Scientific Opinion
Scientific Opinion
Margin of Exposure
Introduction
The margin of exposure ( MOE Is éard is lamháil nochta (MOE) uirlis a úsáidtear i measúnú riosca chun ábhair imní sábháilteachta a eascraíonn as substaint a d’fhéadfadh a bheith tocsaineach a bheith i mbia nó i mbeatha ainmhithe a fhiosrú.) is a tool used by risk assessors to consider possible safety concerns arising from the presence in food and feed of chemical substances when they deem it inappropriate or unfeasible to establish a health-based guidance value (HBGV; a ´safety threshold´) such as an Acceptable Daily Intake ( ADI Is éard is iontógáil laethúil inghlactha (ADI) meastachán ar mhéid na substainte i mbia nó in uisce óil is féidir a ithe go laethúil ar feadh an tsaoil gan riosca suntasach don tsláinte a chruthú. De ghnáth sloinntear é mar mhilleagram den tsubstaint in aghaidh an chileagraim de mheáchan coirp agus baineann sé le substaintí ceimiceacha amhail breiseáin bhia, iarmhair lotnaidicídí agus drugaí tréidliachta.) or a Tolerable Daily Intake ( TDI Is éard atá san iontógáil laethúil inghlactha (TDI) meastachán ar mhéid na substainte i mbia nó in uisce óil nach gcuirtear leis d’aon ghnó (e.g. éilleáin) agus ar féidir é a thomhailt ar feadh an tsaoil gan riosca suntasach don tsláinte a bheith ag baint leis. ).
The two main situations in which this occurs are:
- when assessing substances that are neither genotoxic nor carcinogenic but for which uncertainty about their effects, e.g. due to insufficient toxicological data, does not allow for establishing a HBGV;
- when assessing substances that are both genotoxic and carcinogenic, in which case no HBGV can be established as any level of exposure could theoretically lead to cancer.
Frequently asked questions
The MOE is a tool used by risk assessors to assess possible safety concerns arising from the presence of substances in food and feed when it is not appropriate or possible to establish a HBGV. The MOE is a ratio of:
- the dose at which a low but measurable adverse effect is observed (called “reference point” or “point of departure”), and
- the level of exposure to the substance for a given population.
Importantly, the MOE is not a ‘health-based guidance value’, i.e. it is not a safety threshold below which risk assessors conclude that the daily intake is safe. When there is evidence of harmful effects but not enough to confirm how much is safe, the MOE tells us if current intakes are likely to be harmful or not: a low MOE represents a greater risk than a higher MOE.
Once the reference point/exposure ratio has been calculated, the result indicates the level of concern associated with the exposure to the substance. The minimum magnitude of the MOE needed for concluding that the actual human exposure is of low toxicological concern differs for the two different categories of substances.
- Substances that are neither genotoxic nor carcinogenic but the uncertainty about their effects does not allow establishing a HBGV - the minimum magnitude of an MOE for these substances is usually 100 or larger, i.e. a ratio that is below 100 would be considered a concern for public health.
The figure of 100 is based on long-standing principles in toxicological risk assessment about how to account for uncertainties and differences among and within species. An uncertainty factor (sometimes also called “safety factor”) of 10 accounts for differences between humans and the animals used in experimental studies, then an additional factor of 10 accounts for the variability among humans. Together this results in a minimum factor of 100-fold for substances that are not genotoxic nor carcinogenic.
- Substances that are both genotoxic and carcinogenic
EFSA’s Scientific Committee published a scientific opinion in 2005 recommending the use of the MOE approach for the assessment of substances that are both genotoxic and carcinogenic The Scientific Committee stated that an MOE of 10,000 or higher, if it is based on an animal study, would be of low concern from a public health point of view and might reasonably be considered a low priority for risk management actions. The Scientific Committee stated that while such a judgment is ultimately a matter for the risk managers, an MOE of 10,000 or more should not preclude the application of risk management measures to reduce human exposure.
The 100-fold factor used for substances that are not genotoxic carcinogens is multiplied by an additional factor of 10 to account for differences in the ability of human cells to repair DNA as this influences the carcinogenic process. Then, to account for any other uncertainties in the assessment of genotoxic carcinogens, an additional factor of 10 is added, resulting in the MOE of 10,000, i.e. 100 x 100.
If there are uncertainties arising from gaps in the toxicological data, these need to be embedded in the MOE to conclude on the potential concerns. Therefore, the factor of 100 needs to be multiplied by an additional factor considered adequate to account for these additional uncertainties (often between 2 and 5, resulting in a minimum magnitude of an MOE of 200 to 500).
Alternatively, it is also good practice to set a different minimum MOE if uncertainties about one or more of the conditions described in the answers to question 2 and question 3 can be reduced. This may happen, if there is data to account for differences between humans and experimental animals, or for differences among humans. For example, experts assessing the safety of sulfites used as food additives were able to set an MOE of 80 because they had data on how humans respond differently to sulfites after ingestion.
Substances that are both genotoxic and carcinogenic must not be added intentionally to food. However, their presence in food and feed, while not desirable, is still possible for different reasons:
- their natural presence, e.g. methyleugenol in basil or pyrrolizidine alkaloids in honey
- from microbial activities, e.g. ochratoxin A or aflatoxins produced by mould that may contaminate various crops
- from environmental pollution, e.g. benzo(a)pyrene resulting from incomplete combustion of organic matter
- from the unintended consequences of cooking or other manufacturing processes, e.g. acrylamide naturally forms in starchy food products during high-temperature cooking.
They may also be present in food and feed at very low levels resulting from impurities in substances used in manufacturing processes. EFSA’s Scientific Committee advised in a statement in 2012 that the MOE could be useful in such cases to support risk managers in defining possible actions required to keep exposure to such impurities as low as possible.
They are two different concepts sometimes mistakenly used interchangeably. The margin of safety is the ratio between a safe threshold (i.e. the ‘health-based guidance value’ such as an ADI, instead of the reference point - as in the case of the MOE) and the actual or estimated exposure.
Before 2005, the general advice of risk managers regarding unavoidable substances in food that are both genotoxic and carcinogenic was to reduce exposure to such substances to a level that is ‘as low as reasonably achievable’ (known as the ALARA principle) irrespective of the nature of the carcinogen. This ALARA principle does not allow setting priorities for management action according to the potency of the carcinogenic substances under consideration.
The approach developed by EFSA for use of the MOE for substances that are both genotoxic and carcinogenic aimed at informing risk managers about the level of toxicological concern coming from a given human exposure to such substances and allowing for setting priorities for management action. EFSA’s Scientific Committee is made up of highly experienced scientists from across Europe, who have published widely in scientific literature and are well placed to consider new methodologies for risk assessment. The Scientific Committee recommended using the MOE approach for these substances in 2005, and subsequently again for genotoxic/carcinogenic impurities present in food in 2012.
In November 2005, a joint EFSA/WHO conference reached similar overall conclusions that the MOE approach was a useful and pragmatic option for the risk assessment of substances that are both genotoxic and carcinogenic and had the potential to improve the advice provided to risk managers.
Consequently, expert committees of the United Nations Food and Agriculture Organization (FAO) and World Health Organization (WHO), as well as other UN bodies (e.g. the United Nations Environment Programme) have used the margin of exposure approach. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) routinely uses the MOE approach for assessing the risk of genotoxic and carcinogenic contaminants in foods.