The margin of internal exposure (MOIE) concept for dermal risk assessment based on oral toxicity data – A case study with caffeine

摘要

Highlights ? The concept of Margin of Internal Exposure (MOIE) is proposed for route-to-route extrapolation. ? It is an extension of the Margin of Exposure (MOE) approach for cosmetics in the EU. ? PBK modelling integrates in vitro and in silico predictions of ADME-properties. ? The MOIE approach is transparent and facilitates to make uncertainties explicit. ? The MOIE can be extended to include in vitro toxicity data in animal-free risk assessment. Abstract Route-to-route extrapolation is a common part of human risk assessment. Data from oral animal toxicity studies are commonly used to assess the safety of various but specific human dermal exposure scenarios. Using theoretical examples of various user scenarios, it was concluded that delineation of a generally applicable human dermal limit value is not a practicable approach, due to the wide variety of possible human exposure scenarios, including its consequences for internal exposure. This paper uses physiologically based kinetic (PBK) modelling approaches to predict animal as well as human internal exposure dose metrics and for the first time, introduces the concept of Margin of Internal Exposure (MOIE) based on these internal dose metrics. Caffeine was chosen to illustrate this approach. It is a substance that is often found in cosmetics and for which oral repeated dose toxicity data were available. A rat PBK model was constructed in order to convert the oral NOAEL to rat internal exposure dose metrics, i.e. the area under the curve (AUC) and the maximum concentration (C max ), both in plasma. A human oral PBK model was constructed and calibrated using human volunteer data and adapted to accommodate dermal absorption following human dermal exposure. Use of the MOIE approach based on internal dose metrics predictions provides excellent opportunities to investigate the consequences of variations in human dermal exposure scenarios. It can accommodate within-day variation in plasma concentrations and is scientifically more robust than assuming just an exposure in mg/kg bw/day.