EFSAs Margin of Exposure
Margin of Exposure
As already mentioned, it was adviced by EFSA in 2012 to evaluate health risks of genotoxic carcinogenic chemical substances by means of the BMDL10. To be safe, the actual exposure should be 10,000 times lower than the BMDL10 of experimental animals.
Points missing in the EFSA approach
It is not described by EFSA how to evaluate the MoE for non genotoxic carcinogenic chemicals. As there are many chemicals of which BMDLs were derived, lacking a HBGV, and as there are non-genotic chemicals of which existing HBGVs are withdrawn, there is a need to use BMDLs in exposure assessment for these chemicals also. How large should the MoE be here? Various EFSA Opinions demonstrate, that EFSA is also using the MoE concept for non genotoxic chemicals with a critical level of 100 for a BMDL10 from animal studies. So, apparently the MoE for non genotoxic chemicals is 100.
Besides EFSAs statement does not make clear, what the MoE should be when a BMDL01 or BMDL05 from animal studies is available, or BMDLs from human studies. So it can be concluded that there should be additional critical levels for the MoE, next to the MoE of 10,000 f or 100 or the use of BMDLs in exposure assessment of chemical compounds in food and feed.
Setting critical values for other BMDLs
To create a systematic approach for setting a critical Margin of Exposure value, the following method is proposed.
At first it is needed to discriminate between genotoxic and non genotoxic chemicals. For many chemicals we have studies on genotoxicity, with ambiguous results. So an algorithm must evaluate the available studies. Then, for genotoxic chemicals the critical value for the MoE is to be set at 10,000 using a BMDL10 from experimental animals. For non genotoxic chemical one can use a BMDL10 with a critical value of 100 for an animal study.
Based on the EFSA approach with a critical MoE of 10,000 for genotoxic carcinogens and 100 for non genotoxic chemicals, it is possible to set other critical values for different BMDLs derived from animal or human studies. To do this the following argument applies. The critical levels of 10,000 resp. 100 are quite similar to the Safety (or Uncertainty or Extrapolation) Factors that are used by expert panels setting a HBGV. As a critical value for non genotoxic chemicals of 100 is used for both a NOAEL and a BMDL from animal studies by EFSA, one can conclude that the BMDL is considered to be similar to a NOAEL. The usual safety factors of 10 can now be applied for the extrapolation between animals and humans, and 10 for the normal variation between average and most sensitive individual within a population. Intermediate safety factors of 3 can also be used e.g. when variation is better known. Then the following critical values can be set for non-genotoxic chemicals. Human BMDLs do not need the extrapolation factor of 10 between animals and humans; a critical value of 10 is to be used for a BMDL10, a value of 3 for a BMDL05, and 1 for a BMDL01. For a BMDL of animal studies the extrapolation factor of 10 is to be included, leading to 100 for a BMDL10, 30 for a BMDL05, and 10 for a BMDL01.
For genotoxic carcinogens it can be noted that in former days an extrapolation factor of 10,000 is used, for carcinogenic effects (preferably the number of tumors) using a linear extrapolation calculation. There are no additional extrapolation factors from animal to human. Whether or not to use a lower linear extrapolation when dealing with a BMDL05 or BMDL01 could be considered, but only when the BMDLs are referring to carcinogenic effects in vivo. It is therefore recommended not to decrease the critical MoE of 10,000 for genotoxic carcinogens, except in those cases where one is dealing with a BMDL05 or BMDL01 for true carcinogenic effects.
Summary
It can be observed that EFSA is using a Margin of Exposure of 10,000 for genotoxic carcinogens and of 100 for non genotoxic chemicals between a BMDL10 for animals and human exposure to chemicals in food and feed. These critical levels share strong similarities with Safety Factors used for setting HBGVs. Based on that it is possible also to assign other critical values for the MoE for a BMDL01 and BMDL05 for animals, and for the BMDLs for humans.
| Chemical | Study | BMDL10 | BMDL05 | BMDL01 |
|---|---|---|---|---|
| Non genotoxic | Animal | 100 | 30 | 10 |
| Non genotoxic | Human | 10 | 3 | 1 |
| Genotoxic | Carcinogenic effects | 10,000 | 3,000 | 1,000 |
| Genotoxic | Other effects | 10,000 | 10,000 | 10,000 |