The Toxicologist - Society of Toxicology

etate (immunotoxicity). 2,4-D was tested in response to a regulatory request as an
example of using this protocol for regulatory assessment. Reported here are the efforts
on these four studies, using the protocol proposed by ACSA (Agricultural
Chemical Safety Assessment), conducted in Europe and the U.S. Data indicate that
this protocol, while complex, is technically feasible and sufficiently sensitive to detect
the effects of concern. The study design identified vinclozolin as a reproductive
toxicant, including anti-androgenic developmental effects consistent with the literature.
Results with methimazole demonstrated effects on thyroid endpoints, developmental
delay and reduced brain measurements. The study with lead acetate is
nearing completion. The 2,4-D study illustrated the successful application of decision
criteria for a potential 2nd generation breeding, as well as the utility of TK data
in dose setting and data interpretation, and is expected to establish a robust dataset
for risk assessment.
858 CATALASE IN THE MECHANISM OF METHANOL
DEVELOPMENTAL TOXICITY.
M. Siu 1 and P. G. Wells 1, 2 . 1 Faculty of Pharmacy, University of Toronto, Toronto,
ON, Canada and 2 Department of Pharmacology and Toxicology, University of
Toronto, Toronto, ON, Canada.
Oxidative stress and reactive oxygen species (ROS) have been implicated in the developmental
toxicity and potential carcinogenic effects of methanol (MeOH) in rodent
models, but the mechanisms remain unclear, particularly with regard to catalase,
which in rodents both detoxifies ROS and metabolizes MeOH and its formic
acid (FA) metabolite. To explore the role of ROS and catalase in MeOH teratogenicity,
we are using genetically modified mouse strains that either express high
catalase activity (transgenic mice expressing human catalase, Tg hCat) or low activity
(mutant acatalasemic mice, Acat). Pregnant mice were treated on gestational day
(GD) 8 (plug date = GD 1) with two doses of either MeOH (2 g/kg ip, 20% [w/v]
solution in normal saline, given 4 hr apart, for a total of 4 g/kg), or its saline vehicle.
Dams were sacrificed on GD 19 and fetuses assessed for neural tube defects
(NTDs), ophthalmic abnormalities (anophthalmia and microphthalmia) and cleft
palate. In preliminary studies, MeOH exposure most commonly caused ophthalmic
abnormalities, with an overall incidence of 40-50% in Tg hCat and wildtype
(WT) mice for both strains, and 20% in Acat mice, compared to