Interactions in the tumor-promoting activity of carbon tetrachloride, trichloroacetate, and dichloroacetate in the liver of male B6C3F1 mice.

Journal Article · Thu Jul 01 00:00:00 EDT 2004 · Toxicology, 199(2-3):169-183

DOI:https://doi.org/10.1016/j.tox.2004.02.018· OSTI ID:15010612

Bull, Richard J; Sasser, Lyle B; Lei, Xingye C

Interactions between carcinogens in mixtures found in the environment have been a concern for several decades. In the present study, male B6C3F1 mice were used to study the responses to mixtures of dichloroacetate (DCA), trichloroacetate (TCA), and tetrachloride (CT), each of which acts by a different mode of action. Mice were initiated by vinyl carbamate (VC), and then promoted by DCA, TCA, CT, or the pair-wised combinations of the three compounds. The effect of each treatment or treatment combination on tumor number/animal and tumor size was individually assessed in each animal. Dose-related increases in tumor size were observed with 20 & 50 mg/kg CT, but each produced equal number of tumors at 36 weeks. As the dose of CT was increased to > 100 mg/kg substantial increases in the number of tumors per animal were observed, but the mean tumor size decreased. When administered alone in the drinking water at 0.1, 0.5 and 2 g/L, DCA increased both tumor number and tumor size in a dose-related manner. TCA treatment produced dose-related increases in tumor number at 36 weeks of treatment. For TCA treatment at 2 g/L in drinking water a maximum tumor number was reached by 24 weeks and was maintained until 36 weeks of treatment. DCA treatment did produce a plateau in tumor number, but the numbers observed at the end of the experimental period where similar to TCA and CT. Treatment of mice receiving a high dose of TCA (2 g/L of drinking water) combined with varying doses of DCA (0.1, 0.5 and 2 g/L) produced increased numbers of tumors at 24 weeks and 36 weeks. At 36 weeks of treatment DCA produced a dose-related decrease in the size of tumors promoted by TCA. On the other hand, the low dose of TCA (0.1 g/L) decreased the number of tumors produced by a high dose of DCA, but higher doses of TCA produced the same number as observed with DCA alone. The inhibitory effect on number was not explained by differences in tumor size. DCA inhibited the growth rate of CT-induced tumors (CT dose = 50 mg/kg). TCA substantially increased the numbers of tumors observed early with CT-induced tumors, but coalescence of tumors by 36 weeks appeared to mask this difference. These data suggest that the interactions between tumor promoters are dependent upon their modes of action and the selective advantage they provide to initiated cells. These conditions may be complimentary and additive or competitive and inhibitory. No evidence of synergy was observed.

• Research Organization: Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 15010612
• Report Number(s): PNWD-SA-6534
• Journal Information: Toxicology, 199(2-3):169-183, Journal Name: Toxicology, 199(2-3):169-183
• Country of Publication: United States
• Language: English