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Effects of Endogenous Formaldehyde in Nasal Tissues on Inhaled Formmaldehyde Dosimetry Predictions in the Rat, Monkey, and Human Nasal Passages
Schroeter, J., J. Campbell, J. Kimbell, R. Conolly, H. Clewell, AND M. Andersen. Effects of Endogenous Formaldehyde in Nasal Tissues on Inhaled Formmaldehyde Dosimetry Predictions in the Rat, Monkey, and Human Nasal Passages. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 138(2):412-24, (2014).
There is a broad interest in the risk assessment community about how best to conduct risk assessments for chemicals, such as formaldehye,that occur endogenously, so that the dose at the target site is a function of both endogenous production and exogenous exposure. This new work expands our understanding of this issue. While EPA is developing a new IRIS assessment for formaldehye,this work was conducted entirely independently or the Iris process.
ABSTRACT Formaldehyde, a nasal carcinogen, is also an endogenous compound that is present in all living cells. Due to its high solubility and reactivity, quantitative risk estimates for inhaled formaldehyde rely on internal dose calculations in the upper respiratory tract which are complicated by the presence of background formaldehyde concentrations in the respiratory mucosa. Anatomically accurate three-dimensional computational fluid dynamics (CFD) models of the rat, monkey, and human nasal passages were used to simulate uptake of inhaled formaldehyde. An epithelial structure was implemented in the nasal CFD models to estimate formaldehyde absorption from air:tissue partitioning, species-specific metabolism, first-order clearance, DNA binding, and endogenous formaldehyde production. At an exposure concentration of 1 ppm, predicted formaldehyde nasal uptake was 99.4, 86.5, and 85.3% in the rat, monkey, and human, respectively. Endogenous formaldehyde in nasal tissues did not affect wall mass flux or nasal uptake predictions at exposure concentrations > 500 ppb. Reduced nasal uptake was predicted at lower exposure concentrations due to the presence of endogenous formaldehyde. At an exposure concentration of 1 ppb, predicted nasal uptake was 17.5 and 42.8% in the rat and monkey and net desorption of formaldehyde was predicted in the human model. The nonlinear behavior of formaldehyde nasal absorption will affect the dose-response analysis and subsequent risk estimates at low exposure concentrations. Updated surface area-partitioning of nonsquamous epithelium and average flux values in regions where DNA-protein-cross-links and cell proliferation rates were measured in rats and monkeys are reported for use in formaldehyde risk models of carcinogenesis.