Toxicological Sciences, Vol 50, 195-205, Copyright © 1999 by Society of Toxicology
RM David, MR Moore, MA Cifone, DC Finney and D Guest
This study compared the levels of cell proliferation and peroxisome
proliferation in rodent liver with tumor incidence, to provide more
information on the relationship between these events following chronic
exposure. Fischer 344 rats were treated with 0, 100, 500, 2500, or 12,500
ppm DEHP, and B6C3F1 mice were treated with 0, 100, 500, 1500, or 6000 ppm
DEHP in the diet for up to 104 weeks. Additional groups of rats and mice
received the highest concentration for 78 weeks and then the control diet
for an additional 26 weeks (recovery groups). Animals were terminated at
weeks 79 and 105 for histopathologic examination. Elevated palmitoyl CoA
oxidation activity and higher liver-to-body weight ratios were observed for
the 2500- and 12,500-ppm groups of rats, and for the 500-, 1500-, and
6000-ppm groups of mice at Week 105. No increase in palmitoyl CoA oxidation
activity was evident in the recovery group, and relative liver weights were
near control levels following recovery. No hepatic cell proliferation was
detected at Weeks 79 or 105 in either species although preliminary data
indicated that cell proliferation did occur within the first 13 weeks of
exposure. A significantly higher incidence of hepatocellular tumors was
only observed for the 2500- and 12,500-ppm group and its recovery group of
rats, and for the 500-, 1500-, and 6000-ppm groups and the recovery group
of mice. The tumor incidences were reduced for the recovery groups compared
with the groups fed DEHP continuously for 104 weeks. The data indicate that
high levels of peroxisome proliferation and hepatomegaly are associated
with DEHP hepatocarcinogenesis in rodent liver, and that the tumorigenic
process may be arrested by cessation of DEHP treatment, suggesting that
extended treatment with DEHP acts to promote tumor growth.
ARTICLES
Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery
Eastman Kodak Company, Rochester, New York 14652-6272, USA. davidtox@kodak.com
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