Quantification of chemical toxicity continues to be generally
based
on measured external concentrations. Yet, internal chemical concentrations
have been suggested to be a more suitable parameter. To better understand
the relationship between the external and internal concentrations
of chemicals in fish, and to quantify internal concentrations, we
compared three toxicokinetic (TK) models with each other and with
literature data of measured concentrations of 39 chemicals. Two one-compartment
models, together with the physiologically based toxicokinetic (PBTK)
model, in which we improved the treatment of lipids, were used to
predict concentrations of organic chemicals in two fish species: rainbow
trout (Oncorhynchus mykiss) and fathead minnow (Pimephales promelas). All models predicted the measured
internal concentrations in fish within 1 order of magnitude for at
least 68% of the chemicals. Furthermore, the PBTK model outperformed
the one-compartment models with respect to simulating chemical concentrations
in the whole body (at least 88% of internal concentrations were predicted
within 1 order of magnitude using the PBTK model). All the models
can be used to predict concentrations in different fish species without
additional experiments. However, further development of TK models
is required for polar, ionizable, and easily biotransformed compounds.
We report on the advantages and problems of using toxicokinetic-toxicodynamic (TKTD) models for the analysis, understanding, and simulation of sublethal effects. Only a few toxicodynamic approaches for sublethal effects are available. These differ in their effect mechanism and emphasis on linkages between endpoints. We discuss how the distinction between quantal and graded endpoints and the type of linkage between endpoints can guide model design and selection. Strengths and limitations of two main approaches and possible ways forward are outlined.
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