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During years, it has been widely admitted in the scientific community that there was no threshold in mutagenesis: a compound was or not a mutagen. The meaning of such a proposition was that a risk existed at all exposure level, because, at least theoretically, one molecule is sufficient to cause the formation of a DNA adduct which is able to induce a mutation. However, works carried out in the last few years have shown that in the case of some specific mechanisms of mutagenesis, a threshold could be demonstrated essentially in the case of compounds that do not react directly with DNA. Several types of thresholds exist, and the simple statistical threshold is not sufficient in terms of risk assessment. A biological threshold that is consistent with a mechanism of action of the mutagen should be established. Amongst these mechanisms, we can mention some mechanism with a demonstrated threshold: effects of aneugens, effects of topoisomerases inhibitors, effects of DNA polymerases inhibitors, effects of compounds with a different metabolism at high doses compared to low doses. On the contrary, for some mechanisms, the demonstration of the mechanism is suspected, but not totally demonstrated. It is the case of compounds which induce nucleotides pool imbalance or compounds which are DNA repair inhibitors. In some cases, when a redundancy exists in the repair of damages, like oxidative DNA damage, a threshold is suspected. Some authors even recently proposed the possibility of a threshold in the case of alkylating agents. The majority of mutagenic thresholds were demonstrated in vitro, however some mechanisms were demonstrated in vivo, for example in the case of micronucleus induction by hypo or hyperthermia in rodents bone marrow. The use of threshold in risk assessment requires the use of the most sensitive endpoint for example, non disjunction in the case of aneugens, confusing factors like apoptosis should be eliminated and species sensitivities should be taken into account. A very important point to consider is to demonstrate that the mechanism with threshold was really thee only one involved in the mutagenic effect. The demonstration of such thresholds is of particular interest for human risk assessment in the case of mutagens and of genotoxic carcinogens.

The carrying out of clinical trials with a view to the marketing of drugs for human use is directly related to results of some animal studies. This workshop was devoted to evaluation of the quality and interest of these experimental models in reproductive toxicology. The predictive ability of preclinical trials to make extrapolations from animals to man decreases from foetotoxic to tetratogenic risks respectively and from the effects on fertility in both sexes to postnatal risks. As a result of this workshop, we propose the following improvements: (1) standardization and generalization of fertility test evaluations, especially the spermogram, in order to improve animal and human correlations; (2) development of knowledge and standardization of the follow up of the oestral cycle; (3) improvement of standardization, harmonization and diffusion of postnatal tests that prove relevant in animals; (4) increase in initiatives aimed at better mutual understanding of all drug partners; (5) creation of registers for new drugs, as soon as possible during clinical trials, to study their effects on the whole reproductive process; (6) recommendations for the creation of guidelines for International Conference on Harmonisation (ICH) to enable classification of observed effects in experimental models. This could lead to specific (potentially for each phase of the reproductive cycle) guidelines, precautions for use and/or contraindications which are listed in the summary of product characteristics.

Monitoring of those staff exposed to products or atmospheres containing carcinogenic substances may be carried out using genetic toxicology tests. These tests may highlight primary DNA modifications, genetic or chromosomal mutations, detect mutagens at the urinary level or assess a global effect, expressed by a genotoxic effect. All these tests must be used taking into account exposure kinetics, the substance in question and exposure conditions.

The search for a mutation prone activity on bacteria must be completed by tests on eucaryotes, in vitro as well as in vivo. Tests on eucaryotes enable to study agents inducing gene mutations [on yeats, cultures of mammal cells (V 79, L 5278 Y), lethal recessive mutation linked to the sex chromosome, on drosophils...], chromosomal mutations (metaphases analysis in vitro and in vivo, micronucleus, lethal dominance), the involvement of repair mechanisms of DNA (non-programmed DNA synthesis, exchange of sister chromatides...). One must well differentiate the tests usable routinely for a screening from the tests currently validated and routine tests. It is only at the completion of a set of tests on bacteria and eucaryotes cells that the potential mutation risk of a product for human health, may be ascertained.