Cardiac sensitization: methodology and interpretation in risk assessment

An increased sensitivity of the heart to endogenous epinephrine (adrenaline), a phenomenon referred to as cardiac sensitization, has long been recognized as a risk during exposure to hydrocarbons, principally halogenated hydrocarbons. Cardiac sensitization, which can result in serious arrhythmia and death, requires a certain critical blood level of both the sensitizing agent and epinephrine. The original research and methods utilized an exogenous epinephrine challenge during inhalation exposure to a chemical to assess cardiac sensitization potential in Beagle dogs. These screening tests were developed about 30 years ago, although in the last 15 years some modifications of these methods have occurred in response to testing chlorofluorocarbon (CFC) replacements. Results from these experimental cardiac sensitization studies have been used for semi-quantitative risk evaluation for occupational exposures but now are being used more quantitatively for regulatory purposes. The risks associated with cardiac sensitization from CFC replacements are unknown but expected to be low based on cardiac sensitization studies in the 1970s where dogs were made to generate their own adrenaline. With the advent of physiologically based pharmacokinetic (PBPK) modeling, greater emphasis is being placed on quantitative risk assessment for cardiac sensitization. In this investigation, we have examined the various methodologies used for detection of cardiac sensitization and discussed their limitations and advantages. In addition, we examined the potential concerns involved in using experimental cardiac sensitization data and PBPK modeling to predict exposure scenarios.