1.2.3 Comparison with reference value

To assess whether a certain exposure level may be harmful to human health, the exposure is compared to a toxicological reference value, like a acceptable daily intake (ADI) or tolerable daily intake for chronic exposure and acute reference dose (ARfD) for acute dietary exposure.

These reference values are derived from animal dose studies. In these studies animals are exposed to different levels of a toxic compound to establish the highest dose at which no observable toxic effect occurs – the No Observed Adverse Effect Level (NOAEL). The NOAEL is determined for the most sensitive toxicological effect (e.g. decrease in blood pressure, increase in enzyme activity) in the most sensitive animal specie (e.g. rat, mouse, dog).

Its value results from comparing the various dose groups with the control group. To derive from this NOAEL a safe exposure level in humans, a safety (uncertainty) factor of 100 is usually applied. The 100-fold factor is the product of two 10-fold factors: one 10-fold factor to allow for differences between the test species and humans, and the second 10-fold factor to allow for human variability. The interspecies factor is essentially to allow for the possibility that the dose–response for the critical effect in humans could occur at 10-fold lower external doses than found in animals. The 10-fold intraspecies (human variability) factor is to allow for the possibility that “sensitive” human subjects may be up to 10 times more sensitive to the external dose than the population average.

The safe exposure levels depend on the compound and the duration of the animal study. Short-term animal studies (less than 24 hrs) result in the derivation of acute reference doses, long-term studies in the derivation of ADI or TDI. ADI and TDI have the same meaning. ADI’s are derived for compounds that can be controlled relatively easy, such as food additives, pesticides, and veterinary drugs. For compounds that can not be controlled tolerable intakes are derived on either a daily (TDI) or weekly basis. Example of compounds for which a tolerable intake has been derived are dioxins.