Chronic Toxicity of Dichloroacetic Acid (DCA)
in the Male B6C3F1 Mouse
Harry W. Carter*, Julia H. Carter*, Anthony B. DeAngelo** *Wood Hudson Cancer
Research Laboratory, 931 Isabella St., Newport, KY 41071 and **Health Effects
Research Laboratory, U.S. Environmental Protection Agency, Mail Drop 68,
Research Triangle Park, NC 27711
Dichlororoacetic acid (DCA) is carcinogenic to the male B6C3F1 mouse (DeAngelo
et al., Fund. Appl. Toxicol. 16:337-347, 1991). The purpose of this study
was to determine: 1) the early changes occurring in the liver of mice exposed
to DCA and 2) the persistence of early lesions in a "stop" study.
Male B6C3F1 mice were given DCA in the drinking water (0 g/L, 0.5 g/L, 1.0
g/L, 2.0 g/L or 3.5 g/L) beginning at 28 days of age. Some groups of animals
were sacrificed after 26, 52, 78, and 100 weeks of treatment. After 10,
20, 30, 40, and 50 weeks, other groups of animals were taken off 3.5 g/L
DCA and given water until sacrificed at 100 weeks. At necropsy, all lesions
and two blocks of liver per lobe were fixed in 10% neutral formalin, embedded
in paraffin, sectioned at 5-6 um, stained with H & E and 1,411 sections
were subjected to histopathological analysis. Lesions were classified as
follows: altered foci were small lesions with changes in staining characteristics;
hyperplastic nodules had alterations in liver architecture and staining
characteristics; adenomas had alterations in liver architecture and staining
characteristics and also showed displacement of triads and compression of
adjacent tissue; carcinomas were comprised of cells with a high nuclear/cytoplasm
ratio and with nuclear pleomorphism and atypia, that showed evidence of
invasion. Incidence of hepatocellular carcinomas was increased after 100
weeks of exposure to DCA at concentrations >0.5 g/L DCA. Hepatocellular
neoplasms were found after only 26 weeks of exposure to 3.5 g/L DCA. Numerous
neoplasms arose in animals exposed to 3.5 g/L DCA for 10, 20, 30, 40, or
50 weeks and then placed on water until 100 weeks. Early changes in the
livers of animals exposed to DCA included accumulation of glycogen (which
was lost in lesions and after more than 52 weeks of treatment) and progressive
changes in nuclear size and atypia. Nuclear changes were zonal, being located
near the central veins. Histopathological analysis suggests that following
chronic exposure to DCA, carcinomas can arise "de novo" in liver
as well as within hyperplastic nodules and adenomas.
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