Review of toxicity of chemical mixtures: Theory, policy and regulatory practice

University of Florida, Gainesville, Florida, United States
Regulatory Toxicology and Pharmacology (Impact Factor: 2.03). 08/2006; 45(2):119-43. DOI: 10.1016/j.yrtph.2006.03.004
Source: PubMed


An analysis of current mixture theory, policy, and practice was conducted by examining standard reference texts, regulatory guidance documents, and journal articles. Although this literature contains useful theoretical concepts, clear definitions of most terminology, and well developed protocols for study design and statistical analysis, no general theoretical basis for the mechanisms and interactions of mixture toxicity could be discerned. There is also a poor understanding of the relationship between exposure-based and internal received dose metrics. This confounds data interpretation and limits reliable determinations of the nature and extent of additivity. The absence of any generally accepted classification scheme for either modes/mechanisms of toxic action or of mechanisms of toxicity interactions is problematic as it produces a cycle in which research and policy are interdependent and mutually limiting. Current regulatory guidance depends heavily on determination of toxicological similarity concluded from the presence of a few prominent constituents, assumed from a common toxicological effect, or presumed from an alleged similar toxic mode/mechanism. Additivity, or the lack of it, is largely based on extrapolation of existing knowledge for single chemicals in this context. Thus, regulatory risk assessment protocols lack authoritative theoretical underpinnings, creating substantial uncertainty. Development of comprehensive classification schemes for modes/mechanisms of toxic action and mechanisms of interaction is needed to ensure a sound theoretical foundation for mixture-related regulatory activity and provide a firm basis for iterative hypothesis development and experimental testing.

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Available from: Christopher J Borgert, Jun 30, 2015
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    • "Therefore, climate change and the anthropogenic manipulation of water resources in Mediterranean rivers may lead to enhance human health risks of river water exposure. As humans are exposed to chemical mixtures rather than individual substances, new realistic approaches have been developed to assess the risks associated to combined exposure to sets of pollutants [6] [7]. Classically, two main approaches have been used to evaluate the toxicity of chemical mixtures: concentration addition (CA) and independent action (IA), which assume a similar or different mode of action (MoA), respectively. "
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    ABSTRACT: The hazard of chemical compounds can be prioritized according to their PBT (persistence, bioaccumulation, toxicity) properties by using Self-Organizing Maps (SOM). The objective of the present study was to develop an Integrated Risk Index of Chemical Aquatic Pollution (IRICAP), useful to evaluate the risk associated to the exposure of chemical mixtures contained in river waters. Four Spanish river basins were considered as case-studies: Llobregat, Ebro, Jucar and Guadalquivir. A SOM-based hazard index (HI) was estimated for 205 organic compounds. IRICAP was calculated as the product of the HI by the concentration of each pollutant, and the results of all substances were aggregated. Finally, Pareto distribution was applied to the ranked lists of compounds in each site to prioritize those chemicals with the most significant incidence on the IRICAP. According to the HI outcomes, perfluoroalkyl substances, as well as specific illicit drugs and UV filters, were among the most hazardous compounds. Xylazine was identified as one of the chemicals with the highest contribution to the total IRICAP value in the different river basins, together with other pharmaceutical products such as loratadine and azaperol. These organic compounds should be proposed as target chemicals in the implementation of monitoring programs by regulatory organizations.
    Journal of hazardous materials 06/2013; 263. DOI:10.1016/j.jhazmat.2013.06.006 · 4.53 Impact Factor
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    • "In the first case they may act through concentration addition (CA) and independent action (IA) mechanisms also referred to as Loewe additivity and Bliss independence . CA is thought to be valid for mixtures where the components have similar sites and modes of action, while IA is currently held appropriate for mixtures where the components have different sites and dissimilar modes of action (Greco et al., 1995; McCarty and Borgert, 2006). Fig. 1. "
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    ABSTRACT: Cortical neurons grown on multielectrode array (MEA) chips have been shown to be a valuable alternative method to study electrophysiological properties of the central nervous system neurons and to perform functional toxicological screening. Here we studied the effects of binary mixtures on neuronal networks cultured on MEAs. We have considered compounds with similar and different mode-of-action (MoA) to characterize and assess their combined effects. Individual and binary mixture dose-response curves based on spontaneous neuronal activity have been generated and the IC(50) has been considered as the end-point for neurotoxicity assessment. The two classical approaches of mixtures toxicity studies: concentration addition (CA) and independent action (IA) have been applied to compare calculated and experimental results. Nuclear magnetic resonance (NMR) spectroscopy has been employed to confirm no chemical reaction or complexation between mixtures components. The results suggest that both CA and IA are able to predict the toxicity of the mixture and that the combination of in vitro test methods with theoretical dose-response models has a strong potential as an alternative tool for the prediction of mixtures neurotoxicity.
    Toxicology 06/2012; 299(2-3):172-83. DOI:10.1016/j.tox.2012.05.020 · 3.62 Impact Factor
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    • "Most modeling and field studies consider this aspect, as they focus on the prediction or measurement of the concentration which reaches a certain depth. However, low concentrations of a chemical can potentially pose a risk [Hayes et al., 2003], the toxicity is often uncertain [McCarty and Borgert, 2006], and model predictions of the concentration are often highly uncertain [Giambelluca et al., 1996]. Therefore, there appears to be a need for alternatives to flux prediction for risk assessment. "
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    ABSTRACT: A drainage regime is defined as a prolonged period of nearly constant outflow from a lysimeter. In addition there are rapid transitions between consecutive regimes. Solute transport out of the same lysimeters is shown to follow similar regimes. The causes and occurrence of these flow and transport regimes in lysimeters is briefly explored. We focused on exploiting these regimes for identifying the occurence of above regime transport i.e. the preferential transport of reactive and non-reactive solutes (specifically bromide, and two herbicides ETD and MBT). Different boundary conditions were identified as promoting rapid non-reactive and reactive rapid transport. The results of these studies suggest that acknowledgement of regimes in the unsaturated zone will assist prediction of short and long term changes in chemical loading to groundwater.
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