Assessment Of Mixture Effects Research Articles

Recommendations for international harmonisation, implementation and further development of suitable scientific approaches regarding the assessment of mixture effects

Legal frameworks lay down requirements for risk assessment of combined exposure to multiple chemicals and their implementation where scientific methods are accepted by responsible authorities. In order to protect human health, an assessment of potential risks that might result from co-exposure to multiple chemical substances is requested by European legislation. Several approaches for risk assessment of mixtures of chemicals have been proposed, but none has been widely implemented in regulatory risk assessments, so far. EuroMix, an EU Horizon 2020 funded project, contributed to the improvement of internationally harmonised approaches for risk assessment of chemical mixtures. Based on in vitro and in silico tests, an integrated test strategy involving hazard and exposure assessment was developed and a web tool to conduct such assessments was provided. One further task within EuroMix was to make recommendations for international harmonisation, implementation and further development of suitable scientific approaches regarding the assessment of mixture effects. This paper briefly describes objectives and outcome of the EuroMix project as well as recent findings from OECD, WHO and EFSA addressing combined exposure to multiple chemicals. Building on this, five steps addressing further development needs and implementation of existing tools especially for risk managers and policy makers are proposed.

Defining an additivity framework for mixture research in inducible whole-cell biosensors.

A novel additivity framework for mixture effect modelling in the context of whole cell inducible biosensors has been mathematically developed and implemented in R. The proposed method is a multivariate extension of the effective dose (EDp) concept. Specifically, the extension accounts for differential maximal effects among analytes and response inhibition beyond the maximum permissive concentrations. This allows a multivariate extension of Loewe additivity, enabling direct application in a biphasic dose-response framework. The proposed additivity definition was validated, and its applicability illustrated by studying the response of the cyanobacterial biosensor Synechococcus elongatus PCC 7942 pBG2120 to binary mixtures of Zn, Cu, Cd, Ag, Co and Hg. The novel method allowed by the first time to model complete dose-response profiles of an inducible whole cell biosensor to mixtures. In addition, the approach also allowed identification and quantification of departures from additivity (interactions) among analytes. The biosensor was found to respond in a near additive way to heavy metal mixtures except when Hg, Co and Ag were present, in which case strong interactions occurred. The method is a useful contribution for the whole cell biosensors discipline and related areas allowing to perform appropriate assessment of mixture effects in non-monotonic dose-response frameworks

Project summary: a critical synopsis of mechanisms of action of low-dose xenobiotics in mammalian organisms as a basis for assessing aggregated effects of chemical mixtures and identifying "new" toxicological end points

Abstract Background European chemicals legislation (registration, evaluation, authorisation and restriction of chemical substances (REACH)) requires a broad assessment of chemicals with respect to, inter alia, their health-relevant properties. Due to the extreme number of substances to be assessed and the limited current toxicological knowledge on their respective properties, REACH implicitly requires a paradigm change: away from knowledge generated mainly from costly animal experiments towards the use of mechanistic findings. Moreover, effect mechanisms at the biochemical or cellular level are essential when conclusions shall be drawn about "new" endpoints and mixtures of xenobiotics. This study (funded by the German Federal Environment Agency) describes examples of biochemical processes in the mammalian organism and how xenobiotics interfere with them. Interference with physiological processes expected to lead to adverse health effects is characterised as "toxicity pathway". The study describes toxicological endpoints not usually covered in routine animal testing and the respective toxicity pathways. Results and conclusions Screening for chemicals which exert effects via common toxicity pathways and subsequently conducting targeted short-term tests may generate new information about the toxicity of chemicals without performing extensive substance-by-substance animal experiments. Information on common toxicity pathways may also provide input for the assessment of mixture effects. The U.S. Environmental Protection Agency is working intensely on this concept. It involves the use of enormous amounts of data on relevant biochemical and cellular processes, which are generated by "high-throughput screening" methods, and then are combined with substance-specific kinetic data, experimental apical test outcomes and modelling. Current limitations in the regulatory use of this integrated approach on risk assessment will be outlined.

A general joint action model for herbicide mixtures

The assessment of mixture effects is usually done with isoboles which illustrate whether mixture effects are greater or smaller than would be expected on the basis of the individual activities of the herbicides. Under the assumption of similarity of response curves and by incorporating a function that can model the shape of isoboles, we can statistically test whether divergence from the Additive Dose Model (ADM) is significant. Two dose-response experiments with mixtures of either salt or ester formulations of MCPA and mecoprop-P and one experiment with tribenuron-methyl and mecoprop-P were analysed. Mixtures of tribenuron-methyl and a salt formulation of mecoprop-P showed antagonism. Mixtures of salt formulations of MCPA and mecoprop-P followed ADM, whilst ester formulations of the same compounds showed synergism. To get reliable estimates, the model requires mixture ratios covering the whole isobole © 1998 SCI

A general joint action model for herbicide mixtures

The assessment of mixture effects is usually done with isoboles which illustrate whether mixture effects are greater or smaller than would be expected on the basis of the individual activities of the herbicides. Under the assumption of similarity of response curves and by incorporating a function that can model the shape of isoboles, we can statistically test whether divergence from the Additive Dose Model (ADM) is significant. Two dose-response experiments with mixtures of either salt or ester formulations of MCPA and mecoprop-P and one experiment with tribenuron-methyl and mecoprop-P were analysed. Mixtures of tribenuron-methyl and a salt formulation of mecoprop-P showed antagonism. Mixtures of salt formulations of MCPA and mecoprop-P followed ADM, whilst ester formulations of the same compounds showed synergism. To get reliable estimates, the model requires mixture ratios covering the whole isobole © 1998 SCI