Promotion of Dichloroacetic Acid (DCA) Initiated Hepatocarcinogenesis by Phenobarbital
Harry W. Carter*, Julia H. Carter*, Anthony B. DeAngelo** *Wood Hudson Cancer
Research Laboratory, 931 Isabella St., Newport, KY 41071, and **NHEERL,
U. S. Environmental Protection Agency, Research Triangle Park, NC 27711
ABSTRACT
DCA is a complete hepatocarcinogen and tumor promoter in the male B6C3F1
mouse. The role of DCA as an initiator is uncertain since chloroacetic acids
are non-genotoxic in a variety of test systems. To investigate the role
of DCA as an initiator, 3 groups of male B6C3F1 mice were given drinking
water containing DCA (3.5 g/L) beginning at 28 days of age. Two groups received
distilled water. After 30 weeks, DCA was removed from the drinking water
of 2 groups of animals; one group was given phenobarbital (PB, 0.06%) while
the second group was given distilled water until sacrifice at 100 weeks.
The third group continued to receive DCA for 100 weeks and a fourth group
was given PB instead of distilled water beginning at 30 weeks. After sacrifice,
livers were weighed and blocks of liver as well as all visible lesions were
fixed in 10% phosphate-buffered formalin and processed routinely. Histologic
sections were cut at 5 um and stained with H & E. On average, 6 histological
sections per animal were evaluated for pathologic changes. Hepatic lesions
were classified as follows: altered foci (AF) were small lesions with altered
H&E staining characteristics; hyperplastic nodules (HN) had alterations
in liver architecture and staining characteristics; adenomas (Ad) had alterations
in liver architecture and staining characteristics and also showed displacement
of triads and compression of adjacent tissue; carcinomas (CA) were comprised
of cells with a high nuclear/cytoplasm ratio and with nuclear pleomorphism
and atypia, that showed evidence of invasion. DCA exposure for 100 weeks
promoted the development of putative pre-neoplastic, neoplastic and malignant
lesions. While both DCA exposure for 30 weeks and PB exposure for 70 weeks
promoted development of hepatic lesions, given together, the effects of
these compounds was synergistic. Based upon the H&E staining characteristics,
the data suggest that DCA initiates eosinophilic pre-neoplastic lesions
which are promoted to progress to neoplastic and malignant lesions by PB.
(This abstract does not reflect EPA policy.)
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