Learning Outcomes:

The aims of this module are that the students will be able to understand:

·         Genotoxic/non-genotoxic activity

·         models of comparative dose responses, e.g. exponential and threshold modules

·         Acute and chronic effects, high and low toxicity responses, additive and synergistic effects

·         Lesion induction related to background

·         Study design, quality control, the activity of the TWGT and the validation of test systems

·         Operations of regulatory bodies

·         Strategies of testing

On the successful completion of this module students will:

·         Be aware of the need for careful planning at all phases of an in vivo toxicology study

·         Be able to constructively criticise experimental design

·         Be able to reduce the number of studies whose poor planning means that no useful results are obtained, and hence reduce the number of animals required.

·         Review data sets in light of current regulations

·         Evaluate the designs of studies and debate their significance in light of the 3R’s-Reduction,  Refinement and Replacement

Module content:

·         Genotoxic and non-genotoxic activity. Direct and indirect mechanisms

·         DNA and non-DNA targets.

·         Criteria for the definition of positive, statistical significance fold increases, relationships to historical databases of control and treated values

·         Assay reproducibility. False positives and negatives.

·         Dose response relationships, exponential and threshold models, factors which may include a threshold, nucleoside analogues, aneugens, topoisomerase inhibitors, detoxification, repair etc.

·         Influence of toxicity, acute and chronic toxicity, high and low toxicities.

·         The development of optimal designs. Quality control, the activity of IWGT and the criteria for test system validation.

·         Operation of regulatory bodies

·         Strategies for testing as illustrated by national and international requirements.

·         Examples of data, with interpretation problems. Clear, equivocal and inconclusive data sets, single and multiple assays

·         Test batteries and the problems of conflicting data, weight of evidence considerations.

·         Potency measurements using in vitro and in vivo tests, potential for human risk estimation.

·         Artefacts in the in vitro and in vivo assays. False positive and negative.

·         Biological relevance of responses in vitro and in vivo, influence of species specific metabolism, S9 modifications

·         Interactive workshops evaluating test data.

Pre-course Reading :

·         Friedberg E.C., Walker , G.C., Siede, W., et al (2006) DNA Repair and Mutagenesis, 2nd edn, pub: ASM Press (ISBN 1-55581-319-4) [core reading for all modules of the MTP]

·         A number of relevant papers will be selected from the Mutation Research journal.