Mechanistic studies on baseline toxicity and uncoupling of organic compounds as a basis for modeling effective membrane concentrations in aquatic organisms

Mechanistic studies on membrane toxicity are reviewed and linked to effects observed in-vivo. Time-resolved spectroscopy on energy-transducing membranes is an in-vitro test method that provides information on the toxicodynamics of membrane toxicity, namely baseline toxicity and uncoupling. Without blurring effects of the toxicokinetic phase, the intrinsic potency of membrane toxicants can directly be determined thus allowing the development of a classification system to distinguish between baseline toxicity and uncoupling. Toxicity data of known baseline toxicants and of substituted phenols from literature are reevaluated in light of the information obtained from the mechanistic test system. Exposure-based effect data (aqueous effect concentrations) of substituted phenols (baseline toxicants and uncouplers) from various aquatic organisms (bacteria, protozoa, algae, daphnids, fish) are compared to the corresponding effect concentrations expected from baseline toxicity. The results of the comparison support the view that the membrane is the primary target site for acute toxicity of substituted phenols in aquatic organisms. The classification into baseline toxicants and uncouplers based upon the criteria derived from the mechanistic test system is correct. Nevertheless, the acute toxicity in-vivo cannot be correlated quantitatively to the mechanistic data presumably because bioaccumulation is not directly proportional to intrinsic toxicity and the metabolic transformation is variable within the test set of substituted phenols. The pH-dependence of acute toxicity is mainly determined by the pH-dependence of bioccumulation, the internal effect concentrations are virtually independent on external pH. The internal effect concentrations, also called lethal body burdens or critical body residues, which are taken from the literature or calculated from aqueous effect concentrations and bioconcentration factors, are related to membrane concentrations using a simple three-compartment equilibrium partitioning model. The modeled membrane concentrations of non-polar and polar narcotics turn out to be statistically indistinguishable, which is consistent with the findings from the mechanistic test system. The toxic ratios, i.e., the excess toxicity of uncouplers in relation to their baseline toxicity, agree for most compounds upon comparison of the mechanistic test system with the aquatic organisms thus confirming that uncoupling is the dominant mode of action responsible for lethality