What Contributes to the Combined Effect of a Complex Mixture?

Abstract

The effect of a mixture of 10 compounds, which have previously been identified in an effect-directed analysis as potentially relevant for a specific contaminated riverine sediment (Brack et al. Arch. Environ. Contam. Toxicol. 1999, 37, 164), were investigated for the underlying joint effect. Components identified in an organic sediment extract included several PAHs (benzo[ghi]fluoranthene, benz[a]anthracene, fluoranthene, pyrene, 2-phenylnaphthalene, anthracene, and phenanthrene) plus prometryn, N-phenyl-2-naphthylamine, and parathion-methyl. Experiments were performed using a one-generation algal bioassay with the unicellular green algae Scenedesmus vacuolatus as well as chlorophyll fluorescence quenching analysis to describe the effects of the components and mixtures thereof. Analysis of the mixture effects based on concentration-response modeling of the effect data reveals that indeed effect contributions of several components can be expected although the mixture ratio is not equitoxic and the individual components vary greatly with respect to biological effect. Comparing predicted and observed mixture effects, the combined effect may not be attributed to a joint narcotic effect of the mixture components. Evidently, some of the components act specifically and dissimilar and may therefore be best described in their combined effect by response addition while for others a similar mode of action seems plausible. Chlorophyll fluorescence quenching analysis supports to discriminate between prometryn, N-phenyl-2-naphthylamine, and PAHs. A joint model for calculating the combined effect using concentration addition for the suspected unspecifically acting components in algae (PAHs and parathion-methyl) and subsequently response addition for this group and the other components clearly improves the description of the observed combined effect. Allocation of effect contributions to specific components using toxic units or effect contributions lead to different judgments. The observed combined effect of a 3-compound mixture of prometryn, N-phenyl-2-naphthylamine, and benzo[ghi]fluoranthene is indistinguishable from the effects of the original 10-compound mixture, demonstrating the need in site-specific assessment of complex contamination to account for the mode of action of contaminants. Implications forthe confirmation step in effect-directed analysis of substances causing effects in complex contaminated samples are discussed.

Predicting the aquatic toxicity of commercial pesticide mixtures

“…Because an experimental testing of all potentially relevant environmental mixtures of pesticides is not feasible simply due to the large number of a.s. and their respective combinations, so-called component-based (in silico) approaches can be considered as an alternative option for a predictive environmental risk assessment that takes joint effects of pesticide mixtures into account. Two basic concepts have been established for predicting additive joint effects based on the known toxicity of the individual mixture components: the concept of concentration addition (CA) for mixtures of substances with similar modes of actions and the concept of independent action (IA, also called response addition) for mixtures of substances with dissimilar modes of action [7,10,11]. In addition, combinations of these two concepts for mixtures of dissimilarly and similarly acting substances have been developed [10,8,12].…”

Interactions between estrogenic chemicals in binary mixtures investigated using vitellogenin induction and factorial analysis

“…In fact, the CA model has been suggested as the pragmatic default approach when calculating the quantitative effects of any combination of agents, irrespective of the (dis)similarity of its components (de Zwart and Posthuma, 2005). However, due to the weakness of the mathematical formula and the varying natures of the chemicals tested, no concept currently provides a ''general solution" for assessing the interactions between estrogenic chemicals (Thorpe et al, 2001;Altenburger et al, 2004;Backhaus et al, 2004 Vitellogenin (VTG) is normally synthesized in mature female fish under the control of estrogen, mediated by estrogen receptors (ERs), and is then incorporated into growing oocytes. However, since both sexes carry ERs and the VTG gene, males or juveniles can be induced to synthesize VTG after exposure to estrogen or estrogen-mimics (Denslow et al, 1999;Brion et al, 2002).…”

Organic chemicals jeopardize the health of freshwater ecosystems on the continental scale

“…To date, large-scale analyses have been hindered by the lack of large-scale monitoring databases for organic chemicals and by the scarcity of empirical toxicity data (9). Gaps in missing experimental toxicity data can be filled by modeled or predicted toxicity data from read-across methods (10) or quantitative structure-activity relationship approaches (11), which serve as surrogates for experimental data. Once toxicity data are compiled, the availability of chemical datasets such as Waterbase (12), which accommodates information on the chemical concentrations for more than 8,200 European sites, allows chemical risk (CR) assessment to be conducted on large spatial scales.…”