Mass transport analysis: inhalation rfc methods framework for interspecies dosimetric adjustment

In 1994, the U.S. Environmental Protection Agency introduced dosimetry modeling into the methods used to derive an inhalation reference concentration (RfC). The type of dosimetric adjustment factor (DAF) applied had to span the range of physicochemical characteristics of the gases listed on the Clean Air Act Amendments in 1991 as hazardous air pollutants (HAPs) and accommodate differences in available data with respect to their toxicokinetic properties. A framework was proposed that allowed for a hierarchy of dosimetry model structures, from optimal to rudimentary, and a category scheme that provided for limiting model structures based on physicochemical and toxicokinetic properties. These limiting cases were developed from restricting consideration to specific properties relying on an understanding of the generalized system based on mass transport theory. Physiochemical characteristics included the solubility and reactivity (e.g., propensity to dissociate, oxidize, or serve as a metabolic substrate) of the gas and were used as major determinants of absorption. Dosimetric adjustments were developed to evaluate portal of entry (POE) effects as well as remote (systemic) effects relevant to the toxicokinetic properties of the gas of interest. The gas categorization scheme consisted of defining three gas categories: (1) gases that are highly soluble and/or reactive, absorbing primarily in the extrathoracic airways; (2) gases that are moderately soluble and/or reactive, absorbing throughout the airways, as well as accumulating in the bloodstream; and (3) gases that have a low water solubility and are lipid soluble such that they are primarily absorbed in the pulmonary region and likely to act systemically. This article presents the framework and the mass transport theory behind the RfC method. Comparison to compartmental approaches and considerations for future development are also discussed.