The effect of subsequent administration of chloroform or phenobarbital on the incidence of ethylnitrosourea (ENU) initiated liver and lung tumors was investigated. Fifteen day old Swiss mice were administered ENU, and at weaning they started to receive either 1800 p.p.m. chloroform or 500 p.p.m. sodium phenobarbital in their drinking water. The mice continued to receive either chloroform or phenobarbital until 51 weeks of age. They were sacrificed at 52 weeks of age. ENU at 5 and 20 mg/kg, caused a dose-dependent increase in liver and lung tumors. The male mice were more sensitive to the induction of liver tumors, while no sex preference was observed for the induction of lung tumors. In male mice chloroform inhibited, while in female and male mice phenobarbital promoted spontaneous and ENU-induced liver tumors. Subsequent treatment with either chloroform or phenobarbital did not affect the incidence of ENU-induced lung tumors. In conclusion, when administered in the drinking water, chloroform inhibited while phenobarbital promoted hepatocarcinogenesis in mice.
JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org. . The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives. Haloacetonitriles (HAN) are drinking water contaminants produced during chlorine disinfection. This paper evaluates metabolism, genotoxicity, and tumor-initiating activity of these chemicals. The alkylating potential of the HAN to react with the electrophile-trapping agent, 4-(p-nitrobenzyl)pyridine, followed the order dibromoacetonitrile (DBAN) > bromochloroacetonitrile (BCAN) > chloroacetonitrile (CAN) > dich? loroacetonitrile (DCAN) > trichloroacetonitrile (TCAN). When administered orally to rats, the HAN were metabolized to cyanide and excreted in the urine as thiocyanate. The extent of thiocyanate excretion was CAN > BCAN > DCAN > DBAN ? TCAN. Haloacetonitriles inhibited in vitro microsomal dimethyl? nitrosamine demethylase (DMN-DM) activity. The most potent inhibitors were DBAN and BCAN, with Kt = 3-4 x 10"5 M; the next potent were DCAN and TCAN, with Kt = 2 x 10"4 M; and the least potent inhibitor was CAN, with K{ = 9 x 10~2 M. When administered orally, TCAN, but not DBAN, inhibited hepatic DMN-DM activity.The HAN produced DNA strand breaks in cultured human lymphoblastic (CCRF-CEM) cells. TCAN was the most potent DNA strand breaker, and BCAN > DBAN > DCAN > CAN, which was only marginally active. DCAN reacted with polyadenylic acid and DNA to form adducts in a cell-free system; however, the oral administration of DBAN or DCAN to rats did not result in detectable adduct formation in liver DNA. None of the HAN initiated 7-glutamyltranspeptidase (GGT) foci when assayed for tumor-initiating activity in rat liver foci bioassay. In summary, the HAN were demonstrated to possess alkylating activity and genotoxicity in vitro and appeared after oral administration to possess biological activity as indicated by the inhibition of DMN-DM by TCAN but appeared to lack genotoxic and tumor-initiating activity in rat liver. It is proposed that if the HAN found in drinking water pose a carcinogenic hazard it would be limited to the gastrointestinal tract.
Haloacetonitriles (HAN) are drinking water contaminants produced during chlorine disinfection. This paper evaluates metabolism, genotoxicity, and tumor-initiating activity of these chemicals. The alkylating potential of the HAN to react with the electrophile-trapping agent, 4-(p-nitrobenzyl)pyridine, followed the order dibromoacetonitrile (DBAN) greater than bromochloroacetonitrile (BCAN) greater than chloroacetonitrile (CAN) greater than dichloroacetonitrile (DCAN) greater than trichloroacetonitrile (TCAN). When administered orally to rats, the HAN were metabolized to cyanide and excreted in the urine as thiocyanate. The extent of thiocyanate excretion was CAN greater than BCAN greater than DCAN greater than DBAN much greater than TCAN. Haloacetonitriles inhibited in vitro microsomal dimethylnitrosamine demethylase (DMN-DM) activity. The most potent inhibitors were DBAN and BCAN, with Ki = 3-4 X 10(-5) M; the next potent were DCAN and TCAN, with Ki = 2 X 10(-4) M; and the least potent inhibitor was CAN, with Ki = 9 X 10(-2) M. When administered orally, TCAN, but not DBAN, inhibited hepatic DMN-DM activity. The HAN produced DNA strand breaks in cultured human lymphoblastic (CCRF-CEM) cells. TCAN was the most potent DNA strand breaker, and BCAN greater than DBAN greater than DCAN greater than CAN, which was only marginally active. DCAN reacted with polyadenylic acid and DNA to form adducts in a cell-free system; however, the oral administration of DBAN or DCAN to rats did not result in detectable adduct formation in liver DNA. None of the HAN initiated gamma-glutamyltranspeptidase (GGT) foci when assayed for tumor-initiating activity in rat liver foci bioassay.(ABSTRACT TRUNCATED AT 250 WORDS)
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