bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytogenetic assays in genotoxic studies: Somatic cell effects of benzene and germinal cell effects of dibromochloropropane
Authors: Au William W. , Cantelli ‐Forti Giorgio , Hrelia Patrizia , Legator Marvin S. 
Published: February 2006

AbstractWe have reviewed the results of our cytogenetic studies to evaluate the usefulness of these assays in genotoxic studies. In one study, we observed unusual dose‐response in lymphocyte chromosome aberration frequencies after exposure of mice to low doses of a chemical mixture (benzene, chloroprene, epichlorohydrin, and xylene). The frequency in the high dose group is lower than those of the medium and low dose groups. This reduction of genotoxicity is correlated with a significant induction of a detoxifying enzyme, glutathione‐S‐transferase. The data also suggest that extrapolation of effects from high to low doses for risk assessment may be erroneous. Using benzene as a model clastogen, we found that the clastogenic effect persists for a long time after termination of exposure in mice. This phenomenon is probably due to a gradual release of benzene from absorption of the chemical in body fat. In an inhalation study, we observed that chromosome aberrations are induced in mice after exposure to benzene at below the occupational exposure limit of 1 ppm. Since benzene is a ubiquitous environmental contaminant, it may interact with other environmental agents to modify its genotoxic effects. We found that a nongenotoxic drug, praziquantel, and a free radical scavenger, DMSO, can enhance or reduce respectively the clastogenic activities of benzene in mice. Both modifying agents acted by altering the metabolic pathways of benzene. In a study with rats, we showed that carcinogenic doses of benzene can induce chromosome aberrations in lymphocytes of rats long before the expression of cancer. With dibromochloropropane, we observed that this chemical can induce dominant lethality in rats. In addition, neurobehavioral abnormalities were observed in survived offspring. These studies demonstrate the importance of conducting integrated studies which can provide validated genotoxic information that cannot be provided by using single assays. Our studies also confirm the usefulness of cytogenetic assays for genotoxic studies and suggest that the chromosome aberration endpoint can be used as an early warning signal for development of cancer.
Long‐term assays for carcinogenicity
Authors: Porta Giuseppe Della , Dragani Tommaso A. 
Published: February 2006

AbstractDuring the past two decades, the rodent bioassay for detection of chemical carcinogens has reached a high standard of performance with both an increased number of animals and dose levels and a more detailed assessment of findings. However, the basic principles of testing and evaluation of results have remained essentially unchanged. Problems such as the length of the testing, use of maximum tolerated dose (MTD), selection of strains, variability of spontaneous tumors, discordant results between mouse and rat, and the classification of chemical carcinogens according to their mechanism of action have all remained unsolved. By contrast, the results of short‐term tests and of other biological analyses do not always show a direct correlation with those of the long‐term bioassays; this can be interpreted as an indication of different mechanisms of carcinogenicity. Currently available medium‐term tests may detect carcinogenic activity of chemicals at particular organs in a period of time (weeks to months) relatively shorter than that of the 2‐year carcinogenesis bioassay, and they may also provide additional information on mechanisms of carcinogenicity.
Prediction of toxicological interactions in a binary mixture by using pattern recognition techniques: Proposed approach with a developed model
Authors: Trieff Norman M. , Weller Susan C. , Ramanujam V. M. Sadagopa , Legator Marvin S. 
Published: February 2006

AbstractA model has been suggested to predict the nature of toxicological interaction in binary mixtures. The approach uses the NLM‐HSDB computerized data bases, the ATSDR toxicologic profiles, and other literature for categorizing the nature (synergistic, antagonistic or no interaction) and degree of interaction.
Multivariate modeling (pattern recognition techniques) is the statistical approach utilized to separate groups of compounds into those that interact synergistically or antagonistically with a given toxic compound. Preliminary results indicate (1) that there are sufficient data in the literature on interactions to permit such modeling and (2) that in the case of carbon tetrachloride those compounds that interact synergistically with it are more similar to each other than those that interact antagonistically with respect to a number of structural and toxicologic parameters. This suggested approach of utilizing pattern recognition tools will be quite useful for regulatory agencies in predicting toxicological interactions occurring in complex chemical mixtures in the environment.
Mutagenic and carcinogenic potency indices and their correlation
Authors: Parodi S. , Taningher M. , Romano P. , Grilli S. , Santi L. 
Published: February 2006

AbstractWe have analyzed a significant number of studies existing in the literature, in which the ability of different short‐term tests for predicting carcinogenicity in rodents was investigated. We have separated these studies into two groups. In the better known group of studies, qualitative predictivity was investigated (sensitivity and specificity). In the second group of studies (analyzed in greater detail), positive results were examined for the correlation between carcinogenic potency and potency of response in a given short‐term test. There is substantial agreement between qualitative and quantitative predictivity; both appear to be situated between a low and moderate level. We have analyzed the interesting possibility of using the quantitative approach not only for positive data but for combined positive and negative data as well. We have stressed that short‐term tests of genotoxicity should be asked to predict only initiation and irreversible alterations in the genome and not to predict a combination of these events, including promotion and modulation of differentiation. Even with regard to only initiation, genotoxicity data should be related to comparative metabolism, as well as to considerations of the significance of different end points and structure‐‐activity relationship data. In conclusion, the information coming from short‐term tests of genotoxicity is probably useful but should be used in conjunction with other types of information and only for predicting one particular class of events in the entire process of carcinogenesis.
Strategies and governmental regulations
Authors: Carere A. , Benigni R. 
Published: February 2006

AbstractAn overview of testing strategies for the detection of genotoxins under OECD Guidelines and the EEC Directive 79/831 (VI Amendment) is outlined. The viewpoint of the Italian National Advisory Committee on Toxicology is also presented. In this context, the main issues of Genetic Toxicology (e.g., role of tests, tests recommended, classification of mutagens) are discussed.
Development and application of biomarkers exploitable for human exposure monitoring
Authors: De Flora Silvio 
Published: February 2006

AbstractThe objectives, applications and limitations of laboratory methods for assessing human exposure to carcinogens are concisely discussed. The available technologies include cytological, cytogenetic and molecular analyses, somatic cell mutation, carcinogen‐DNA or carcinogen‐protein adducts, metabolic markers, and chemical or biological analyses of expired air, body fluids, and excreta.
32P‐postlabeling of 7‐methylguanine adducts in DNA
Authors: Hemminki Kari , Mustonen Riitta 
Published: February 2006

AbstractThe 32P‐postlabeling technique introduced by Randerath and co‐workers has been particularly successful with stable and nonpolar DNA adducts, but the assay has not been used to any large extent to detect 7‐alkylguanine derivatives. In the present communication, we have investigated the phosphorylation reaction by T4 polynucleotide kinase using 7‐methyl‐3′‐dGMP, ring‐opened 7‐methyl‐3′‐dGMP and enzyme‐digested methylated DNA as substrates.The methylated substrates were detected at femtomol (fmol) sensitivities. 7‐methyl‐3′‐dGMP was quantitatively phosphorylated at these low concentrations. The efficiency of phosphorylation of the ring‐opened product was less. It was shown that ring‐opened 7‐methyl‐3′‐dGMP was resistant to digestion with nuclease P1, making alkali‐treatment and enzyme digestion of DNA possible approaches to the determination of 7‐methyl‐guanine in DNA.
International symposium on strategies for the control of mutagenic and carcinogenic risk: Current status and perspectives, Friday, May 5, 1989, Bologna
Authors: Sobels F. H. 
Published: February 2006

AbstractThe 18 posters, grouped under mutagenicity testing, metabolic activation, mechanisms of mutation and chromosome damage, human monitoring and safety are critically discussed. It is pointed out that rather than applying a single test, a battery of well‐validated in vitro and in vivo tests is required. As a testing strategy, the one developed by Ashby (2) is briefly mentioned. The value of the Salmonella assay and of in vitro cytogenetics as short term tests for detecting carcinogens, and of the bone marrow micronucleus test as one for assessing germ cell mutagenesis is pointed out. Various assays now available for measuring gene mutations in human lymphocytes and erythrocytes are briefly described. Since we have a considerable data‐base for germ cell mutations in the mouse and data are now being collected for mutations in human somatic cells, the importance of studies on mutation induction in somatic cells of the mouse is emphasized. Such data on mouse somatic cells will help to define with greater precision mutation induction to be expected in human germ cells; that is genetic risks in humans on the basis of a “parallelogram‐like” extrapolation using somatic mutations in man and germ cell mutations in the mouse can now be calculated.
Dimethylsulfoxide as modifier of the organospecific mutagenicity of metronidazole in mice
Authors: Hrelia Patrizia , Scotti Miriam , Morotti Marta , Vigagni Fernanda , Paolini Moreno , Sapigni Ester , Cantelli‐Forti Giorgio 
Published: February 2006

AbstractMutagenicity and carcinogenicity of metronidazole (MT) are imputable to the formation of toxic intermediates, which include radical forms derived from the nitroreductive process. Since dimethylsulfoxide (DMSO) the “universal” solvent, can quench free radicals in vitro, it was suggested that DMSO might protect by scavenging free radical generation in vivo. This study wanted to evaluate if DMSO (given concomitantly or prophylactically) protects against the organospecific mutagenicity of MT in vivo by means of the intrasanguineous host‐mediated assay. DMSO used as solvent showed a 20%–30% reduction in the mutation frequencies by MT. Prophylactic administration of DMSO for 3 d caused a suppression of the organospecific mutagenicity. However, some increases in the spontaneous mutation frequency and enhancement of MT mutagenicity in kidney were observed. The protective effect was paralleled by a decrease in NADPH cytochrome c (P450) reductase in liver, kidney, and to a lesser extent in lung microsomes from pretreated mice. Inhibition of mutagenic activity might be related to scavenging of radical species as supported by the lack of tissue specificity and no appreciable changes in specific enzyme activity. However, changes in reductase content in prophylactically pretreated mice can affect the quantitative biotransformation of MT to the proximal mutagen contributing to the observed suppression in mutation frequencies.
Effects of alkylating antineoplastics alone or in combination with 3‐aminobenzamide on genotoxicity, antitumor activity, and NAD levels in human lymphocytes in vitro and on ehrlich ascites tumor cells in vivo
Authors: Petrou C. , Mourelatos D. , Mioglou E. , Dozi‐Vassiliades J. , Catsoulacos P. 
Published: February 2006

AbstractEnhanced cytogenetic damage by the homo‐aza‐steroidal ester of p‐bis (2‐chloroethyl)‐aminophenylacetic acid (ASE) was observed when human lymphocytes in vitro or Ehrlich ascites tumor (EAT) cells in vivo were exposed to nontoxic concentrations of 3‐aminobenzamide (3‐AB). 3‐AB at these concentrations was found to enhance synergistically the cytogenetic damage induced in vivo by cyclophosphamide (CP), a metabolically activated chemotherapeutic, or chlorambucil (CBC) in EAT cells. One hour before i.p. injection of 5‐bromodeoxyuridine (BrdUrd) adsorbed to activated charcoal, EAT‐bearing mice treated i.p. with ASE or CP showed a dose‐dependent increase in sister chromatid exchange (SCE) rates and cell division delays. The treatment of human lymphocytes in vitro with ASE led to the depletion of cellular NAD, and addition of 3‐AB, a potent inhibitor of poly(ADP‐ribose)polymerase [P(ADPR)polymerase], to ASE‐treated human lymphocytes prevented the drop of NAD, which remained at approximately control levels. Also, the in vivo treatment of EAT cells with CBC, ASE, or CP led to the depletion of NAD, whereas addition of 3‐AB to CBC‐, ASE‐, or CP‐treated cells prevented the drop of NAD, which remained at nearly control levels. 3‐AB in conjunction with CBC, ASE, or CP increased the survival time of the EAT‐bearing mice and markedly reduced the ascitic volume. Thus cytogenetic damage induced by ASE plus 3‐AB in vitro and by CBC, ASE, or CP plus 3‐AB in vivo correlates well with (1) the prevention of NAD depletion in the presence of 3‐AB in cells treated with the same alkylating agents in vitro or in vivo and (2) the in vivo antitumor effect by ASE, CBC, or CP in combination with 3‐AB.
Image analysis and mathematical correlation between cell number and diameter of colonies in soft agar as a measurement of growth in soft agar
Authors: Lewis John C. , Milo George E. 
Published: February 2006

AbstractAutomated image analysis was used to measure the colony diameter and estimate the cell number in colonies under conditions for anchorage‐independent growth (AIG). The calculated values for the number of AIG cells in a colony of a diameter ⩾ 60 μm were decidedly different from the actual values obtained by either automated or manual cell counting. Like animal cells that exhibit AIG, these colonies demonstrating anchorage independence can be enumerated reproducibly. However, the assumption is incorrect that the number of cells (N) in a colony expressing AIG varies directly with a change in the diameter of a colony (d). Whether one counts the number of cells manually in a colony of a definite diameter or arbitrarily uses a diameter function of ⩾ 60 μm as a linear distance that indicates the presence of 50 or more cells in a colony, each procedure has its own built‐in bias. In procedures that require quantitative data, the most reliable procedure is to standardize the values for diameter of colonies with cell numbers in colonies.
Acetaminophen toxicity to cultured rat embryos
Authors: Weeks Benjamin S. , Gamache Paul , Klein Norman W. , Hinson Jack A. , Bruno Mary , Khairallah Edward 
Published: February 2006

AbstractWe tested the effects of acetaminophen on cultured rat embryo development. When added directly to culture media at 300 μM, a concentration approximately twice the human therapeutic blood level, acetaminophen caused abnormalities in the cultured embryos. Sera from both rats and monkeys following gavage with acetaminophen were also toxic to cultured embryos. The sera toxicities were related to acetaminophen concentrations, and the toxicity could be removed by serum dialysis. With regard to the metabolism of acetaminophen, glutathione levels in the yolk sac decreased in a concentration related fashion with addition of the drug. Also, buthionine sulfoximine, an inhibitor of glutathione synthesis, appeared to enhance acetaminophen embryo toxicity, and N‐acetylcysteine, a glutathione precursor, appeared to protect embryos from acetaminophen toxicity. These results suggested that acetaminophen embryo toxicity resulted from direct exposure of embryos to acetaminophen and not a maternal metabolite.
Analysis of the syndrome of congenital malformations induced in genetically defined mice by acute riboflavin deficiency
Authors: Kalter H. 
Published: February 2006

AbstractThe role of genetics in the expression of a complex syndrome of teratologically induced congenital malformations was examined by the use of three inbred strains and 15 related crosses of mice. The syndrome, which included various limb, brain, orofacial, gastrointestinal, and miscellaneous malformations, was induced by an intense riboflavin deficiency produced by feeding the antagonist galactoflavin during midgestation. Analyses of the data showed that, although all three strains shared the major and most other features of the syndrome, there occurred in its manifestation vast quantitative and qualitative differences among them, in which they were resembled by their related crosses, such as to constitute strain‐specific malformation patterns. The results can be regarded as typifying an animal counterpart of human situations, the three strains representing in toto the mouse family, each strain individually exhibiting the variety that occurs between siblings in expressing a single syndrome.
Induction of micronuclei and toxic effects in embryos of pregnant rats treated before implantation with anticancer drugs: Cyclophosphamide, Cis‐platinum, adriamycin
Authors: Giavini E. , Lemonica I. P. , Lou Y. , Broccia M. L. , Prati M. 
Published: February 2006

AbstractTo evaluate a possible relationship of maternal exposure to anticancer drugs during the preimplantation period to blastopathies and postimplantation embryotoxicity, CD female rats were injected intraperitoneally on day 3 of pregnancy with 15 and 30 mg/kg of cyclophosphamide (CPA), 2 and 4 mg/kg of Adriamycin (ADR), 3 and 6 mg/kg of cis‐platinum (Cis‐Pt), or with 5 ml/kg of saline. Blastocysts were collected on day 5 of gestation and evaluated for gross morphology, cell number, and micronuclei. Some females were sacrificed on day 21 of pregnancy in order to evaluate postimplantation embryotoxicity. A reduction in cell number/blastocyst was observed only in animals exposed to Cis‐Pt 6 mg/kg; vice versa, a dose‐related increase of micronuclei and of blastocysts with micronuclei was found in all groups treated with the anticancer agents. A significant increase of postimplantation loss was recorded in the groups treated with high doses of Cis‐Pt and ADR, but no clear signs of teratogenicity were observed.
Analysis of the mechanism of isoniazid‐induced developmental toxicity with frog embryo teratogenesis assay: Xenopus (FETAX)
Authors: Fort Douglas J. , Bantle John A. 
Published: February 2006

AbstractThe developmental toxicity of isoniazid (INH) and the metabolites acetylhydrazide (AH) and isonicotinic acid (INA) were examined with the frog embryo teratogenesis assay‐Xenopus (FETAX). Late Xenopus laevis blastulae were exposed to INH, AH, and INA for 96 h in two separate static‐renewal tests with and without the presence of three differently induced metabolic activation systems (MAS). The MAS consisted of uninduced, Aroclor 1254‐induced, and INH‐induced rat liver microsomes. Addition of the INH‐induced MAS decreased the 96 h LC50 of INH and AH approximately 1.6‐fold and 7.9‐fold, respectively. The 96 h EC50 (malformation) of INH was virtually unaffected; however, the INH‐MAS decreased the teratogenic index (TI) [96 h LC50/96 h EC50 (malformation)] nearly 1.8‐fold. The 96 h EC50 (malformation) of AH increased approximately 2.0‐fold, decreasing the teratogenic index value 15.8‐fold. INA yielded a teratogenic index value of 2.5. Neither the uninduced MAS nor the Aroclor 1254‐induced MAS had an effect on any of the compounds tested and none of the MAS affected the developmental toxicity of INA. Results from this study suggest that mixed functional oxidase metabolism may alter the developmental toxicity of INH in vitro by producing a more embryolethal, but less teratogenic metabolite(s) than INH or AH themselves. Results are indicative of the utility and versatility of FETAX in evaluating toxicological mechanisms of teratogenesis in vitro.
Induction of fetal malformations after treatment of mouse embryos with methylnitrosourea at the preimplantation stages
Authors: Nagao Tetsuji , Morita Yasunobu , Ishizuka Yasuo , Wada Azusa , Mizutani Masahiro 
Published: February 2006

AbstractThe effects of methylnitrosourea (MNU) on the development of preimplantation mouse embryos were investigated in this study. ICR mice were treated intraperitoneally with single doses of 10, 20, and 30 mg MNU/kg body wt on day 0, 1, 2, or 3 of pregnancy. The uterine contents were examined on day 18 of pregnancy. The fetuses were examined for external and skeletal abnormalities. No significant differences were observed in the number of implantation sites between all the MNU‐treated groups and controls. MNU treatment on day 2 or 3 of pregnancy caused dose‐dependent significant increases in the incidence of abnormal fetuses over the control level, while treatment on day 0 or 1 failed to cause an increase of abnormalities. Cleft palate, exencephalus, and malformed vertebrae were the most common types of abnormalities. In the embryo transfer experiments, the frequency of fetal abnormalities induced when embryos were transferred from MNU‐treated females to untreated pseudopregnant females was significantly higher than that induced when embryos were transferred from untreated females to MNU‐treated or untreated pseudopregnant females. The results in the present study confirm and extend the previously proposed hypothesis that the direct effects of MNU on preimplantation embryos make a significant contribution to the induction of fetal malformations.
Isotretinoin (13‐cis‐retinoic acid) metabolism, cis‐trans isomerization, glucuronidation, and transfer to the mouse embryo: Consequences for teratogenicity
Authors: Kraft J. Creech , Eckhoff Chr. , Kochhar D. M. , Bochert G. , Chahoud I. , Nau H. 
Published: February 2006

AbstractIt has been reported that fractionated doses of 13‐cis‐retinoic acid are disproportionately more embryotoxic in pregnant mice than is the same dose given in a single bolus. Here, we examined limited pharmacokinetic profiles of a single (100 mg/kg dose given to NMRI mice on day 11 of gestation) versus multiple (3 × 100 mg/kg, 4 h apart) doses in an effort to assess the relative contribution to teratogenicity made by the drug and/or its metabolites. The major plasma metabolite of 13‐cis‐retinoic acid in the mouse was 13‐cis‐retinoyl‐β‐glucuronide, followed by the 4‐oxo metabolites and all‐trans‐retinoic acid. Transfer to the mouse embryo was very efficient for all‐trans‐retinoic acid, whereas, it was tenfold less efficient for 13‐cis‐retinoic acid and 100‐fold less efficient for 13‐cis‐retinoyl‐β‐glucuronide. The isomer all‐trans‐retinoic acid was found in the placenta at concentrations two‐ to three‐fold higher than in the plasma, suggesting placental accumulation as well as placental cis/trans isomerization. Since 13‐cis‐retinoyl‐β‐glucuronide and 13‐cis‐ and all‐trans‐retinoic acid were detected in the embryo after this multiple dosing schedule, any of the three or their combinations may have been involved in the induction of malformations, but all‐trans‐retinoic acid, a well‐known potent teratogen detected at concentrations of between 590 and 80 ng/g for 10 critical hours during gestation, could have been the major component.
A genotoxicological study of hexachlorobenzene and pentachloroanisole
Authors: Siekel Peter , Chalupa Ivan , Beňo Jozef , Blaško Milan , Novotný Jozef , Burian Ján 
Published: February 2006

AbstractThe potential mutagenic activity of hexachlorobenzene (HCB) and pentachloroanisole (PCA) was investigated. No genotoxicity after application on Salmonella typhimurium (Ames test), Escherichia coli, and human peripheral blood lymphocytes in vitro was observed.