Workplan

The ACuteTox project is structured into nine workpackages (WPs), in addition to a WP on management, dissemination and exploitation issues. The nine WPs are interlinked as illustrated in the  Project structure (download pdf 224kB) and their contents are briefly described in the following.

 

WP1: Generation of a database with toxicity data from animal tests and human accidents (in-vivo data)

The main objective of this WP is to generate a database of in-vivo toxicity data from both animal tests and human poisoning accidents. The results of previous research projects will be merged into the new database, which will ultimately include in-vivo toxicity data for 100-140 chemicals. The main purpose of this database is to enable evaluation and calibration of the data generated by in-vitro toxicity testing in other WPs of the project and in particular to allow validation of the ensuing in-vitro test strategy. (Retrospective biometrical studies will also be performed to evaluate the quality and predictive capabilities of in-vivo data, so as to provide a reference on how accurate the in-vitro test strategy has to be to achieve regulatory approval.)

 

WP2: Generation of a database with toxicity data from animal-free tests (in-vitro data)

In analogy with WP1, WP2 will create an in-vitro database from the results of two ongoing research projects (wherein ACuteTox partners participate). The database will be further extended through additional tests carried out within other WPs of the project using human, mouse and rat cell lines, so as to build up a complete set of toxicity data for the reference chemicals selected. WP2 will result in a database containing in-vitro toxicity data for the same 100-140 chemicals as in WP1.

 

WP3: Gradual improvement of predictive capabilities of in-vitro tests

The aim of WP3 is to iteratively improve the in-vitro/in-vivo correlations (determined from the data compiled in WP1 and WP2) for the cases where correlation is unsatisfactory. The influence of a range of parameters (cf. WP5, WP6 and WP7) will be determined through in-vitro testing and kinetic modelling in order to allow improvement of in-vitro/in-vivo correlations. Moreover, a robotic testing system will be adapted to the specific needs of the project to facilitate the large number of tests required. The work is expected to yield “alert” tests to indicate when a test result may not be valid and “corrector” tests to improve the predictive capabilities of a test.

 

WP4: New cell systems and innovative test methodologies

In an attempt to improve the predictive capabilities of in-vitro tests, innovative tools as well as new and modified cell lines will be explored to better anticipate animal and human toxicity.

 

WP5, WP6 and WP7: Improving in-vitro/in-vivo correlations

While these three WPs have in common that they all aim to identify factors that influence the correlation between in-vitro toxicity (concentration) and in-vivo toxicity (dosage) and to develop an algorithm that accounts for this, they have different foci. WP5 investigates the influence of ADE (administration, distribution and elimination) on the kinetics of chemicals using modelling and in-vitro testing. WP6 addresses the issue that the metabolism of a chemical may influence its toxicity, since it may actually be a metabolite (a substance produced by the degradation of the chemical in the body) that is responsible for the observed toxicity. WP7 examines organ-specific toxicity responses for nervous system, kidney and liver, which are expected to explain some cases of poor in-vitro/in-vivo correlation.

 

WP8: Development of test strategy

The results produced in the other WPs will be integrated into an in-vitro test strategy capable of i) predicting the in-vivo toxic dose of a chemical,

ii) proposing which in-vitro tests to employ to experimentally quantify its acute toxicity and

iii) interpreting the results of the tests to provide an authoritative value for a chemical’s acute in-vivo toxicity.

 

WP9: Pre-validation of test strategy

During the last two years of the project, the in-vitro test strategy will be pre-validated to demonstrate the reproducibility and relevance of each building block. Pre-validation will be carried out by 3-4 laboratories and the results will be independently assessed. It is expected that further validation will lead to regulatory approval of the test strategy and its incorporation into standardised test guidelines for chemicals’ hazard assessment.