The case for isogenic strains in toxicological screening.

The fundamental principle of the controlled experiment is that treated and control groups should be identical, with minimal within-group variability. Toxicologists recognise this and control age, body weight, disease and the physical environment of the test animals. However most toxicological screening in done with genetically variable outbred stocks, even though isogenic inbred strains, F1 hybrids or identical siblings are usually available. The result is poor experiments with the inevitable genetic differences between groups resulting in increased false positive and negative results, and no indication that the response is under genetic control. It is also illogical to treat genetic variation differently from other types of variation. The argument that it is essential to use outbred animals to model outbred man is illogical. If bacteria can be used to model man (as in the Ames test), so can inbred animals. The uncontrolled variation present in an outbred stock can not be used efficiently to increase the range of phenotypes tested because it also introduces "noise" which obscures experimental effects. The use of two or more isogenic strains gives a much more efficient experimental design with low "noise" and an indication of whether the response is under genetic control. Inbred and F1 hybrid strains (but not identical siblings) have the added advantage of an immortal genotype which outlives any individual animal. Such immortal genotypes may be studied in detail to gather background information. Toxicologists should treat genetics like every other variable and control it, using several isogenic strains in cases where testing needs to be done on more than one genotype.