Workshop Report no.29 – Defining the role of chemical activity in environmental risk assessment within the context of mode of action: Practical guidance and advice

In a Nutshell

Brussels, August 2016

At its most basic level, chemical risk assessment involves an assessment regarding both the toxicity and exposure mechanisms associated with a specific chemical.  It is well understood that the toxic effects of a given chemical depend on the dose (how much), frequency of exposure (how often), and the route by which the chemical enters the body.  Mechanisms that influence toxicity and exposure of chemicals are governed by thermodynamics.  As such, understanding these mechanisms can be useful in identifying chemicals that represent unacceptable risks to humans and the environment.

Recently there have been a number of studies that have aimed at demonstrating that chemicals that interact with biological systems through relatively weak and reversible hydrophobic interactions to cause non-specific baseline toxicity, or ‘narcosis’, are associated with a narrow range of internal body concentrations (2-8 mmol/kg).  Alternatively, the same information can also be expressed based on the concept of a dimensionless thermodynamic chemical activity, of between 0.1 to 0.01.  The chemical activity concept is attractive in that it is possible to compare the chemical activity of a chemical, or mixture of chemicals, not only between different biological organisms, but also between various environmental media, such as air, water, soil, and sediment.  Consequently, the concept of chemical activity provides a relatively simple and coherent framework for shaping the study of toxicity pathways and assessing risks for both terrestrial and aquatic ecosystems.

To date the use of the chemical activity concept, however, has largely been targeted at interpreting acute toxicity data for chemicals with non-specific, or baseline toxicity.  Concerns related to long-term exposures of low concentrations of individual chemicals, and chemical mixtures, however, are increasing.  There is thus a need for an improved basis for assessing the risks associated with chronic exposures.  Given the appeal of chemical activity as an integrating concept for baseline toxicants, it would be of interest to assess the utility of the concept to chronic toxicity of baseline toxicants as well as to the acute toxicity of chemicals with more specific modes of action.

ECETOC in collaboration with RIFM organised a two-day workshop to assess the feasibility and applicability domain of the chemical activity concept within chemical risk assessment.  The workshop reviewed the use of chemical activity as an applied tool for assessing the environmental risks of neutral hydrophobic chemicals known to act as baseline toxicants, and worked towards identifying data gaps.  The accompanying workshop report summarises a research strategy defined to address existing data gaps needed to expand the applicability domain to miscible and ionisable organic chemicals with specific modes of action, and application of the concept to chronic toxicological endpoints.

A description and findings of the workshop is available in ECETOC Workshop Report No. 29: Defining the role of chemical activity in environmental risk assessment within the context of mode of action: Practical guidance and advice.


Chemical activity has recently been promoted as a useful concept for interpreting and classifying ecotoxicological data and for performing environmental risk assessment of chemicals.  The most common approach to estimate chemical activity in the aqueous phase is as the fraction of the water solubility (liquid or sub-cooled liquid, if the substance is a solid at room temperature).  Accordingly, LC50s from acute and chronic aquatic toxicity tests can readily be converted to lethal chemical activities (La50s) using the appropriate water solubility.  For example, La50s for baseline toxicants have been shown to cluster around a value of 0.01 for chemicals spanning a large range of hydrophobicity.  While the chemical activity approach is attractive due to its apparent simplicity, it is important to recognise that there can be substantial challenges regarding the implementation of the concept as a practical environmental risk assessment tool.  The goal of this Experts Workshop entitled, “Defining the role of chemical activity in environmental risk assessment: Practical guidance and advice” was thus to assess the feasibility of the chemical activity concept as a risk assessment tool, highlighting where the concept is and is not useful.  The workshop was a recommendation of ECETOC Technical Report no. 120, and follows the work of Cefic LRI project ECO16.

Workshop participants concluded that there were both opportunities and challenges with respect to the chemical activity concept.  The opportunities identified include:

  • Chemical activity is a useful metric that can directly relate chemical exposure and toxicity more effectively than concentration, because concentrations are media-dependent while activity applies to all media, allowing exposure and toxicity to be expressed on a common basis.
  • Activity provides a good metric for characterising baseline toxicity for single non-polar organic chemicals and mixtures of non-polar organic chemicals.
  • Activity data is a useful metric for discriminating between baseline toxicity (MOA 1 and MOA2), which occurs at activities between 0.01 and 0.1, and excess toxicity, which occurs at activities less than 0.01.
  • Activity can also be used to identify poor quality data, such as toxicity data from experiments where dosing concentrations were above the solubility of the chemical in the exposure medium, and exposure data from experiments subject to background contamination.
  • The application of activity to describe the toxicity of mixtures of non-polar organic chemicals represents a novel tool in chemical risk assessment that can be particularly useful in addressing chemical risks in real world environments.

The challenges associated with advancing the chemical activity concept within environmental risk assessment include:

  • Application of the chemical activity concept to chronic toxicity endpoints and reactive and specifically acting chemicals needs to be better understood. In order for relationships to advance there is a need to refine existing chemical toxicity classification schemes using a variety of tools, including the use of Adverse Outcome Pathways (AOPs) and Omics data.
  • Translation from concentration to activity is crucial in studies where existing data are converted into the chemical activity space. However, this translation can be challenging and can add error to measurement error.
  • Quantification of the uncertainties/error in measured or estimated water solubilities needs to be addressed, as well as clarification/guidance regarding the conversion of concentration data to chemical activity using partition coefficients.
  • Improved communication of the activity concept is a major issue and will be central to future application and impact. Communication of the activity approach to a non-scientific audience may not be easy. Whether a broader acceptance of the chemical activity framework can be achieved might also be a matter of semantics.

Suggestions for future research were separated into three primary themes, (i) the chemical activity concept, (ii) application of the chemical activity approach and (iii) classification of chemicals. Given that a major challenge associated with advancing the chemical activity concept relates to its application towards chemicals with specific toxicological modes of action, a common theme between each of the primary themes was the recommendation for a need to refine existing chemical toxicity classification schemes.  Suggestions for refining chemical classification include the adoption of weight-of-evidence approaches that include AOPs and omics data, in which conversion of concentration data to chemical activities may prove useful, particularly with respect to possibly helping to better understand observations of the cytotoxic-burst phenomenon reported for in vitro data.  To help better communicate the utility of the chemical activity concept within environmental risk assessment, there is a need to further advance the effectiveness of the concept as applied to chemicals known to act as baseline toxicants.  Specifically, continued efforts are needed to further demonstrate the application of the concept towards :

  • Data rich chemicals, in which the conversion of concentration data to chemical activities enable information to be presented as a single ‘currency’. Such actions thus provide a basis for comparisons of data both temporally and spatially, enabling better utilisation of all existing data, and helps to  facilitate the process towards assessing and managing risks.
  • Activity-based species sensitivity distributions, in which toxicity tests could be conducted at controlled chemical activity in order to provide an improved estimate of actual sensitivities between species.
  • Application of the chemical activity concept to interpret and estimate mixture toxicity.
  • Development of an online freely available chemical activity calculator.