Determination of the NOAEL

For the determination of the NOAEL, a series of doses is used. In order to establish the dose-effect relationship, the dose levels are chosen in such a way that the highest dose causes an adverse effect that is not observed after the lowest dose.

Ideally, in a long-term toxicity study, the highest dose should evoke symptoms of toxicity without causing excessive mortality, and the lowest dose should not interfere with development, normal growth, and longevity. In between, doses should be selected sufficiently high to induce minimal toxic effects. The determination of an adverse effect in a particular study depends not only on the doses tested, but also on the types of parameters measured and the ability to distinguish between a real adverse effect and a false positive finding. In long-term toxicity tests, the average value of a specific parameter at a particular dose level is compared with the average value of the parameter in control animals. An effect can then be defined in purely statistical terms as a significant deviation of a control value. However, in determining an adverse effect, the biological relevance of this deviation should be taken into consideration. If, for example, a slight but significant alteration is only observed at the highest dose level, it is difficult to define it as a real adverse effect. More weight should be given to a particular change in a parameter, if a dose-response relationship can be established, or if the observed change is related to changes in other functional or morphological parameters. If an effect is irreversible, the relevance of the effect is unquestionable. In some cases, however, the biological relevance of an effect must be interpreted in relation to historical control values. This is often the case when the value of the particular parameter is highly variable among the control animals used in a number of different toxicological studies. The historical control data should originate from the same species, strain, age, sex, supplier, and laboratory to enable proper comparison.

There are many sources of uncertainty in toxicity testing. For example, effects may not show themselves if the number of animals is too small (to discriminate between various test groups), the time of observation is too short for the manifestation of a particular effect, or the experimental design is too limited to obtain conclusive evidence. In addition, the differences in sensitivity to a particular substance between man and experimental animals may not be known. Therefore, safety factors are applied in the setting of guide values for man based on animal data to compensate for these uncertainties.

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