Risk assessment of genotoxic chemicals according to EFSA

Margin of Exposure

In former days, the European countries used the approach of assessing genotoxic contaminants using the method of linear extrapolation. So one can still find assessments in the EU from previous times based on this method. EFSA did however propose another approach in its Statement on the applicability of the Margin of Exposure approach for the safety assessment of impurities which are both genotoxic and carcinogenic in substances added to food/feed of 2012. Here it is described to calculate a "Margin of Exposure" (MoE). This is ratio between the exposure of an person (or animal) and the lowest effect dose level. For that effect dose a BMDL is to be used. In this paper the Scientific Committee reiterates its view expressed in 2005 that in general a margin of exposure of 10,000 or higher is of low concern, if it is based on the BMDL10 of an animal study. This approach does not calculate risk quantitatively as the slope factor does.

Permissible exposure level

As already noted, the permissible exposure level for genotoxic carcinogens in the EU is 1 person in 10,000 for lifetime exposure. This means that exposure where the MoE is less than 10,000 should be considered as a situation with unacceptable risk ("unsafe"). In the information provided by EFSA one does however not find any statement how to deal with the permissible level of an MoE that is based on a BMDL01 or BMDL05 of experimental animals, or BMDLs derived from human studies.

Although it is not mentioned in EFSA documents, most experts consider the level of 10,000 as a guidance value based upon the safety factor approach of the treshold procedure. Here factors of ten are used to extrapolate for various issues, e.g. animal to human, variation within a population, from lowest dose with effect to a NOAEL, or for short term exposure to chronic exposure. Following this reasoning, the MoE for an permissible situation can be lowered with factors of ten for BMDLs of human studies and for BMDL01 or BMDL05 of experimental studies. It is left to the risk assessor to decrease the critical MoE level with the appropriate arguments.

Other chemicals

The EFSA approach of the Margin of Safety can also being used for other chemicals than genotoxic carcinogens. For some contaminants it was concluded in EFSAs latest opinions that setting a TDI or TWI was not possible any more due to lacking essential data (e.g. a NOAEL). In these cases existing HBGVs were withdrawn, but the use of the MoE could be considered as an alternative. See for example the evaluation of lead. In 2005 EFSA copied the TWI of 25 ug/kg.week (JECFA, 2000), but in 2010 EFSA concluded that this TWI is to be redrawn. Various BMDLs were then reported, based on a human study with volunteers, e.g. for clinical chemistry and neurologic effects, so an exposure assessment for lead could now be made by means of a MoE.