| Background Review Document (BRD) | Overview | Other Validation Study Documents |
| Peer Review Panel | Test Method Evaluation Report | Recommendations and Agency Responses |
Overview
The NICEATM/ECVAM In Vitro Cytotoxicity Validation Study generated in vitro cytotoxicity data to predict rodent in vivo LD50 values and starting doses for acute oral systemic toxicity test methods. The in vitro tests evaluated used rodent (mouse fibroblast [3T3]) and human (normal human epidermal keratinocyte [NHK]) cells.
The objectives of the validation study were to:
- Further standardize and optimize the in vitro basal cytotoxicity protocols to maximize test reliability (intra- and inter-laboratory reproducibility)
- Assess the accuracy of the standardized in vitro cytotoxicity test methods for estimating rodent oral LD50 values across the five United Nations Globally Harmonized System of Classification and Labelling of Chemicals categories of acute oral systemic toxicity, as well as unclassified toxicities
- Estimate the reduction and refinement in animal use achievable from using the in vitro basal cytotoxicity test methods to identify starting doses for in vivo acute oral systemic toxicity tests
- Develop databases containing high quality data from in vivo acute oral lethality and in vitro basal cytotoxicity tests that can be used to support the investigation of other in vitro test methods necessary to improve the prediction of in vivo acute oral lethality
Upon conclusion of the study, an independent scientific review panel evaluated the validation status of the 3T3 and NHK basal cytotoxicity test methods in May 2006 for use as adjuncts to in vivo acute oral systemic toxicity tests for the purpose of determining starting doses. ICCVAM concurred with the peer review evaluation that these in vitro cytotoxicity test methods should be considered for use in a weight-of-evidence approach to determine starting doses for acute oral systemic toxicity test methods (i.e., the Up-and-Down Procedure and the Acute Toxic Class method) to reduce the use of animals required for these methods. Additionally, ICCVAM agreed with the panel that these in vitro cytotoxicity test methods could not be used to determine the hazard classification of chemicals.
The validation study results were used as the basis for the ACuteTox project, which is funded
by the European Union through the European Centre for the Validation of Alternative Methods (ECVAM).
The aim of ACuteTox is to develop a battery of in vitro tests sufficiently robust and powerful
enough to replace in vivo tests used for determining the acute toxicity of chemicals and
products.
Visit the ACuteTox website.
Federal Register notice announcing availability of the ICCVAM Test Method Evaluation Report and final Background Review Document, and transmittal of ICCVAM test method recommendations to Federal agencies (73 FR 15757, March 25, 2008) [PDF]
View ICCVAM Test Method Evaluation Report: In Vitro Cytotoxicity Test Methods for Estimating Starting Doses for Acute Oral Systemic Toxicity Tests (NIH Publication 07–4519)
View final Background Review Document (BRD): In Vitro Cytotoxicity Test Methods for Estimating Acute Oral Systemic Toxicity (NIH Publication 07–4518)
