Scientific Opinion
Scientific Opinion
Margin of Exposure
Introduction
The margin of exposure A tool used in risk assessment to explore safety concerns arising from the presence of a potentially toxic substance in food or animal feed. ( MOE The margin of exposure (MOE) is a tool used in risk assessment to explore safety concerns arising from the presence of a potentially toxic substance in food or animal feed.) 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 Guidance on safe consumption of substances that takes into account current safety data, uncertainties in these data, and the likely duration of consumption. (HBGV; a ´safety threshold A dose or exposure below which adverse effects are not detected.´) such as an Acceptable Daily Intake The amount of a substance (e.g. nutrient or chemical) that is ingested by a person or animal via the diet. ( ADI An estimate of the amount of a substance in food or drinking water that can be consumed daily over a lifetime without presenting an appreciable risk to health. It is usually expressed as milligrams of the substance per kilogram of body weight per day and applies to chemical substances such as food additives, pesticide residues and veterinary drugs.) or a Tolerable Daily Intake ( TDI The tolerable daily intake (TDI) is an estimate of the amount of a substance in food or drinking water which is not added deliberately (e.g contaminants) and which can be consumed over a lifetime without presenting an appreciable risk to health. ).
The two main situations in which this occurs are:
- when assessing substances that are neither genotoxic nor carcinogenic but for which uncertainty Scientific concept used in risk assessment to describe all types of limitations in available knowledge at the time an assessment is conducted, with the agreed resources, that affect the probability of possible outcomes to the assessment. 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 Concentration or amount of a particular substance that is taken in by an individual, population or ecosystem in a specific frequency over a certain amount of time. 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 The total amount of a substance (e.g. a chemical or nutrient) given to, consumed or absorbed by an individual organism, population or ecosystem. at which a low but measurable adverse effect A change in the health, growth, behaviour or development of an organism that impairs its ability to develop or survive is observed (called “reference point” or “ point of departure The point on a dose–response curve established from experimental data used to derive a safe level.”), and
- the level of exposure to the substance for a given population Community of humans, animals or plants from the same species..
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 A specialised field of applied science that involves reviewing scientific data and studies in order to evaluate risks associated with certain hazards. It involves four steps: hazard identification, hazard characterisation, exposure assessment and risk characterisation. about how to account for uncertainties and differences among and within species A subdivision of the genus, a species is a group of closely related and similar-looking organisms; for example, in the case of Homo sapiens (humans), the second part of the name (sapiens) represents the 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 Natural variations observed between members of a population, or observed over time or in different geographical locations; for example, individual variations in susceptibility to a particular toxic chemical. 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 The management of risks which have been identified by risk assessment. It includes the planning, implementation and evaluation of any resulting actions taken to protect consumers, animals and the environment. 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 A complex chain-like molecule that carries the genetic material, present in living organisms and some viruses. DNA (deoxyribonucleic acid) is capable of copying itself and carries the instructions for all the proteins used to create and sustain life. 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 The gap between the actual intake of a substance by a given population and the estimated daily dose over a lifetime that experts consider to be safe. is the ratio between a safe threshold (i.e. the ‘health-based guidance value’ such as an ADI An estimate of the amount of a substance in food or drinking water that can be consumed daily over a lifetime without presenting an appreciable risk to health. It is usually expressed as milligrams of the substance per kilogram of body weight per day and applies to chemical substances such as food additives, pesticide residues and veterinary drugs., 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 A measure of the capacity of a chemical substance to exert an effect, described in terms of the relationship between the dose used and the magnitude of the resulting effect. 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.