Relative contributions of endogenous and exogenous formaldehyde to formation of deoxyguanosine monoadducts and DNA-protein crosslink adducts of DNA in rat nasal mucosa.

ABSTRACT

Understanding the dose-response for formaldehyde-induced nasal cancer in rats is complicated by (1) the uneven distribution of inhaled formaldehyde across the interior surface of the nasal cavity and, (2) the presence of endogenous formaldehyde (endoF) in the nasal mucosa. In this work, we used computational fluid dynamics (CFD) modeling to predict flux of inhaled (exogenous) formaldehyde (exogF) from air into tissue at the specific locations where DNA adducts were measured. Experimental work has identified DNA-protein crosslink (DPX) adducts due to exogF and deoxyguanosine (DG) adducts due to both exogF and endoF. These adducts can be considered biomarkers of exposure for effects of endoF and exogF on DNA that may be part of the mechanism of tumor formation. We describe a computational model linking CFD-predicted flux of formaldehyde from air into tissue, and the intracellular production of endoF, with the formation of DPX and DG adducts. We assumed that, like exogF, endoF can produce DPX. The model accurately reproduces exogDPX, exogDG, and endoDG data after inhalation from 0.7 to 15 ppm. The dose-dependent concentrations of exogDPX and exogDG are predicted to exceed the concentrations of their endogenous counterparts at about 2 and 6 ppm exogF, respectively. At all concentrations examined, the concentrations of endoDPX and exogDPX were predicted to be at least 10-fold higher than that of their DG counterparts. The modeled dose-dependent concentrations of these adducts are suitable to be used together with data on the dose-dependence of cell proliferation to conduct quantitative modeling of formaldehyde-induced rat nasal carcinogenicity.