Biomedical Engineering Reference
In-Depth Information
model-predicted results imply that humans are actually more, not less,
sensitive than mice when both are exposed continuously to the same
airborne methanol concentration. This implication stands in direct contra-
diction to the extensive body of evidence in the scientific literature
indicating that the mouse is uniquely sensitive, relative to all other species
tested, to the toxic effects of methanol, due principally to its limited
metabolic capability for methanol (CERHR, 2002; Clary, 2003).
6.3 ARE THE TWO MODELS' PREDICTIONS OF HUMAN
BLOOD METHANOL CONCENTRATIONS AT STEADY
STATE CONSISTENT WITH EACH OTHER?
The Bouchard et al. (2001) model is a multicompartment, biologically
based, dynamic model that describes the time evolution of methanol and
its metabolites in the whole body, excreted urine, and expired air. A
single system of first-order differential equations with species-specific
parameter values for rats, monkeys, and humans accounts for the
uptake, distribution, and metabolic conversion of methanol into form-
aldehyde, formate, and carbon dioxide. Bouchard et al. determined
human parameter values by fitting the model outputs to blood and
urinary methanol concentration time-course data obtained by other
investigators using either cynomolgus monkeys (Dorman et al., 1994)
or human volunteers (Osterloh et al., 1996; Sedivec et al., 1981). They
then validated the human version of the model with completely inde-
pendent methanol time-course data from human volunteer inhalation
exposures as reported by Batterman et al. (1998).
A key feature of the Bouchard et al. (2001) model is that the kinetics
of methanol in humans and monkeys are linear throughout the concen-
tration ranges where human data are available. Only the rat version of
this model required saturable Michaelis-Menten metabolism, and that
was required only for the first metabolic step, namely, conversion of
methanol to formaldehyde by catalase. An important consequence of
linear kinetics in the human volunteer exposure range (up to 800 ppm) is
that the increment in blood methanol concentration resulting from
inhalation exposure is directly proportional to the airborne methanol
