Dosimetry Modeling of Inhaled Formaldehyde: Binning Nasal Flux Predictions for Quantitative Risk Assessment

Abstract

Interspecies extrapolations of tissue dose and tumor response have been a significant source of uncertainty in formaldehyde cancer risk assessment. The ability to account for species-specific variation of dose within the nasal passages would reduce this uncertainty. Three-dimensional, anatomically realistic, computational fluid dynamics (CFD) models of nasal airflow and formaldehyde gas transport in the F344 rat, rhesus monkey, and human were used to predict local patterns of wall mass flux (pmol/[mm(2)-h-ppm]). The nasal surface of each species was partitioned by flux into smaller regions (flux bins), each characterized by surface area and an average flux value. Rat and monkey flux bins were predicted for steady-state inspiratory airflow rates corresponding to the estimated minute volume for each species. Human flux bins were predicted for steady-state inspiratory airflow at 7.4, 15, 18, 25.8, 31.8, and 37 l/min and were extrapolated to 46 and 50 l/min. Flux values higher than half the maximum flux value (flux median) were predicted for nearly 20% of human nasal surfaces at 15 l/min, whereas only 5% of rat and less than 1% of monkey nasal surfaces were associated with fluxes higher than flux medians at 0.576 l/min and 4.8 l/min, respectively. Human nasal flux patterns shifted distally and uptake percentage decreased as inspiratory flow rate increased. Flux binning captures anatomical effects on flux and is thereby a basis for describing the effects of anatomy and airflow on local tissue disposition and distributions of tissue response. Formaldehyde risk models that incorporate flux binning derived from anatomically realistic CFD models will have significantly reduced uncertainty compared with risk estimates based on default methods.

Derivation of Mass Transfer Coefficients for Transient Uptake and Tissue Disposition of Soluble and Reactive Vapors in Lung Airways

“…The intersection time point of the two lines bounding the saturable pathway of elimination must be found to determine the applicability range of Eqs. (16), (20), and (21). By equating elimination rates obtained from the solution of Eq.…”

“…6,20,31,36,38,45 This distributed parameter approach simulates the airflow dynamics and transport and uptake of vapors in 3D models of the respiratory system. The advantage of this approach is that localized predictions of gas dosimetry can be obtained that are based on accurate geometries representative of the respiratory system.…”

Inherited mutations impair responses to environmental carcinogens: Cancer prevention in mutation carriers

“…The exposure of oral cavity structures to formaldehyde markedly increases during heavy exercise, [38] as breathing shifts to oral. Cancers of the oral cavity are the most frequent solid tumors in Fanconi homozygotes with relative risk >200 times normal [23,21].…”

Transient Absorption of Inhaled Vapors into a Multilayer Mucus–Tissue–Blood System

“…36,38,42 Studies considering solubility and potential reactions in a mucus layer include Keyhani et al, 22 Zhang and Kleinstreuer, 43 and Zhao et al 45 Other studies have considered solubility and reactivity in a mucus-tissue representation of the URT. 9,10,14,24 However, as with previous studies, all computational models assume that steady state diffusion through the mucus or mucus and tissue layers is reached instantaneously. That is, the concentration profiles are immediately linear and a constant flux is assumed through the mucus and tissue walls into the blood.…”