Macromolecular adducts of ethylene oxide: a literature review and a time-course study on the formation of 7-(2-hydroxyethyl) guanine following exposures of rats by inhalation

Walker, Vernon E.; Fennell, Timothy R.; Boucheron, Joyce A.; Fedtke, N.; Ciroussel, Françoise; Swenberg, James A.

doi:10.1016/0027-5107(90)90159-2

Cited by 61 publications

(27 citation statements)

References 54 publications

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“…Although similar concentrations of7-HEG have been found in target and nontarget tissues of rats and mice after single ET3O exposures (19)(20)(21) and multiple exposures that saturated DNA repair (22,24), thetissue-dependent variation in the half-life for this adduct indicates that there will be species, tissue, and even cell differences in the extentof 7-HEG accumulation during multiple exposures to lower concentrations ofETO. However, other critical factors appear to be involved in the species and tissue specificity for tumor induction by this chemical.…”

Section: Implications For Human Biomonitoringmentioning

confidence: 91%

“…The methodological details of these investigations have been published elsewhere (22)(23)(24). Thus, only a briefsummary ofthe methods is given here.…”

Section: Methodsmentioning

confidence: 99%

“…Whole tissues from individual rats or sets of four mice were homogenized, and DNA was isolated using an automated phenolic extraction procedure (22,24). DNA samples from rats exposed to 300 ppm ETO were analyzed for 7-(2-hydroxyethyl)-guanine (7-HEG) using neutral thermal hydrolysis and acid precipitation, cation-exchange HPLC separation, and fluorescence detection (22).…”

Section: Assay For 7-(2-hydroxyethyl)guaninementioning

confidence: 99%

“…DNA samples from rats exposed to 300 ppm ETO were analyzed for 7-(2-hydroxyethyl)-guanine (7-HEG) using neutral thermal hydrolysis and acid precipitation, cation-exchange HPLC separation, and fluorescence detection (22). The detection limit for the assay was 20 pmole 7-HEG/mg DNA.…”

Section: Assay For 7-(2-hydroxyethyl)guaninementioning

confidence: 99%

“…However, many DNA adducts can be lost by processes such as repair and chemical depurination (14), whereas hemoglobin adducts of ETO appear to be stable. Therefore, it is essential to examine the relationships between hemoglobin and DNA adduct formation in rats and mice over a range of exposures and times ofexposure to ETO (22)(23)(24). The molecular dosimetry studies reviewed here demonstrate that the ratios between DNA and hemoglobin adduct concentrations change over time during repeated exposures to ETO and that the nature ofthe relationship between DNA and hemoglobin alkylation is both tissue and species dependent due to differences in the life span of the erythrocyte and differences in DNA repair.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Dosimetry of DNA and Hemoglobin Adducts in Mice and Rats Exposed to Ethylene Oxide

Walker¹,

Fennell²,

Upton³

et al. 1993

Environmental Health Perspectives

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Experiments involving ethylene oxide (ETO) have been used to support the concept of using adducts in hemoglobin as a surrogate for DNA adducts in target tissues. The relationship between repeated exposures to ETO and the formation of N-(2-hydroxyethyl)valine (HEtVal) in hemoglobin and 7-(2-hydroxyethyl)guanine (7-HEG) in DNA was investigated in male rats and mice exposed by inhalation toO, 3,10,33, or 100 ppm ETO for 6 hr/day for 4 weeks, or exposed to 100 ppm (mice) or 300 ppm (rats) for 1, 3, 5,10, or 20 days (5 days/week). HEtVal was detennined by Ednan degradation, and 7-HEG was quantitated by HPLC separation and fluorescence detection. HEtVal formation was linear between 3 and 33 ppm ET1O and increased in slope above 33 ppm. The dose-response curves for 7-HEG in rat tissues were linear between 10 and 100 ppm ETO and increased in slope above 100 ppm. In contrast, only exposures to 100 ppm ETO resulted in significant accumulation of 7-HEG in mice. Hemoglobin adducts were lost at a greater rate than predicted by normal erythrocyte life span. The loss of 7-HEG from DNA was both species and tissue dependent, with the adduct half-lives ranging from 2.9 to 5.8 days in rat tissues (brain, kidney, liver, lung, spleen, testis) and 1.0 to 2.3 days in all mouse tissues except kidney (tlm = 6.9 days). The concentrations of HEtVal were similar in concurrently exposed rats and mice, whereas DNA from rats had at least 2-fold greater concentrations of 7-HEG than DNA from mice. Due to differences in formation, persistence, repair, and chemical depurination, the relationships between HEtVal and 7-HEG concentrations varied with length of exposure, interval since exposure, species, and tissue. Thus, it appears unlikely that HEtVal adducts in hemoglobin will provide accurate predictions ofDNA adducts in specific tissues of humans under conditions where actual exposure scenarios are unknown.

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Section: Implications For Human Biomonitoringmentioning

confidence: 91%

“…The methodological details of these investigations have been published elsewhere (22)(23)(24). Thus, only a briefsummary ofthe methods is given here.…”

Section: Methodsmentioning

confidence: 99%

Section: Assay For 7-(2-hydroxyethyl)guaninementioning

confidence: 99%

Section: Assay For 7-(2-hydroxyethyl)guaninementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Dosimetry of DNA and Hemoglobin Adducts in Mice and Rats Exposed to Ethylene Oxide

Walker¹,

Fennell²,

Upton³

et al. 1993

Environmental Health Perspectives

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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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Epoxy Compounds—Olefin Oxides (Ethylene Oxide, Propylene Oxide, and Miscellaneous Oxides)

Klapacz

Doskey

2023

Patty's Toxicology

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This chapter discusses the chemistry, uses, health information, and industrial hygiene handling procedures of epoxides, that is, substances containing strained, three‐membered rings with two adjacent carbons and one oxygen atom. This functionality underlies epoxides' high reactivity, physicochemical properties, and toxicity. The majority of the content is dedicated to ethylene oxide and propylene oxide, but other epoxides are also of industrial interest and are described here; their databases have evolved over the last couple of decades and this new understanding is highlighted here. These are 1,2‐butylene oxide, 2,3‐epoxybutane, butadiene diepoxide, vinylcyclohexene monoxide, vinylcyclohexene dioxide, and styrene oxide.

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Macromolecular adducts of ethylene oxide: a literature review and a time-course study on the formation of 7-(2-hydroxyethyl) guanine following exposures of rats by inhalation

Cited by 61 publications

References 54 publications

Molecular Dosimetry of DNA and Hemoglobin Adducts in Mice and Rats Exposed to Ethylene Oxide

Molecular Dosimetry of DNA and Hemoglobin Adducts in Mice and Rats Exposed to Ethylene Oxide

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

Epoxy Compounds—Olefin Oxides (Ethylene Oxide, Propylene Oxide, and Miscellaneous Oxides)

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