Margin of exposure

Limitations of the ALARA principle Before the adoption of MOE in 2005, the standard regulatory advice in Europe for genotoxic and carcinogenic substances was the ALARA ("As Low As Reasonably Achievable"). While the ALARA principle is based on the assumption that there is not safe dose for direct-acting genotoxic carcinogens, it was recognized as unpractical and inadequate for practical risk management. This is because it does not provide any basis for comparison of relative risk of different substances and therefore, it does not allow setting priorities for regulatory action based on the magnitude of the concern. This is particularly ineffective when considering unavoidable contaminants such as acrylamide, aromatic amines, or other process‑related genotoxicants. Moreover, evidence for thresholds or sublinear responses at low doses (including adaptive and protective effects) means simple linear scaling from high to low doses can misrepresent true risk. == Definition and calculation ==

Basic formula As defined by EFSA, the MOE is the ratio between the Reference Point (RP) and the estimated human exposure: :MOE = {\operatorname{Reference\,Point\,(RP)}\!\over\operatorname{Estimated\,Human\,Exposure}\!} Both the RP and the exposure must be expressed in the same units (typically micrograms or miligrams per kilogram of body weight per day (µg/kg bw/day or mg/kg bw/day). The Reference Point is a dose derived from an experimental or observational dose-response relationship that reflects the critical toxicological effect. It is important to note that, unlike the NOAEL-based approach, the RP in the MOE framework does not imply the existence of a safe threshold, it is simply a defined point on the dose-response curve used for comparative purposes., and are derived from country-specific dietary assessments. == Interpretation ==

The MOE, as a numerical number does not directly represent a probability of harm, but rather the relative distance between the dose response reference point and the human exposure. EFSA has come up with a threshold of 10,000 for genotoxic carcinogens, This value of 10,000 is derived from various sources of uncertainty considered by EFSA. Three main sources of uncertainty were identified: • Inter-species differences (extrapolation from experimental data on animals to humans) and intra-species differences (individual human variability), which are accommodated by a 10-fold factor each (100-fold total) • Additional uncertainties specific to genotoxic carcinogens, derived from individual differences in DNA repair capacity and cell cycle control. An additional 10-fold factor is considered to account for this. • Uncertainty around the BMDL result, as it is not a threshold, as effects can occur below it. An additional 10-fold factor is considered to account for this. Combining these three factors yields a total uncertainty factor or 10,000 (100×10×10). EFSA therefore concluded that a MOE of 10,000 or greater generally shows a substance is of low concern from a public health perspective, and it may be considered a low priority for risk management action. It is to note that a MOE of 10,000 would not be considered of low concern in circumstances of greater uncertainty such as when T25 is used instead of BMDL10. == MOE versus MOS (margin of safety) ==

The Margin of Safety (MOS) is a related concept to MOE. MOS is used interchangeably to MOE by some regulating bodies, while others define it differently. Typically its defined as the ratio between a HBGV (such as TWI - Tolerable Weekly Intake) and the estimated exposure. This distinction means that the MOS considers the existence of a safe threshold, while the MOE does not. == Limitations and criticism ==

The MOE approach has several acknowledges limitations. It does not directly quantify the risk of cancer, neither a probability of harm. This means it cant be used to communicate risk in absolute terms to the public. The choice of a reference point also substantially affects the MOE: a T25-based MOE will be numerically different from a BMDL10-based MOE for the same substance. Moreover, the 10,000 threshold, while scientifically motivated, ultimately reflects a policy judgement about acceptable levels of uncertainty, rather than a biological boundary. Additionally, the approach was developed for a single substance. To approach this, EFSA created cumulative assessment tools, such as the MOET (Margin of Exposure Total), calculated as the reciprocal of the sum of the reciprocals of the individual substance MOEs. Exposure estimation at higher percentiles also becomes increasingly unreliable due to sparse data on the distribution tails. ==References==