WN Choy (ed)
Published by Marcel Dekker (2001)
ISBN: 0-8247-0294-8. 371 pages plus index.
This short and concise text offers the reader an authoritative, practical insight to the status of genetic toxicology testing in industry. It deals with accepted protocols and controversial issues. Both these aspects are discussed in the context of current basic research, allowing the reader to surmise the potential resolution of some of these controversies.
The introductory paragraphs summarise the molecular events underpinning human cancer genetics, the major types of genetic toxicity tests in use at this time and provide a broad classification of mechanisms of carcinogenesis. The historical classification of carcinogenic mechanisms is rapidly becoming outdated: genotoxic mechanisms (the initial perturbation results in a genetic change or mutation) versus nongenotoxic mechanisms (the first change affects an epigenetic mechanism, altering gene expression which may lead to secondary genetic changes and effects such as increased cell growth – there is no DNA sequence change as the first step). For example, the epigenetic process of DNA methylation (hypo- and perhaps hypermethylation), previously considered to be a nongenotoxic process, has direct effects on genetic events such as imprinting and mismatch repair of point mutations. This is of practical relevance because to date, chemicals considered to be nongenotoxic are assumed to have a threshold effect (that is, for there potentially to be a “safe” lower dose) compared with genotoxic carcinogens, for which no safe dose is assumed (ie a linear dose-response curve, although accurate data is not available in most contexts).
A detailed explanation of structure-activity relationship is provided, as this process (computer-assisted) is required for prioritisation of new or existing chemicals when their use in industry is being considered, prior to the initiation of in vitro tests or expensive, time-consuming rodent models. This is followed by a discussion of the way in which the genetic toxicology tests are utilised: bacterial mutagenicity tests and mammalian tests, such as the in vitro mouse lymphoma cell assay for genetic mutation, in vitro or in vivo chromosome aberration (a required test, performed by metaphase spread) and newer in vivo tests such as the micronucleus test (for example, performed on peripheral blood of rodents which have undergone the relevant exposure). The latter test is an interesting recent advance for analysis of dividing cells as it directly demonstrates the loss of chromatin: a small separate nucleus from the main nucleus forms during telophase when the nuclear envelope is reconstituted (structural damage to a chromosome will lead to an acentric chromosomal fragment(s) or damage to the spindle apparatus will lead to loss of a whole chromosome(s)). By definition, the changes observed have been passed on through a cell division, ie inherited by the daughter cell (in contrast to information from metaphase spreads from cells which have not yet undergone a cell division). This is a simple process that requires only a small amount of biological material and can be automated.
The guidelines from the relevant international bodies are clarified in terms of context and process. A recent move away from requiring in vivo animal testing for chemicals identified as being produced in high volume and for which there is likely significant human exposure is discussed. The in vitro micronucleus test may well become established in this context, presumably leading the way for other areas of genotoxicity assessment to adopt a similar approach.
The difficulties of discerning the basis of a carcinogen dose-response curve and its dependency on both chronicity of exposure and individual susceptibility is detailed. Molecular biomarkers and epidemiological evaluation of individual susceptibility are discussed and these presumably will become of increasing importance as genomic tools such as SNPs and HAPMAPs allow us to better understand the genetic basis of individual susceptibility and the identification of specific at-risk groups.
This book provides an excellent generic understanding of the relevant issues involved in genetic toxicology and subsequent cancer risk assessment using specific examples in an illustrative way, rather than also being a source of information regarding individual chemicals. It has a lot to teach us, both in terms of critical analysis of research data and extrapolation of that data into our daily thinking about the basis of cancer risk assessment.
Seligson Fellow, Cancer Centre
Cold Spring Harbor Laboratory
New York, USA
(formerly of the Walter and Eliza Hall Institute of Medical Research)