Biologically-Based Risk Assessment of Vinyl Acetate. M. S. Bogdanffy and D. R. Plowchalk, Haskell Laboratory for Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Co., P.O. Box 50, Newark, DE, 19714; and M. E. Andersen, I.C.F. Kaiser, Morrisville, NC 27560
Vinyl acetate (VA) is used in the manufacturing of latex paints, adhesives, polyvinyl alcohol, and paper board coatings. VA is on the Clean Air Act list of priority pollutants requiring estimation of residual risk following implementation of mandated control technologies. Two-year inhalation studies in rats and mice showed that VA induces lesions of the olfactory epithelium characteristic of many inhaled esters. VA also induced nasal tumors but this response was significant only in rats at the highest concentration tested (600 ppm). A multiphase research program was established to investigate the mode of cytotoxicity, and genotoxicity and to develop a biologically-based dosimetry model useful for interspecies extrapolation. Use of an in vitro nasal turbinate system revealed that VA is metabolized in nasal tissue by carboxylesterase which liberates acetic acid, a cytotoxicant and acetaldehyde (AAld), a genotoxicant. Acetic acid, when formed intracellularly in sufficient quantities, is proposed to reduce intracellular pH (pH1) to cytolethal levels. AAld is oxidized to acetic acid by an NAD+-dependent dehydrogenase adding further to the intracellular proton burden. Both VA and AAld were shown to produce DNA-protein crosslinks, a lesion that putatively precedes clastogenesis. VA-induced crosslinks were inhibited by blocking carboxylesterase activity. Finally, inhalation exposure to VA was shown to induce nasal epithelial cell proliferation. Together, the results suggest a mode of action in which VA is deposited on the nasal mucosal surface where it is metabolized in mucus or partitions into the cell. Within the cell, biotransformation of VA is proposed to induce cytotoxic drop in pH1, DNA-protein crosslinks, and cell proliferation. This sequence of events are captured within a biologically-based pharmacokinetic and pharmacodynamic model. Unidirectional VA vapor deposition studies in rats are used to test the model’s predictions of deposition by measuring amount of VA deposited in the nasal cavity and amount of AAld vapor in the expired airstream. Species-specific parameters such as nasal airflow patterns, carboxyfesterase kinetic constants, distribution of enzyme in tissue subcompartments, and blood-flow rates are incorporated into the model for purposes of interspecies extrapolation. The results predict that exposure of rats to 200 ppm VA vapor results in intracellular pH values of ˜ 6.8 with essentially no change in pH1 predicted at 50 ppm. This prediction is consistent with the observation of degeneration of olfactory epithelium of rats and mice exposed to š 200 ppm VA and a 50 ppm NOAEL. Sustained epithelial degeneration and induced cell proliferation, coupled with clastogenic effects of acetaldehyde are proposed to contribute to increased risk of nasal carcinogenesis. Using pH1 as the dosimetric, the human exposure concentration equivalent to the rat NOAEL is predicted to be approximately 5 ppm.
This research was supported, in part by the Vinyl Acetate Toxicology Group, Inc.