Toxicological Sciences, Vol 51, 19-35, Copyright © 1999 by Society of Toxicology
MS Bogdanffy, R Sarangapani, DR Plowchalk, A Jarabek and ME Andersen
The 1990 Clean Air Act Amendments require that health risk from exposure to
vinyl acetate be assessed. Vinyl acetate is a nasal carcinogen in rats, but
not mice, and induces olfactory degeneration in both species. A
biologically based approach to extrapolating risks of inhalation exposure
from rats to humans was developed, which incorporates critical determinants
of interspecies dosimetry. A physiologically based pharmacokinetic (PBPK)
model describing uptake and metabolism of vinyl acetate in rat nose was
validated against nasal deposition data collected at three airflow rates.
The model was also validated against observations of metabolically derived
acetaldehyde. Modifying the rat nose model to reflect human anatomy created
a PBPK model of the human nose. Metabolic constants from both rats and
humans specific for vinyl acetate and acetaldehyde metabolism enabled
predictions of various olfactory tissue dosimeters related to the mode of
action. Model predictions of these dosimeters in rats corresponded well
with observations of vinyl acetate toxicity. Intracellular pH (pHi) of
olfactory epithelial cells was predicted to drop significantly at airborne
exposure concentrations above the NOAEL of 50 ppm. Benchmark dose methods
were used to estimate the ED10 and LED10 for olfactory degeneration, the
precursor lesion thought to drive cellular proliferation and eventually
tumor development at excess cellular acetaldehyde levels. A concentration x
time adjustment was applied to the benchmark dose values. Human-equivalent
concentrations were calculated by using the human PBPK model to predict
concentrations that yield similar cellular levels of acetic acid,
acetaldehyde, and pHi. After the application of appropriate uncertainty
factors, an ambient air value of 0.4 to 1.0 ppm was derived. The
biologically based approach supports a workplace standard of 10 ppm.
ARTICLES
A biologically based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity
Haskell Laboratory for Toxicology and Industrial Medicine, E.I. du Pont de Nemours and Co., Inc., Newark, Delaware 19714, USA. matthew.s.bogdanffy@usa.dupont.com
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