The current state of mutagenicity testing 217 adequate testing protocols, interpretation of data may still be difficult especially with results within the control range or on the border-line of statistical significance. Inter- pretations may differ depending on whether results from treatment groups are compared with historical (accumulated) or concurrent controls, the type of statistical analysis or whether results are compared at equitoxic doses. If the experiments are repeated, similar equivocal results may be obtained and if not there is the problem of whether the first or repeat experiment is correct. The difficulty is in proving and accepting negative data. By comparison the handling of positive data is much more clear-cut. Systems giving negative results are often considered insensitive, e.g. the dominant lethal test. However, such a test might truly reflect the situation in the germ cells and the testes may really be incapable of metabolising many compounds to their active inter- mediates. Microbial systems need large concentrations of compounds to detect a positive result by comparison with concentrations expected to be present in whole mammals, and thus could equally be considered insensitive. ASSESSMENT OF GENETIC EFFECT Making a quantitative risk evaluation for man from data obtained in testing procedures is an even more difficult task. First it must be determined if the data are biologically and/ or statistically significant. Chemicals with unknown mutagenic potential are probably more difficult to assess than data for radiation or known mutagens (many of which are 'radio-mimetic' agents) unless there are clear-cut dose responses, since chemicals behave differently with different cells, organs and organisms. One of the recommended ways of assessing risk is by comparing the values obtained from chemical data with corresponding radiation data. Crow (10) recommended that the population genetic effects of clinical mutagens be assessed, taking radiation as an equi- valent and equating the population dose of chemical mutagens to the radiation dose admissible for that population. Bridges (43, 44) in his papers describing the three-tier system also recommends the principle of a radiation-equivalent dose. With this system only those substances which have passed through the first two tiers and are of great social, medical and economic importance are subjected to a quantitative assessment. Chemicals that have shown a positive effect in the first two tiers should, if not widely used, be prohibited or used with a non-mutagenic derivative substituted for the mutagenic radical. Those that are positive in the third tier should be expressed as the equivalent of a radiation dose producing the same effect, and this makes it possible to standardise the level of chemical mutagens to the limits of the level of ionising radiation. However, with extrapolation back to very small doses it would be diffcult to decide which is the line of best fit, and with some chemicals there may be shoulders of varying size on dose response curves due to permeability problems with a chemical or other unknown factors. Yet another 'radiation-equivalent concept', the ABCW model (101), is based on the hypothesis that the radiation induced mutation rate per radiation unit and gene locus in a variety of organisms from microbes to mammals is proportional to their genome size. This model has been extended to chemical compounds (104). As a result it would seem possible to estimate risks for man on the basis of an upward extrapolation. However, this model has been criticised by Sankaranarayanan (105). The problem with these radiation concepts is that chemicals may behave differently from radiation induced free radicals and often have species type specificity. This problem has been highlighted by Auerbach (106) and Sobels (107).

218 Diana Anderson Bochkov (17) recommend that the assessment should be based on individual and population prognoses. The individual prognosis should be determined by the quantity of chemical and its mutagenic activity. The population prognosis should be determined by the number of persons of reproductive age who are in contact with the chemical mutagen and the average quantity of this substance for each of them. To make such an assessment. various factors need to be considered: (a) data on the test specimen for which the highest and clearest quantitative dependencies are obtained, (b) the quantity of substance with which an individual comes into contact over a period of a year, (c) the fraction of the population up to the age of 30 who are subject to the action of a mutagen, (d) the mean population dose of substance which can be calculated from the above data, (e) the limit for the admissible level of genetic changes. They suggest prohibiting a substance with mutagenic activity, replacing it with a non- mutagenic compound, or restricting its use to persons of non-reproductive age in cases where its mean population dose causes an increase of 0.1 •o above the spontaneous level and a doubling of the spontaneous level on an individual basis. Again, this approach depends on the reliability of the experimental data obtained and being able to determine information concerning the above-mentioned factors. Auerbach (106) and Sobels (107) also criticise the concept of the doubling dose. Considering the difficulties of interpreting results obtained in a test system, any single test can hardly provide absolute answers. Negative results are often underweighted. Results from several practical test methods should be processed and decisions based on the biological and statistical significance of all the results observed, having regard for the normal range of control values in the test systems used. If a socially and economically useful compound is found to be 'hazardous' for man, then a detailed examination can be made of levels to which workers are exposed and attempts made to improve plant hygiene where the product is manufactured. Further investigations can be made to determine if and how much other groups or people or the general population are exposed, e.g. in the case of vinyl chloride, manufacturing plant exposure levels have been reduced and attention has been focused on whether any free monomer occurs in plastic food wrappings, etc. Auerbach (106) feels that in the benefit/risk calculations of a compound, on the benefit side the calculation should carry a correction factor for the special econo- mic, social or medical situation of the country concerned, e.g. in a country where millions suffer from malaria, the benefits of an efficient preventive or curative drug should be weighted accordingly, or in countries where there is famine problem, pesticides should be considered similarly. CONCLUSIONS Both academic and industrial scientists are well aware of the need for safety evaluation in general toxicological testing and this is certainly true in the field of genetic toxicology. We still do not understand if positive or negative results in a laboratory model test system are really relevant to man because of man's unique metabolism and because of the absence of any convincing 'no-effect' level data for animals or man. Epidemiological evidence for