Integrated Decision-tree Testing Strategies for Acute Systemic Toxicity and Toxicokinetics with Respect to the Requirements of the EU REACH Legislation

Abstract

Liverpool John Moores University and FRAME conducted a joint research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for acute systemic toxicity and toxicokinetic testing. The paper reviews in vitro tests based on basal cytotoxicity and target organ toxicity, along with QSAR models and expert systems available for this endpoint. The use of PBPK modelling for the prediction of ADME properties is also discussed. These tests are then incorporated into a decision-tree style, integrated testing strategy, which also includes the use of refined in vivo acute toxicity tests, as a last resort. The implementation of the strategy is intended to minimise the use of animals in the testing of acute systemic toxicity and toxicokinetics, whilst satisfying the scientific and logistical demands of the EU REACH legislation.

Anti‐Oxidative Abilities of Essential Oils from Atractylodes ovata Rhizome

“…The normal rat cardiomyocytes (H9C2) cell line was chosen because of the TBH-induced heart lipid peroxidation assay. In addition, based on the European Centre for the Validation of Alternative Methods (ECVAM, ISO 9001), NIH-3T3 and WI-38 cell lines were used to evaluate the alternative non-animal cytotoxicity tests [31]. As shown in Table 5, AT displayed the strongest cytotoxicity effects among the three sesquiterpenoids.…”

The virtual cell based assay: Current status and future perspectives

“…One of the challenges in this field is to predict acute toxic classes using alternative methods at least as accurately as the current in vivo tests do. The use of basal cytotoxicity to predict acute oral toxicity in vivo has been extensively studied ( Combes et al, 2008 ). The ACuteTox project ( http://www.acutetox.eu/ ) evaluated the use of a battery of in vitro and in silico tests to predict acute oral systemic toxicity.…”

Outcome of the public consultation on the draft scientific opinion on Guidance on risk assessment concerning potential risks arising from applications of nanoscience and nanotechnologies to food and feed

“…After each tier, all information gathered so far is evaluated to determine if a scientifically sound safety assessment is already possible. For the assessment of repeat dose toxicity and toxicokinetics of non-nanoform substances, Grindon et al (2008) and Combes et al (2008) present concrete schemes on how such integrated decision-tree testing strategies should be performed. For ENM, the EU Commission's Joint Research Centre JRC, together with the Netherlands Environmental Assessment Agency RIVM and BASF SE have put forward a tiered testing strategy that meets the above-mentioned requests (Sauer, 2010; see also comments to 5.3).…”