Dynamic energy-based modeling of uranium and cadmium joint toxicity to Caenorhabditis elegans.

Toxicokinetic - toxicodynamic energy-based models offer new alternatives to the commonly used approaches for the analysis of mixture toxicity data. Based on the Dynamic Energy Budget theory, DEBtox models enable the description of several endpoints over time simultaneously under the same framework. However, such model still has to be faced with experimental data in a multi-contamination context. In this study, the predictive capacities of a DEBtox model to describe the uranium and cadmium joint toxicity over the entire growth and reproduction period of the soil nematode Caenorhabditis elegans was examined. The two reference additivity approaches, Concentration Addition and Response addition, implemented in the DEBtox model were tested. Assuming no interaction between the two toxicants through Response addition, the DEBtox model allowed a rather accurate fit of the U and Cd joint effects on the growth and reproduction of C. elegans: an interaction between the two metals at the toxicokinetic or toxicodynamic level seems thus unlikely or has only minor consequences. Interestingly, this study underlines that even if the compounds of a mixture share the same DEBtox physiological mode of action (in this case a decrease in assimilation), the Response addition approach may provide a better fit of joint toxicity data than the Concentration addition approach. Moreover, the present work highlighted limitations in the model predictions which are related to the simplifications of the DEBtox framework and its adaptations to the physiology of C. elegans and which lead to an overestimation of the U and Cd joint toxicity in some cases.

Nested interactions in the combined toxicity of uranium and cadmium to the nematode Caenorhabditis elegans.

Uranium is a natural, ubiquitous radioactive element for which elevated concentrations can be found in the vicinity of some nuclear fuel cycle facilities or intensive farming areas, and most often in mixtures with other contaminants such as cadmium, due to co-occurrence in geological ores (e.g. U- or P-ore). The study of their combined effects on ecosystems is of interest to better characterize such multi-metallic polluted sites. In the present study, the toxicity of binary mixture of U and Cd on physiological parameters of the soil nematode Caenorhabditis elegans was assessed over time. Descriptive modeling using concentration and response addition reference models was applied to compare observed and expected combined effects and identify possible synergistic or antagonistic interactions. A strong antagonism between U and Cd was identified for length increase and brood size endpoints. The study revealed that the combined effects might be explained by two nested antagonistic interactions. We demonstrate that the first interaction occurred in the exposure medium. We also identified a significant second antagonistic interaction which occurred either during the toxicokinetic or toxicodynamic steps. These findings underline the complexity of interactions that may take place between chemicals and thus, highlight the importance of studying mixtures at various levels to fully understand underlying mechanisms.