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Maximum Residue Limits (MRLs) for Agricultural Compounds in Food: The Purpose and Procedure for Determining MRLs

Appendix 2: Establishing an ADI, ADE, or PDE_(food)

The lowest 'no observed adverse effect level' (NOAEL) or 'no observed effect level' (NOEL) is taken from a consideration of all the toxicological studies submitted in support of the registration of a substance. For most compounds where the long-term (chronic) hazard is of concern, long-term or lifetime feeding studies are the most appropriate. For those compounds that pose a short-term (acute) hazard, short-term studies are the most appropriate.

The ADI is defined by the WHO (The WHO Environmental Health Criteria Series, No. 70: Principles for the Safety Assessment of Food Additives and Contaminants in Food, Geneva: World Health Organization, 1987) as being:

'the daily intake which, during an entire lifetime, appears to be without appreciable risk on the basis of all the known facts at the time’

Without appreciable risk is further defined by the WHO to mean:

'the practical certainty that injury will not result even after a lifetime of exposure’

The Acceptable Daily Exposure (ADE) is estimated by ERMA NZ in the same way as the Average Daily Intake (ADI), and essentially has the same definition. The difference between the ADI and the ADE is that the ADE is to cover intakes of a substance from all routes of exposure (including dermal and inhalation exposures), whereas the ADI refers to oral intakes only. Usually, because the same data is used to estimate the ADE, the numerical value of the ADE will be the same as that of the ADI.

The Potential Daily Exposure from food (PDE_(food)) is estimated from the ADE for a substance, based on the likely routes of exposure to that substance, and the likely contribution of the route of exposure to the overall exposure of an individual. In no case may the sum of all exposure routes (PDE_(total)) exceed the ADE. In the absence of any specific data enabling the establishment of specific contributions to the overall exposure of an individual to a substance, the PDE_(food) is normally assumed to be 50% of the ADE.

Usually, two 'uncertainty' factors (or 'safety' factors) are applied to the NOAEL to establish the ADI or ADE. The first factor (the NOAEL divided by 1 to 10) is to accommodate the variation between species in susceptibility. This factor allows for the possibility that people may be even more sensitive to the toxic effects of the chemical than the most sensitive test species.

The second factor is to accommodate the variation within the human species - the human population is far more diverse and lives longer in a far more complex environment than do laboratory animal populations. The second factor (NOAEL divided by 1 to 10 again) allows for the possibility that some individuals within the general population may be more sensitive to the toxic effects of the chemical than the majority of the population. Young children are often considered to be part of this group of particularly sensitive individuals.

A further uncertainty factor (NOAEL divided by 1 to 10 a third time) may be used if the toxicological data package is deficient in some way (but still allows a proper assessment of the substance), or some other circumstance indicates that an even greater margin is required (such as the severity of a known toxic effect at higher dose levels).

Therefore, the ADI or ADE equals the NOAEL divided by the combined factor, usually 100 or 1000, depending on the specific details presented in the toxicological evaluation.