Modes of action in ecotoxicology: classification, chemical activity and dose metrics

Joop Hermens

Institute for Risk Assessment Sciences, Utrecht University, The Netherlands

The chemical activity concept is a promising approach in the understanding and prediction of ecotoxicological effect concentrations of organic contaminants. This concept has successfully been applied to compounds that are known to act via non-polar narcosis (Reichenberg and Mayer, 2006). Application of this concept to compounds beyond non-polar narcosis to other modes of action (MOA) is not yet explored. It is believed that the chemical activity approach could provide a complementary approach towards an improved understanding of an Adverse Outcome Pathway (AOP), as it has the potential to link exposure with the Molecular Initiating Event (MIE) in a single metric.

Different systems have been developed to classify chemicals according to their mode of action (MOA) (Russom et al., 1997; Verhaar et al., 1992). In this presentation, the focus was on the Verhaar classification system that distinguishes four MOA classes:

MOA 1, non-polar narcosis,

MOA 2, polar narcosis,

MOA 3, modes of actions related to reactive chemicals and

MOA 4, specific modes of action.

Chemical activities for effect data of compounds with other modes of action than narcosis are scarce. There are a few publications with initial analyses of fathead minnow LC50 data (Mackay et al., 2011, 2014). In this presentation, the Utrecht guppy LC50 data set was used to illustrate how chemical activity can be applied in the analysis of acute fish toxicity data. Chemical activity was calculated from the LC50 data and the estimated aqueous solubility. The following observations were presented and discussed:

• Chemical activities for MOA 1 compounds are in the range known for narcosis and the variability in activities is strongly reduced in comparison with aqueous effect concentrations.
• Activities for MOA 2 are slightly lower.
• Chemical activities of MOA 3 and 4 compounds cover a broad range and vary between 10-1 and 10-6.

While chemical activities of MOA 3 and 4 are often substantially lower than of MOA 1 chemicals, the more hydrophobic compounds tend to have activities close to values for MOA 1 compounds. An example with acrylates was discussed in more detail at the workshop based on data analysed by Freidig et al. (1999) This example was also used to show that information about the target site and target site environment is important in the analysis of effect data. The same example also shows that chemicals from one particular class may have multiple MOA’s. MOA 3 chemicals will also act via narcosis and which MOA dominates depends on the internal distribution within an organism or within a cell.

The examples presented show that plotting data as chemical activity represents a useful tool for potentially interpreting toxicity data. It easily shows baseline- and excess toxicity for MOA 3 and 4. For modelling effects of MOA 3 and 4 chemicals, more complex toxicokinetic and dynamic (TKTD) approaches (Ashauer et al., 2015; Jager et al., 2011) are essential to obtain a better understanding of effect data.

Figure 3.3.1. Two modes of action of reactive chemicals: narcosis and “reactive toxicity. These two modes of action can be active at the same time. EC is effect concentration, SL is the subcooled liquid solubility, Kmw is the membrane-water partition coefficients and k is a rate constant of chemical with a nucleophile