Towardin vitrobiomarkers for developmental toxicity and their extrapolation to thein vivosituation

Abstract

Relevance of readouts in in vitro developmental toxicity assays as predictive biomarkers for in vivo developmental toxicity should be evaluated by comparing the obtained in vitro effect concentrations with in vivo internal concentrations at dose levels causing developmental toxicity. Extrapolation of the in vitro effect concentrations to in vivo dose levels using PBK modeling (i.e., reverse dosimetry) is promising in its use to derive points of departure for risk assessment, enabling the use of in vitro toxicity data in the safety assessment of compounds.

Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

“…Finally, as we discussed before (Louisse et al 2010a(Louisse et al , 2012, the ES-D3 cell differentiation assay may not produce the right in vitro effect concentrations for specific in vivo developmental toxicity endpoints, indicating that research is needed as to whether specific in vitro tests would be required for specific in vivo developmental toxicity endpoints. The in vitro ES-D3 cell differentiation assay used in the present study should be regarded as a simplified first tier model of the developing embryo and cannot be used to predict specific in vivo developmental toxicity end points with the greatest possible accuracy.…”

Assessment of food toxicology

“…Usually, a comprehensive clinical chemistry profile is performed employing a variety of tissue-specific biomarkers as indicators for organ-specific damage such as liver, kidney, brain, heart, vascular system and muscles (Table 1) Table 2. Integration of data obtained by these two approaches as first line of toxicity assessment is usually validated by histology which may potentially lead to causative relationships relevant to degenerative diseases [3,[169][170][171][172][173].…”

“…The predictive value of QSARs can be greatly enhanced by quantitative in vitro to in vivo extrapolation when toxicokinetic data on xenobiotic biotransformation, chemical-chemical interactions, absorption, distribution, bioavailability, metabolism and/or excretion of the substance under study are available [2,7,32,34,172,179,180]. Advances of these in silico tools to assess toxicity in food has led to a wealth of mechanistic information of adverse effects of food toxicants and a significant reduction in the number of animals required for toxicological tests for a new active substance [5-8, 27, 33].…”

“…Advances of these in silico tools to assess toxicity in food has led to a wealth of mechanistic information of adverse effects of food toxicants and a significant reduction in the number of animals required for toxicological tests for a new active substance [5-8, 27, 33]. Therefore, in silico models are being increasingly recognized as predictive tools to analyze hepatotoxicity, cardiotoxicity and nephrotoxicity [9,33,34,39,172,[181][182][183].…”

A physiologically based toxicokinetic (PBTK) model for moderately hydrophobic organic chemicals in the European eel ( Anguilla anguilla )

“…Organs and tissues are explicitly represented as individual compartments within PBTK models, where each compartment is characterised by its volume (as a fraction of total body weight), its total lipid and water contents (as a fraction of tissue wet weight [w.w.]), and by the blood flow to the compartment (as a fraction of cardiac output). PBTK models are capable of predicting the concentration of neutral organic pollutants in the whole fish and in different tissues at any time during exposure (Louisse et al, 2012;Yoon et al, 2012). Furthermore, they facilitate application of the results of in vitro bioassays, which have a higher throughput and reduce the requirement for experimental animals, to predict the effects in vivo; these models thus have the potential to make a valuable contribution to predictive toxicology (Brinkmann et al, 2014a;Stadnicka-Michalak et al, 2014).…”