The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans

Abstract

SummaryThe role that in vitro systems can play in toxicological risk assessment is determined by the appropriateness of the chosen methods, with respect to the way in which in vitro data can be extrapolated to the in vivo situation. This report presents the results of a workshop aimed at better defining the use of in vitro-derived biomarkers of toxicity (BoT) and determining the place these data can have in human risk assessment. As a result, a conceptual framework is presented for the incorporation of in vitro-derived toxicity data into the risk assessment process. The selection of BoT takes into account that they need to distinguish adverse and adaptive changes in cells. The framework defines the place of in vitro systems in the context of data on exposure, structural and physico-chemical properties, and toxicodynamic and biokinetic modeling. It outlines the determination of a proper point-of-departure (PoD) for in vitro-in vivo extrapolation, allowing implementation in risk assessment procedures. A BoT will need to take into account both the dynamics and the kinetics of the compound in the in vitro systems. For the implementation of the proposed framework it will be necessary to collect and collate data from existing literature and new in vitro test systems, as well as to categorize biomarkers of toxicity and their relation to pathways-of-toxicity. Moreover, data selection and integration need to be driven by their usefulness in a quantitative in vitro-in vivo extrapolation (QIVIVE). Keywords: biomarker of toxicity, integrated testing strategies, quantitative in vitro-in vivo extrapolations

Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling

“…A BoT is defined as ''a parameter that provides quantitative information that is mechanistically relevant to and predictive of an adverse effect'' (Blaauboer et al, 2012). Biomarkers play an important role especially for in vivo studies to get early and sensitive indications of liver or kidney injury (Dedeoglu et al, 2013;Schomaker et al, 2013).…”

“…disturbed migration in the MINC) links to intermediate changes inside the cells. One assumption is that toxicants causing the same type and degree of complex adverse outcome, also lead to similar changes of relevant transcripts, proteins or other potential biomarkers of toxicity (Blaauboer et al, 2012). …”

Alternative methods for the use of non-human primates in biomedical research

“…Integration of all available data in a stepwise (hierarchical) approach improves the transparency and efficacy of the risk assessment process and will reduce the number of animals needed in safety testing. Challenges remain, such as the selection of the most important parameters to assess risk and the assessment of what can be called no effect, adaptive effects or adverse effects of a compound (Blaauboer et al, 2012).…”

REPRINT: Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice 1

“…the increasing use of animals for research in the last years has been accelerated by the widespread generation of transgenic mice. the increase in animal experimentation in most biomedical areas has overcompensated all successful efforts to substitute animals in some research fields (Hartung and Leist, 2008;Blaauboer et al, 2012;leist et al, 2012a;Hasiwa et al, 2011). the hard evidence for the belief in the usefulness of animal experimentation across fields (in terms of hundreds of millions of dollars and euros invested on basis of this assumption) is overwhelming.…”