Carcinogenesis, Vol 19, 187-193, Copyright © 1998 by Oxford University Press
MV Templin, AA Constan, DC Wolf, BA Wong and BE Butterworth
It has been reported that chloroform administered to BDF1 mice by
inhalation for 2 years at concentrations of 5, 30 or 90 p.p.m. for 6 h/day,
5 days/week induced an increase in renal cell tumors in male but not female
mice exposed to the doses of 30 and 90 p.p.m. A small increase in liver
tumors was statistically significant in the female mice at 90 p.p.m. if the
incidences of carcinomas and adenomas were combined. Because chloroform is
not a DNA reactive mutagen, a 13-week time-course and dose-response study
was conducted under conditions of the original bioassay to examine whether
regenerative cell proliferation was an underlying mechanism of
carcinogenesis. Mice were given bromodeoxyuridine via infusion during the
last 3.5 days prior to necropsy to label cells in S-phase. Chloroform
induced pathology and regenerative cell proliferation, measured as the
labeling index (LI, percentage of cells in S-phase), were assessed
microscopically and immunohistochemically. Male mice exposed to 30 and 90
p.p.m. exhibited a dose-dependent increase in regenerating tubules within
the renal cortex and up to a 31-fold increase in LI. No renal lesions or
increased LI were observed in females. Increased centrilobular to midzonal
hepatocyte degeneration and vacuolation and a 7-fold increase over controls
in the hepatocyte LI were observed in the female mice at 90 p.p.m. at 13
weeks. Males exhibited similar pathology, but the increase in LI was not
sustained. The observed correlations between cytolethality and regenerative
cell proliferation with tumor formation supports extensive evidence that
chloroform induces cancer via a non- genotoxic-cytotoxic mode of action. A
concentration of 5 p.p.m. is the no-observed-adverse-effect level for
nephrotoxicity, cell proliferation and cancer. An appropriate safety factor
applied to this value is a straightforward approach to cancer risk
assessment that is consistent with the mode of action of chloroform.
ARTICLES
Patterns of chloroform-induced regenerative cell proliferation in BDF1 mice correlate with organ specificity and dose-response of tumor formation
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709-2137, USA.
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