Technical Report

TR 105 – Evaluation of Cardiac Sensitisation Test Methods

TR 105 : Evaluation of Cardiac Sensitisation Test Methods | October 2009

Cardiac sensitisation means that the normal heart rhythm becomes perturbed, for example, when high concentrations of some halogenated or unsubstituted hydrocarbon vapours are inhaled, for a short time, in combination with situations causing high internal adrenaline levels (stress). The resulting cardiac arrhythmias may be fatal. Therefore, the cardiac sensitisation potential (and other toxicological properties) of development fluorocarbon products needs to be known before those products can be safely used, especially in air-conditioning and fire-fighting applications.

This report reviews how cardiac sensitisation studies have been conducted and the way in which those test results are used in the prediction of human risk. Critical aspects of the test protocol are the selection of the dose of adrenaline used to ?challenge? the heart and the definition of a positive response (i.e. cardiac arrhythmia). Risk assessment of cardiac sensitisation is based on the extrapolation of the animal data to humans, but should also take account of individual susceptibility and health status, and other factors such as medication. The current protocols appear to provide accurate, robust scientific information and are designed conservatively with built-in safety factors. Thus no additional safety factors need to be applied in the risk assessment process. For improved risk assessment, human blood levels of the inhaled compounds can be estimated using biokinetic modelling techniques. This kind of modelling can also account for sensitive sub-populations.

Little is known about the biological mechanism of the cardiac sensitising effects of halogenated and unsubstituted hydrocarbons. The report reviews several aspects and possible contributing factors in detail. Compared to volatile anaesthetics, which have an adverse impact on cardiac electrophysiology, cardiac sensitisation seems to be a complex event that is not fully understood at present.

There is no clear alternative test system for cardiac sensitisation. The report discusses the utility of various possible alternatives to replace or refine the current adrenaline-treated dog model.