Biomedical Engineering Reference
In-Depth Information
The Battelle work was aimed, at least in part, at developing estimates
of the maximum blood methanol concentration (C
max
) achieved during
either 7 or 24 (i.e., continuous) hours of inhalation exposure and estimates
of 24-hour AUC, following either 7- or 24-hour inhalation exposures to
methanol. TheBattelle investigators concluded that the human equivalent
concentration corresponding to the inhalation route No Observed Effect
Level (NOEL) of 1000 ppm from the Rogers et al. (1993) studywas either
461.2 ppm (600mg/m
3
), based on an AUC dose metric, or 659 ppm
(857mg/m
3
), based on a C
max
dose metric (Battelle, 2006). Using the
same uncertainty factors of 3 (for possible pharmacodynamic differences
between species) and 10 (for interindividual differences in sensitivity)
employed by Starr and Festa (2003), these values led to methanol
inhalation RfCs of 20 or 28.6mg/m
3
, respectively, that is, 10- to
15-folds lower than the Starr and Festa (2003) maximum likelihood
estimate. This chapter describes a systematic exploration and comparison
of various predictions made by the Battelle (2006) and Bouchard et al.
(2001) pharmacokinetic models of methanol disposition. This compari-
son has yielded a number of insights that should prove useful in future
pharmacokinetic modeling and quantitative risk assessment efforts for
methanol, as well as for other volatile compounds.
6.2 ARE HUMANS MORE OR LESS SENSITIVE THAN MICE
TO THE TOXIC EFFECTS OF METHANOL?
The Battelle (2006) report (Table 2 and Figure 13, data not shown)
provides results from PBPK model simulations of mouse and human
AUC and C
max
as functions of airborne methanol concentration.
Inspection of the AUC results revealed that the predicted human
AUC always exceeds the corresponding mouse AUC. At 1 ppm, the
difference is a factor of 3.62, but the predicted human to mouse AUC
ratio grows to almost 16.4 at 1000 ppm. Then it declines gradually to 7.9
at 5000 ppm. Similarly, the human C
max
always exceeds the mouse
C
max
. At 1 ppm, the difference is quite small, a factor of 1.06, but at
1000 ppm, the predicted human to mouse C
max
ratio grows to 3.95 and
then declines gradually to 2.86 at 5000 ppm.
