Simulation modeling of the tissue disposition of formaldehyde to predict nasal DNA-protein cross-links in Fischer 344 rats, rhesus monkeys, and humans.
Formaldehyde inhalation causes formation of DNA-protein cross-links (DPX) in the nasal mucosa of Fischer 344 (F344) rats and rhesus monkeys. DPX are considered to be part of the mechanism by which cytotoxic and carcinogenic effects of formaldehyde in laboratory animals are exerted, and DPX data have been used as a measure of tissue dose in cancer risk assessments for formaldehyde. Accurate prediction of DPX concentrations in humans is therefore desirable. The goal of this work was to increase confidence in the prediction of human DPX by refining earlier models of formaldehyde disposition and DPX kinetics in the nasal mucosa. Anatomically accurate, computational fluid dynamics models of the nasal airways of F344 rats, rhesus monkeys, and humans were used to predict the regional flux of formaldehyde to the respiratory and olfactory mucosa. A previously developed model of the tissue disposition of formaldehyde and of DPX kinetics was implemented in the graphical simulation tool SIMULINK and linked to the regional flux predictions. Statistical optimization was used to identify parameter values, and good simulations of the data were obtained. The parameter estimates for rats and monkeys were used to guide allometric scale-up to the human case. The relative levels of nasal mucosal DPX in rats, rhesus monkeys, and humans for a given inhaled concentration of formaldehyde were predicted by the model to vary with concentration. This modeling approach reduces uncertainty in the prediction of human nasal mucosal DPX resulting from formaldehyde inhalation.
Conolly
R B
RB
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina, USA. rconolly@ciit.org
Lilly
P D
PD
Kimbell
J S
JS
D000818:Animals; D002273:Carcinogens / Q000009:adverse effects* / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000009:adverse effects* / Q000378:metabolism*; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects*; D008253:Macaca mulatta; D008657:Metabolic Clearance Rate; D023421:Models, Animal; D009297:Nasal Mucosa / Q000187:drug effects* / Q000473:pathology; D011237:Predictive Value of Tests; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment / Q000379:methods; D013997:Time Factors; D014018:Tissue Distribution
D002273:Carcinogens; D004268:DNA-Binding Proteins; D005557:Formaldehyde