Chapter 13: The Parallelogram Approach to Assess Human Relevance of Toxicogenomics-derived Toxicity Pathways in Human Health Risk Assessment

Human health risk assessment is traditionally performed using rodent in vivo studies. Novel approaches to traditional risk assessment include in vitro testing and toxicogenomics. We summarize studies that show the applicability of the parallelogram approach and the concordance model to evaluate human relevance of toxicogenomics data. The principle is that increasing overlap in toxicogenomics derived toxicity pathways between species and in vivo–in vitro (including human-based in vitro assays) increases the confidence in the human relevance of these pathways. These approaches can currently be applied for hazard identification in risk assessment. Additionally, our studies have demonstrated the usefulness of these approaches for evaluating in vitro assays for toxicity assessment. Recent studies have also shown the promise of quantitative toxicogenomics for dose–response modeling in human health risk assessment. Challenges for implementation of quantitative toxicogenomics in regulatory frameworks include interpretation of toxicogenomics data in terms of toxicity pathways and discrimination between adverse and adaptive responses. Despite these challenges, it is worth starting implementing toxicogenomics for regulatory purposes. In this respect, both the parallelogram approach and the concordance model may aid in selecting the most sensitive human relevant pathways linked to the underlying mode(s) of action in order to derive benchmark doses.