Precision of Estimates of an ADI (or TDI or PTWI)

Abstract Factors influencing the precision of an acceptable daily intake (ADI) are discussed in this paper. As the same principles apply to tolerable daily intake (TDI) or provisional tolerable weekly intake (PTWI), although not specifically mentioned, this paper also refers to TDI and PTWI. The allocation of an ADI is in principle based on the most critical (many times the lowest) no-observed (adverse)-effect level [NO(A)EL] established in toxicological studies in experimental animals or in humans by applying a uncertainty factor for extrapolation from animals or humans to the general human population (and for the extrapolation from high to low intake levels). As the ADI predicts a virtual safe intake level for a life span exposure, to establish a NO(A)EL in general the toxicological database should include long-term studies, otherwise only a provisional ADI will be allocated for which a higher uncertainty factor is applied. The validity of an ADI greatly depends on the precision of the toxicological studies considered for the safety of a food additive or contaminant. The precision of the ADI is also inversely related to the uncertainty factors applied, although these uncertainty factors are not totally independent of the completeness and precision of the toxicological data from which a NO(A)EL is derived. This paper focuses on the precision of the toxicological data and the established NO(A)EL. Human data on the toxicity of a chemical which are preferred for the safety evaluation or hazard assessment are frequently not available or incomplete with respect to a quantitative dose–response assessment. Epidemiological studies will have inherent difficulties for hazard assessment such as possible confounders, restricted number of toxicological end points which can be studied, and limited quantitative data on oral exposure levels. Case report studies include the same limitations but in addition the exposure data are usually very imprecise due to reconstruction of the possible dose level(s). Case reports of intoxication are mainly restricted to acute and at best subacute effects. Controlled human exposure studies (human volunteer studies) are restricted in their experimental design such as the level of the dose and the toxicological end points due to medical ethical reasons. Therefore, quite rarely a safety evaluation of a food chemical will be solely based on human data. In the practice of hazard assessment of chemicals in foods the experimental animal studies will be totally or partly the basis for establishing an ADI. In these toxicological studies in animals there are many experimental variables which can affect the precision of an ADI, such as (1) duration of the experiment, dose ranges, identity, and purity of the substance; (2) the parameters and toxicological end points studied; (3) the species and strain used; (4) the gut microflora of the test animals; (5) dietary composition; (6) statistics performed; and (7) knowledge about the kinetic behavior and metabolism (e.g., elimination half-life and bioavailability of the chemical and its main metabolites) of the chemical considered. How these factors can influence the precision of a NO(A)EL, respectively the ADI, is illustrated by several examples. In relation to the question of incidental excursions of an ADI, it can be concluded that due to the variation in precision of experiments slight incidental excursions would not lead to an increased risk. However, to answer in general the question of how often and/or how much the total intake of a chemical in food may exceed the ADI is not possible. This should be considered case by case. To answer such a question, the precision for those studies representative for incidental excursions should be considered. Other factors which should be considered are (1) type of effect on which the ADI was based, (2) mechanism of toxicity, (3) toxicokinetics and metabolism, and (4) difference in NO(A)ELs from short-term toxicity studies with the NO(A)EL on which the ADI was based. Nevertheless, slight excursions of the intake above the ADI for a substance should always trigger additional consideration and if possible additional studies with high precision.