Biomedical Engineering Reference
In-Depth Information
FIGURE 7.1 Species differences in the enzymes catalyzing the metabolism
of methanol (MeOH) to formaldehyde and formic acid (FA) in mice and
primates, including humans. In addition to its role in MeOH and FA metabo-
lism in mice, catalase is used by all species in the detoxification of reactive
oxygen species (ROS). Source: From Sweeting et al. (2010).
reflective of humans, based in part on their remarkable species differ-
ence from mice in susceptibility to birth defects caused by the ROS-
initiating sedative drug thalidomide (Parman et al., 1999).
The intraperitoneal (i.p.) route, as opposed to inhalation or oral
intake, was used in our studies to ensure that the dose delivered was as
consistent as possible, in part for a precise determination of pharmaco-
kinetic parameters, particularly across species such as mice, rabbits, and
primates. Equally important, the resulting consistency in embryonic
exposure allows a more reliable interpretation of results from mecha-
nistic studies relating molecular changes to teratological outcomes. The
high dose of MeOH, well above the lethal dose in humans, was based on
published studies of MeOH teratogenicity in mice (Rogers et al., 2004)
and retained in rabbits and primates to ensure that any teratogenic
potential was not missed owing to an insufficiently high dose as well as
to facilitate cross-species comparisons. MeOH was administered
acutely rather than chronically to avoid the complicating secondary
