Proposal of new uncertainty factor application to derive tolerable daily intake

Abstract

We propose new uncertainty factors (UFs) and a new subdivision of default factors in chemical risk assessment using a probabilistic approach based on the latest applicable information. Rounded values of 150 for mice, 100 for hamsters and rats, and 40 for rabbits, monkeys and dogs for inter- and intra-species differences (UF(AH)) were derived from the probabilistic combination of two log-normal distributions. Further calculation of additional UFs when chronic data (UF(S)) or NOAEL (UF(L)) are lacking was conducted using available log-normal distribution information. The alternative UF(S) and UF(L) values of 4 are considered to be appropriate for both cases where data are lacking. The default contributions of inter-species difference (UF(A)) and intra-species difference (UF(H)) to the UF(AH) of 100 for hamsters and rats as an example are considered to be 25 and 4, respectively. The UF(A) of 25 was subdivided into 25(0.6) (i.e., 7.0) for pharmacokinetics (PK) (UF(A,PK)) and 25(0.4) (i.e., 3.6) for pharmacodynamics (PD) (UF(A,PD)), and the UF(H) of 4 was evenly subdivided into 4(0.5) (i.e., 2) (UF(H,PK) and UF(H,PD)), to account for chemical-specific difference data between humans and laboratory animals for PK and/or PD. These default UFs, which come from actual experimental data, may be more appropriate than previous default UFs to derive tolerable daily intake values.