Biomedical Engineering Reference
In-Depth Information
However, the mouse results cited earlier pertain to exposure condi-
tions in the Rogers et al. (1993) study, that is, C
max
is the blood
concentration immediately following 7 hours of exposure, and the
AUC is computed for a 24-hour period starting at the onset of a
7-hour exposure period. In contrast, the human results pertain to
continuous 24-hour exposure, so C
max
is the predicted blood methanol
concentration at steady state, and the 24-hour AUC is just 24
C
max
.
Thus, the comparison of mouse and human C
max
and AUC values as
provided in the Battelle (2006) report is confounded by the different
durations of the mouse and human exposure regimens. Indeed, it could
be argued that the different exposure durations (7 hours for mice,
24 hours for humans) are responsible for most of the apparent discrep-
ancy between the mouse and human C
max
and AUC values.
To resolve this species sensitivity question, an “apples to apples”
comparison of the two species responses is required. Since lifetime
continuous exposure at the fence line is the primary concern of the
inhalation RfC process, a comparison of human and mouse C
max
and
24-hour AUC is most appropriately undertaken for continuous exposure
conditions.
This was accomplished by solving (algebraically) the differential
equations representing the Battelle PBPK model under steady-state
exposure conditions.
At steady state, the Battelle PBPK model reduces to the following
equations, using the notation employed in Appendix B.1 of the Battelle
(2006) report:
Arterial Blood
:
CVLu
¼
CAB
Fat
:
CVF
¼
CAB
Rest of Body
:
CVR
¼
CAB
CVL
ð
QL
ð
Liver
:
CAB
¼
1
þ
V
max
=ð
KM
þ
CVL
ÞÞ
QL
ð
þ
V
max
2
=ð
KM2
þ
CVL
ÞÞÞ
Þ
CVB
Þ
CAB
KL
VVB
QL
CVL
Mixed Venous Blood
: ð
QC
þ
¼ð
QF
þ
QR
þ
QP
ð
FRACin
CCh
CVB
=
PB
Þ¼
QC
ð
CAB
CVB
Þ
Lungs
:
These nonlinear equations can be manipulated so as to express the
steady-state arterial and mixed venous blood methanol concentrations
