System for the evaluation of the risk from chemical mutagens for man: basic principles and practical recommendations.

A testing system is recommended that permits (1) reduction in cost and time requirements, (2) analysis of gene and chromosome mutations in germ and somatic cells, (3) evaluation of mutagenic effects of a chemical substance and its metabolites, (4) guarantee of the minimal variability between separate experiments and (5) evaluation of the dose--effect relationship. The testing scheme has two parts, a screening system and a complete test system. The screening system consists of two tests: (a) test on microorganisms with a metabolic activation in vitro (or test on Drosophila) and (b) cytogenetic analysis of mammalian bone marrow. The complete test system includes 4 tests: (a) test on microorganisms with a metabolic activation in vitro and in vivo (or test on Drosophila), (b) dominant-lethal test on mammals, (c) cytogenetic analysis of mammalian bone marrow and (d) cytogenetic analysis of the culture of human lymphocytes. The decision whether the selected chemical substance is to be tested according to the screening or complete test system is based on: its occurrence in the population, its economic (or medical) significance, and on information concerning its mutagenic, carcinogenic or teratogenic effects. The group of chemicals to be tested according to the screening system involves: industrial chemicals, organophosphate insecticides, drugs used by a limited group of patients. The group of chemicals to be tested according to the complete test system consists of pesticides, food additives, drugs in general use as well as chemicals of the former group, if at least one of the screening system tests detected some genetic effect. Genetic risk estimation should be governed by the following considerations. A positive effect identified in any test of the testing system must have a direct bearing on man. Quantitative evaluation of mutagenic risk from a chemical substance can be determined by the increased level of spontaneous mutations in the most sensitive test on the basis of an average dose of, and exposure to, the given chemical substance in the human population. Chemicals showing a mutagenic activity in any of recommended tests are subject to the quantitative evaluation, they are usually widespread and because of their social or economic value they cannot be replaced or excluded. Genetic aspects require that any substance with a mutagenic activity be considered dangerous and its use should be prohibited or it should be replaced by another non-mutagenic chemical, or at least the contact with it should be limited to persons of non-reproductive age. From the hygienic aspect it is recommended, as a temporary measure, to evaluate a chemical mutagen and to prohibit or limit its use if its average population dose produces a 0.1% or greater increase in the spontaneous level of mutations.