title: The margin of internal exposure (MOIE) concept for dermal risk assessment based on oral toxicity data - A case study with caffeine.
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 (Cmax), 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.
authors.affiliation: Directorate Health, Consumers and Reference Materials, European Commission, Joint Research Centre, Ispra, Italy.
authors.forename: Jos G M
authors.initials: JGM
authors.lastname: Bessems
authors.affiliation: Directorate Health, Consumers and Reference Materials, European Commission, Joint Research Centre, Ispra, Italy. Electronic address: alicia.paini@ec.europa.eu.
authors.forename: Alicia
authors.initials: A
authors.lastname: Paini
authors.affiliation: Directorate Health, Consumers and Reference Materials, European Commission, Joint Research Centre, Ispra, Italy.
authors.forename: Monika
authors.initials: M
authors.lastname: Gajewska
authors.affiliation: Directorate Health, Consumers and Reference Materials, European Commission, Joint Research Centre, Ispra, Italy.
authors.forename: Andrew
authors.initials: A
authors.lastname: Worth
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D002110:Caffeine / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics / Q000633:toxicity; D002138:Calibration; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D023421:Models, Animal; D008962:Models, Theoretical; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012869:Skin Absorption / Q000187:drug effects*; D018675:Toxicity Tests
chemical_list: D002110:Caffeine
keywords: Caffeine; Margin of internal exposure (MOIE); Physiologically based kinetic (PBK) model; Physiologically based pharmacokinetic (PBPK) model; Risk assessment; Route-to-route extrapolation