The Relationships between Alkylation of Haemoglobin and DNA in Fischer 344 Rats Exposed to [14C]Ethylene Oxide

Potter, David M.; Blair, D.; Davies, Ronnie; Watson, William P.; Wright, A. N.

doi:10.1007/978-3-642-74117-3_44

Cited by 40 publications

(14 citation statements)

References 6 publications

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“…However, the concentrations of the epoxide metabolites in organs were found to be one half of the concentration in blood (32). This has earlier also been shown for the chemically related compound ethylene oxide through the comparison of Hb-and DNA-adduct levels (35). This supports that the DD, estimated from the dose in blood, should be reduced by 50% to give an appropriate estimate of the dose in target tissues in the cancer tests with BD (13,36).…”

Section: Discussionsupporting

confidence: 67%

Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

2008

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In cancer tests with 1,3-butadiene (BD), the mouse is much more sensitive than the rat. This is considered to be related to the metabolism of BD to the epoxide metabolites, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane, and 1,2-epoxy-3,4-butanediol. This study evaluates whether the large difference in outcome in cancer tests with BD could be predicted quantitatively on the basis of the concentration over time in blood (AUC) of the epoxide metabolites, their mutagenic potency, and a multiplicative cancer risk model, which has earlier been used for ionizing radiation. Published data on hemoglobin adduct levels from inhalation experiments with BD were used for the estimation of the AUC of the epoxide metabolites in the cancer tests. The estimated AUC of the epoxides were then weighed together to a total genotoxic dose, by using the relative genotoxic potency of the respective epoxide inferred from in vitro hprt mutation assays using EB as standard. The tumor incidences predicted with the risk model on the basis of the total genotoxic dose correlated well with the earlier observed tumor incidences in the cancer tests. The total genotoxic dose that leads to a doubling of the tumor incidences was estimated to be the same in both species, 9 to 10 mmol/LÂh EB-equivalents. The study validates the applicability of the multiplicative cancer risk model to genotoxic chemicals. Furthermore, according to this evaluation, different epoxide metabolites are predominating cancer-initiating agents in the cancer tests with BD, the diepoxide in the mouse, and the monoepoxides in the rat.

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Section: Discussionsupporting

confidence: 67%

Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

2008

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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: 88%

“…However, previous studies investigating the formation ofboth hemoglobin and DNA adducts have used only single exposures of rats (19,20) and mice (21 ) to ETO. The data from these studies showed a constant ratio between DNA and hemoglobin alkylation over the range of doses of ETO investigated, supporting the suggestion that the determination ofthe hemoglobin dose in vvo is a valid indicator ofthe dose to DNA in target tissues (20). 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.…”

Section: Introductionmentioning

confidence: 99%

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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“…Hence, the dependence of the quantities of 7-(2-hydroxyethyl)guanine on external doses, in low dose ranges, can be based only on studies with radiolabelled, preferably a4C-labelled, ethylene oxide. Potter et al (1989) have performed such a study, but this has been published only in a preliminary form without providing full documentation. Hence, we decided to perform a similar study to compare its results with the data of Potter et al (1989).…”

Section: Sirmentioning

confidence: 98%

Dose-DNA adduct relationship for ethylene oxide

Bolt

Leutbecher

1993

Arch Toxicol

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The Relationships between Alkylation of Haemoglobin and DNA in Fischer 344 Rats Exposed to [14C]Ethylene Oxide

Cited by 40 publications

References 6 publications

Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

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

Dose-DNA adduct relationship for ethylene oxide

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