Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice

Jorgenson, T.A.

doi:10.1016/0272-0590(85)90200-3

Cited by 191 publications

(50 citation statements)

References 7 publications

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“…CHC13 and BDCM induced renal adenomas and carcinomas when tested in chronic rodent bioassays (4,16,20,21). Although BDCM is mutagenic (16), CHC13 shows no mutagenic potential.…”

Section: Discussionmentioning

confidence: 99%

“…CHC13 is nephrotoxic in rats and mice, although the extent of toxicity varies among different strains and sexes of animals (6-8). CHC13 induces renal neoplasms in male rats; however, it exhibits only hepatocarcinogenicity in mice (4,20,21).…”

Section: Discussionmentioning

confidence: 99%

“…BDCM administered by intragastric gavage at a dose of 10 mg/kg for 10 days did not induce any histopathologic changes in the kidneys of male F344 rats (10). Both CHCl3 and BDCM were shown to be tumorigenic to male rat kidney (4,11,20,21). CHCl3 was also carcinogenic to male and female mouse liver (20,21), and BDCM was carcinogenic in female rat kidney, male and female rat colon/rectum, male mouse kidney, and female mouse liver (16 The last dose in each experiment was administered the day before sacrifice.…”

Section: Introductionmentioning

confidence: 89%

“…CHCl3 induces hepatic and renal toxicity in mice and renal toxicity in male rats (4)(5)(6)(7)(8)(9). BDCM induces renal toxicity in rats and hepatic toxicity in mice (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

Lipsky

Skinner

O’Connell

1993

Environ Health Perspect

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We have been investigating the actions of chloroform (CHC13) and bromodichloromethane (BDCM) in rat kidney after different routes of exposure. Male F344 rats were exposed by gavage with corn oil or water as the diluting vehicle. All experiments lasted 30 days with gavage exposures 5 days per week for 4 weeks (20 doses). All animals were injected IP with bromodeoxyuridine (BrdU) 3 times over a 6-day period at 50 mg/kg/injection. Kidney tissue was fixed and slides were stained with hematoxylin and eosin for routine viewing and by the PAP (peroxidaseantiperoxidase) technique using anti-BrdU to label cells in DNA synthesis. There were no significant changes in gross parameters evaluated between the control rats and the rats exposed to CHCl3 or BDCM. Rats exposed via corn oil gavage to CHC13 displayed a segment-specific epithelial cell necrosis (6/6 high dose, 2/6 low dose). The lesions were primarily localized to the second segment of the proximal tubule, although some spread to cells in the first segment was occasionally observed. No histologic lesions were observed in the kidneys of rats exposed to BDCM.Preliminary results indicate a significant increase in DNA synthesis in the CHCI3-treated rats and a slight increase in DNA synthesis in BDCM-treated rats with corn oil as the diluent. The increase in BrdU labeling was primarily in cells of the S2 segment of the proximal tubule and interstitial cells of CHC13-exposed animals and in cells of the S3 segment of BDCM-exposed animals. The rats exposed using water as the vehicle did not show significant pathology (except for one rat in the high-dose CHC13 group, which had mild necrosis of proximal tubule epithelium). There were no changes in DNA synthesis in the CHCL3-treated rat kidneys when water was used as the vehicle. There was a slight increase in total DNA synthesis in the BDCM-treated rat kidneys, and the increase was mainly in the third segment of the proximal tubule. These data indicate differences in histopathologic alterations and levels of DNA synthesis that appear to depend on the vehicle that the chemicals were dissolved in and/or the route of administration. CHC13-induced pathologic alterations were more severe in the animals exposed by corn oil gavage. BDCM, an established renal carcinogen in rats, failed to induce any histopathologic alterations under the different experimental conditions of this study.

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“…CHC13 and BDCM induced renal adenomas and carcinomas when tested in chronic rodent bioassays (4,16,20,21). Although BDCM is mutagenic (16), CHC13 shows no mutagenic potential.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

“…CHCl3 induces hepatic and renal toxicity in mice and renal toxicity in male rats (4)(5)(6)(7)(8)(9). BDCM induces renal toxicity in rats and hepatic toxicity in mice (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

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Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

Lipsky

Skinner

O’Connell

1993

Environ Health Perspect

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“…It has been reported that chloroform-induced hepatocellular adenomas or adenocarcinomas in B6C3F 1 mice and renal epithelial tumors in Osborne-Mendel rats in long-term carcinogenicity studies (15,23). In the liver treated with chloroform in this study, hepatocellular adenomas were observed in the males given 28 mg/kg and females given 240 mg/kg.…”

Section: Brdu Labeling Indexmentioning

confidence: 99%

Twenty-Six-Week Carcinogenicity Study of Chloroform in CB6F1 rasH2-Transgenic Mice

Sehata¹,

Maejima²,

Watanabe³

et al. 2002

Toxicol Pathol

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The carcinogenic potential of chloroform was evaluated in a short-term carcinogenicity testing system using CB6F 1 rasH2-Tg (rasH2-Tg) mice. Chloroform was administered to rasH2-Tg males at doses of 28, 90, or 140 mg/kg and rasH2-Tg females at 24, 90, or 240 mg/kg by oral gavage for 26 weeks. Wild-type (non-Tg) male and female mice received doses of 140 mg/kg and 240 mg/kg, respectivel y. N-methyl-N-nitrosourea was administered to rasH2-Tg mice by single intraperitoneal injection (75 mg/kg) as a positive control. In both the rasH2-Tg and non-Tg mice, there was no signi cant increase in the incidence of neoplastic lesions by chloroform treatment. The incidence of hepatocellular foci in the rasH2-and non-Tg females receiving 240 mg/kg was increased. Forestomach tumors and malignant tumors occurred in most of the rasH2-mice in the positive control group. Swelling or vacuolation of hepatocytes , a toxic change induced by chloroform, occurred in both the rasH2-Tg and non-Tg mice. It is concluded that chloroform, a putative human noncarcinogen , did not show evidence of carcinogenic potential in the present study using rasH2-Tg mice. This study suggests that the rasH2-Tg mouse model may not be appropriate for detecting nongenotoxi c carcinogens. However, the sensitivity of rasH2-Tg mice to nongenotoxi c carcinogen s should be assessed with consideration of the results from the other ILSI-HESI project studies.

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Long-term mutagenicity studies with chloroform and dimethylnitrosamine in femalelacI transgenic B6C3F1 mice

Butterworth

Templin

Constan

et al. 1998

Environ. Mol. Mutagen.

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The weight of evidence indicates that chloroform induces cancer in the female B6C3F1 mouse liver via a nongenotoxic‐cytotoxic mode of action. However, it is probable that DNA damage occurs secondary to events associated with cytolethality and regenerative cell proliferation. The purpose of the present study was to evaluate the potential mutagenic activity of chloroform in the B6C3F1 lacI transgenic mouse liver mutagenesis assay including mutagenic events that might occur secondary to cytolethality. The positive control, dimethylnitrosamine (DMN) is a DNA‐reactive mutagen and carcinogen. DMN‐induced mutations were anticipated to require only a brief exposure and without further treatment were predicted to remain unchanged over time at those frequencies. Chloroform‐induced mutations secondary to toxicity were anticipated to require longer exposure periods and to occur only under conditions that produced sustained cytolethality and regenerative cell proliferation. Female B6C3F1 lacI transgenic mice were treated with daily doses of 2, 4, or 8 mg/kg of DMN by gavage for 4 days and then held until analysis 10, 30, 90, and 180 days postexposure. Livers from DMN‐treated mice exhibited a dose‐related 2‐ to 5‐fold increase over control mutant frequencies and remained at those levels for 10 through 180 days postexposure. Thus, following the initial induction by DMN no selective mutation amplification or loss was seen for this extended period of time. Female B6C3F1 lacI mice were exposed daily for 6 hr/day 7 days/week to 0, 10, 30, or 90 ppm chloroform by inhalation, representing nonhepatotoxic, borderline, or overtly hepatotoxic chloroform exposures. Timepoints for determination of lacI mutant frequency were 10, 30, 90, and 180 days of exposure. No increase in lacI mutant frequency in the liver was observed at any dose or timepoint with chloroform, indicating a lack of DNA reactivity. DNA alterations secondaryto toxicity either did not occur or were of a typenot detectable by lacI mutant frequency analysis,such as large deletions. Environ. Mol. Mutagen. 31:248–256, 1998 © 1998 Wiley‐Liss, Inc.

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Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice

Cited by 191 publications

References 7 publications

Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

Twenty-Six-Week Carcinogenicity Study of Chloroform in CB6F1 rasH2-Transgenic Mice

Long-term mutagenicity studies with chloroform and dimethylnitrosamine in femalelacI transgenic B6C3F1 mice

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