期刊
TOXICOLOGY
卷 392, 期 -, 页码 119-129出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.tox.2017.03.012
关键词
Risk assessment; Route-to-route extrapolation; Physiologically based kinetic (PBK) model; Margin of internal exposure (MOIE); Caffeine; Physiologically based pharmacokinetic (PBPK) model
资金
- COSMOS (Integrated In Silico Models for the Prediction of Human Repeated Dose Toxicity of COSMetics to Optimize Safety) - European Commission (FP7) [266835]
- European Cosmetics Association Cosmetics Europe
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. (C) 2017 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据