MSc Genetic Toxicology and Environmental Mutagenesis

Applicants will normally possess a minimum of a science degree in a relevant subject, together with workplace experience in genetic toxicology or a closely related field.

Registration requires two scientific referees willing to support the application. Application to register for the Postgraduate Certificate, Diploma or MSc can be made following the third module attended. Retrospective application is permitted, provided not more than four modules have been completed.

There are no formal entrance requirements for participants not wishing to register for the MSc/Postgraduate Diploma/Postgraduate Certificate, although a scientific background to at least degree level is recommended. Proficiency in English is a prerequisite.

English language requirements

IELTS minimum overall: 7.0

IELTS minimum by component: 6.5

All fees are subject to increase or review for subsequent academic years. Please note that not all visa routes permit part-time study and overseas students entering the UK on a Tier 4 visa will not be permitted to study on a part-time basis.

Compulsory Modules

Testing Methods in Genetic Toxicology and Environmental Mutagenesis I

This module provides an overview of the diversity of methods ranging from the use of viruses to whole animals to assess the potential genotoxicity of chemicals. Information sources on the methods that are available in the literature will be reviewed.

The concept of assay sensitivity and specificity will be covered. The international collaborative studies and the range of assays used will be critically evaluated. Development and understanding of those methods with appropriate range of qualities and sensitivities for testing and the limitations of many methods will be considered.

The development of the basic testing will be discussed with emphasis on specialised strains, for example, for oxidative damage, cross-linking agents and so on. Modifications to the tests, for example fluctuation tests, will also be inluded in the lectures.

The use of in vitro cytogenetics, human and rodent cultures to guage denotoxicity of chemicals will be used to illustrate how data is collected. Basic metaphase analysis, structural and numerical changes, molecular methods, FISH methods and fluorescent probes will be used to demonstrate how to analyse data.

In vitro micronucleus assay, structural numerical changes, centromere and kinetochore staining, binucleate cell assay and measurement of non-disjunction will also be included.

In vitro gene mutation assays, HPRT methods, thymidine kinase (TK) mutations and the value of the mouse lymphoma assay will be considered.

The transition from in vitro to in vivo assessment will also be critically reviewed in light of the 3Rs. Factors that may influence the relationships between in vitro and in vivo response will also be considered.

The module will also discuss in vitro methods, namely bone marrow cytogenetics, bone marrow and peripheral blood micronucleus assays. The comet assays, both in vitro and in vivo, tissue specificity, the role of the in vivo/in vitro rat-liver UDS assays will be included. Use of DNA adduct measurements and their impact on data analysis with respect to genotoxicity will be considered.

Testing Methods in Genetic Toxicology and Environmental Mutagenesis II

This second module will concentrate on SARs (Structure 1 activity) models, their development and application. This module applies the basic knowledge of genotoxicity testing and its relationship to the base set of toxicology tests, namely: chronic and acute toxicity, reproductive toxicity and cancer bioassays. Relationships to genetic toxicology tests, their design and application will be considered. Hazard and risk assessment as illustrated by UK Committee on Carcinogenicity recommendations will be provided in syndicate groups for discussion.

Transgenic animal mutation models, principles, development, application and interpretation will form a major part of this module. Application of mutagenicity testing to the environment, terrestrial and aquatic models (species selection) will be discussed in light of regulatory requirements. Selection and general application of the new model systems, their integration into testing schemes will be introduced. An introduction to statistical methods in genetic toxicology, data analysis and report preparation will be provided in case studies. Mechanistic investigation of a specific compound will be used as past of an interactive workshop.

Mutations and Human Health

This is a basic introductory module in which the rationale for the scientific discipline of genetic toxicology is explained and discussed. The basic structure of human genome, the karyotype, gene organisation, nuclear and mitochondrial organisation will form the basis of this module. Areas of consideration will be:

• DNA structure, replication fidelity, base selection, enzymes and components of replication, mismatch repair correction of replication errors
• Cell cycles, mitosis and meiosis, male and female germ cell cycles. Targets for chemical interactions, cell division, spindle etc
• Transposons and their significance, mechanisms of transposition
• Chromosome changes, types of rearrangements and modifications of the karyotype
• Gene mutation changes in human germ and somatic cells (including multifactorial disease), examples of gain and loss of function mutations. Imprinting discussion of the most relevant examples of diseases, nuclear and mitochondrial changes
• Chromosome changes, structural and numerical in human congenital disease, discussion of most relevant examples
• Genetic changes in human cancer, oncogene and tumour suppressor gene changes
• Chromosome structural and numerical changes in human cancers, for example, such as translocation and aneuploidy in leukaemias

The module will consider what happens when gene signals go wrong. Case studies and group work will consider this.

DNA Lesions, Repair and Mutation Induction

This module reviews DNA lesions, their repair following exposure to chemicals, induction and mutations. What reference has this for man? Topics covered are:

• DNA modifications by ionising and non-ionising radiations
• Chemically induced lesions, small adducts as illustrated by the alkylating agents
• Endogenous lesions, for example, oxidative damage, the spontaneous lesion background
• Bulky adducts, for example, polycyclic aromatic hydrocarbons such as benzo(a)pyrene, aflatoxins, synthetic molecules
• DNA reactive anti-cancer drugs, for example, cis-platin, tamoxifen, non-DNA reactive anti-cancer drugs, for example, vinca alkaloids, taxol
• Lesion and adduct detection methods, 32P postlabelling, comet assay, immunological methods, radiolabelled compounds, mass spectrometry
• Replication fidelity, mismatch repair, sensitivity to colorectal cancer. Base excision repair
• Nucleotide excision repair, post-replication and double strand break repair
• Repair defective mutations. Human repair syndromes and their implications
• Detection methods for gene and chromosome changes such as SSCP, RSM, FISH, CGH
• The conversion of DNA lesions into gene and chromosome changes

Metabolism and Human Variation

General principles covering the passage of xenobiotic chemicals through the mammalian body will be discussed with emphasis on pharmacokinetics, pharmacodynamics and toxicokinetics. This will include metabolism, principles of Phase I metabolism, oxidation, reduction, hydroysis and the enzymes involved. Areas that will be discussed are:

• The Cytochrome P450s, history of identification and characterisation. Basic biochemistry
• Classification, cloning and sequencing
• Genetic factors, polymorphisms and SNPs. Examples of variation. Environmental factors, enzyme induction, inhibition. Phase 1
• Genetic factors, polymophisms and SNPs. Examples of variation. Environmental factors, enzyme induction, inhibition. Phase 2
• Experimental activation preparations for Phase ½ metabolism
• Influence of metabolism on effects of genotoxic exposure
• Case studies, such as genetic engineering of cell lines, their development and application
• Enzyme variation, genotyping, pharmaceutical development
• Food industry
• Overview and future developments

Study Design, Quality and Interpretation in Genotoxicity Testing

How are studies designed to assess genotoxicity so that clear interpretations can be made, particularly in light of false positives? The genotoxic and non-genotoxic activity will be discussed in light of mechanisms. What do we understand by direct and indirect mechanisms? What non-DNA targets influence results?

Criteria for the definition of positive, statistical significance fold increases, relationships to historical databases of control and treated values will be critically analysed together with assay reproducibility. Assay reproducibility. False positive and negative results. Dose response relationships, exponential and threshold models, factors which may include a threshold, nucleoside analogues, aneugens, topoisomerase inhibitors, detoxification, repair etc, will all be considered.

The influence of toxicity, acute and chronic toxicity, high and low toxicities will be discussed. The development of optimal designs, together with quality control, the activity of IWGT and the criteria for test system validation, will be reviewed. Other areas considered are:

• The operation of regulatory bodies
• Strategies for testing as illustrated by national and international requirements
• Examples of data, with interpretation problems
• 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 will be provided during the one-week module.

Optional Modules

Supplementary modules can currently be selected from the programmes that are part of the modular training programmes offered by the Faculty of Health and Medical Sciences, including Applied Toxicology, and Pharmaceutical Medicine/Clinical Pharmacology.

For a complete list of available modules, please contact the programme administrator.

E: fhms-pg@surrey.ac.uk