Lesion locations have been correlated with high levels of formaldehyde-induced DNA–protein cross-links (DPX Casanova et al., 1991, 1994) and with local inspiratory airflow patterns in both species ( Morgan et al., 1991). Uncertainty from interspecies extrapolation of target tissue dose in formaldehyde risk assessments to date arises primarily from an inability to account for both the site- and species-specific patterns of nasal lesions induced by formaldehyde in rats and monkeys. Extrapolations of target tissue dose and tumor response among species have been significant sources of uncertainty in all these assessments. Since formaldehyde was first shown to be a rat nasal carcinogen ( Swenberg et al., 1980), research on respiratory effects of inhaled formaldehyde in laboratory animals has led to several human health risk assessments ( Health and Welfare Canada, 1987 U.S. Because epidemiological associations between human cancer incidence and formaldehyde exposure are equivocal ( Blair et al., 1990 Collins et al., 1997 Partanen, 1993), the extrapolation of dose and response from laboratory animals to humans is necessary when assessing potential carcinogenic risk in humans exposed to formaldehyde. Formaldehyde is a nasal carcinogen in rodents chronically exposed by inhalation to 6 ppm or higher ( Kerns et al., 1983 Monticello et al., 1996). People can be exposed to formaldehyde in both occupational and environmental settings, typically at concentrations well below 1 ppm. 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.įormaldehyde, nasal passages, nasal airflow, nasal uptake, F344 rat, rhesus monkey, human, regional dosimetry, local dosimetry, computational fluid dynamics 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.

Human nasal flux patterns shifted distally and uptake percentage decreased as inspiratory flow rate increased.

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 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. Rat and monkey flux bins were predicted for steady-state inspiratory airflow rates corresponding to the estimated minute volume for each species. 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. 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/).

The ability to account for species-specific variation of dose within the nasal passages would reduce this uncertainty. Interspecies extrapolations of tissue dose and tumor response have been a significant source of uncertainty in formaldehyde cancer risk assessment.

Deltagraph curvefit