Learning Outcomes:

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

·         All the basic testing methods from Salmonella to whole animal studies

·         In vitro versus in vivo relevance

·         Transgenic models

·         Basis statistical methods

·         General outlines of methods for cancer bioassay and reproductive toxicity

·         Acute and chronic toxicity tests

·         Report writing, key quality criteria for each assay, data interpretation

On the successful completion of the module the students should be able to assess study reports in the context of overall toxicological evaluation. This will require:

·         An understanding and recognition of the mechanisms of interaction of the chemicals with genetic material the DNA

·         An understanding of the mechanisms of repair of DNA damage

·         An appreciation of the relevance of the conversion of DNA lesions into mutations

·         An appreciation of the role of mutations in the induction of cancer

·         An understanding of the contribution of the role of mutations in the production of birth defects

·         The ability to demonstrate the use and ability to  select and apply suitable statistical methods to analyse and critically evaluate genetic toxicology data

·         Critically assess and interpret the data.

Module content:

·         Historical basis of mutagenicity testing

·         Diversity of methods ranging from the use of viruses to whole animals

·         Information sources on the methods that are available in the literature

·         Basic principles behind genetic toxicology

·         Role and place of test methods in compound development

·         Selection of the key informative test methods

·         The concept of assay sensitivity and specificity

·         The international collaborative studies and the range of assays evaluated

·         Development and understanding of those methods with appropriate range of qualities and sensitivities for testing and the limitations of many methods

·         The handling of published data, limitations e.g. lack of GLP etc

·         Assay Validation

·         The development of the Bacterial Gene Mutation Assay. Basic battery, specialised strains, e.g. for oxidative damage, cross-linking agents etc

·         Modifications, e.g. fluctuation tests

·         In vitro cytogenetics, human and rodent cultures

·         Basic metaphase analysis, structural and numerical changes, molecular methods, FISH methods, fluorescent probes

·         In vitro micronucleus assay, structural numerical changes, centromere and kinetochore staining, binucleate cell assay, measurement of non-disjunction

·         In vitro gene mutation assays, HPRT methods, thymidine kinase (TK) mutations

·         The value of the mouse lymphoma assay, range of endpoints (chromosome and point mutation

·         Experimental design

·         The transition from in vitro to in vivo assessment , test selections. Factors that may influence the relationships between in vitro and in vivo response

·         In vitro methods, bone marrow cytogenetics, bone marrow and peripheral blood micronucleus assays

·         Comet assays in vitro and in vivo, tissue specificity, the role of the in vivo/in vitro rat-liver UDS assays. Use of DNA adducts measurements.

Pre-course Reading :

·         Parry, J. (2000). Guidance On A Strategy For Testing Of Chemicals For Mutagenicity.

·         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]