Inbred Strains Should Replace Outbred Stocks in Toxicology, Safety Testing, and Drug Development

Abstract

Methods of toxicity testing, barely changed for several decades, need to be improved. One way forward would be to use a small battery of inbred strains instead of the single outbred stock currently used in toxicity screening. Inbred strains are more stable, more uniform, more repeatable, and better defined than outbred stocks. Genetic variation would be observed as the difference between strains. Safety could be based on the most susceptible strain. Sometimes it may be possible to identify the genes involved. Mechanisms could be explored using gene expression profiling of susceptible and resistant strains. Two committees of toxicologists have concluded that the use of inbred strains, by controlling interindividual variability, would reduce the number of animals needed in toxicity screening, although both ''preferred'' outbred stocks. This preference appears to have been based on intuition rather than scientific principles. Data from a previously published study on the response to chloramphenicol in an outbred stock and four inbred strains is used to explain the advantages of the multistrain design. Toxicologists, safety pharmacologists, regulatory authorities, and pharmaceutical companies should take a critical look at the types of animals they use if they want to reduce the attrition rate of new drugs.

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

“…The "2B/-"mice are maintained on a hybrid C57BL/6xCD1 background (83). The CD1 mouse strain is known to differ from other mouse strains on physiological and genetic measures (72)(73)(74)(75). Given similar myocyte culture conditions between our study and those of Hayhurst et al (65) and Boyer et al (36), we believe that the differences in results are most likely due to the different mouse models used, including their genetically different controls.…”

The pilocarpine model of temporal lobe epilepsy: Marked intrastrain differences in female Sprague–Dawley rats and the effect of estrous cycle

“…Outbred rat strains are known to be genetically heterogeneous populations with a high intrastrain variation [16,17,32,33]. In contrast to inbred strains, outbred strains (or stocks) are "genetically undefined" in the sense that each animal is genetically unique and the genes it carries are unknown [33].…”

“…In contrast to inbred strains, outbred strains (or stocks) are "genetically undefined" in the sense that each animal is genetically unique and the genes it carries are unknown [33]. The Wistar rat and, to a lesser extent, the SD rat are the most popular rat strains for biomedical research.…”

“…Like other outbred strains, SD and Wistar rats are randomly outbred; hence, allelic variations can occur across separate colonies. Thus, stock names such as SD or Wistar can be misleading because stocks with the same name from different breeders will have different characteristics [33]. The phenotypic characteristics of an outbred stock can change relatively rapidly as a result of random genetic drift in gene frequency, selective breeding (say for large litter size, body weight, blood pressure, etc.…”

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