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. 2017 Dec 1:392:119-129.
doi: 10.1016/j.tox.2017.03.012. Epub 2017 Mar 10.

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

Jos G M Bessems  1 , Alicia Paini  2 , Monika Gajewska  1 , Andrew Worth  1
Affiliations

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

Jos G M Bessems et al. Toxicology. .

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.

Keywords: Caffeine; Margin of internal exposure (MOIE); Physiologically based kinetic (PBK) model; Physiologically based pharmacokinetic (PBPK) model; Risk assessment; Route-to-route extrapolation.

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Figures

Fig. 1
Fig. 1
Conceptual depiction of the margin of internal exposure (MOIE) approach based on comparison of internal dose metrics. The individual assessment factor (AF) of 4 that should cover interspecies differences in toxicokinetics (TK) can be left out in the MOIE approach as these differences are taking into account using the PBK approach (animal PBK model and human PBK model). aPBK = animal PBK model; hPBK = human PBK model. SED = Systemic exposure dose; SPOD = Systemic Point of Departure.
Fig. 2
Fig. 2
Two options to take assessment factors (AFs) into account in the risk characterisation process. Option 1 is the a priori use of AFs to establish a ‘Human Limit Value’ based on the Hazard Characterisation. Option 2 establishes whether the Margin of Exposure (MOE) between the exposure and the POD is larger than the overall assessment factor (being the product of the individual AFs or a probability distribution of the product of the distributions of the individual AFs. The result of option 1 is a Risk Characterisation Ratio (RCR). RCR < 1 means risk is under control. The result of option 2 is an MOE being smaller or larger than the overall AF (concern/no concern).
Fig. 3
Fig. 3
Caffeine and major metabolites formed in the liver.
Fig. 4
Fig. 4
a. General structure of the PBK model. b. Sub-compartments of the GI tract, which here is divided into sub-compartments in the human PBK model. c. Skin divided into sub-compartments in human PBK model for dermal exposure.
Fig. 5
Fig. 5
Internal (blood) concentrations of caffeine in humans following dermal exposure of 2.5 mg/kg bw (single and multiple doses).
See this image and copyright information in PMC

References

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