Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens

Doak, Shareen H.; Jenkins, Gareth; Johnson, George E.; Quick, Emma; Parry, Elizabeth M.; Parry, James M.

doi:10.1158/0008-5472.can-06-4061

Cited by 187 publications

(173 citation statements)

References 38 publications

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“…AUC measurement in blood, e.g., by Hb adduct measurements, bypass the problems of species-and high-to-low dose differences in metabolism of reactive compounds/intermediates. Deviations from linearity in dose-response due to DNA repair, etc., at very low exposure levels could exist for certain compounds (48). These are, however, not detected with the sensitivity in the standard test systems.…”

Section: Discussionmentioning

confidence: 94%

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: Discussionmentioning

confidence: 94%

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

2008

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“…Datasets were identified that included a suitable number of replicates (preferably three or more), with a suitable number of cells/targets (e.g., mostly >10,000 cells analyzed per dose for the analysis of MN) and with several doses resulting in genotoxic event frequencies similar to the NOGEL and solvent control. In fact, the in vitro micronucleus datasets from Doak et al [2007] had several additional replicates at four doses surrounding the NOGEL, in order to reach 10,000 or more cells at this critical region, while LeBaron et al [2008] evaluated >10,000 cells per replicate. Experimental datasets that fit these requirements were very limited and are presented in Tables I and II.…”

Section: No-observed-genotoxic-e¡ect-levelmentioning

confidence: 99%

Quantitative approaches for assessing dose–response relationships in genetic toxicology studies

Gollapudi

Johnson

Hernández

et al. 2012

Environ and Mol Mutagen

132

130

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Genetic toxicology studies are required for the safety assessment of chemicals. Data from these studies have historically been interpreted in a qualitative, dichotomous ''yes'' or ''no'' manner without analysis of doseresponse relationships. This article is based upon the work of an international multi-sector group that examined how quantitative dose-response relationships for in vitro and in vivo genetic toxicology data might be used to improve human risk assessment. The group examined three quantitative approaches for analyzing dose-response curves and deriving point-of-departure (POD) metrics (i.e., the no-observed-genotoxic-effectlevel (NOGEL), the threshold effect level (Td), and the benchmark dose (BMD)), using data for the induction of micronuclei and gene mutations by methyl methanesulfonate or ethyl methanesulfonate in vitro and in vivo. These results suggest that the POD descriptors obtained using the different approaches are within the same order of magnitude, with more variability observed for the in vivo assays. The different approaches were found to be complementary as each has advantages and limitations. The results further indicate that the lower confidence limit of a benchmark response rate of 10% (BMDL 10 ) could be considered a satisfactory POD when analyzing genotoxicity data using the BMD approach. The models described permit the identification of POD values that could be combined with mode of action analysis to determine whether exposure(s) below a particular level constitutes a significant human risk. Subsequent analyses will expand the number of substances and endpoints investigated, and continue to evaluate the utility of quantitative approaches for analysis of genetic toxicity dose-response data. Environ. Mol. Mutagen. 54:8-18, 2013. V V C 2012 Wiley Periodicals, Inc.

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“…A Duplex 1-modified electrode (containing all normal DNA bases and no uracil) was first exposed to MMS, a known carcinogenic chemical [56]. During the reaction, MMS would methylate some of the DNA bases.…”

Section: Detection Of Chemical-induced Ap Sitesmentioning

confidence: 99%

A chemical toxicity sensor based on the electrochemiluminescence quantification of apurinic/apyrimidinic sites in double-stranded DNA monolayer

Feng

Liang

Guo

et al. 2017

Sensors and Actuators B: Chemical

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a b s t r a c tA new chemical toxicity sensor was developed based on the electrochemiluminescence (ECL) quantification of apurinic/apyrimidinic sites (AP sites) in a DNA monolayer with a covalent aldehyde reactive probe (ARP). In the sensor, a uracil-containing DNA duplex was first immobilized on a gold electrode by self-assembly. The duplex was then reacted with uracil-DNA glycosylase (UDG) to convert uracils into AP sites. ARP was employed to tag the AP site with a biotin. After reacting with a ruthenium complex labeled streptavidin, ECL was measured for quantitative analysis. The DNA monolayer was characterized by cyclic voltammetry, electrochemical impedance spectroscopy and chronocoulometry, and its density was measured to be 2.89 × 10 −12 mol/cm 2 . Characterization of the reaction product between ARP and DNA AP sites in solution by nondenaturing polyacrylamide gel electrophoresis and mass spectrometry confirmed successful biotinylation. ECL intensity of the labeled DNA monolayer on the electrode was found to correlate with the number of AP sites, and the detection limit was estimated to be about 1 lesion in 512 DNA bases, which meant that 8.5 fmol AP bases on the electrode were detected. ECL response of the DNA monolayers containing either 8-oxodGuo or methylated bases was very low, indicating that ARP-based AP sites detection method was highly selective. The sensor successfully detected the AP sites in normal DNA induced by methylmethane sulfonate, a carcinogenic chemical. The novel combination of covalent probe and ECL measurement in a sensor configuration therefore provides unique advantages in selectivity and sensitivity, and can be potentially employed in the screening of chemicals for their genetic toxicity.

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Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens

Cited by 187 publications

References 38 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

Quantitative approaches for assessing dose–response relationships in genetic toxicology studies

A chemical toxicity sensor based on the electrochemiluminescence quantification of apurinic/apyrimidinic sites in double-stranded DNA monolayer

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