title: Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys: pharmacokinetics, rat-to-monkey interspecies scaling, and extrapolation to man.
abstract: DNA-protein cross-links were formed in the respiratory tract of rhesus monkeys exposed to [14C]formaldehyde (0.7, 2, or 6 ppm; 6 hr). Concentrations of cross-links (pmol/mg DNA) were highest in the mucosa of the middle turbinates; lower concentrations were produced in the anterior lateral wall/septum and nasopharynx. Very low concentrations were found in the larynx/trachea/carina and in the proximal portions of the major bronchi of some monkeys exposed to 6 ppm but not to 0.7 ppm. No cross-links were detected in the maxillary sinuses or lung parenchyma. The pharmacokinetics of cross-link formation in the nose were interpreted using a model in which the rate of formation is proportional to the tissue concentration of formaldehyde. The model includes both saturable and nonsaturable elimination pathways and describes regional differences in DNA binding as having an anatomical rather than a biochemical basis. Using this model, the concentration of cross-links formed in corresponding tissues of different species can be predicted by scaling the pharmacokinetic parameter that depends on minute volume (V) and quantity of nasal mucosal DNA (MDNA). The concentration-response curve for the average rate of cross-link formation in the turbinates, lateral wall, and septum of rhesus monkeys was predicted from that of F-344 rats exposed under similar conditions. There was significant overlap between predicted and fitted curves, implying that V and MDNA are major determinants of the rate of cross-link formation in the nasal mucosa of different species. Concentrations of cross-links that may be produced in the nasal mucosa of adult men were predicted based on experimental data in rats and monkeys. The results suggest that formaldehyde would generate lower concentrations of cross-links in the nasal mucosa of humans than of monkeys, and much lower concentrations in humans than in rats. The rate of formation of DNA-protein cross-links can be regarded as a surrogate for the delivered concentration of formaldehyde. Use of this surrogate should decrease the uncertainty of human cancer risk estimates derived by interspecies extrapolation by providing a more realistic measure of the delivered concentration at critical target sites.
authors.affiliation: Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709.
authors.forename: M
authors.initials: M
authors.lastname: Casanova
authors.forename: K T
authors.initials: KT
authors.lastname: Morgan
authors.forename: W H
authors.initials: WH
authors.lastname: Steinhagen
authors.forename: J I
authors.initials: JI
authors.lastname: Everitt
authors.forename: J A
authors.initials: JA
authors.lastname: Popp
authors.forename: H D
authors.initials: HD
authors.lastname: Heck
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000633:toxicity; D004247:DNA / Q000032:analysis / Q000378:metabolism*; D005557:Formaldehyde / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008954:Models, Biological; D009297:Nasal Mucosa / Q000187:drug effects; D011506:Proteins / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344; D012044:Regression Analysis; D012137:Respiratory System / Q000378:metabolism*; D013045:Species Specificity; D014420:Turbinates / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D011506:Proteins; D005557:Formaldehyde; D004247:DNA