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Application of a physiologically based pharmacokinetic model for reference dose and reference concentration
P Robinan Gentry1, Tammie R Covington, Harvey J Clewell
1ENVIRON International Corporation, Ruston, Louisiana 71270, USA. rgentry@environcorp.com
Journal of Toxicology and Environmental Health. Part A
|November 13, 2003
Summary
This study introduces a novel risk assessment for acetone, utilizing a physiologically based pharmacokinetic (PBPK) model to establish health reference values. The PBPK model enables a tissue-based approach, reducing uncertainty factors and yielding lower reference dose (RfD) and reference concentration (RfC) estimates for acetone.
Area of Science:
- Toxicology
- Environmental Health
- Pharmacokinetics
Background:
- Previous health risk assessments for acetone relied on traditional No-Observed-Adverse-Effect Level (NOAEL) and Uncertainty Factor (UF) methodologies.
- These traditional methods often resulted in higher uncertainty factors and consequently, higher reference dose (RfD) estimates for acetone.
- A data gap existed for acetone's inhalation toxicity, particularly when considering only oral study data for RfD derivation.
Purpose of the Study:
- To conduct a risk assessment for acetone using systemic toxicity data from subchronic and developmental studies.
- To estimate an oral reference dose (RfD) and an inhalation reference concentration (RfC) for acetone.
- To apply a physiologically based pharmacokinetic (PBPK) model to bridge data gaps and reduce uncertainty in risk assessment.
Main Methods:
- Utilized a physiologically based pharmacokinetic (PBPK) model previously developed for isopropanol (IPA) and its metabolite acetone.
- Integrated data from an oral subchronic study (Dietz et al., 1991) and an inhalation developmental toxicity study (Mast et al., 1988) for acetone.
- Incorporated toxicology data from isopropanol (IPA) studies to assess potential acetone-related effects.
Main Results:
- The PBPK model facilitated a tissue-based risk assessment, allowing derivation of an oral RfD from inhalation study data.
- Application of the PBPK model supported a reduced composite Uncertainty Factor (UF) of 60 for the subchronic study, compared to 300-3000 in prior assessments.
- Derived an oral RfD of 16 mg/kg/d based on the subchronic study and an RfD of 8.7 mg/kg/d from the inhalation developmental study.
- Estimated an inhalation reference concentration (RfC) of 29 ppm for acetone.
Conclusions:
- The PBPK model provides a more refined, tissue-based approach to acetone risk assessment, reducing reliance on traditional uncertainty factors.
- The PBPK model enabled the derivation of lower, more protective RfD and RfC values for acetone compared to previous assessments.
- Incorporating inhalation developmental study data alongside the PBPK model addresses existing data gaps and strengthens the overall risk assessment for acetone.