Abstract
Within the REACH Regulation (EC/1907/2006), the substitution principle for chemicals classified as Substances of Very High Concern (SVHC) for either human health or environmental risks has been implemented in order to support their replacement by suitable alternatives. Considering the thousands of chemicals to be tested within the frame of REACH, animal testing by internationally-accepted guidelines sounds unreasonable in terms of the required time, costs as well ethical issues. Hence, REACH recommended also the use of alternative methods to animal experimentation although no validated in silico or in vitro tools were available when regulation entried into force. To search for suitable alternatives to SVHC having an Endocrine Disruptor (ED)-like Mode-of-Action (MoA) by means of an integrated, tiered in silico-in vitro approach, the EU-granted project LIFE-EDESIA (contract no. LIFE12 ENV/IT/000633) is combining computational-based tools and cell-based bioassays, in order to develop a no-animal testing procedure to screen for chemicals having less or no toxicity in terms of endocrine disruption-like activities. A general view of the no-animal testing approach implementing REACH and the substitution principle will be given, emphasising ligand-nuclear receptor (NR) assessment by molecular docking (one of the LIFE-EDESIA in silico approaches) and the use of clinical biomarkers in in vitro toxicology to detect ED-like adverse effects in cell-based bioassays.
Highlights
IntroductionThe Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH, EC/1907/ 2006) Regulation [1, 2], entered into force on June 2007, is a regulation of the European Union (EU), adopted to improve the protection of human health and the environment from the risks that can be posed by chemicals
Within the REACH Regulation (EC/1907/2006), the substitution principle for chemicals classified as Substances of Very High Concern (SVHC) for either human health or environmental risks has been implemented in order to support their replacement by suitable alternatives
The focus of the review will be the use of no-animal testing within the frames of the substitution principle and the REACH Regulation, highlighting the ligand-nuclear receptor (NR) assessment by molecular docking as well as the use of clinical biomarkers as biomarkers of effect in vitro toxicology to detect Endocrine Disruptor (ED)-like adverse effects in cell-based bioassays. doi:10.11131/2017/101205
Summary
The Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH, EC/1907/ 2006) Regulation [1, 2], entered into force on June 2007, is a regulation of the European Union (EU), adopted to improve the protection of human health and the environment from the risks that can be posed by chemicals. The focus of the review will be the use of no-animal testing within the frames of the substitution principle and the REACH Regulation, highlighting the ligand-nuclear receptor (NR) assessment by molecular docking (one of the LIFE-EDESIA in silico, computational approaches) as well as the use of clinical biomarkers as biomarkers of effect in vitro toxicology to detect ED-like adverse effects in cell-based bioassays. Some EDs has been shown to act via epigenetic mechanisms that can be transgenerally inherited [12, 13] Such mechanism-based tools and body of proof, largely used by the scientific community and under validation at the EU level by the EURL ECVAM [14], have the inherent weakness to detect a molecular event and a subsequent intra-nuclear effect, but without to show if there is any consequence as a downstream functional response of the cell, in which the chemical exposure has been tested. Within the LIFE-EDESIA project, different cell-based bioassays are used to search for an ED-like MoA relying on the in vitro evaluation of cell-specific, hormone-regulated biomarkers of effect—already in use in clinical practice as indicators of either a disease or a patho-physiological alteration—in order to detect the cellular response upon chemical exposure [8]
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