The concept of multispecies testing in industrial toxicology

The multispecies approach in toxicity testing was originally motivated by the frequent findings of species differences in responsiveness to the pharmacological and acute toxic effects of chemicals. When the guidelines for repeated-dose toxicity experiments were developed in the early 1940s, the concept of using several species of animals was automatically included without careful scientific validation. In response to demands from the U.S. Food and Drug Administration and other national and international regulatory bodies, the protocols for acute and repeated-dose toxicity testing became highly formalized, and the requirement to conduct all studies in a rodent and a nonrodent species was established. With time, most guidelines also specified the species that had to be used, and the most common recommendation was to use the rat as the rodent and the dog as the nonrodent. In recent years, many reasons for differences in responsiveness of various animal species and man to the toxic effects of chemicals have been identified. This knowledge is now used extensively to assess contradictory findings in routine safety studies in the rodent and the nonrodent species. It is often possible to identify the species that appears to be more predictive for man than the other, and risk assessment for man is then based mainly on the findings in the more representative species. Since contrary toxicological findings in rodents and nonrodents occur frequently, one could propose to perform detailed scientific investigations prior to the selection of the species for toxicological investigations, as it has already been suggested by the working group of the European Society for the Study of Drug Toxicology in 1965 and is still an option mentioned in the currently valid EEC drug safety guidelines of 1983. For practical reasons such early investigations of biological properties and pharmacokinetic and metabolic characteristics of test chemicals in various laboratory animal species are hardly ever done prior to the initiation of safety studies. However, techniques are now developed with which species selection for toxicity testing can be made on the basis of rational scientific investigations.