A 90-Day Chloroform Inhalation Study in F-344 Rats: Profile of Toxicity and Relevance to Cancer Studies

Templin, Michael V.; Larson, Jeffrey; Butterworth, Byron E.; Jamison, Keith C.; Leininger, Joel R.; Mèry, Stephane; Morgan, Kevin T.; Wong, Brian A.; Wolf, Douglas C.

doi:10.1006/faat.1996.0113

Cited by 54 publications

(7 citation statements)

References 30 publications

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“…Our results with chloroform corroborate the findings of previous studies in which the exposure of target organs to toxic substances such as cigarette smoke and formaldehyde caused an influx of macrophages and polymorphonuclear cells by inducing oxidative stress. 18,38,39 The total cell counts in the BALF fluid of male mice corroborated results published by Templin et al, 9 Golden et al, 10 and Wolf and Butterworth. 40 The presence of chloroform in the lung parenchyma in mice in both the FEG and the MEG induced an inflammatory response.…”

Section: Discussionsupporting

confidence: 87%

“…The inhalation of chloroform induces inflammation in various organs from the respiratory tree to the liver and kidneys. 9 Acute lung inflammation derives mainly from macrophages and neutrophils, which release inflammatory mediators and reactive oxygen species (ROS) in response to irritants, as well as from a variety of elastolytic enzymes, including neutrophil elastase, metalloproteinases 2, 8, 9, 12, cathepsin G, K, L, and S, and proteinase 3, which contribute to the destruction of the lung parenchyma. 30…”

Section: Discussionmentioning

confidence: 99%

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Influence of Sexual Dimorphism on Pulmonary Inflammatory Response in Adult Mice Exposed to Chloroform

et al. 2015

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Chloroform is an organic solvent used as an intermediate in the synthesis of various fluorocarbons. Despite its widespread use in industry and agriculture, exposure to chloroform can cause illnesses such as cancer, especially in the liver and kidneys. The aim of the study was to analyze the effects of chloroform on redox imbalance and pulmonary inflammatory response in adult C57BL/6 mice. Forty animals were divided into 4 groups (N = 10): female (FCG) and male (MCG) controls, and females (FEG) and males (MEG) exposed to chloroform (7.0 ppm) 3 times/d for 20 minutes for 5 days. Total and differential cell counts, oxidative damage analysis, and protein carbonyl and antioxidant enzyme catalase (CAT) activity measurements were performed. Morphometric analyses included alveolar area (Aa) and volume density of alveolar septa (Vv) measurements. Compared to FCG and MCG, inflammatory cell influx, oxidative damage to lipids and proteins, and CAT activity were higher in FEG and MEG, respectively. Oxidative damage and enzyme CAT activity were higher in FEG than in FCG. The Aa was higher in FEG and MEG than in FCG and MCG, respectively. The Vv was lower in FEG and MEG than in FCG and MCG, respectively. This study highlights the risks of occupational chloroform exposure at low concentrations and the intensity of oxidative damage related to gender. The results validate a model of acute exposure that provides cellular and biochemical data through short-term exposure to chloroform.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Influence of Sexual Dimorphism on Pulmonary Inflammatory Response in Adult Mice Exposed to Chloroform

et al. 2015

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“…Cytotoxicity of chloroform to the liver and the kidney requires continuous exposure. When exposure stops, there is recovery from the tissue damage sustained ( Templin et al, 1996b ).…”

Section: Case Study: Chloroformmentioning

confidence: 99%

“…Proliferation, as measured by the bromodeoxyuridine (BrdU) labelling index, is dependent on both the duration and magnitude of exposure to chloroform. For example, in an inhalation study in F344 rats, it was necessary to expose the animals for more than 4 days to a dose of at least 30 ppm before any increase in proliferation could be detected in the kidney ( Templin et al, 1996b ). At 4 days, doses of up to 300 ppm (highest tested) had no effect on proliferation and similarly, with a dose of 10 ppm or less even after 13 weeks of exposure, there was no change in proliferation.…”

Section: Case Study: Chloroformmentioning

confidence: 99%

“…At 4 days, doses of up to 300 ppm (highest tested) had no effect on proliferation and similarly, with a dose of 10 ppm or less even after 13 weeks of exposure, there was no change in proliferation. The increase in proliferation was reversible, so that 6 weeks after exposure to 300 ppm for 13 weeks, the proliferation rate had returned to baseline values ( Templin et al, 1996b ). In the liver, no change in proliferation was observed at doses less than 300 ppm.…”

Section: Case Study: Chloroformmentioning

confidence: 99%

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Application of Key Events Analysis to Chemical Carcinogens and Noncarcinogens

Boobis

Daston

Preston

et al. 2009

Critical Reviews in Food Science and Nutrition

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The existence of thresholds for toxicants is a matter of debate in chemical risk assessment and regulation. Current risk assessment methods are based on the assumption that, in the absence of sufficient data, carcinogenesis does not have a threshold, while noncarcinogenic endpoints are assumed to be thresholded. Advances in our fundamental understanding of the events that underlie toxicity are providing opportunities to address these assumptions about thresholds. A key events dose-response analytic framework was used to evaluate three aspects of toxicity. The first section illustrates how a fundamental understanding of the mode of action for the hepatic toxicity and the hepatocarcinogenicity of chloroform in rodents can replace the assumption of low-dose linearity. The second section describes how advances in our understanding of the molecular aspects of carcinogenesis allow us to consider the critical steps in genotoxic carcinogenesis in a key events framework. The third section deals with the case of endocrine disrupters, where the most significant question regarding thresholds is the possible additivity to an endogenous background of hormonal activity. Each of the examples suggests that current assumptions about thresholds can be refined. Understanding inter-individual variability in the events involved in toxicological effects may enable a true population threshold(s) to be identified.

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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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A 90-Day Chloroform Inhalation Study in F-344 Rats: Profile of Toxicity and Relevance to Cancer Studies

Cited by 54 publications

References 30 publications

Influence of Sexual Dimorphism on Pulmonary Inflammatory Response in Adult Mice Exposed to Chloroform

Influence of Sexual Dimorphism on Pulmonary Inflammatory Response in Adult Mice Exposed to Chloroform

Application of Key Events Analysis to Chemical Carcinogens and Noncarcinogens

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

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