Lm. Sweeney et al., Proposed occupational exposure limits for select ethylene glycol ethers using PBPK models and Monte Carlo simulations, TOXICOL SCI, 62(1), 2001, pp. 124-139
Methoxyethanol (ethylene glycol monomethyl ether, EGME), ethoxyethanol (eth
ylene glycol monoethyl ether, EGEE), and ethoxyethyl acetate (ethylene glyc
ol monoethyl ether acetate, EGEEA) are all developmental toxicants in labor
atory animals. Due to the imprecise nature of the exposure data in epidemio
logy studies of these chemicals, we relied on human and animal pharmacokine
tic data, as well as animal toxicity data, to derive 3 occupational exposur
e limits (OELs). Physiologically based pharmacokinetic (PBPK) models for EG
ME, 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
at, 2000, Toxicol. Appl. Pharmacol. 165, 63-73). These models were used to
calculate estimated human-equivalent no adverse effect levels (NAELs), base
d upon internal concentrations in rats exposed to no observed effect levels
(NOELs) for developmental toxicity. Estimated NAEL values of 25 ppm for EG
EEA and EGEE and 12 ppm for EGME were derived using average values for phys
iological, thermodynamic, and metabolic parameters in the PBPK model. The u
ncertainties in the point estimates for the NOELs and NAELs were estimated
from the distribution of internal dose estimates obtained by varying key pa
rameter values over expected ranges and probability distributions. Key para
meters were identified through sensitivity analysis. Distributions of the v
alues of these parameters were sampled using Monte Carlo techniques and app
ropriate dose metrics calculated for 1600 parameter sets. The 95th percenti
le values were used to calculate interindividual pharmacokinetic uncertaint
y factors (UFs) to account for variability among humans (UFh.pk). These val
ues 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 wer
e divided by UFh.pk and the default UFs for pharmacodynamic variability amo
ng animals and among humans to calculate the proposed OELs. This methodolog
y indicates that OELs (8-h time-weighted average) that should protect worke
rs from the most sensitive adverse effects of these chemicals are 2 ppm EGE
EA and EGEE (11 mg/m(3) EGEEA, 7 mg/m(3) EGEE) and 0.9 ppm (3 mg/m3) EGME,
These recommendations assume that dermal exposure will be minimal or nonexi
stent.