Abstract
In numerous cases, the German health-related indication value (HRIV) concept has proved its practicability for the assessment of drinking water relevant trace substances (Umweltbundesamt 2003). The HRIV is based on the toxicological profile of a substance. An open point of the HRIV concept has been the assignment of standardized test procedures to be used for the assessment. The level of the HRIV is at its lowest as soon as the genotoxicity of the substance is detected. As a single test on its own, it is not sufficient enough to assess the human toxicological relevance of a genotoxic effect or exclude it in the case of a negative result; a reasonable test battery was required, technically oriented towards the already harmonized international, hierarchical evaluation for toxicological assessment of chemicals. Therefore, an important aim of this project was to define a strategy for the genotoxicological assessment of anthropogenic trace substances. The basic test battery for genotoxicity of micropollutants in drinking water needs to fulfill several requirements. Although quick test results are needed for the determination of HRIV, a high degree of transferability to human genotoxicity should be ensured. Therefore, an in vitro genotoxicity test battery consisting of the Ames fluctuation test with two tester strains (ISO 11350), the umu test and the micronucleus test, or from the Ames test with five tester strains (OECD 471) and the micronucleus test is proposed. On the basis of selected test substances, it could be shown that the test battery leads to positive, indifferent, and negative results. Given indifferent results, the health authority and the water supplier must assume that it is a genotoxic substance. Genetically modified tester strains are being sensitive to different chemical classes by expression of selected mammalian key enzymes for example nitroreductase, acetyltransferase, and glutathione-S-transferase. These strains may provide valuable additional information and may give a first indication of the mechanism of action. To check this hypothesis, various additional strains expressing specific human-relevant enzymes were investigated. It could be shown that the additional use of genetically modified tester strains can enhance the detectable substance spectrum with the bacterial genotoxicological standard procedures or increase the sensitivity. The additional use provides orienting information at this level as a lot of data can be obtained quite quickly and with little effort. These indications of the mechanism of action should be however verified with a test system that uses mammalian cells, better human cells, to check their actual relevance. The selection of appropriate additional tester strains has to be defined from case to case depending on the molecular structure and also still requires some major expertise.
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27 January 2017
An erratum to this article has been published.
References
Agency for Toxic Substances and Disease Registry U.S. Public Health Service1992: Toxicological profile for 1,2-dibromo-3-chloropropane. [http://www.atsdr.cdc.gov/toxprofiles/tp36.pdf] Sep 1992
Ames BN, Mccann J, Yamasaki E (1975) Methods for detecting carcinogens and mutagens with the salmonella/mammalian-microsome mutagenicity test. Mutat Res 31(6):347–364
Brinkmann M, Blenkle H, Salowsky H, Bluhm K, Schiwy S, Tiehm A, Hollert H (2014) Genotoxicity of heterocyclic PAHs in the micronucleus assay with the fish liver cell line RTL-W1. PLoS One 9(1):e85692
Brüschweiler BJ (2010) TTC-based risk assessment of tetrachlorobutadienes and pentachlorobutadienes—the in vitro genotoxic contaminants in ground and drinking water. Regul Toxicol Pharmacol 58(2):341–344
Carroll CC, Warnakulasuriyarachchi D, Nokhbeh MR, Lambert IB (2002) Salmonella typhimurium mutagenicity tester strains that overexpress oxygen-insensitive nitroreductases nfsA and nfsB. Mutat Res Fundam Mol Mech Mutagen. 501(1–2):79–98
Clements J (2000) The mouse lymphoma assay. Mutat Res 455(1–2):97–110
COM (The Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment)2011: Guidance on a strategy for genotoxicity testing of chemical substances
Cooper MT, Porter TD (2001) Cytochrome b(5) coexpression increases the CYP2E1-dependent mutagenicity of dialkylnitrosamines in methyltransferase-deficient strains of Salmonella typhimurium. Mutat Res 484(1–2):61–68
Couch DB, Allen PF, Abernethy DJ (1981) The mutagenicity of dinitrotoluenes in Salmonella typhimurium. Mutat Res 90(4):373–383
Delbanco EH, Bolt HM, Huber WW, Beken S, Geller F, Philippou S, Brands FH, Brüning T, Thier R (2001 Jan) Glutathione transferase activities in renal carcinomas and adjacent normal renal tissues: factors influencing renal carcinogenesis induced by xenobiotics. Arch Toxicol 74(11):688–694
Dieter HH (2009) Grenzwerte, Leitwerte, Orientierungswerte, Maßnahmenwerte - Aktuelle Definitionen und Höchstwerte. Bundesgesundheitsblatt 52:1202–1206
Dieter HH, Frank D, Herrmann H, Konietzka R, Moll B, Six E, Stockerl R, von der Trenck TK 2009: Ableitung von Geringfügigkeitsschwellenwerten für das Grundwasser NSO-Heterozyklen. LAWA
Directive 2000/78/EC (2000) considered as priority hazardous substances under the Water Framework Directive 2000
Dunkel VC, Zeiger E, Brusick D, McCoy E, McGregor D, Mortelmans K, Rosenkranz HS, Simmon VF (1985) Reproducibility of microbial mutagenicity assays: II. Testing of carcinogens and noncarcinogens in Salmonella typhimurium and Escherichia coli. Environ Mutagen 7(Suppl 5):1–248
Eastmond DA, Hartwig A, Anderson D, Anwar WA, Cimino MC, Dobrev I, Douglas GR, Nohmi T, Phillips DH, Vickers C (2009a) Mutagenicity testing for chemical risk assessment: update of the WHO/IPCS harmonized scheme. Mutagenesis 24(4):341–349
Eisentraeger A, Brinkmann C, Hollert H, Sagner A, Tiehm A, Neuwoehner J (2008) Heterocyclic compounds: toxic effects using algae, daphnids, and the salmonella/microsome test taking methodical quantitative aspects into account. Environ Toxicol Chem 27(7):1590–1596
Fujita K, Kamataki T (2001 Nov 1) Role of human cytochrome P450 (CYP) in the metabolic activation of N-alkylnitrosamines: application of genetically engineered Salmonella typhimurium YG7108 expressing each form of CYP together with human NADPH-cytochrome P450 reductase. Mutat Res 483(1–2):35–41
German drinking water ordinance, 2001
Grummt T, Kuckelkorn J, Bahlmann A, Baumstark-Khan C, Brack W, Braunbeck T, Feles S, Gartiser S, Glatt H, Heinze R, Hellweg K, Hollert H, Junek R, Knauer B, Kneib-Kissinger B, Kramer M, Krauss M, Küster E, Maletz S, Meinl W, Noman A, Prantl E-M, Rabbow E, Redelstein R, Rettberg P, Schadenboeck W, Schmidt C, Schulte T, Seiler T-B, Spitta L, Stengel D, Waldmann P, Eckhardt A (2013) Tox-Box: securing drops of life – an enhanced health-related approach for risk assessment of drinking water in Germany. Environ Sci Eur 25:27
Hagiwara Y, Watanabe M, Oda Y, Sofuni T, Nohmi T (1993) Specificity and sensitivity of Salmonella typhimurium YG1041 and YG1042 strains possessing elevated levels of both nitroreductase and acetyltransferase activity. Mutat Res 291(3):171–180
Happel O, Mertineit S, Brauch HJ, Wunderlich HG, Dölling E, Grummt T, Kramer M, Schmidt CK (2013) Bewertung von Transformationsprodukten bei der Trink-wasseraufbereitung. Abschlussbericht zum Forschungsvorhaben. Scientific publications Technologiezentrum Wasser 60
Joss A, Siegrist H, Ternes TA (2008) Are we about to upgrade wastewater treatment for removing organic micropollutants? Water Sci Technol 57(2):251–5
Jurado J, Alejandre-Durán E, Pueyo C (1994) Mutagenicity testing in Salmonella typhimurium strains possessing both the His reversion and Ara forward mutation systems and different levels of classical nitroreductase or O-acetyltransferase activities. Environ Mol Mutagen 23(4):286–93.
Kataoka H, Hayatsu T, Hietsch G, Steinkellner H, Nishioka S, Narimatsu S, Knasmüller S, Hayatsu H (2000) Identification of mutagenic heterocyclic amines (IQ, Trp-P-1 and AαC) in the water of the Danube River. Mutat Res 466(1):27–35
Kirkland D, Reeve L, Gatehouse D, Vanparys P (2011) A core in vitro genotoxicity battery comprising the Ames test plus the in vitro micronucleus test is sufficient to detect rodent carcinogens and in vivo genotoxins. Mutat Res 721(1):27–73
Kuhlmann B, Skark C, Zullei-Seibert N (2010) Definition und Bewertung von trinkwasserrelevanten Chemikalien im Rahmen der REACH Verordnung und Empfehlungen zum Screening nach potentiell kritischen Substanzen im Auftrag des Umweltbundesamtes (Sachverständigengutachten). Institut für Wasserforschung GmbH Dortmund
Låg M, Søderlund EJ, Brunborg G, Dahl JE, Holme JA, Omichinski JG, Nelson SD, Dybing E (1989) Species differences in testicular necrosis and DNA damage, distribution and metabolism of 1,2-dibromo-3-chloropropane (DBCP). Toxicology 58(2):133–144
Lemieux CL, Lynes KD, White PA, Lundstedt S, Oberg L, Lambert IB (2009) Mutagenicity of an aged gasworks soil during bioslurry treatment. Environ Mol Mutagen 50(5):404–412
Little JW, Mount DW (1982) The SOS regulatory system of Escherichia coli. Cell 29(1):11–22
Marquardt H, Schäfer SG, Barth H 2013: Toxikologie; 3, book edition
Mizuno T, Takamura-Enya T, Watanabe T, Hasei T, Wakabayashi K, Ohe T (2007 Jun 15) Quantification of a potent mutagenic 4-amino-3,3′-dichloro-5,4′-dinitrobiphenyl (ADDB) and the related chemicals in water from the Waka River in Wakayama. Japan Mutat Res 630(1–2):112–121
Moore MM, Clive D, Hozier JC, Howard BE, Batson AG, Turner NT, Sawyer J (1985) Analysis of trifluorothymidine-resistant (TFT) mutants of L5178Y/TK mouse lymphoma cells. Mutat Res 151(1):161–174
Moore MM, Doerr CL (1990) Comparison of chromosome aberration frequency and small-colony TK-deficient mutant frequency in L5178Y/TK+/−−3.7. 2C mouse lymphoma cells. Mutagenesis 5(6):609–614
Oda Y, Shimada T, Watanabe M, Ishidate M Jr, Nohmi T (1992) A sensitive umu-test system for the detection of mutagenic nitroarenes in Salmonella typhimurium NM1011 having a high nitroreductase activity. Mutat Res 272(2):91–99
Oda Y, Hirayama T, Watanabe T (2009) Genotoxic activation of the environmental pollutant 3,6-dinitrobenzo[e]pyrene in Salmonella typhimurium umu strains expressing human cytochrome P450 and N-acetyltransferase. Toxicol Lett 188(3):258–262
Oda Y, Yamazaki H, Watanabe M, Nohmi T, Shimada T (1993) Highly sensitive umu-test system for the detection of mutagenic nitroarenes in Salmonella typhimurium NM3009 having high O-acetyltransferase and nitroreductase activities. Environ Mol Mutagen 21(4):357–364
Oda Y, Nakamura S, Oki I, Kato T, Shinagawa H (1985) Evaluation of the new system (umu-test) for the detection of environmental mutagens and carcinogens. Mutat Res 147(5):219–229
OECD Guideline 4872010: In vitro mammalian cell micronucleus test. OECD Guideline for the testing of chemicals
OECD Guideline 476 1997: In vitro mammalian cell gene mutation test. OECD Guideline for the testing of chemicals
Omichinski JG, Brunborg G, Søderlund EJ, Dahl JE, Bausano JA, Holme JA, Nelson SD, Dybing E (1987) Renal necrosis and DNA damage caused by selectively deuterated and methylated analogs of 1,2-dibromo-3-chloropropane in the rat. Toxicol Appl Pharmacol 91(3):358–370
Omichinski JG, Brunborg G, Holme JA, Søderlund EJ, Nelson SD, Dybing E (1988) The role of oxidative and conjugative pathways in the activation of 1,2-dibromo-3-chloropropane to DNA-damaging products in rat testicular cells. Mol Pharmacol 34(1):74–79
Oztürk K, Durusoy M (1999) The detection and comparison of the genotoxic effects of some nitro aromatic compounds by the umu and SOS chromotest systems. Toxicol Lett 108(1):63–68
Programme “Clean River Ruhr” (2012 ) Strategy of the state NRW aimed at the improvement of the water body and drinking water quality in the Ruhr region [http://www.masterplan-wasser.nrw.de/fileadmin/user_upload/Downloads/programm_reine_ruhr_2012.pdf]
Rajagopalan M, Lu C, Woodgate R, O'Donnell M, Goodman MF, Echols H (1992) Activity of the purified mutagenesis proteins UmuC, UmuD′, and RecA in replicative bypass of an abasic DNA lesion by DNA polymerase III. Proc Natl Acad Sci U S A 89(22):10777–10781
Ramel C, Drake J, Sugimura T (1980) International Commission for Protection against environmental mutagens and carcinogens. ICPEMC publication no. 5: an evaluation of the genetic toxicity of dichlorvos. Mutat Res 76(3):297–309
Rehn C (1995) Theoretische Studien zur Interkalation von Anthrachinon-, 9-Aminoacridin-,Isochinolin- und Pyrrolocarbazol-1,3-dion-Derivaten sowie Synthese von Pyrrolocarbazol-1,3-dionen
Reifferscheid G, Heil J (1996) Validation of the SOS/umu-test using test results of 486 chemicals and comparison with the Ames test and carcinogenicity data. Mutat Res 369(3–4):129–145
Reifferscheid G, Grummt T (2000) Genotoxicity in German surface waters—results of a collaborative study. Water Air Soil Pollut 123:67–79
Reifferscheid G, Ziemann C, Fieblinger D, Dill F, Gminski R, Grummt HJ, Hafner C, Hollert H, Kunz S, Rodrigo G, Stopper H, Selke D (2008) Measurement of genotoxicity in wastewater samples with the in vitro micronucleus test: results of a round-robin study in the context of standardisation according to ISO. Mutat Res 649(1–2):15–27
Reifferscheid G, Maes HM, Allner B, Badurova J, Belkin S, Bluhm K, Brauer F, Bressling J, Domeneghetti S, Elad T, Fluckiger-Isler S, Grummt HJ, Gurtler R, Hecht A, Heringa MB, Hollert H, Huber S, Kramer M, Magdeburg A, Ratte HT, Sauerborn-Klobucar R, Sokolowski A, Soldan P, Smital T, Stalter D, Venier P, Ziemann C, Zipperle J, Buchinger S (2012) International round-robin study on the Ames fluctuation test. Environ Mol Mutagen 53(3):185–197
Richardson C, Williams DA, Allen JA, Amphelett G, Chanter DO, Phillips B (1989) Analysis of data from in vitro cytogenetic assays. In: Kirkland DJ (ed) Statistical evaluation of mutagenicity test data, vol 102. Cambridge University Press, Cambridge, pp. 141–154
Shimada T, Yamazaki H, Oda Y, Hiratsuka A, Watabe T, Guengerich FP (1996) Activation and inactivation of carcinogenic dihaloalkanes and other compounds by glutathione S-transferase 5-5 in Salmonella typhimurium tester strain NM5004. Chem Res Toxicol 9(1):333–340
Søderlund EJ, Meyer DJ, Ketterer B, Nelson SD, Dybing E, Holme JA (1995) Metabolism of 1,2-dibromo-3-chloropropane by glutathione S-transferases. Chem Biol Interact 97(3):257–272
Simula TP, Glancey MJ, Söderlund EJ, Dybing E, Wolf CR (1993) Increased mutagenicity of 1,2-dibromo-3-chloropropane and tris(2,3-dibromopropyl)phosphate in salmonella TA100 expressing human glutathione S-transferases. Carcinogenesis 14(11):2303–2307
Speit G (1986) The relationship between the induction of SCEs and mutations in Chinese hamster cells. I. Experiments with hydrogen peroxide and caffeine. Mutat Res 174(1):21–26
Tennant RW, Margolin BH, Shelby MD, Zeiger E, Haseman JK, Spalding J, Caspary W, Resnick M, Stasiewicz S, Anderson B et al (1987) Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. Science 236(4804):933–941
Tielemans, M, Fischer A, Bannink, A, Houtman CJ (2011 ) List of compounds relevant for drinking water for the Dutch Ministry of Infrastructure and Environment (RIWA, HWL) Relevant substances for Drinking Water production from the river Meuse - An update of selection criteria and substances list
Tsukatani H, Tanaka Y, Sera N, Shimizu N, Kitamori S, Inoue N (2002) Mutagenic activity in roadside soils. J Toxicol Sci 27(3):183–189
Umweltbundesamt (2003) Bewertung der Anwesenheit teil- oder nicht bewertbarer Stoffe im Trinkwasser aus gesundheitlicher Sicht. Bundesgesundheitsblatt-Gesundheitsforschung- Gesundheitsschutz 46:249–251
Watanabe T, Takahashi K, Konishi E, Hoshino Y, Haei T, Asanoma M, Hirayama T, Wakabayashi K (2008) Mutagenicity of surface soil from residential areas in Kyoto city, Japan, and identification of major mutagens. Mutat Res 649(1–2):201–212
Weber GL, Steenwyk RC, Nelson SD, Pearson PG (1995) Identification of N-acetylcysteine conjugates of 1,2-dibromo-3-chloropropane: evidence for cytochrome P450 and glutathione mediated bioactivation pathways. Chem Res Toxicol 8(4):560–573
Winckler K, Obe G, Madle S, Kocher-Becker U, Kocher W, Nau H (1987) Cyclophosphamide: interstrain differences in the production of mutagenic metabolites by S9-fractions from liver and kidney in different mutagenicity test systems in vitro and in the teratogenic response in vivo between CBA and C 57 BL mice. Teratog Carcinog Mutagen 7(4):399–409
Wolf CR, Berry PN, Nash JA, Green T, Lock EA (1984) Role of microsomal and cytosolic glutathione S-transferases in the conjugation of Hexachloro-1:3-butadiene and its possible relevance to toxicity. J Pharmacol Exp Ther 228(1):202–208
Zeiger E (1987) Carcinogenicity of mutagens: predictive capability of the salmonella mutagenesis assay for rodent carcinogenicity. Cancer Res 47(5):1287–1296
Zenser TV, Lakshmi VM, Rustan TD, Doll MA, Deitz AC, Davis BB, Hein DW (1996) Human N-acetylation of benzidine: role of NAT1 and NAT2. Cancer Res 56(17):3941–3947
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We thank the German Federal Ministry of Education and Research (BMBF) for funding the project “Risk Management of Emerging Compounds and Pathogens in the Water Cycle (RiSKWa),” funding number 02WRS1282I.
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Responsible editor: Philippe Garrigues
An erratum to this article is available at https://doi.org/10.1007/s11356-017-8464-0.
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Prantl, EM., Kramer, M., Schmidt, C.K. et al. Comparison of in vitro test systems using bacterial and mammalian cells for genotoxicity assessment within the “health-related indication value (HRIV) concept. Environ Sci Pollut Res 25, 3996–4010 (2018). https://doi.org/10.1007/s11356-016-8166-z
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DOI: https://doi.org/10.1007/s11356-016-8166-z