Genetic endpoint

Another kind of genetic endpoint presently under consideration for regulation is recombination. Recombination in a molecular sense is a reciprocal exchange of DNA between homologous chromatids, and is detected by changes in the association of genetically linked markers. 

Assay Alternative name/abbreviation Genetic endpoint tested Specific damage detected... 

Mixed results were observed for in vitro tests of pyrene. Negative results were obtained for pyrene in DNA damage assay in Escherichia coli and Bacillus subtilis. Both positive and negative results were observed in bacterial gene mutation test. Pyrene did not induce an increase in sex-linked recessive lethal gene in Drosophila. It increased the incidence of mitotic gene conversion but not other genetic endpoint in yeast. 

A promising system designed a few years ago and recently optimised [78, 79] is the hen s egg test for micronucleus induction (HET-MN). The test combines the commonly accepted genetic endpoint induction of micronuclei (MN test) with the well-characterized and complex model of the incubated hen s egg. 

Theodorakis CW, Integration of genotoxic and population genetic endpoints in biomonitoring and risk assessment, Ecotoxicology, 10, 245, 2001. 

Fig. 1. The effects of Trp-P-2 and IQ on cell killing, mutations, SCEs, and chromosomal aberrations in normal and repair-deficient CHO cells. Data for the normal cells (AA8) is given by open symbols and for UV-5 cells by closed symbols. The applied dose of compound is indicated on the left side and te data for IQ on the right. Cultures were exposed as described (Thompson et al., 1983) and for each genetic endpoint the data are presented as induced values. Reprinted with permission of author and published from Thompson et al. (1983).

Selection of a testing scheme or test battery to be employed must in most cases be based on the nature and use of the test substance. Testing schemes are probably as diverse as the laboratories that conduct the tests, although a battery of four or five tests selected from those listed in Table 2 would be expected to generate a reasonable data base for most chemicals under development. It is important, however, to select a battery that includes all possible types of genetic endpoints (e.g., gene mutation, chromosome alterations, and nonspecific DNA damage). 

A good clinical trial is designed to take account of the variability in response (either efficacy or adverse event) that is expected when a new active drug is tested. This response depends on an individual s genetic make-up, and on a number of environmental factors, such as disease state, other drugs and age. The size of the trial and the selection of study subjects are carefully determined to reduce the variability in response to a minimum (i.e. to maximise the sensitivity of the trial) so that the trial endpoints can be determined with as much certainty as possible. 

The need for bridging studies depends on whether the medicine is ethnically sensitive or insensitive on the basis of the criteria discussed above. For example, if the product was metabolised through a route that displayed no genetic polymorphism, had a wide therapeutic index, a shallow dose-response curve and there were universally agreed endpoints to determine efficacy and safety, then no bridging studies would be needed. 

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