Biomedical Engineering Reference
In-Depth Information
prevalent keto form, 7,8-dihydro-8-oxoguanine, commonly termed 8-
oxo-2
0
-deoxyguanine (8-oxodG). 8-OxodG is the most abundant pro-
mutagenic oxidation product of guanine, yielding G-to-T transversion
mutations that could activate oncogenes or inactivate tumor suppressor
genes linked to the development of cancers (Hsu et al., 2004; Klaunig
and Kamendulis, 2004). Genetically altered mice with deficiencies in
DNA glycosylases that protect against G-to-T transversions provide
strong evidence of a causal role for oxidatively damaged DNA in
tumorigenesis (Russo et al., 2004; Xie et al., 2004; Kinoshita et al.,
2007). Dimethylarsinic acid strongly increases 8-oxodG levels and
carcinogenicity in lungs of Ogg1 knockout (KO) mice (Kinoshita et
al., 2007). In double mutant mice deficient in Ogg1 and Myh, 8-oxodG
accumulates in lung and small intestine, and these organs have multi-
fold increases in cancer incidence with a high frequency of G-to-T
transversion mutations that activate the K-ras oncogene in lung cancers
(Xie et al., 2004). Deficiencies in the repair of 8-oxoG have also been
suggested to be risk factors for the development of human lung cancer
(Paz-Elizur et al., 2003; Mambo et al., 2005).
There are no human data regarding the carcinogenic potential of
MeOH, and only four rodent studies, which have reported conflicting
results (Table 7.10). Inhalation studies in mice and rats performed by
the NEDO (1987) in Japan concluded that carcinogenic effects were not
evident following chronic exposure to MeOH, and that there were no
differences in the incidence of leukemias or lymphomas. The lack of
developmental effects in nonhuman primates is not entirely consistent
with the published evidence of developmental toxicity discussed earlier
in Section 7.3.2. The NEDO studies were initially difficult to assess as
they were available only as summary reports, but more complete
English translations are now available from the Methanol Institute
(
www.methanol.org
). An extensive chronic carcinogenic study per-
formed in Sprague-Dawley rats by the Ramazzini Foundation (Soffritti
et al., 2002) exposed rats to a range of MeOH concentrations in drinking
water and reported dose-dependent increases in lympho-immunoblastic
lymphomas and ear duct carcinomas. However, the Ramazzini Foun-
dation studies have been questioned and its results are not widely
accepted (NTP, 2004; Cruzan, 2009). First, its methodology does not
