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.