Proper knowledge on toxicokinetics improves human hazard testing and subsequent health risk characterisation. A case study approach

Abstract

In the current EU legislative frameworks on chemicals safety, the requirements with respect to information on general kinetic parameters (absorption, distribution, metabolism and excretion or ADME) or integrated toxicokinetic parameters (TK, i.e. plasma concentration-time curve, area under the curve etcetera) in humans and experimental animals vary widely. For agrochemicals and cosmetics, there are regulatory requirements whereas for other frameworks, such as food ingredients, biocides, consumer products and high production volume chemicals (REACH) there are very little or no requirements. This paper presents case studies that illustrate the importance of ADME and TK data in regulatory risk characterisations. The examples were collected by interviewing regulatory risk assessors from various chemicals (non-pharmaceutical) frameworks. The case studies illustrate how (1) applying ADME/TK in an early phase of toxicity testing can be used to improve study design and support the 3R-goals and how (2) increased use of ADME/TK data can improve the final risk assessment.

Keywords: ADME; AUC; Absorption; BMDL; Bioavailability; C,t-curve; NOAEL; Risk assessment; Risk characterisation; Route-to-route extrapolation; Species selection; TK; Toxicokinetics; absorption, distribution, metabolism and excretion; area under the blood/plasma concentration time curve; benchmark dose lower limit; blood/plasma concentration-time curve; no-observed-adverse-effect level; toxicokinetics.