{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:25:56Z","timestamp":1760171156400,"version":"3.37.3"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T00:00:00Z","timestamp":1596153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012327","name":"Foundation for Chemistry Research & Initiatives","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012327","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007824","name":"American Chemistry Council","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007824","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Although formaldehyde is a normal constituent of tissues, lifetime inhalation exposures at 6\u2009h\/day, 5\u2009days\/week at concentrations \u22656\u2009ppm caused a nonlinear increase in nasal tumors in rats with incidence reaching close to 50% at 15\u2009ppm. Studies with heavy isotope labeled [13CD2]-formaldehyde permit quantification of both the mass-labeled exogenous and endogenous DNA-formaldehyde reaction products. An existing pharmacokinetic model developed initially to describe 14C-DNA-protein crosslinks (DPX) provided a template for describing the time course of mass-labeled adducts. Published datasets included both DPX and N2-HO13CD2-dG adducts measured after a single 6-h exposure to 0.7, 2, 6, 9, 10, or 15\u2009ppm formaldehyde, after multi-day exposures to 2\u2009ppm for 6\u2009h\/day, 7\u2009days\/week with interim sacrifices up to 28\u2009days, and after 28-day exposures for 6\u2009h\/day, 7\u2009days\/week to 0.3, 0.03, or 0.001\u2009ppm. The existing kinetic model overpredicted endogenous adducts in the nasal epithelium after 1-day [13CD2]-formaldehyde exposure, requiring adjustment of parameters for rates of tissue metabolism and background formaldehyde. After refining tissue formaldehyde parameters, we fit the model to both forms of adducts by varying key parameters and optimizing against all 3 studies. Fitting to all these studies required 2 nonlinear pathways\u2014one for high-exposure saturation of clearance in the nasal epithelial tissues and another for extracellular clearance that restricts uptake into the epithelial tissue for inhaled concentrations below 0.7\u2009ppm. This refined pharmacokinetic model for endogenous and exogenous formaldehyde acetal adducts can assist in updating biologically based dose-response models for formaldehyde carcinogenicity.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa122","type":"journal-article","created":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T19:13:30Z","timestamp":1595618010000},"page":"325-333","source":"Crossref","is-referenced-by-count":8,"title":["A Kinetic Analysis of DNA-Deoxy Guanine Adducts in the Nasal Epithelium Produced by Inhaled Formaldehyde in Rats\u2014Assessing Contributions to Adduct Production From Both Endogenous and Exogenous Sources of Formaldehyde"],"prefix":"10.1093","volume":"177","author":[{"given":"Jerry L","family":"Campbell Jr","sequence":"first","affiliation":[{"name":"Department of Health and Safety, Ramboll US Corporation, Raleigh, North Carolina 27612"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P Robinan","family":"Gentry","sequence":"additional","affiliation":[{"name":"Department of Health and Safety, Ramboll US Corporation, Monroe, Louisiana 71201"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harvey J","family":"Clewell III","sequence":"additional","affiliation":[{"name":"Department of Health and Safety, Ramboll US Corporation, Raleigh, North Carolina 27612"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melvin E","family":"Andersen","sequence":"additional","affiliation":[{"name":"Andersen ToxConsulting LLC, Denver, North Carolina 28037"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,7,31]]},"reference":[{"key":"2022031510260730500_kfaa122-B1","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1093\/toxsci\/kfq303","article-title":"Formaldehyde: Integrating dosimetry, cytotoxicity, and genomics to understand dose-dependent transitions for an endogenous compound","volume":"118","author":"Andersen","year":"2010","journal-title":"Toxicol. Sci"},{"key":"2022031510260730500_kfaa122-B2","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1289\/ehp.00108s5919","article-title":"Simulation modeling of the tissue disposition of formaldehyde to predict nasal DNA-protein cross-links in Fischer 344 rats, rhesus monkeys, and humans","volume":"108","author":"Conolly","year":"2000","journal-title":"Environ. Health Perspect"},{"key":"2022031510260730500_kfaa122-B3","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1093\/toxsci\/kfg182","article-title":"Biologically motivated computational modeling of formaldehyde carcinogenicity in the F344 rat","volume":"75","author":"Conolly","year":"2003","journal-title":"Toxicol. 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