Validation of Human Physiologically Based Pharmacokinetic Model for Vinyl Acetate Against Human Nasal Dosimetry Data

Abstract

Vinyl acetate has been shown to induce nasal lesions in rodents in inhalation bioassays. A physiologically based pharmacokinetic (PBPK) model for vinyl acetate has been used in human risk assessment, but previous in vivo validation was conducted only in rats. Controlled human exposures to vinyl acetate were conducted to provide validation data for the application of the model in humans. Five volunteers were exposed to 1, 5, and 10 ppm 13C1,13C2 vinyl acetate via inhalation. A probe inserted into the nasopharyngeal region sampled both 13C1,13C2 vinyl acetate and the major metabolite 13C1,13C2 acetaldehyde during rest and light exercise. Nasopharyngeal air concentrations were analyzed in real time by ion trap mass spectrometry (MS/MS). Experimental concentrations of both vinyl acetate and acetaldehyde were then compared to predicted concentrations calculated from the previously published human model. Model predictions of vinyl acetate nasal extraction compared favorably with measured values of vinyl acetate, as did predictions of nasopharyngeal acetaldehyde when compared to measured acetaldehyde. The results showed that the current PBPK model structure and parameterization are appropriate for vinyl acetate. These analyses were conducted from 1 to 10 ppm vinyl acetate, a range relevant to workplace exposure standards but which would not be expected to saturate vinyl acetate metabolism. Risk assessment based on this model further concluded that 24 h per day exposures up to 1 ppm do not present concern regarding cancer or non-cancer toxicity. Validation of the vinyl acetate human PBPK model provides support for these conclusions.

Comparative Risks of Aldehyde Constituents in Cigarette Smoke Using Transient Computational Fluid Dynamics/Physiologically Based Pharmacokinetic Models of the Rat and Human Respiratory Tracts

“…In animal studies, micro-dissection and analysis of airway tissues or newer imaging techniques, such as mass spectrometry imaging Lanekoff et al, 2012Lanekoff et al, , 2013Laskin et al, 2012) may prove useful for some materials. For humans, less invasive approaches such as regionspecific breath analysis (Hinderliter et al, 2005) or breath analysis using controlled breathing maneuvers that target different regions of the respiratory system as has been done with particles and cigarette smoke (Darquenne and Prisk, 2004;Darquenne et al, 2000;McGrath et al, 2009;Mills et al, 2002;Peterson et al, 2008) could be used to improve confidence in model predictions.…”

Aldehydes

“…Oxidation of AcH and ionization of resulting acetic acid can lead to acidification of cells. It has been proposed that tissue responses include acidificationinduced mitogenic cellular proliferation of nasal epithelium and acidification-induced cytotoxic (compensatory) cellular proliferation in the nasal olfactory epithelium (Hinderliter et al, 2005). It has been proposed that tissue responses include acidificationinduced mitogenic cellular proliferation of nasal epithelium and acidification-induced cytotoxic (compensatory) cellular proliferation in the nasal olfactory epithelium (Hinderliter et al, 2005).…”

Deposition of Inhaled Gases and Vapors

“…This has been observed experimentally in multiple species including the rat, hamster, and mouse. Xenobiotic metabolizing enzymes are expressed in the human nose, and studies using vinyl acetate indicate that local nasal metabolism occurs and serves a similar role in the human nose as well (Hinderliter et al, 2005).…”

“…This process cannot be mimicked by unidirectional (constant inspiration) flow regimes. However, data collected under unidirectional flow can be used to validate models that incorporate absorption/ desorption cycling (Gloede et al, 2011;Hinderliter et al, 2005;Plowchalk et al, 1997).…”