A biologically based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity

Abstract

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.

Toxicokinetic modeling and its applications in chemical risk assessment

“…The Hazardous Air Pollutants Test Rule (Federal Register, 1996) invited increased efficiency/efficacy in testing by providing possible substitution of certain oral toxicity tests instead of requiring new inhalation studies, for those instances where a validated PBPK model is available to conduct extrapolations across dose-routes. Several case studies under the proposed cancer guidelines (US EPA, 1996), for example, those with formaldehyde (CIIT, 1999), chloroform (International Life Sciences Institute, 1977) and VA (Bogdanffy et al, 1999), base low-dose extrapolation on mode of action specific target tissue doses calculated with dosimetry models. In Chapter 8 of the US EPA's dioxin reassessment (US EPA, 2000b), a variety of mechanistic protein induction models are evaluated to assess the predictions for low-dose risks for each of them.…”

“…The physiological models for tissue dosimetry are more completely developed than are the models for biological response. A particularly good risk assessment example of the extension of PBPK modeling to include a more PD portion is pH control models in respiratory tract epithelial tissues following exposures to vinyl acetate (VA) (Plowchalk et al, 1997;Bogdanffy et al, 1999).…”

“…PBPK/PT models developed for these esters (Plowchalk et al, 1997;Bogdanffy et al, 1999;Andersen et al, 1999) calculate tissue dose metrics in the epithelial tissue compartments of the nose in support of estimations of cancer risks (with VA) or estimations of RfCs (with both VA and MMA). The target tissue compartments in the ester models differ from the liver compartment with the models for CH 2 Cl 2 and VCM.…”

“…Another advantage of the explicit construction of these models was the ability to conduct sensitivity analyses to assess the relative importance of the various model parameters in controlling achieved tissue doses. The sensitivity analysis was especially useful with VA (Plowchalk et al, 1997;Bogdanffy et al, 1999) where the model is highly non-linear due to a several potentially saturable processes, including two distinct esterase pathways, proton pumping, and the sequential arrangement of compartments within the nose. These nasal dosimetry models should play an important role in RfC estimations for a variety of chemicals of interest in the Integrated Risk Information System (IRIS) Pilot Project at the US EPA (www.epa.gov\iris\).…”

Sicherheitsfaktoren in der Risikobewertung von Chemikalien

“…Für Vinylacetat z. B. wurde von Bogdanffy und anderen vorhergesagt, dass beim Menschen eine niedrigere Empfindlichkeit vorliegt als bei der Ratte[20,21]. In diesem Fall würde die RfC-Methode das Risiko für den Menschen überschätzen.Für die Auslösung von toxischen Effekten in der Lunge sagt die EPA-Methode bei nominal gleichen externen Expositionskonzentrationen voraus, dass beim Menschen im Vergleich zur Maus eine dreifach geringere Dosis wirksam ist.…”