034904 

Journal Article 

Review 

Application of a physiologically based pharmacokinetic model for isopropanol in the derivation of a reference dose and reference concentration 

Gentry, PR; Covington, TR; Andersen, ME; Clewell, HJ, III 

2002 

Regulatory Toxicology and Pharmacology
ISSN: 0273-2300
EISSN: 1096-0295 

36 

1 

51-68 

English 

12383718 

http://www.ncbi.nlm.nih.gov/pubmed/12383718  

An interspecies physiologically based pharmacokinetic (PBPK) model describing isopropanol (IPA) and its major metabolite, acetone, was applied to perform route-to-route and cross-species dosimetry to derive reference dose (RfD) and reference concentration (RfC) values for IPA. Adult PBPK models for rats and humans were extended to simulate exposure to IPA during pregnancy and used to estimate internal dose metrics in the mother and fetus during development. Endpoints from chronic, developmental, and reproductive toxicity studies were considered for the derivation of RfDs and RfCs. Due to uncertainties in the mode of action of toxicity for IPA and acetone, the dose metric used for most responses was the total area under the blood concentration curve (AUC) for the combination of IPA and acetone. This combined dose metric provided a more conservative estimate than those based on AUCs for IPA or acetone. Peak blood concentration of IPA was the dose metric for neurobehavioral effects. The recommended RfD and RfC for IPA are 10 mg/kg/day and 40 ppm, respectively, based on decreased fetal body weights. All of the PBPK-derived RfD or RfC values for various endpoints were similar (within a factor of 3), regardless of route of exposure in the animal study. 

2-Propanol/administration & dosage/*pharmacokinetics/*toxicity; Acetone/administration & dosage/pharmacokinetics/toxicity; Adult; Algorithms; Animals; Area Under Curve; Decision Trees; Dose-Response Relationship, Drug; Drug Administration Routes; Embryonic and Fetal Development/drug effects; Female; Fetus/drug effects; Humans; *Models, Biological 

• ISA-Lead
     Considered
• Methanol (Non-Cancer) (Draft, 2011)
     Cited in External Review Draft
     Cited in 2013 ERD
 

2-Propanol 
Acetone 
Adult 
Algorithms 
Animals 
Area Under Curve 
Decision Trees 
Dose-Response Relationship, Drug 
Drug Administration Routes 
Embryonic and Fetal Development 
Female 
Fetus 
Humans 
Models, Biological 
No-Observed-Adverse-Effect Level 
Pregnancy 
Rats 
Reference Values 
Reproduction 
Risk Assessment 
Toxicity Tests 
Toxicity Tests, Chronic 
Uncertainty