains supplementary material, which is available to authorized users.
We derive and study two-dimensional generalizations of integrate-and-fire models which can be found from a piecewise linear idealization of the FitzHugh-Nagumo or Morris-Lecar model. These models give rise to new properties not present in one-dimensional integrate-and-fire models. A detailed analytical study of the models is presented. In particular, ͑i͒ for the piecewise linear FitzHugh-Nagumo model, we determine analytically the bistability regime between stationary solutions and oscillations, that is, typical for class-II models. ͑ii͒ In the piecewise Morris-Lecar model, we find a noncanonical class-I transition from a stationary state to oscillations with logarithmic dependence similar to that found for leaky integrate-and-fire models. ͑iii͒ Furthermore, we establish a relation to the recently proposed resonate-and-fire model and show that a short input current pulse can trigger several spikes.
Within the context of Liénard equations, we present the FitzHugh-Nagumo model with an idealized nonlinearity. We give an analytical expression (i) for the transient regime corresponding to the emission of a finite number of action potentials (or spikes), and (ii) for the asymptotic regime corresponding to the existence of a limit cycle. We carry out a global analysis to study periodic solutions, the existence of which is linked to the solutions of a system of transcendental equations. The periodic solutions are obtained with the help of the harmonic balance method or as limit behavior of the transient regime. We show how the appearance of periodic solutions corresponds either to a fold limit cycle bifurcation or to a Hopf bifurcation at infinity. The results obtained are in agreement with local analysis methods, i.e., the Melnikov method and the averaging method. The generalization of the model leads us to formulate two conjectures concerning the number of limit cycles for the piecewise linear Liénard equations.
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