Advantages of a combined testing protocol (CTP) with multiple endpoints: the reverse tier approach

A multi-endpoint CTP approach provides an efficient procedure to investigate the hazards of chemicals in our environment. Genotoxicity to multiple tissues is assessed after an exposure of limited duration by using a variety of sensitive short-term tests. Resources are thus conserved and results obtained without long delays. Additional information helpful in understanding the observed genotoxic effects is readily obtained in the same experiment by inclusion of additional nongenotoxic endpoints. Numbers of animals required to test chemicals are substantially decreased by increasing the amount of information obtained from each animal. Flexibility is a basic asset of a CTP approach. Therefore, pharmacokinetics of the test chemical or mixture and concerns about subpopulations of exposed humans can guide all aspects of the design of CTP protocol including the animal species, the exposure protocol and the endpoints. The procedures selected for evaluating potential mutagens should be based primarily on the usefulness of the information generated and secondarily on the cost and resources required to perform the procedure. The most expensive procedure is that procedure which does not generate useful information, regardless of the initial cost. The CTP as presently discussed is an attempt to maximize useful information in the most efficient manner possible. Although considerably more expensive than in vitro procedures, the protocol is far less expensive than conducting individual short-term animal procedures, and a fraction of the cost and time required to perform a typical cancer bioassay. Chemicals that are of major concern, for example as in the case of extensive human exposure, would be a prime candidate for initial testing by this methodology.