title: Proposed occupational exposure limits for select ethylene glycol ethers using PBPK models and Monte Carlo simulations.
abstract: Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (ethylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glycol monoethyl ether acetate, EGEEA) are all developmental toxicants in laboratory animals. Due to the imprecise nature of the exposure data in epidemiology studies of these chemicals, we relied on human and animal pharmacokinetic data, as well as animal toxicity data, to derive 3 occupational exposure limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EGME, EGEE, and EGEEA in pregnant rats and humans have been developed (M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 53-62; M. L. Gargas et al., 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to calculate estimated human-equivalent no adverse effect levels (NAELs), based upon internal concentrations in rats exposed to no observed effect levels (NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EGEEA and EGEE and 12 ppm for EGME were derived using average values for physiological, thermodynamic, and metabolic parameters in the PBPK model. The uncertainties in the point estimates for the NOELs and NAELs were estimated from the distribution of internal dose estimates obtained by varying key parameter values over expected ranges and probability distributions. Key parameters were identified through sensitivity analysis. Distributions of the values of these parameters were sampled using Monte Carlo techniques and appropriate dose metrics calculated for 1600 parameter sets. The 95th percentile values were used to calculate interindividual pharmacokinetic uncertainty factors (UFs) to account for variability among humans (UF(h,pk)). These values of 1.8 for EGEEA/EGEE and 1.7 for EGME are less than the default value of 3 for this area of uncertainty. The estimated human equivalent NAELs were divided by UF(h,pk) and the default UFs for pharmacodynamic variability among animals and among humans to calculate the proposed OELs. This methodology indicates that OELs (8-h time-weighted average) that should protect workers from the most sensitive adverse effects of these chemicals are 2 ppm EGEEA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m(3)) EGME. These recommendations assume that dermal exposure will be minimal or nonexistent.
authors.affiliation: The Sapphire Group, Inc., 2928 Idaho Falls Drive, Suite 100, Beavercreek, Ohio 45431, USA. lms@thesapphiregroup.com
authors.forename: L M
authors.initials: LM
authors.lastname: Sweeney
authors.forename: T R
authors.initials: TR
authors.lastname: Tyler
authors.forename: C R
authors.initials: CR
authors.lastname: Kirman
authors.forename: R A
authors.initials: RA
authors.lastname: Corley
authors.forename: R H
authors.initials: RH
authors.lastname: Reitz
authors.forename: D J
authors.initials: DJ
authors.lastname: Paustenbach
authors.forename: J F
authors.initials: JF
authors.lastname: Holson
authors.forename: M D
authors.initials: MD
authors.lastname: Whorton
authors.forename: K M
authors.initials: KM
authors.lastname: Thompson
authors.forename: M L
authors.initials: ML
authors.lastname: Gargas
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D019570:Inhalation Exposure; D008954:Models, Biological; D009010:Monte Carlo Method; D019055:No-Observed-Adverse-Effect Level; D016273:Occupational Exposure; D013045:Species Specificity; D020711:Threshold Limit Values
chemical_list: D005026:Ethylene Glycols; C022278:ethylene glycol monoethyl ether acetate; C005219:methyl cellosolve; C021296:2-ethoxyethanol