Biomedical Engineering Reference
In-Depth Information
methanol as an alternative (and preferred) dose metric to that of the
methanol concentration in the inhalation chambers.
The CERHR Expert Panel review concluded that “blood methanol
concentrations provide a useful dosimetric for comparison of results
among various studies.” Indeed, the Expert Panel explicitly character-
ized its levels of concern regarding the potential toxicity of different
airborne methanol exposures in terms of the corresponding methanol
concentrations in circulating blood. The Panel's characterization of
blood methanol concentration as the “preferred” dose metric singles out
methanol pharmacokinetics as a critical factor that needs careful
consideration in any quantitative risk assessment of potential adverse
human health effects that might arise from methanol exposure.
Starr and Festa (2003) undertook such a quantitative assessment
using the developmental toxicity and blood methanol data collected by
Rogers et al. (1993) to first determine a blood methanol RfC, and then
convert that blood methanol RfC to a corresponding inhalation RfC
with a physiologically based pharmacokinetic (PBPK) model of human
methanol disposition that had been developed previously by Bouchard
et al. (2001). The maximum likelihood estimate of their proposed
methanol inhalation RfC was 298mg/m
3
, with a lower 95% confidence
bound of 135mg/m
3
.
Subsequent discussions with USEPA regarding this proposal
revealed several Agency concerns. First, the Agency commented
that steady state might not have been reached in the Rogers et al.
(1993) study where the mouse inhalation exposures lasted for only
7 hours each day. In contrast, the Starr and Festa (2003) analysis
assumed that steady state had been reached well prior to exposure
termination on each day of exposure. Second, the Agency commented
that area under the blood methanol concentration curve (AUC) might
be preferred over blood methanol concentration as the dose metric for
USEPA's risk assessment purposes, and AUC data were not collected
during the Rogers et al. (1993) study. These concerns eventually led
USEPA to award a contract to investigators from Battelle's Pacific
Northwest National Laboratory to develop a new PBPK model
capable of describing methanol disposition in both mice and humans
in a variety of exposure situations.
