General scheme for Ecotoxicological Risk Classification (ERC)

The original Canadian scheme for Ecotoxicological Risk Classification (ERC) is developed to assess and prioritize chemicals based on various (eco)toxicological information, including the assessment of ADME properties [1]. The final outcome of the scheme includes different layers of information associated with: the hazard and exposure classification, risk assessment, confidence level and severity rating and is considered as very useful for classification and prioritization purposes. Given the complexity of the original Canadian approach, the version of the ERC classification scheme implemented within the QSAR Toolbox is assumed as a prototype of the original Canadian scheme and is developed based on the following general considerations:

• The Toolbox ERC scheme considers the hazard descriptors and pre-filters related to the ADME properties, only.
• The hazard assessment, confidence level and severity rating are estimated considering the available information on the hazard descriptors.
• The ERC scheme is implemented in Toolbox v.4.9 as a dendroid scheme (using the functionalities of the Profiling module) and should be considered as a beta-version.
• The scheme relies on the data, profilers and models which are available in Toolbox or comes from external modules via the Toolbox repository (e.g., iSafeRat® Mechanisms of toxic Action profiler and OPERA models).
• Hazard classification and confidence scores are assigned for: 1) each data level independently and 2) final evaluation of hazard following the hierarchy of toxicological data.
• Metabolism is an important layer for the hazard evaluation; however, it is not considered on this stage of development due to the complexity it brings to the design of the workflow.
• The ERC scheme is currently disseminated through the Toolbox repository module.

The ADME pre-filter is engaged to provide alerts for substances that present a highly confident outcome of very low internal and environmental bioavailability or that upon uptake, become distributed in the blood plasma of organisms (protein plasma binding). In general, the logic flow includes three layers of chemical assessment: 1) bioavailability of chemicals, 2) distribution in plasma, and 3) special toxicokinetic considerations.

The layer for estimating the toxicological hazard is performed using specific descriptors for: 1) receptor-mediated interactions; 2) chemical reactivity/genotoxicity; and 3) mode of toxic action. The hazard assessment considers the principal interactions (high level MIEs) a chemical can have with various biological tissues. The ERC integrates in silico, in chemico, in vitro and in vivo data (mammalian, acute and chronic aquatic) according to the following data hierarchy: in silico < in chemico < in vitro < in vivo.

The three hazard profiling modules and the ADME pre-filter are incorporated in the General scheme for Ecotoxicological Risk Classification (ERC) profiler which summarizes the collected information by all individual modules. The main output of the scheme is classification of chemicals into hazard class 1, 2 or 3 (associated with low, moderate, or high concern, respectively) depending on the collected weight-of-evidences. Along with the assignment of hazard classification and confidence score for each descriptor the scheme also summarizes the confidence scores of all individual descriptors and converted it into the respective confidence category: Very Low (confidence score between 1 and 10), Low (confidence score between 11 and 25), Moderate (confidence score between 26 and 60), High (confidence score between 61 and 100), and Very High (confidence score above 100). In addition, once the ERC scheme is executed, all profiling results are presented in a transparent way and could be easily explained, which allows the user to obtain more information on the classification pathway covered by a target.

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