Are highly lipophilic volatile compounds expected to bioaccumulate with repeated exposures?

With non-volatile compounds, high lipophilicity (i.e., fat:blood partition coefficients, Pf, in the range of several hundred to a thousand or higher) typically leads to concerns for bioaccumulation. To evaluate the extent to which highly cleared, lipophilic vapors are expected to accumulate in blood and tissues, we conducted pharmacokinetic (PK) analysis, using both a generic physiologically based (PBPK) model for inhalation of volatile compounds (VCs) and a more detailed PBPK model specifically developed for a highly lipophilic volatile (decamethylcyclopentasiloxane, D5). The generic PBPK model for inhalation of VCs in humans showed that highly metabolized, lipophilic compounds, with a low blood:air partition coefficient (Pb), do not accumulate in blood or systemic tissues with repeat exposures although a period of days to weeks may be required for fat to reach periodic steady state. VCs with higher Pb (in the hundreds) and lower hepatic extraction accumulate in blood on repeat exposures. The more detailed PBPK model for D5 also showed that this lipophilc VC does not accumulate in blood and predictions of the increases in D5 in fat with repeat exposures in rats agreed with experiments. In general, the major characteristic favoring accumulation of VCs in blood and systemic tissues is poor whole-body clearance, not lipophilicty. The term bioaccumulation should be used to refer to cases where repeat exposures lead to increases in VC blood (or central compartment) concentration. Based on this definition, highly cleared VCs, such as D5, would not be considered to bioaccumulate on repeat exposures.