{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T13:10:13Z","timestamp":1761311413521},"reference-count":64,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,9,21]],"date-time":"2018-09-21T00:00:00Z","timestamp":1537488000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Ministry of Science and Technology (MOST) of the People's Republic of China","award":["2015ZX09501004-002"],"award-info":[{"award-number":["2015ZX09501004-002"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2019,1]]},"abstract":"<jats:p>The utility and sensitivity of the newly developed flow cytometric <jats:italic>Pig\u2010a<\/jats:italic> gene mutation assay have become a great concern recently. In this study, we have examined the feasibility of integrating the <jats:italic>Pig\u2010a<\/jats:italic> assay as well as micronucleus and Comet endpoints into acute and subchronic general toxicology studies. Male Sprague\u2013Dawley rats were treated for 3 or 28 consecutive days by oral gavage with procarbazine hydrochloride (PCZ) or ethyl carbamate (EC) up to the maximum tolerated dose. The induction of CD59\u2010negative reticulocytes and erythrocytes, micronucleated reticulocytes in peripheral blood, micronucleated polychromatic erythrocytes in bone marrow, and Comet responses in peripheral blood, liver, kidney, and lung were evaluated at one, two, or more timepoints. Both PCZ and EC produced positive responses at most analyzed timepoints in all tissue types, both with the 3\u2010day and 28\u2010day treatment regimens. Furthermore, comparison of the magnitude of the genotoxicity responses indicated that the micronucleus and Comet endpoints generally produced greater responses with the higher dose, short\u2010term treatments in the 3\u2010day study, while the <jats:italic>Pig\u2010a<\/jats:italic> assay responded better to the cumulative effects of the lower dose, but repeated subchronic dosing in the 28\u2010day study. Collectively, these results indicate that integration of several <jats:italic>in vivo<\/jats:italic> genotoxicity endpoints into a single routine toxicology study is feasible and that the <jats:italic>Pig\u2010a<\/jats:italic> assay may be particularly suitable for integration into subchronic dose studies based on its ability to accumulate the mutations that result from repeated treatments. This characteristic may be especially important for assaying lower doses of relatively weak genotoxicants. Environ. Mol. Mutagen. 60:56\u201371, 2019. \u00a9 2018 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/em.22227","type":"journal-article","created":{"date-parts":[[2018,9,22]],"date-time":"2018-09-22T09:25:22Z","timestamp":1537608322000},"page":"56-71","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Assessment of the <i>Pig\u2010a<\/i>, micronucleus, and comet assay endpoints in rats treated by acute or repeated dosing protocols with procarbazine hydrochloride and ethyl carbamate"],"prefix":"10.1002","volume":"60","author":[{"given":"Gaofeng","family":"Chen","sequence":"first","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"},{"name":"Center of Safety Evaluation on New Drug, School of Pharmaceutical Science, Sun Yat\u2010sen University  Guangzhou People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hairuo","family":"Wen","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihui","family":"Mao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"},{"name":"Center of Safety Evaluation on New Drug, School of Pharmaceutical Science, Sun Yat\u2010sen University  Guangzhou People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Song","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weifan","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yufa","family":"Miao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiying","family":"Huang","sequence":"additional","affiliation":[{"name":"Center of Safety Evaluation on New Drug, School of Pharmaceutical Science, Sun Yat\u2010sen University  Guangzhou People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Beijing for Safety Evaluation of Drugs, National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,9,21]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1218(93)90038-F"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5742(97)00024-0"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.2147\/tcrm.2007.3.2.213"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/geu084"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/109158197226865"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1218(79)90077-6"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20379"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfl075"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfq070"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2011.01.009"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20672"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfs258"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20627"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1997.8233"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2014.09.007"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx00022a003"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.1017"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.19.6619"},{"key":"e_1_2_7_20_1","unstructured":"IARC.1981. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Some antineoplastic and immunosuppressive agents. Available at:http:\/\/monographs.iarc.fr\/ENG\/Monographs\/vol1-42\/mono26.pdf."},{"key":"e_1_2_7_21_1","unstructured":"ICH.2011. Guidance on genotoxicity testing and data interpretation for pharmaceuticals intended for human use S2(R1) (step 4version). Available at:http:\/\/www.ich.org\/fileadmin\/Public_Web_Site\/ICH_Products\/Guidelines\/Safety\/S2_R1\/Step4\/S2R1_Step4.pdf."},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-1218(97)00031-1"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1218(89)90098-0"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2014.02.001"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1994.1544"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2013.06.006"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2008.05.002"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-2280(1998)32:2<115::AID-EM6>3.0.CO;2-6"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2015.03.011"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrrev.2005.04.002"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00280485"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20414"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20413"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2009.05.014"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.2850180420"},{"key":"e_1_2_7_36_1","doi-asserted-by":"crossref","unstructured":"OECD.1997. Test No. 474: Mammalian erythrocyte micronucleus test. Available at:https:\/\/doi.org\/10.1787\/9789264071285-en.","DOI":"10.1787\/9789264071285-en"},{"key":"e_1_2_7_37_1","doi-asserted-by":"crossref","unstructured":"OECD.2008. Test No. 407: Repeated dose 28\u2010day oral toxicity study in rodents. Available at:https:\/\/doi.org\/10.1787\/9789264070684-en.","DOI":"10.1787\/9789264070684-en"},{"key":"e_1_2_7_38_1","doi-asserted-by":"crossref","unstructured":"OECD.2014. Test No. 474: Mammalian erythrocyte micronucleus test. Available at:https:\/\/doi.org\/10.1787\/9789264224292-en.","DOI":"10.1787\/9789264224292-en"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2009.09.002"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2008.08.011"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfp289"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.21758"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/18.11.2191"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.2131\/fts.3.167"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/gex032"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1161(90)90011-C"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2010.12.005"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5718(98)00002-3"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408440008951123"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5718(01)00157-7"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1177\/074823379000600106"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/15.8.1675"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/gev013"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/2.1.27"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1383-5718(99)00060-1"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2012.10.004"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.1051"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfg143"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.20081"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrgentox.2006.10.006"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-7992(90)90056-P"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-7992(91)90091-H"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/0027-5107(78)90200-2"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/13.2.133"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1218(91)90126-7"}],"container-title":["Environmental and Molecular Mutagenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fem.22227","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/em.22227","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T23:25:27Z","timestamp":1694733927000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/em.22227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,21]]},"references-count":64,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,1]]}},"alternative-id":["10.1002\/em.22227"],"URL":"https:\/\/doi.org\/10.1002\/em.22227","archive":["Portico"],"relation":{},"ISSN":["0893-6692","1098-2280"],"issn-type":[{"value":"0893-6692","type":"print"},{"value":"1098-2280","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,21]]},"assertion":[{"value":"2018-03-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-06-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}