FDA procedures and policies to estimate risks of injury to the male reproductive system.

Two decades ago, the Food and Drug Administration (FDA) undertook a testing and research program to study and assess the mutagenic properties of so-called "Generally Recognized as Safe" (GRAS) substances which have a long history of use in food. Initially, the program employed three highly regarded mutagenicity tests; the host mediated assay, somatic cell cytogenetics, and the dominant lethal test. Only the latter measures male germ cell events. Eventually, research and testing results revealed major problems in the deployment of these tests for such purposes. A new approach involving a three tiered system was instituted in which the first tier was a relatively inexpensive pre-screen ostensibly capable of detecting any and all potential mutagens. For reasons of economy, this pre-screen used micro-organisms. The objective of the second tier was to determine if substances positive in the first tier of tests would be mutagenic for higher organisms. Gene mutation in mammalian cells in culture, gene plus chromosomal mutation in Drosophila and heritable translocation in male mice were used for this purpose. The final tier was intended to assess the quantitative risk of mutation in mammals and depended entirely upon genetic studies in animals. Again, the heritable translocation test would be used as well as the specific locus test in mice. At the same time, efforts were made to refine and improve the usefulness of the dominant lethal and the heritable translocation test for toxicological purposes. More recently, studies have been undertaken to develop a practical test for nondisjunction in male germ cells. Currently, standard test requirements for food additive approval include only short-term in vitro mutagenicity tests.(ABSTRACT TRUNCATED AT 250 WORDS)