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Using Data Associated with a Developmental and Reproductive Toxicity Adverse Outcome Network to Aid Safety Assessments

pdf fileMyden A; Cayley A; Fowkes A; Kane S; Newman D; Oliveira A; Hill E;

Developmental and reproductive toxicity (DART) is an important safety assessment endpoint. Traditional (in vivo) methods used to assess DART endpoints involve large numbers of animals and are time consuming and costly. With the drive towards animal-free toxicity testing, increasing volumes of alternative assays, models and data are being developed.

To conclusively undertake a risk assessment, all available relevant data should be utilised. However, as alternative assays often measure discrete biological steps in a mechanism of toxicity (and not traditional toxicity endpoints), it can be difficult to understand the context and significance of their results in isolation. Adverse outcome pathways (AOPs), a formalised approach to documenting mechanisms of toxicity, provide this contextualisation. AOPs comprise key events (KEs) linked to each other through key event relationships (KERs). Each KE must be measurable – as a result, it should be possible to link an assay to each KE.

This feature can provide a mechanistic understanding for relevant assays, and allows for the review of multiple assay types within the framing of a mechanism of toxicity. Many potential uses of AOPs have been hypothesised and discussed in the literature – however, for AOPs to become a useful tool in risk assessment, it is likely that comprehensive networks of mammalian-relevant pathways leading to AOs of regulatory significance will be needed.

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