Tissue residue approach for chemical mixtures

Abstract

At the SETAC Pellston Workshop "The Tissue Residues Approach for Toxicity Assessment," held in June 2007, we discussed mixture toxicology in terms of the tissue residue approach (TRA). This article reviews the literature related to the TRA for mixtures of chemicals and recommends a practical, tiered approach that can be implemented in regulatory or risk assessment applications. As with the toxicity of individual chemicals, addressing mixture toxicity by means of the TRA has a number of significant advantages. Early work provided a theoretical basis and experimental data to support the use of TRA for mixtures; later work provided a field-based validation of the integration. However, subsequent development has been hindered by the lack of mixture toxicity data expressed in tissue or preferably target-site concentrations. We recommend a framework for addressing the toxicology of mixtures that integrates the TRA and mixture toxicology in a 3-tier approach. Tier I uses concentration addition (CA) to estimate the toxicity of mixtures regardless of the mechanism of action of the components. However, the common approach that uses a bioaccumulation factor (BAF) to predict TR from the exposure-water concentration for organics must be modified slightly for metals because, unlike organics, the BAF for a metal changes as 1) the aqueous exposure concentration changes, and 2) the concentration of other metals changes. In addition, total tissue residues of a metal are not a good predictor of toxicity, because some organisms store high concentrations of metals internally in detoxified forms. In tier I, if the combination of measured concentrations in the mixture exceeds that predicted to produce adverse effects or above-reference levels, it is necessary to proceed to tier II. Tier II is a mixed model that employs CA and independent action to estimate mixture toxicity. Tiers I and II estimate the toxicity of mixtures to individual species. In tier III, the TRA is integrated with the multisubstance potentially affected fraction (ms-PAF) method to derive TR levels that are protective of a selected percentage of species in aquatic communities (e.g., hazardous concentration for 5% of the species [HC5]).

Quantifying reduction in ecological risk in Penrhyn Estuary, Sydney, Australia, following groundwater remediation

“…From a theoretical perspective (Plackett and Hewlet 1952), mixtures that contain chemicals with the same mode of action and that do not interact should exert a toxicity that conforms to the concentration addition (CA) model of joint action. This theoretical prediction has repeatedly been shown to be valid (refer to literature cited in Dyer et al 2011). In addition, a number of studies have shown that the CA model provides a more conservative estimate of mixture toxicity than the independent action model of mixture toxicity (Faust et al 1994; Backhaus et al 2000a, 2000b; Dyer et al 2000; Junghans et al 2006; Chèvre et al 2006) that applies where mixtures contain chemicals that do not interact but have different modes of action.…”

“…In addition, a number of studies have shown that the CA model provides a more conservative estimate of mixture toxicity than the independent action model of mixture toxicity (Faust et al 1994; Backhaus et al 2000a, 2000b; Dyer et al 2000; Junghans et al 2006; Chèvre et al 2006) that applies where mixtures contain chemicals that do not interact but have different modes of action. Given the preceding, frameworks for estimating the toxicity of mixtures have been developed (Altenberger et al 2004; Junghans 2004; De Zwart and Posthuma 2005; Posthuma et al 2008; Dyer et al 2011) all of which recommend the use of the CA model in the first instance. Therefore, the CA model was used to provide an estimate of the risk posed by the mixture of VCHs in the surface waters of Penrhyn Estuary.…”

Use of prospective and retrospective risk assessment methods that simplify chemical mixtures associated with treated domestic wastewater discharges

“…This process of risk additivity corresponds to the concept of “concentration addition,” that is, assuming all materials have a similar mode of action. Although we recognize this is not necessarily true, there is a general consensus that this is a suitable screening level approach (Dyer et al ). If the cumulative RCR (sum of individual RCRs) is <1.0 at tier 1, the mixture risk is considered to be acceptably low and further steps, including retrospective analyses, are not warranted.…”

From Incorporation to Toxicity

“…Very simplistically, the first tier consists in an estimation of the toxicity of mixtures by using concentration addition regardless of the mechanism of action of the components. If the combination of measured concentrations in the mixture exceeds that predicted to produce adverse effects or previously referenced levels, Dyer et al (2011) consider that it is necessary to proceed to tier II. The general scheme used for organics must be modified for metals, taking into account the background concentration of elements that are natural constituents of the body burden and differential tolerance according to taxa (Luoma and Rainbow, 2008;Adams et al, 2011).…”