Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment

Abstract

There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening-level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4.

Explanation of non-additive effects in mixtures of similar mode of action chemicals

“…Current frameworks of risk assessments deal in most cases with a single chemical, but at the same time, as there are multiple chemicals used together, there are concerns regarding the cumulative or combined effects of chemical mixtures (Berenbaum, 1977;Feron et al, 1995;Teuschler and Hertzberg, 1995;Groten et al, 2001;Feron and Groten, 2002;McCarty and Borgert, 2006;Boobis et al, 2011;Meek et al, 2011;Cedergreen, 2014). In particular, for pesticides or biocides, risk assessments for combined effects have been conducted, and guidelines or documents for combined effects have also been published by governmental and international organizations (USEPA, 2002(USEPA, , 2003Kortenkamp et al, 2009;OECD, 2011;European Commission, 2012).…”

A decision tree for assessing effects from exposures to multiple substances

“…Boobis et al [21] provided additional support for this finding in a detailed review of the literature on the toxicity of mixtures. Therefore, this…”

Efeito protetor da melatonina sobre intoxicações por herbicidas

“…Além disso, na literatura científica, existe poucas pesquisas sobre os efeitos danosos decorrentes dessas associações em diferentes organismos com relatos de estudos reprodutivos e de desenvolvimento animal (McCarty & Borgert 2006). O mesmo acontece quando se trata dos feitos sinérgicos de doses subletais (Boobis et al 2011). Neste contexto, alguns estudos sinalizam a importân-cia do problema.…”