Genetic variation in outbred rats and mice and its implications for toxicological screening.

There are two basic types of laboratory rodent used in toxicological screening. Isogenic (inbred) strains are rather like clones of genetically identical individuals whereas outbred stocks are usually more variable, though the amount of variability depends on the previous history of the colony. In some cases outbred stocks may be genetically quite uniform. Many different strains of both types are available. Both types and a variety of strains are used for toxicological screening. There is clear evidence of important genetic variation both in spontaneous disease and in response to toxic agents, yet little account is taken of this in choosing suitable animals. Three options appear to be available. The first is to ignore genetic variation and use a single isogenic strain. However, if the strain happens to be insensitive to the test chemical, a toxic chemical may be judged to be relatively safe. The second option would be to synthesize a genetically heterogeneous stock by crossing two or more strains. However, this could lead to both increased false positive and false negative results as experimental "noise" either obscures true treatment effects, or is mistaken for a treatment effect. The third option is to use more than one strain, but without increasing the total number of animals used. This would provide a broad range of genotypes, so reducing the chance that they are all insensitive, without increasing experimental noise. This appears to be the only sensible way of broadening the genetic base in toxicological screening. Where strain differences are found, they may provide a tool for studying toxic mechanisms, which may be helpful in extrapolating to human populations.