May 7-10, 2005

THE ROLE OF CHEMICAL REACTIVITY IN PREDICTIVE TOXICOLOGY

This past May 7 – 10 the Knoxville Reactivity Workshop on “The Role of Chemical Reactivity in Predictive Toxicology” met at The University of Tennessee, College of Veterinary Medicine. The Workshop would not have been possible without the support of:

1. Persons for the Ethical Treatment of Animals;

2. Society of Toxicology;

3. Wildriver Consulting.

The Knoxville Workshop brought together researchers in the areas of chemistry and toxicology with the express purpose of evaluating the use of model nucleophiles as an organizing intermediate for predicting the adverse effects of reactive chemicals.

The goals of the workshop were to:

1. conduct a critical review of reactive toxicity models for soft electrophiles, and

2. identify the primary science gaps for more reliable methods for the prediction of reactive toxicity.

The context for structuring adverse effects from chemicals in these discussions is the regulatory risk assessment paradigm for the classification and labeling of chemicals. A framework for organizing the discussions on the role of model nucleophiles in QSAR models was the toxicity pathway cartoon below.

The Workshop found that a systematic database of relative reactivity with the thiol moiety of cysteine of the tripeptide glutathione could be correlated to excess aquatic toxicity, skin sensitizers, respiratory irritants and hepatocyte toxicity from selected soft electrophiles. The thiol nucleophile database provides a convenient separation of the need to estimate the thiol reactivity from chemical structure and the need to define the critical downstream nodes in the toxicity pathways.

The Workshop agreed that the softer end of reactivity toxicity targets molecular site in proteins. The flow diagram below points out the major aspects such reactivity. Specifically, soft reactive toxicity is molecular mechanism (e.g., Michael addition, Schiff base) dependent and caused by either the parent compound are a metabolite. The molecular initiating event is irreversible protein modification. The down stream adverse effects are either a non-immune, local effect restricted to the exposed surface or an immune, systemic effect.

Research needs identified by the Workshop include:

1. the completion of the glutathione database;

2. development of an amine nucleophile database;

3. development of methods for estimating reactivity from chemical structure;

4. identifying the broad structural requirements for forming antigens in skin, liver, and lung, and

5. reorganizing test data with the toxicity pathway framework.