The Center for Alternatives to Animal Testing is an academic center affiliated with the Division of Toxicological Sciences in the Department of Environmental Health Sciences of the Johns Hopkins University Bloomberg School of Public Health.

 

Johns Hopkins School of Public Health

Abstract for TestSmart--A Humane and Efficient Approach to Screening Information Data Sets (SIDS) Data

A Proposal for the Practical Application of the MEIC Results in the HPV Challenge Program

Björn Ekwall
Cytotoxicity Laboratory Uppsala (CTLU)

As a result of the MEIC multicentre evaluation program, a battery of three simple human cell line assays was shown to predict acute lethal blood concentrations of chemicals in man better (R2 0.77) than the prediction of human doses of the same chemicals by rat and mouse LD50 values (R2 0.65). This 1,9,5/16-battery is a very informative adjunct to any standard animal toxicity test. According to other MEIC results, this battery might be the core of an extended battery of toxicity and, notably, kinetic in vitro assays, with the capacity to predict also human lethal doses, symptoms and mechanisms. CTLU has designed a blueprint of such an extended battery and from now on invites all interested laboratories to develop the "missing" tests of this battery within the frames of the EDIT (Evaluation-guided Development of In Vitro Tests) program. The aim of EDIT is to provide a full replacement of the animal acute toxicity tests.

The EDIT research program is published on the internet. The most urgent developments are assays on accumulation of chemicals in cells (test of Vd), passage across the intestinal and blood-brain barriers, and biotransformation to more toxic metabolites. CTLU will provide developing laboratories with human reference data and evaluate results as single components of complex models.

The MEIC results as well as the forthcoming EDIT results could be applied to reduce animal testing in the HPV program, as follows:

  1. Formal validation by ECVAM/ICCVAM of the existing MEIC battery.
  2. If passed - use of the validated battery to test every chemical in the HPV program (provides cheap and important supplementary data).
  3. Financial support (from agencies and industry) of development of new supplementary in vitro tests on acute toxicity and kinetics, including the EDIT replacement blueprint.
  4. Work by an EPA expert committee to use some of the HPV chemicals to evaluate a battery of in vitro toxicity and toxicokinetic tests on acute toxicity (EDIT and similar models):
    • Engage poison information experts to select a set of HPV chemicals with good human acute toxicity data, including all-important time-related lethal blood concentrations.
    • Priority standard testing of the same chemicals in the HPV programme.
    • Testing of the same chemicals in the newly developed in vitro systems (EDIT, etc.), including modelling of acute toxicity by the new assays.
    • Evaluation of the new in vitro batteries by comparion of HPV standard animal data and the new models from in vitro data with the human data for the selected set of chemicals.
  5. If the new in vitro models can be shown to predict human acute toxicity better than the animal HPV tests (as expected by CTLU) in vitro batteries may totally replace the animal acute toxicity tests in further HPV testing.