Physiologically based pharmacokinetics and the dermal absorption of 2-butoxyethanol vapor by humans

It has generally been assumed that the skin contributes only minor amounts to the total uptake of solvent vapors, relative to the respiratory tract. Contrary to this assumption, the widely used glycol ether solvent, 2-butoxyethanol (BE), has been reported to be more effectively absorbed through the skin (75% of the total uptake) than through the lungs of humans (Johanson and Boman, 1991, Br. J. Ind. Med. 48, 788). The possibility that the finger prick blood sampling technique used in the Johanson and Boman study was confounded by locally high concentrations of BE at the site of absorption was suggested using a previously developed PBPK model (Corley et al., 1994, Toxicol. Appl. Pharmacol. 129, 61). The current study was conducted to verify the PBPK analysis and to determine whether or not the skin was the major site for absorption of BE vapor by exposing one arm from each of six human volunteers to 50 ppm 13C2-BE vapor for 2 hr. To evaluate the potential consequences of blood sampling techniques, samples were taken from both the unexposed arm (catheter; during and after exposure) and the exposed arm (finger prick; end of the exposure only) for analysis of both BE and its major metabolite, butoxyacetic acid (BAA). Butoxyacetic acid is responsible for the hemolysis observed in toxicity studies with laboratory animals. Humans, however, are significantly less sensitive to this effect. The concentration of BE in the finger prick blood samples averaged 1500 times higher than the corresponding concentration in venous blood sampled from a catheter installed in the unexposed arm at the end of the exposure. Blood BAA levels were generally within a factor of 4 of each other for the two techniques and, therefore, was considered a better indicator of systemic absorption. Urine was collected for 24 hr and analyzed for the following metabolites found in rat metabolism studies: free and conjugated BE, BAA, ethylene glycol (EG), and glycolic acid (GA), with only BAA detected in the human urine. More importantly, urinary BAA was found to be extensively conjugated ( approximately 67%) with glutamine, confirming recent reports. These results, coupled with PBPK modeling of worst-case exposure scenarios (no clothing, 100% of the body was exposed), demonstrated that no more than 15-27% (low-to-high relative temperatures and humidities), not 75%, of the total uptake of BE could be attributed to the skin of humans during simulated 8-hr exposures to the ACGIH TLV concentration of 25 ppm. Even less of the total uptake was attributed to the skin during simulations of exercise with whole-body exposures (5-9%) or by more realistic exposures of only the arms and head (1-8%). As a result, humans are unlikely to reach hemolytic concentrations of the metabolite BAA in blood following vapor exposures to BE.