Biomedical Engineering Reference
In-Depth Information
of developmental toxicity is not well understood, but FA accumulation
is unlikely to be involved. Pharmacokinetic studies comparing blood
plasma concentrations of both MeOH and FA in different strains of
mice and NZW rabbits, together with complementary in utero MeOH
exposure studies in the same animals, indicate that pharmacokinetics
alone are insufficient to explain the marked differences in susceptibility
between strains and species to MeOH developmental toxicity (Sweeting
et al., 2010, 2011). Similarly, among mouse strains (C57BL/6J, C3H,
and CD-1), pharmacokinetic profiles are similar (see Section 7.2.2),
yet each strain has a different susceptibility to MeOH in utero
exposure; C57BL/6J mice and CD-1 mice are susceptible to morpho-
logical anomalies, and even these strains exhibit strain-specific abnor-
malities, whereas C3H mice are relatively resistant (Sweeting et al.,
2011) (see Section 7.3.2). Only morphological abnormalities were
measurably affected by MeOH administration, whereas litter parame-
ters such as litter size or the incidence of resorptions and stillbirths were
not altered. Furthermore, NZW rabbits exhibited a pharmacokinetic
profile more similar to that of humans, in that FA levels accumulated
and were sustained for more than twice the time observed in
mice (Sweeting et al., 2011) (Figure 7.11). Rabbits also proved to
be resistant to MeOH developmental toxicity, despite their substantially
different metabolism of MeOH, including FA accumulation (Sweeting
et al., 2011).
7.3.2 Teratogenesis
Species differences in teratogenicity are clearly exemplified in the case
of thalidomide, whereby rodents are resistant while rabbits, non human
primates, and humans are susceptible. Additionally, in utero thalido-
mide exposure significantly increased DNA oxidation in rabbit embryos
but not in mouse embryos, suggesting oxidatively damaged DNA may
be involved in the observed species difference (Parman et al., 1999).
There have been only two documented cases of human MeOH
developmental toxicity. Animal models, mostly rodents, have shown
species- and strain-specific sensitivity to MeOH during pregnancy, with
a variable spectrum of morphological abnormalities. Rodent studies
