Basic concepts of mixture toxicity and relevance for risk evaluation and regulation

Abstract

Exposure to multiple substances is a challenge for risk evaluation. Currently, there is an ongoing debate if generic “mixture assessment/allocation factors” (MAF) should be introduced to increase public health protection. Here, we explore concepts of mixture toxicity and the potential influence of mixture regulation concepts for human health protection. Based on this analysis, we provide recommendations for research and risk assessment. One of the concepts of mixture toxicity is additivity. Substances may act additively by affecting the same molecular mechanism within a common target cell, for example, dioxin-like substances. In a second concept, an “enhancer substance” may act by increasing the target site concentration and aggravating the adverse effect of a “driver substance”. For both concepts, adequate risk management of individual substances can reliably prevent adverse effects to humans. Furthermore, we discuss the hypothesis that the large number of substances to which humans are exposed at very low and individually safe doses may interact to cause adverse effects. This commentary identifies knowledge gaps, such as the lack of a comprehensive overview of substances regulated under different silos, including food, environmentally and occupationally relevant substances, the absence of reliable human exposure data and the missing accessibility of ratios of current human exposure to threshold values, which are considered safe for individual substances. Moreover, a comprehensive overview of the molecular mechanisms and most susceptible target cells is required. We conclude that, currently, there is no scientific evidence supporting the need for a generic MAF. Rather, we recommend taking more specific measures, which focus on compounds with relatively small ratios between human exposure and doses, at which adverse effects can be expected.

The Cocktail Effects on the Acute Cytotoxicity of Pesticides and Pharmaceuticals Frequently Detected in the Environment

“…In general, the most frequently observed type of synergism occurs when the toxic effect of one substance, referred to as the ‘driver’, is enhanced by a second substance, called the ‘enhancer’. The enhancer can reduce the metabolic inactivation or excretion of the driver, leading to a situation where more of the driver substance is present at the site of effect [ 80 ]. On a vertebrate model organism, terbuthylazine and atrazine increased the toxicity of chlorpyrifos, presumably by accelerating its metabolic conversion into a more toxic form, highlighting the possibility of interactions between pesticides when co-occurring in the environment [ 81 ].…”