bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic effects of methylmercury in human chromosomes: I. A cytogenetic study of people exposed through eating contaminated fish
Authors: Monsalve M. V. , Chiappe C.
Published: February 2007

An analysis of chromosomal aberrations (structural and numerical) and sister chromatid exchange (SCE) was carried out on 16 people exposed to methylmercury through eating fish caught in Cartagena Bay (Colombia), an area of known methylmercury contamination. Fourteen people whose diet consisted mainly of fish caught in another, noncontaminated area of the Atlantic acted as controls. The results showed a significant difference between the experimental and control groups in methylmercury (MM) concentrations measured in hair and peripheral blood. Subsequently, significant differences between levels of organic mercury in blood and hair were found when all the individuals studied were classified in two groups according to their blood mercury levels. When achromatic lesions were included, the frequency of structural chromosome aberrations differed significantly between the exposed and control groups. Furthermore, a significant correlation (p < 0.05) was found between structural chromosome aberrations and groups (exposed and control). When achromatic lesions were excluded from the analyses, these differences were not found. There was a significant correlation between SCE and age. This is the first report of a study on the frequency of SCE in a population exposed to methylmercury.
Increased chromosome damage in pediatric heart catheterization patients after diagnostic fluoroscopy and cineangiography
Authors: Shafer David A. , Raviele Anthony A. , Dunbar Virginia G. , Click Lorie A.
Published: February 2007

Chromosome damage (CD) and sister chromatid exchange (SCE) levels were studied in lymphocytes from 30 pediatric heart catheterization patients receiving radiation during diagnostic fluoroscopy and cineangiography procedures. Forty‐eight‐hour CD and 72‐hr SCE cultures were prepared from sequential samples taken from each patient: samples 1–3 via the catheter the same day (1) before exposure, (2) after fluoroscopy, and (3) after cineangiography; and sample 4 by venipuncture the next morning. Significant increases in CD (dicentrics, rings, and fragments), but not SCE, were observed. From a mean base level of 0.4% cells with CD, the CD levels increased 2‐3‐fold in samples 3 and 4 (p = .001). Rings only occurred in samples 3 and 4. While increased CD levels also correlated with increasing age, body surface area, and weight, partial correlations controlling for these factors clearly indicate that the CD effects are principally attributable to the radiological procedures (p = .001). Increased CD levels correlated with both the roentgen dose of cineangiography exposure (p = .002) and the volume of contrast medium (p = .000); however, partial correlations, controlling for either factor, indicate that the contrast medium was the principal factor (p = .006).
Presence and measurement of sample histidine in the ames test: Quantification and possible elimination of a source of false‐positive mutagenicity test results
Authors: Busch David B. , Bryan George T.
Published: February 2007

Both histidine and dipeptides that can be converted to histidine can potentially interfere with the Ames test by increasing the number of spontaneous revertants. Such interference might be especially evident when urine and other biological samples are studied in this assay. We have developed a turbidimetric bioassay that utilizes a nonrevertible Salmonella typhimurium histidine auxotroph, NS1135. The assay is linear with histidine over at least a 300‐fold range (0.015‐5 μg/ml of L‐histidine·HCl·H2O). Data indicate that several histidine‐containing dipeptides can be utilized as efficiently as free histidine. Our data suggest that this assay may be used to measure biological samples accurately for their histidine content and thereby permit an adjustment for sample histidine during the setup of Ames assays, thus eliminating increased reversion caused by sample histidine.
Cytogenetic and chemical detection of human exposure to polyhalogenated aromatic hydrocarbons
Authors: Lundgren K. , Collman G. W. , Wang‐Wuu S. , Tiernan T. , Taylor M. , Thompson C. L. , Lucier G. W.
Published: February 2007

Peripheral lymphocytes from Taiwanese women (n = 35) exposed to polychlorinated aromatic hydrocarbons and from matched controls (n = 24) were assessed for the levels of sister chromatid exchanges (SCEs) after a 72‐hour incubation of whole blood in the presence or absence of alpha‐naphthoflavone (ANF) and for chromosome aberrations after 48 hours of incubation. Serum levels of polychlorinated biphenyl (PCB) congeners were measured for all individuals, and serum levels of several polychlorinated dibenzofurans (PCDFs) were measured for 12 exposed individuals by gas chromatography‐mass spectometry. Blood concentrations of total PCBs in the exposed population averaged approximately 15 ppb, whereas mean PCDF values were 14 ppt. Major PCB congeners detected were 2,2′ 4,4′, 5,5′‐hexa CB and 2,2′3,4,4′,5‐hexa CB. PCDFs detected were primarily 1,2,3,4,7,8,‐hexachlorodibenzofuran (10.8 ppt) and 2,3,4,7,8‐pentachlorodibenzofuran (2.7 ppt). Average SCE frequencies were 7.61 for controls and 7.30 for exposed individuals when assays were conducted in the absence of ANF, whereas respective values were 8.85 and 10.75 in the presence of ANF. Differences in the level of ANF‐induced SCEs between the two populations were highly significant (P < .001). Moreover, the ANF‐induced SCEs were highly correlated with the serum concentrations of total PCBs and of several PCB congeners (P < .001). Increases in ANF‐induced SCEs appeared to be linear up to a PCB concentration of approximately 30 ppb. Chromosome aberration frequencies were similar in control and exposed populations. These studies demonstrate that in vivo exposure to PCBs and PCDFs result in an enhanced sensitivity of lymphocytes to the SCE‐causing actions of ANF.
Use of the microscreen phage‐induction assay to assess the genotoxicity of 14 hazardous industrial wastes
Authors: Houk Virginia Stewart , Demarini David M.
Published: February 2007

The Microscreen phage‐induction assay, which quantitatively measures the induction of prophage λ in Escherichia coli WP2s(λ), was used to test 14 crude (unfractionated) hazardous industrial waste samples for genotoxic activity in the presence and absence of metabolic activation. Eleven of the 14 wastes induced prophage, and induction was observed at concentrations as low as 0.4 pg per ml. Comparisons between the ability of these waste samples to induce prophage and their mutagenicity in the Salmonella reverse mutation assay indicate that the phage‐induction assay detected genotoxic activity in all but one of the wastes that were mutagenic in Salmonella. Moreover, the Microscreen assay detected as genotoxic five additional wastes that were not detected in the Salmonella assay. The applicability of the Microscreen phage‐induction assay for screening hazardous wastes for genotoxic activity is discussed, as are some of the problems associated with screening highly toxic wastes containing toxic volatile compounds.
A method for studying the mutagenicity of some gaseous compounds in salmonella typhimurium
Authors: Victorin Katarina , Ståhlberg Margareta
Published: February 2007

A dynamic flow‐through exposure system was designed for mutagenicity studies of gaseous compounds in Salmonella. Salmonella typhimurium strain TA100 was the primary tester strain. The dose ranges were 0.5–20% of vinyl chloride, ethene, propene, and 1,3‐butadiene, 1–200 ppm of ethylene oxide, 0.5–20 ppm of nitrogen dioxide, and 0.1–3.5 ppm of ozone. The gas flow rate was 250, 500, or 1,000 ml/min, and the exposure time was 6 or 7 hours. Of the tested gases, vinyl chloride, ethylene oxide, and nitrogen dioxide were mutagenic. Ethene, propene, and 1,3‐butadiene were not mutagenic in this system. Ozone is bacteriotoxic, and no mutagenic effect could be demonstrated in the nontoxic dose range. The exposure system was considered suitable for studies on gaseous chemicals.
Responses of the L5178Y tk+/tk− mouse lymphoma cell forward mutation assay ii: 18 coded chemicals
Authors: McGregor Douglas B. , Brown Alison , Cattanach Pamela , Edwards Ian , McBride Douglas , Caspary William J.
Published: February 2007

Eighteen chemicals were tested for their mutagenic potential in the L5178Y tk+/− mouse lymphoma cell forward mutation assay by the use of procedures based upon those described by Clive and Spector [Mutat Res 44:269–278, 1975] and Clive et al [Mutat Res 59:61–108, 1979]. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), 3 μg/ml. The chemicals were tested at least twice. Significant responses were obtained with benzofuran, benzyl chloride, bromodi‐chloromethane, butylated hydroxytoluene, chlorendic acid, o‐chlorobenzalmalo‐nitrile, 1,2,3,4‐diepoxybutane, dimethyl formamide, dimethyl hydrogen phosphite, furfural, glutaraldehyde, hydroquinone, 8‐hydroxyquinoline, and resorcinol. Apart from bromodichloromethane, butylated hydroxytoluene and dimethyl hydrogen phosphite, rat liver S9 mix was not a requirement for the activity of any of these compounds. Chemicals not identified as mutagens were water, tert‐butyl alcohol, pyridine, and witch hazel.
Occurrence in vivo of sister chromatid exchanges at the same locus in successive ceil divisions caused by nonrepairable lesions induced by gamma rays
Authors: Morales‐Ramírez Pedro , Vallarino‐Kelly Teresita , Rodríguez‐Reyes Regina
Published: February 2007

The capacity of lesions induced by gamma radiation to produce sister chromatid exchanges (SCE) in successive divisions in mouse bone marrow cells in vivo was evaluated using a protocol for the three‐way differentiation of sister chromatids.

Evidence was obtained that exposure to gamma radiation induces DNA lesions that result in the formation of SCE at the same locus in two successive cell divisions. The relevance of this observation with respect to DNA repair and mutagenesis is discussed.
No evidence found for induction of dominant lethal mutations and heritable translocations in male mice by calcium cyclamate
Authors: Cain Katherine T. , Cornett Carolyn V. , Cacheiro Nestor L. A. , Hughes Lori A. , Owens James G. , Generoso Walderico M.
Published: February 2007

Calcium cyclamate, an artificial sweetener, was studied for its effectiveness in inducing transmissible chromosomal aberrations in germ cells of male mice. Both the dominant‐lethal and the heritable translocation tests were carried out following daily treatment (on weekdays) of males by oral intubation with the maximum tolerated dose for 6 weeks. Calcium cyclamate is negative in both tests; therefore, there is no evidence of induced chromosome breakage and exchange.
Adaptive response of escherichia coli to alkylation damage
Authors: Volkert Michael R.
Published: February 2007

Treatment of cells with low levels of alkylating agents for extended periods of time causes them to become resistant to the lethal and mutagenic effects of subsequent high‐level challenge treatments with alkylating agents. This increased resistance has been called the adaptive response to alkylation damage and results from the induction of an alkylation‐specific DNA repair response. The adaptive response is most efficiently induced by methylating agents and is most effective against the lethal and mutagenic effects of methylation damage to DNA. Four genes have been identified as components of this response, ada, alkA, alkB and aidB. The functions of two of these genes are known. AlkA protein functions as a glycosylase that repairs N3‐meA, N3‐meG, O2‐meT, and O2‐meC residues in DNA, and Ada protein functions as an alkyltransferase that removes alkyl groups from O6‐meG, O4‐meT residues as well as methylphosphotriesters. After it interacts with methylated DNA, Ada protein functions as a positive regulatory element that controls the expression of the adaptive response by stimulating the expression of the ada‐alkB operon, and the alkA and aidB genes.
Effect of treatment medium on induction of aneuploidy by nocodazole in saccharomyces cerevisiae
Authors: Taylor‐Mayer Rhoda E. , Mayer Vernon W. , Goin Carol J.
Published: February 2007

While studying ways to improve responsiveness of Saccharomyces cerevisiae strain D61.M to agents that induce aneuploidy, we noted that nocodazole, which strongly induces aneuploidy when yeast cells are treated in yeast extract‐peptone‐dextrose (YEPD) medium, had no effect when a synthetic complete (SC) medium was used. Further study revealed that the presence of peptone was necessary for induction. Other aneuploidy‐inducing agents, including ethyl acetate, acetone, and methyl benzimi‐dazoie‐2‐yl‐carbamate (MBC), were equally active in either medium. Benomyl, which degrades to MBC, was less active in SC than in YEPD medium.
Recontacting subjects in mutagen‐exposure‐monitoring studies: II. Results of a questionnaire study of mutagenesis researchers, with review of the pertinent literature
Authors: Busch David B. , Easterling Douglas , Leventhal Howard , Bryan George T.
Published: February 2007

A questionnaire on the attitudes of mutagenesis researchers regarding the health significance of and the use of data from tests of human mutagen exposure or genetic damage was completed by 71 of 312 (23%) individuals who had been participants in meetings or organizations concerned with mutagenesis research. On a point scale of 0 to 10, with 0 indicating strong disagreement, 5 indicating uncertainty, and 10 indicating strong agreement, the average respondent felt (8.31 ± 2.27) that data indicating a probable health hazard should be shared automatically with the subjects, but was also moderately concerned about psychological distress of subjects learning of study results indicating abnormally high mutagen exposure (6.14 ± 2.57) or genetic damage (6.94 ± 2.48). The average respondent felt that follow‐up of subjects could improve the quality of mutagen‐exposure‐monitoring studies (8.33 ± 1.49), disagreed that subjects whose laboratory data suggested unusually severe exposure or damage should not be asked about possible sources of exposure (1.15 ± 1.32), and disagreed that it was ethical to follow up but not discuss results with subjects having laboratory evidence of abnormal mutagen exposure (3.78 ± 3.43) or genetic damage (3.06 ± 3.17) to see how many developed cancer relative to a control group.

Fifteen specific tests for measuring mutagen exposure or genetic damage were rated on a scale of 0 to 10, with 0 being “totally experimental” and 10 being “absolutely diagnostic of degree of exposure or genetic damage.” Values ranged from 6.13 ± 2.67 for karyotyping leukocytes to 3.43 ± 2.43 for quantifying frequency of rare red cells with mutant protein.
Selenium‐mediated reduction in the mutagenicity of cigarette smoke
Authors: Chortyk O. T. , Baker J. L. , Chamberlain W. J.
Published: February 2007

Cigarette smoke contains carcinogens and mutagens and affects the health of smokers. Recently, increased research has proven the potentially protective activity of selenium (Se) against heavy metal toxicity, cancer, and other health disorders. Accordingly, we have proposed the fortification of tobacco with Se to develop safer cigarettes. As a start in evaluating any biological effects of added Se, we have determined the mutagenicity of inhaled, mainstream (MS) cigarette smoke condensate (CSC), with and without Se, in the preincubation assay of the Ames test. Initially, it was shown that Se, as sodium selenite, was not mutagenic at high concentrations (up to 80 μg/plate) with strains TA1538 and TA1978. Subsequently, the effects of different levels of Se, added to MS CSC, were examined with TA98, TA100, and TA1538. On the average, addition of 10 μg Se produced mutagenicity reductions of about 50%. Higher levels of added Se yielded further reductions. Cigarette sidestream (SS) smoke, collected between puffs, was also tested. Again, Se added to SS‐CSC gave similar reductions, confirming its antimutagenic effect for both mainstream and sidestream smoke.
Inhibition of aminoimidazoquinoxaline‐type and aminoimidazol‐4‐one type mutagen formation in liquid‐reflux models by the amino acids L‐proline and/or L‐tryptophan
Authors: Jones R. Conrad , Weisburger John H.
Published: February 2007

Laboratory models were used to study the inhibition of mutagen formation by Maillard‐type reactions during cooking of meats or fish. The amino acid L‐proline (L‐pro) was an effective, dose‐dependent inhibitor of the development of mutagenicity (Ames test) in a liquid‐reflux model of glucose + glycine + creatinine known to produce IQ‐type mutagens (MeIQx and 7,8‐DiMeIQx). L‐pro also inhibited formation of mutagens in a reflux model of threonine + creatinine, developed in our laboratory, which yields a novel class of IQ‐“like” aminoimidazol‐4‐one mutagens. A mixture of L‐pro and L‐tryptophan (L‐trp) at lower concentrations of each yielded increased inhibition, compared with the findings when each inhibitor was tested by itself.
In vivo evaluation of the genotoxic potential of curacron in somatic cells of mice
Authors: Nahas Soheir M. El , De Hondt H. A. , Ramadan Hassan A. I.
Published: February 2007

Cytogenetic effects produced in somatic cells by Curacron, a phosphoric acid ester insecticide, were assessed in mice by three criteria: chromosome aberrations, sister chromatid exchange (SCE), and micronucleus induction. Curacron significantly increased the frequency of all three in an apparent dose‐dependent manner. Curacron also inhibited the mitotic activity. The increased number of micronuclei is comparable to the increase in chromosome aberrations; the latter were mainly breaks. The frequency of SCE was considerably less than the frequencies of micronuclei and chromosome aberrations.
Identification of aneuploidy‐inducing agents using cytokinesis‐blocked human lymphocytes and an antikinetochore antibody
Authors: Eastmond David A. , Tucker James D.
Published: February 2007

The identification of agents causing aneuploidy in humans, a condition associated with carcinogenesis and birth defects, is currently limited due to the highly skilled and time‐consuming nature of cytogenetic analyses. We report the development of a new simple and rapid assay to identify aneuploidy‐inducing agents (aneuploidogens). The assay involves the chemical‐ or radiation‐induced formation of micronuclei in cytokinesis‐blocked human lymphocytes and the use of an antikinetochore antibody to determine whether the micronuclei contain centromeres—a condition indicating a high potential for aneuploidy. All agents tested produced dose‐related increases in the frequency of micronucleated cells. The micronucleated cells induced by the known aneuploidogens—colchicine, vincristine sulfate, and diethylstilbestrol—contained kinetochore‐positive micronuclei 92, 87, and 76% of the time, respectively. In contrast, the micronucleated cells induced by the potent clastogens—ionizing radiation and sodium arsenite—contained kinetochore‐positive micronuclei only 3 and 19% of the time, respectively. These results indicate that this relatively simple assay can discriminate between aneuploidogens and clastogens and may allow a more rapid identification of environmental and therapeutic agents with aneuploidy‐inducing potential.
Role of oxygen free radicals in the induction of sister chromatid exchanges by cigarette smoke
Authors: Lee Chin K. , Brown Buddy G. , Rice William Y. , Doolittle David J.
Published: February 2007

Cigarette smoke has been reported to contain free radicals and free radical generators in both the gas and particulate phases. Studies in our laboratory have shown that both cigarette smoke condensate (CSC) and smoke bubbled through phosphate buffered saline solution (smoke‐PBS) increased sister chromatid exchanges (SCE) in Chinese hamster ovary cells in a dose‐dependent manner. Since oxygen free radicals have been shown to cause SCEs and other chromosomal damage, we investigated the role of these radicals in the induction of SCEs by CSC and smoke‐PBS. Addition of the antioxidant enzymes catalase and superoxide dismutase or the oxygen‐radical scavenger ascorbic acid failed to reduce the SCE frequency in the presence of either CSC or smoke‐PBS. Additional studies indicated that the quantity of hydrogen peroxide produced in CSC or smoke‐PBS is too small to account for the observed SCE induction. It appears, therefore, that SCE induction by CSC or smoke‐PBS does not involve the participation of oxygen free radicals.
Testing of sunset yellow and orange II for genotoxicity in different laboratory animal species
Authors: Wever J. , Münzner R. , Renner H. W.
Published: February 2007

The azo dyes Sunset Yellow and Orange II were gavaged to rodent species to check bile, urine, and fecal extracts for possible mutagenic activity in the Ames test or in bone marrow cells for clastogenicity using cytogenetic test systems. After oral application the dyes showed a negative response in bile, excrements, and bone marrow. When an exogenous metabolic activation was performed, increased revertant numbers using Salmonella strain TA100 were obtained only in fecal extracts of Sunset Yellow‐treated animals. It is concluded that no genotoxic harm is to be expected from the ingestion of Sunset Yellow or Orange II.
Application of the carcinogenicity prediction and battery selection method to recent national toxicology program short‐term test data
Authors: Ennever Fanny K. , Rosenkranz Herbert S.
Published: February 2007

Identification of potentially cancer‐causing chemicals is a priority in our society. Short‐term assays for mutation or chromosomal damage, which are rapid, inexpensive, and reproducible, have found widespread use; however, concern has arisen recently because such assays do not coincide completely with the standard rodent bioassay for carcinogenesis. Lack of perfect correlation is not surprising, given the complex, multicausal nature of the carcinogenic process. We have developed methodologies for interpreting short‐term tests to predict carcinogenicity, which allow consideration of the influence of the proportion of carcinogens expected in the tested chemicals, the complexities of the rodent carcinogenesis bioassay, and factors affecting the worth of information. These methodologies are applied to a set of data on genotoxicity and carcinogenicity of 73 chemicals (NTP‐73) recently published by the National Toxicology Program; they illustrate that with this approach, batteries of short‐term tests can indeed be predictive of rodent carcinogenicity or noncarcinogenicity and that batteries are more predictive than the Salmonella assay alone. The analysis is validated using an additional group of chemicals with results in the same short‐term tests as NTP‐73.
Results of tests for micronuclei and chromosomal aberrations in mouse bone marrow cells with the human carcinogens 4‐aminobiphenyl, treosulphan, and melphalan
Authors: Shelby Michael D. , Gulati D. K. , Tice Raymond R. , Wojciechowski J. P.
Published: February 2007

Three human carcinogens, 4‐aminobiphenyl, treosulphan, and melphalan, were tested for the induction of micronuclei or chromosomal aberrations in the bone marrow cells of male B6C3F1 mice. These studies were conducted to provide further information on the in vivo genetic toxicity of compounds known to cause cancer in humans. All three compounds gave positive results in the mouse bone marrow micronucleus test, and melphalan, the only compound tested for aberration induction, was positive in this assay. These results extend the evidence that nearly all known human carcinogens are detected in relatively simple and widely employed short‐term in vivo tests.
Evaluation of a rat tracheal epithelial cell culture assay system to identify respiratory carcinogens
Authors: Steele Vernon E. , Arnold Julia T. , Van Arnold John , Mass Marc J.
Published: February 2007

To evaluate a short‐term epithelial cell assay system to detect respiratory carcinogens, primary cultures of rat tracheal epithelial cells were exposed to a series of 17 compounds and scored for morphologically transformed cell colonies 28 days later. The test compounds included known carcinogens and noncarcinogens in volatile or liquids form. Tracheal epithelial cells were isolated from F344 rats, plated onto collagen‐coated dishes, and exposed to the test compounds on day 1 for 24 hours. At day 30 the cultures were fixed, stained, and scored for colonies having a density greater than 1,300 cells/mm2. With standardized protocols, such colonies are very infrequent in media and sol‐vent control cultures. Concentration levels for each chemical were chosen over a range from nontoxic to toxic levels. Highly positive compounds in this assay included benzo(a)pyrene, benzo(l)acean‐thrylene, 3‐methylcholanthrene, and formaldehyde. Compounds which were negative in this assay included pyrene, benzo(e)pyrene, and 4‐nitroquinoline‐N‐oxide. Examining the concordance of in vitro results with whole animal car‐cinogenesis studies revealed an accuracy of 88% with one false‐positive and one false‐negative compound. The results of these studies indicate that the rat tracheal epithelial cell assay may be useful in identifying potential respiratory carcinogens in our environment.
Morphological and neoplastic transformation of C3H/10T1/2 Cl 8 mouse embryo cells by insoluble carcinogenic nickel compounds
Authors: Miura Takeshi , Patierno Steven R. , Sakuramoto Toshio , Landolph Joseph R.
Published: February 2007

We studied induction of cytotoxicity and morphological transformation in C3H/10T1/2 Cl 8 (10T1/2) mouse embryo fibroblasts by soluble and insoluble carcinogenic nickel compounds. Soluble nickel sulfate and nickel chloride caused dose‐dependent cytotoxicity in the concentration range from 0.5 μM to 100 μM after 48 hr treatments, but neither compound induced morphological transformation even at concentrations causing up to 94% cytotoxicity. Insoluble nickel subsulfide, nickel monosulfide, and nickel oxide caused dose‐dependent cytotoxicity and a low, dose‐dependent frequency of morphological transformation in the concentration ranges from 0.5 to 40 μM, 5 to 50 μM, and 50 to 400 μM, respectively, after 48 hr exposure of cells to these compounds. Foci were predominantly of type II morphology; type III foci were rare. The insoluble nickel compounds studied caused no induction of base substitution mutations to ouabain resistance in 10T1/2 cells over concentration ranges that induced morphological transformation. Nickel subsulfide and nickel monosulfide were taken into cells by phagocytosis, since particles were visible in intracytoplasmic vacuoles. Numerous nickel oxide particles were found associated with cells, but true phagocytic uptake was difficult to detect since no vacuoles were observed. We twice cloned type II and type III foci induced by insoluble nickel compounds, established independent cell lines, and characterized their phenotypes. Four of seven of these cell lines had three‐ to fourfold increased saturation densities compared to 10T1/2 cells, formed type II and type III foci in reconstruction assays, and grew in soft agarose. One cell line induced by nickel oxide formed tumors in nude mice. These data indicate that insoluble carcinogenic nickel compounds induced type II foci in 10T1/2 cells, some of which were tumorigenic, and that the 10T1/2 cell system is suitable for studying mechanisms of nickel compound‐induced morphological transformation in mammalian cells.
Intralitter variation in murine fetal sister chromatid exchange responses to the transplacental carcinogen ethyl carbamate
Authors: Neeper‐Bradley T. L. , Conner Mary K.
Published: February 2007

Gravid Swiss Webster dams were injected via tail vein with a single (1.1, 2.2, or 3.3 mmol/kg) dose of ethyl carbamate (urethane) on days 13–17 of pregnancy. Relative sister chromatid exchange (SCE) responses in maternal bone marrow vs. individual fetal liver cells were assessed. In addition, in order to evaluate the significance of intralitter variability in fetal SCE responses, SCE in combined (“pooled”) fetal liver tissue preparations were measured and compared with average individual responses. In contrast to maternal responses, average fetal SCE responses to ethyl carbamate varied with gestational age. In addition, significant variation was observed among individual littermate responses at all dose levels. Nonetheless, fetal SCE responses determined from “pooled” tissue preparations provided a valid estimate of average litter responses. Regardless of the method of SCE evaluation in fetal tissue or gestational age, maternal bone marrow exhibited greater sensitivity than fetal liver to SCE induction by ethyl carbamate.
Lack of genotoxicity with acrylate polymers in five short‐term mutagenicity assays
Authors: Thompson E. D. , Aardema M. J. , Leboeuf R. A.
Published: February 2007

Two linear polymers of acrylic acid (average molecular weight = 2,000 and 4,500) and one linear copolymer of acrylic and maleic acids (average molecular weight = 12,000) were tested for mutagenicity with the Salmonella mammalian microsome assay, the L5178Y mouse lymphoma assay at the TK locus, an unscheduled DMA synthesis assay in primary cultures of rat hepatocytes, and either an in vitro cytogenetic assay with CHO cells or the bone marrow micronucleus assay in mice. The results of all the assays were uniformly negative for the three polymers.
5‐azacytidine induces sex chromosome loss and interchange in immature germ cells of Drosophila mei‐9 males
Authors: Osgood Christopher J. , Seward Sonya M.
Published: February 2007

5‐Azacytidine (5‐AZ) profoundly affects gene expression and chromosome structure in higher eukaryotes, presumably by disrupting normal patterns of DNA methylation. The DNA of several eukaryotic species, including Drosophila melanogaster, is virtually devoid of 5‐methylcytosine, and the spectrum of mutagenic effects induced by 5‐AZ in such organisms is less well characterized. To investigate the mutagenicity of 5‐AZ in Drosophila germ cells, DNA repair‐deficient (mei‐9) Drosophila 72‐hr‐old larvae were fed on medium containing 5‐AZ, and recovered adult males were tested for induced losses and interchanges involving the paternal sex chromosomes. Moderately toxic doses of 5‐AZ were found to induce significant rates of apparent complete losses (CL) of the paternal sex chromosomes, partial losses (PL) of one of the arms of‐the submetacentric Y‐chromosome, and interchanges (X‐Y) between the X‐chromosome and the short arm of the Y‐chromosome. The data suggest that, of the stages tested, germ cells in the early primary spermatocyte stage of development are maximally sensitive to 5‐AZ‐induced sex chromosome loss and rearrangement. X‐Y interchanges comprised a substantial fraction of the 5‐AZ‐induced breakage events involving the Y‐chromosome; in contrast with classical clastogens such as X‐rays, the pattern of interchange products suggests that 5‐AZ acts by enhancing the frequency of pairing‐dependent interchanges between the paternal sex chromosomes.
Mutagenesis and mathematics: The allure of numbers
Authors: Haynes Robert H.
Published: February 2007

This paper sets out the “formal,” “empirical,” and “mechanistic” equations that my colleagues and I have developed for the description and analysis of dose‐response data on the lethal and genetic effects of mutagens in microorganisms. These three types of equations are interrelated inasmuch as they are all based ultimately on the use of the Poisson distribution in the formal definition of lethal and mutational hit functions. Explicit mathematical expressions for these functions can be written down in either empirical or mechanistic terms. The empirical equations are obtained simply by writing the hit functions as finite polynomials with adjustable coefficients. The mechanistic equations are based on the assumptions of the “DNA damage‐repair hypothesis.” The mathematical formulation of this hypothesis entails an important change in the definition of the word “hit” from that used in the classical hit/target theory of radiation biology. The theoretical and practical applications of these various equations in mutation research are summarized briefly and their merits are assessed in light of recent advances in our understanding of the biochemical basis of mutagenesis.
Assays of three carcinogen/non‐carcinogen chemical pairs for in vivo induction of chromosome aberrations, sister chromatid exchanges and micronuclei
Authors: McFee Alfred F. , Jauhar Prem P. , Lowe Karen W. , Macgregor James T. , Wehr Carol M.
Published: February 2007

Three pairs of structurally similar carcinogenic/ non‐carcinogenic chemicals were tested for in vivo genotoxic activity in B6C3F1 mice. The carcinogenic/non‐carcinogenic pairs, respectively, were o‐toluidine hydrochloride/o‐anthranilic acid, 4‐chloro‐o‐phenylenediamine/4‐nitro‐o‐phenylenediamine, and 3‐(chloromethyl)pyridine hydrochloride/2‐(chloromethyl)pyridine hydrochloride. Bone marrow cells from mice given intraperitoneal injections of up to the maximum tolerated dose were evaluated for chromosomal aberration, sister chromatid exchange, and micronucleus induction, o‐anthranilic acid and o‐toluidine hydrochloride did not increase the frequency of chromosomal aberrations or micronuclei. o‐Toluidine hydrochloride increased the frequency of sister chromatid exchanges in two successive trials, while o‐anthranilic acid had a positive effect on sister chromatid exchanges in two of three trials. Both 2‐(chloromethyl) and 3‐(chloromethyl)pyridine hydrochloride were negative for all three endpoints. Assays for chromosomal aberrations and micronuclei each distinguished between 4‐chloro‐o‐phenylenedi‐amine and its non‐carcinogenic companion, 4‐nitro‐o‐phenylenediamine. In the aberration test, 4‐chloro‐o‐phenylenediamine produced a few cells with very large numbers of aberrations rather than an even distribution of damage among cells.
Effects of human placental S9 and induced rat liver S9 on the mutagenicity of drinking waters processed from humus‐rich surface waters
Authors: Vartiainen T. , Lampelo S.
Published: February 2007

The mutagenicity of chlorinated drinking waters processed from humus‐rich surface waters has been shown to be very high. The effect of placental S9 on the mutagenicity of drinking waters has not been studied previously. The purpose of this study was to compare the effects of human placental and rat liver microsomal fractions on the mutagenicity of drinking waters processed from humus‐rich surface waters. The samples of 34 drinking and two raw waters from 26 localities in Finland were tested for mutagenicity in Ames Salmonella typhimurium tester strain TA100 with and without metabolic activations. Between the drinking water samples, clear differences were recorded in the presence of placental and rat liver S9, suggesting different mutagens in the drinking waters. Rat liver S9 decreased the mutagenicities of drinking water concentrates, but placental S9 increased, decreased, or had no effect. It is not known if placental mutagenicity enhancing system might cause any health hazard to a developing fetus.
A concerted approach to the study of the aneuploidogenic properties of two chelating agents (EDTA and NTA) in the germ and somatic cell lines of Drosophila and the mouse
Authors: Zordan M. , Russo A. , Costa R. , Bianco N. , Beltrame C. , Levis A. G.
Published: February 2007

The genetic effects of nitrilotriacetic acid (NTA) and ethylenedinitrilotetraacetic acid (EDTA), two widely used chelating agents, were investigated by using a somatic mutation and recombination test (SMART) after treatment of larvae and the FIX test for aneuploidy after treatment of adult female Drosophila melanogaster. Chloral hydrate (CH) and 5‐fluorodeoxyuridine (FdUr) were used as positive controls. Effectively absorbed amounts of the test compounds assayed in Drosophila were estimated at the single fly level by a method using 3H‐leucine. NTA and EDTA were also assayed in tests for aneuploidy based on chromosome counting in mouse germ and somatic cells. We previously showed that NTA was able to induce aneuploidy (chromosomal gain) in the germ cells of both Drosophila and the mouse when tested at the exposure levels of 5 × 10−2 M and 275 mg per kg body weight, respectively Costa et al., Environ Mol Mutagen 12:397‐407, 1988). In the present experiments, EDTA was assayed at 2.5 × 10−2 M and 7.5 × 10−3 M in the FIX test adopting a three‐stage brooding scheme. Significant increases (with respect to controls) in chromosomal loss were observed in the second brood and in the combined three‐brood total for both exposure levels of EDTA. In the SMART test, treatments with EDTA in the same exposure range produced negative results over all end‐points, whereas significant increases in the frequency of small single spots (possibly due to aneuploidy) were produced by NTA 5 × 10−2 M. In the cytogenetic assays for aneuploidy both in the germ and somatic cells of the mouse, negative results were also obtained following the i.p. administration of 93 and 186 mg EDTA per kg b.w. The previously observed induction of germ cell aneuploidy by NTA (275 mg per kg b.w.) was confirmed in the present experiments on a different strain of mice. NTA (138‐275 mg per kg b.w.) did not induce aneuploidy in somatic cells of the mouse Russo et al., Mutat Res 226: 111‐114, 1989, however. These results are compared and discussed with reference to the characteristics of the different test systems used and to the different chelating properties of NTA and EDTA.
Observation of frequencies of lymphocytes with micronuclei in human peripheral blood cultures from workers in a sulphuric acid factory
Authors: Meng Ziqiang , Zhang Lianzhen
Published: February 2007

Frequencies of lymphocytes with micronuclei (MNF) in human peripheral blood cultures from workers in a sulphuric acid factory (the SO2 concentrations in the workplace ranged from 0.34 mg/m3 to 11.97 mg/m3 air) were investigated. It was shown that among 40 workers, the MNF of 28 workers was more than 0.1 %, and the MNF of 7 workers was greater than the upper limit of the normal range (0.2%). The mean MNF of the worker and the control group was 0.168% and 0.071%, respectively. The difference between them was statistically significant (P < 0.001). It implies that SO2 is a clastogenic and genotoxic agent. No positive correlation between the MNF and length of service in workers has been observed. In the control population, the MNF of smokers was significantly higher than that of non‐smokers (P < 0.001).
Cytogenetic analyses of mice exposed to dichloromethane
Authors: Allen James , Kligerman Andrew , Campbell James , Westbrook‐Collins Barbara , Erexson Gregory , Kari Frank , Zeiger Errol
Published: February 2007

Chromosome damage was studied in female B6C3F1 mice exposed to dichloromethane (DCM) by subcutaneous or inhalation treatments. No increase in the frequency of either sister chromatid exchanges (SCEs) or chromosome aberrations (CAs) in bone marrow cells was observed after a single subcutaneous injection of 2,500 or 5,000 mg/kg DCM. Inhalation exposure to DCM for 10 days at concentrations of 4,000 or 8,000 ppm resulted in significant increases in frequencies of SCEs in lung cells and peripheral blood lymphocytes, CAs in lung and bone marrow cells, and micronuclei (MN) in peripheral blood erythrocytes. Lung cell CAs and blood erythrocyte MN reached frequencies of approximately two times control levels. Following a 3‐month inhalation exposure to 2,000 ppm DCM, mice showed small but significant increases in lung cell SCEs and peripheral blood erythrocyte MN. These findings suggest that genotoxicity may play a role in the carcinogenicity of DCM in the lungs of B6C3F1 female mice.
Identification of carcinogenic tryptophan pyrolysis products in human bile by high‐performance liquid chromatography
Authors: Manabe Shigeo , Wada Osamu
Published: February 2007

The carcinogenic tryptophan pyrolysis products 3‐amino‐1,4‐dimethyl‐5H‐pyrido[4,3‐b]indole (Trp‐P‐1) and 3‐amino‐1‐methyl‐5H‐pyrido[4,3‐b]indole (Trp‐P‐2) have been demonstrated to be present in human bile through use of a highperformance liquid chromatography (HPLC) method. The method consists of the acid‐induced release of the carcinogens from bile components and their extraction with methylene chloride and subsequent quantification by HPLC. In seven subjects who had received cath‐eterization of the bile duct and external biliaryd‐rainage, the average amounts of Trp‐P‐1 and Trp‐P‐2 excreted daily in the bile were 408 fmol/ day (n = 7) and 864 fmol/day (n = 7), respectively. In one subject, furthermore, significant daily changes of these carcinogen levels in bile and plasma were confirmed during 2 weeks of observation. These results indicate that one of the excretory pathways of these carcinogens is via bile. Our data also may suggest that Trp‐P‐1 and Trp‐P‐2 are derived from everyday foods.
Colony hybridisation in escherichia coli: A rapid procedure for determining the distribution of specific classes of mutations among a number of preselected sites
Authors: Halliday Jennifer A. , Zielenska Maria , Awadallah Safwat S. , Glickman Barry W. , Skopek T. R.
Published: February 2007

Colony probe oligonucleotide hybridisation was used for the unambiguous identification of DNA alterations and the determination of distributions and frequencies of forward mutation at the molecular level. To demonstrate the reliability and versatility of this technique, distributions of spontaneous and ethyl methanesulfonate (EMS)‐induced mutations have been reproduced using a battery of oligonucleotide probes complementary to specific sites and classes of mutation. These studies are indicative of the diagnostic potential of oligonucleotide colony hybridisation to the characterisation of mutation; oligonucleotide hybridisation used in conjunction with a well studied mutational target provides a rapid and reliable alternative to DNA sequencing for the characterisation of all classes of mutations.
Effect on SCE in Human chromosomes in vitro of low‐level pulsed magnetic field
Authors: García‐Sagredo J. M. , Parada L. A. , Monteagudo J. L.
Published: February 2007

We analyzed sister chromatid exchanges (SCE) frequencies as an indicator of DNA damage induced in human lymphocytes in vitro by a low‐level pulsed electromagnetic field.

We studied the effect of low‐level pulsed electromagnetic fields on human chromosomes with the cytogenetic assay of sister chromatid exchange (SCE) analysis. After the human peripheral lymphocyte cultures were exposed in vitro to the electromagnetic field at different intensities, no significant differences were observed when comparing with the control group as to the number of SCE.
Stability of the mutagenicity in stored cigarette smokers' urine and extract
Authors: Williams R. W. , Watts R. , Inmon J. , Pasley T. , Claxton L. , Einstadt E.
Published: February 2007

Urine from cigarette smokers was analyzed for the effect upon mutagenic activity when stored for as long as 175 days. Frozen aliquots of urine were thawed out at various time points in the study and prepared for bioassay. These urine extracts were not bioassayed immediately, but rather refrozen until all of the unprocessed urine samples had eventually been prepared for bioassay. All extracts were obtained using cyanopropyl solid phase extraction techniques. At the end of 175 days, all extracts were bioassayed using a microsuspension assay of Salmonella typhimurium TA98. Urine from smokers was found to be mutagenic (14.4—30.9 revertants/ml equivalent) while a control set of urine from non‐smokers was not. Data from the storage study when analyzed by analysis of variance techniques indicated no statistical loss of mutagens occurred over the 175‐day period although near significance was observed (P = 0.054). This near significance was the result of decreasing mutant response as storage time increased for two of the higher doses tested.
The feasibility of using chinese hamsters as an animal model for aneuploidy
Authors: Sheu Chingju W. , Lee Jung K. , Arras Carol A. , Jones Robert L. , Lavappa Kantharajapura S. , Morgan W. F.
Published: February 2007

The utility of Chinese hamsters as a test species for aneuploidy analysis was studied using four chemicals & mdashvincristine, methyl 2‐benzimidazole carbamate (MBC), nocodazole, and cyclophosphamide. Ten or more male Chinese hamsters were used per dose and bone marrow was removed at intervals of 6—96 hr. Slides were coded and 50—100 metaphases were analyzed per animal. A metaphase with more than 22 chromosomes was classified as a hyperploid cell, and the data were evaluated by using a one‐tailed Fisher's exact test. In experiments using vincristine, MBC, and nocodazole, the frequencies of hyperploid cells were 0.43, 1.14, and 0.91%, respectively, for the control groups. In the experiment using cyclophosphamide, the control value frequency was 3.75%. The treated groups showed no significant increase in hyperploid frequencies when compared to concurrent controls at each of the treated times, except the value at 24 hr for the group that had been treated with vincristine at 0.75 mg/kg. However, this increase was not significant when compared to the overall value for pooled controls, with or without the cyclophosphamide control. Therefore, no significant effects due to chemical treatment were obtained in the present study. The results illustrate the extent of animal‐to‐animal as well as experiment‐to‐experiment variability in hyperploid frequencies and the importance of incorporating concurrent controls in assays for aneuploidy.
Quantitative structure‐activity relationships of heterocyclic amine mutagens formed during the cooking of food
Authors: Hatch F. T. , Knize M. G. , Felton J. S. , Morgan R. W.
Published: February 2007

The major protein‐rich foods, particularly muscle meats, contain part‐per‐billion quantities of potent mutagens formed by frying or broiling to a well‐done state. Related mutagens are formed by pyrolysis of amino acids or proteins and in heated model systems. The thermic mutagens so far identified are heterocyclic aromatic amines of aminoimidazo‐azaarene (AIA) and amino‐carboline classes. The chemicals require activation by enzymes to form metabolites reactive with nucleic acids. These thermic mutagens, and numerous synthetic congeners, exhibit an enormous range of potency as frameshift mutagens in the Ames/Salmonella assay. However, structural variations are nominal within the two classes. Structural parameters that appeared relevant to determining potency were selected for 38 AlAs and 23 amino‐carbolines. For the AlA class these were: the number of fused rings, the number of heteroatoms in Rings 2 and 3, methyl substitution on imidazo ring nitrogen atoms, and methyl substitution on ring carbon atoms. For the amino‐carboline class the structural parameters were: the position of the pyridine‐type nitrogen atom in Ring 1, the substitution position of the exocyclic amino group on Ring 1, and methyl substitution on ring carbon atoms. These structural parameters may influence mutagenic potency in the following ways. 1) Electronic or steric effects may determine the reactivity and stability of the ultimate mutagenic metabolite. Optimal balance of reactivity and lifetime of this transient intermediate may be required for access to and reaction with nuclear DNA to cause mutations. 2) Substitution on the rings may block detoxication reactions. The structural parameters identified should prove useful in predicting the mutagenicity of untested compounds of these types.