Inhalation toxicity of cinnamaldehyde: A physiologically based kinetic modeling approach to study route-to-route extrapolation

Abstract

Layman summary A physiologically based kinetic modeling approach to study route-to-route extrapolation The cigarette is slowly disappearing from the streets all over the world. In its stead a relatively new phenomenon the electronic cigarette has risen from cigarette stopping aid to new prominence. A electronic cigarette is a relatively simple device that heats up a carrier liquid such as propylene glycol together with nicotine and often an assortment of flavouring agents this combination can then be inhaled. This method of ingesting nicotine has been hailed as advancement in public health as it appears considerably less toxic in comparison to the smoking of tobacco. This has lead to increased scrutiny to the assorted flavouring agents that can be found in the electronic cigarettes. These flavouring agents often have a long history of safe use in food and/or perfume applications. but history has taught us that the method of exposure for a chemical determines in large part the toxicity that it causes. And unfortunate many of these flavouring agents have had no inhalation toxicity test performed to assess if they pose a hazard. This represents a possible problem in toxicological assessment of these chemicals for use in electronic cigarettes as animal testing is expensive, potentially misleading and progressively more frowned upon. This report explores a route to route extrapolation approach using a physiologically based kinetic model (PBK) to assess the possible risk of adverse health effects due to cinnamaldehyde exposure in electronic cigarette emissions. A PBK is a mathematical model that attempts to predict the movement of a chemical through the body by defining the body in organ compartments which are connected by a circulatory system. The chemical can move through the circulatory system and its movement is dictated by chemical properties such as its lipophilicity. This allows researchers to model novel exposure scenarios without the need of testing animals. The chemical of interest is cinnamaldehyde which is the main component of cinnamon flavour. It is a common flavouring agent found in food, perfumes and electronic cigarettes. It has been found in concentration up to 300 mg/ml in electronic cigarettes. It has been found to cause induce toxicity in vitro systems at concentration as low as 40 µM. Using PBK models for both rat and human oral and inhalation exposures this report has found significant differences between exposure routes in how cinnamaldehyde is metabolised. This difference in metabolic profiles means that cinnamaldehyde concentrations are considerably higher during inhalation exposure compared to oral exposure. Cinnamaldehyde concentration in the lung reached concentration found to cause adverse effects in in vitro systems during simulated electronic cigarette usages. Some population differences were also found between simulated males and females. With cinnamaldehyde concentrations being higher on average. This report underlines the importance of the exposure route during risk assessment and the possibilities of PBK modelling going forward. Important next steps in PBK risk assessments are solving the problem of lack of validation data when trying to avoid animal testing. Major drawbacks of the report are a lack of validation data and the lack of Glutathione modelling in the lung.