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• W4239849498 abstract "Free Access Hydrazine [BAT Value Documentation, 1995] 1995. Documentations and Methods First published: 31 January 2012 https://doi.org/10.1002/3527600418.bb30201e0002 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Published in the series Biological Exposure Values for Occupational Toxicants and Carcinogens, Vol. 2 (1995) The article contains sections titled: Metabolism and Kinetics Critical Toxicity Exposure and Effects Selection of the Indicators Hydrazine in Urine and in Plasma Hydrazine-induced DNA Methylation Methodology Evaluation of the Biological Exposure Equivalents for Carcinogenic Substances (EKA) Exposure Parameters - Hydrazine in Urine and in Plasma Effect Parameters - Hydrazine-induced Methylation of DNA Interpretation of the Data EKA for exposure to hydrazine and its salts The correlation between external and internal exposure yields the following data: Air Urine1 Plasma1 Hydrazine (µg Hydrazine hydrazine/g (ml/m3) (mg/m3) creatinine) (µg/l) 0.01 0.013 35 27 0.02 0.026 70 55 0.05 0.065 200 160 0.08 0.104 300 270 0.10 0.130 380 340 1) Sampling: end of exposure or end of shift Date of evaluation 1991 Synonym Diamide Formula NH2NH2 (water-free) NH2NH2 (H2O)x (hydrates) NH2NH3A; NH3NH3A2 (salts, A = anion, acid residue) Molecular weight 32.05 Melting point 1.8 °C Boiling point 113.5 °C Vapour pressure at 20 °C 1.3 hPa MAK [last established: 1985] Carcinogenic substance: category IIIA2 of the List of MAK and BAT Values Details of the metabolism and toxicology of hydrazine have been published by the DFG Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area [11]. 1 Metabolism and Kinetics Hydrazine (or hydrazine hydrate) is quickly absorbed by inhalation and through the skin [9, 25]. It is excreted in urine mainly as the monoacetylated and diacetylated forms [13, 21, 35]. An accumulation of hydrazine has so far not been observed in humans [14, 28]. Hydrazine, particularly in toxic doses, causes an indirect methylation of the O6 and N7 position of the deoxyguanosine of the liver DNA (experimental data from rat liver) [2, 14] (cf. Fig. ). Postulated mechanism of the DNA methylation by free hydrazine [26, 27]. Exogenous hydrazine (II) is thought to react with endogenous substances of the C1 metabolic pool, e.g., formaldehyde (I) bound to tetrahydrofolic acid, to form a formaldehyde-hydroxymethyl-hydrazone (III) [31]. This intermediate (III) could then, in analogy to the alkylhydrazines, be activated enzymatically via methylazomethanol (V) to the electrophilic methyldiazonium ion (VI) which then methylates DNA bases [15]. The resulting base adducts are N7-methyldeoxyguanosine and O6-methyldeoxyguanosine [2, 23] as well as O6-methylthymidine [17] and N3-methyldeoxyadenosine [8, 16]. Investigations into the alkylation of proteins show that as well as DNA other macromolecules are indirectly methylated by hydrazine. The nature of these adducts is so far unknown [21]. Hydrazine-induced methylation of the N-terminal valines in the globin of haemoglobin could, however, not be demonstrated either by animal experiments nor in persons exposed to hydrazine [16]. It can be assumed that the individual acetylation capacity modifies the genotoxicity of hydrazine. Thus, in persons exposed to hydrazine, methylation of deoxyguanosine of the leucocyte DNA is then observed when the incorporated hydrazine is acetylated “slowly” and therefore apparently cannot be eliminated quickly enough [16]. 2 Critical Toxicity Acute intoxication with hydrazine in animal experiments resulted in kidney and liver damage [9, 33]. Oral application of high hydrazine doses to rats and mice led to pulmonary adenomas, adenocarcinomas, hepatomas and hepatocarcinomas. After an intraperitoneal hydrazine dose lymphomas and leukaemia were reported [12]. With acute hydrazine intoxication central nervous effects with vomiting, muscular tremor, convulsions and paraesthesia but also liver and kidney damage were described [9]. (For further details on the symptoms of acute intoxication see the MAK documentation for hydrazine [11]). According to currently available data, a carcinogenic effect of hydrazine in humans after exposure to hydrazine as it occurs at the workplace cannot be demonstrated (for further details see the MAK documentation for hydrazine [11] – in English translation in the series “Occupational Toxicants”, obtainable from VCH Vcrlagsgesellschaft mbH, Weinheim). 3 Exposure and Effects External exposure is to be understood as one that can lead to absorption by inhalation or through the skin. The internal exposure is the biologically relevant concentration of the hydrazine or the products of its metabolism in the target tissue. As parameters for internal exposure the hydrazine concentrations in the plasma and urine can be used. Methylated DNA bases can be regarded as parameters of internal hydrazine effects. The determination of the incidence of DNA strand breaks in leucocytes represents a further parameter of effect of internal hydrazine exposure [20, 31]. As this parameter is very unspecific it is not recommended for biological monitoring. 4 Selection of the Indicators Internal exposure to hydrazine and its effects can be determined through the hydrazine concentrations in urine and plasma or via hydrazine-induced methylation rates in the blood and liver cells. 4.1 Hydrazine in Urine and in Plasma The hydrazine concentrations in plasma and excretion of hydrazine in urine observed after occupational contact with hydrazine have only recently been routinely determined. For this reason correlation investigations between inhaled hydrazine levels and the corresponding hydrazine concentration in plasma or urinary excretion of free and conjugated hydrazine are lacking in the literature. The data listed in this EKA documentation are based on examination of workers with continual occupational exposure to hydrazine. Plasma is preferred for analysis in acute accident cases with hydrazine. Chronic, intermittent and retrospective hydrazine exposures are usually determined via urine excretion. 4.2 Hydrazine-induced DNA Methylation In DNA the positions N7 and O6 in guanine as well as N3 in adenine are the preferred targets for the methylation induced by hydrazine [2, 14, 16]. The biological half-life of O6-methyldeoxyguanosine is determined above all by the individual repair capacity [7, 24, 32]. The N3-methyladenine formation which is independent of endogenous methylation can serve as a measure of the methylation potential of absorbed hydrazine [8, 16, 22, 29]. Biological monitoring is in principle possible via the determination of the ratio of N7-methylguanine to O6-methylguanine in the leucocyte DNA as well as the N3-methyladenine excretion in urine [1, 34]. To what extent the value of the N7-methylguanine to O6-methylguanine ratio in leucocytes or the N3-methyladenine excretion in urine can be correlated with adverse effects needs further investigation [4, 6, 18, 19]. 5 Methodology The analysis of free and monoacetylated hydrazine takes place after derivatisation and extraction by capillary gas chromatography with an ECD detector or via GC/MS (gas chromatography/mass spectrometry) [17]. Methylation of the DNA of leucocytes can be analysed with a GC/MS [3, 29] or immunologically [5]. N3-Methyladenine in urine is determined immunologically [8, 22, 30] or chromatographically [1]. Further methods of investigation are described in the literature [10, 17]. The determination of the incidence of DNA strand breaks is carried out after alkaline elution of the DNA [20, 31]. 6 Evaluation of the Biological Exposure Equivalents for Carcinogenic Substances (EKA) The concentration of hydrazine in target tissues after inhalation of hydrazine and/or percutaneous hydrazine exposure cannot be determined directly. The pharmacokinetic situation is such that the hydrazine concentrations in urine and in plasma, the N3-methyladenine concentration in urine and the ratio of N7-methylguanine to O6-methyl guanine in the leucocyte DNA can serve as indicators of internal exposures and effects. 6.1 Exposure Parameters - Hydrazine in Urine and in Plasma Occupational contact with hydrazine concentrations below the currently valid TRK value (0.1 ml hydrazine/m3) leads to a dose-dependent increase in the hydrazine levels in the plasma and in the urine. Correlations between external and internal exposure can therefore be established for the evaluation of EKA values. In the literature such data are still not available. The Commission has at its disposal, however, extensive data from a company in the chemical industry (for the years 1978–1991). The most important results are summarised in table 1. Table 1. Relationship between the external concentration of hydrazine in the ambient air and the plasma and urine concentrations of hydrazine in workers with continual exposure to hydrazine (J. Lewalter, unpublished investigations) Persons Air Urine1 Plasma1 n ml N2H4/m3. µg N2H4/g creatinine µg N2H4/l 372 0.01 35 (5–70) 27 (15–45) 3 03 0.02 70 (25–120) 55 (40–65) 3 0.05 195 (150–210) = 2004 160 (135–180) 2 0.08 300 (300; 305) 270 (255; 285) - 0.10 3805 3405 1 Sampling: end of exposure or end of shift 2 14 smokers 3 9 smokers 4 Rounded-up value 5 Extrapolated data The table contains, in addition to the mean values, also information on variation. Particularly the internal exposure was very variable in some cases. The individual differences can be due to differing metabolism (acetylation and methylation) and differing routes of absorption (inhalation and percutaneous). Therefore both parameters should be simultaneously determined where possible. 6.2 Effect Parameters - Hydrazine-induced Methylation of DNA After exposure to hydrazine concentrations at the currently valid TRK value (0.1 ml hydrazine/m3), no additional methylation of the guanine in the leucocyte DNA was found, only the normally observed methylation levels. The N3-methyladenine excretion in urine is not affected in this range of exposure. This agrees with the lack of cytotoxic effects [9] and statistically inconspicuous incidence of DNA strand breaks [20, 31] at these hydrazine doses. For this reason no parameters of effect can be given as EKA values for exposure levels up to the TRK value valid at present. 7 Interpretation of the Data For the reasons mentioned above, only the determination of hydrazine in plasma and in urine is suitable for monitoring persons with chronic occupational hydrazine exposure in the concentration range below the TRK value. After acute intoxication in addition to this determination in plasma and in urine, determination of the N3-methyladenine excretion in urine and the level of N7-methylation of guanine in the leucocytes is to be recommended. This monitors not only current exposures but also any exposures within the previous week. The hydrazine determinations in urine and in plasma, as well as the N3-methyladenine determination in urine, must be carried out after the end of the shift or after an accident. The samples must be analysed immediately or at least stabilised by immediate reaction with the detection reagent. The breakdown of the hydrazine can also be prevented by immediate freezing. The hydrazine content in urine has been expressed in terms of the creatinine level as no other correlation data are available. References 1Autrup, H.: Human exposure to genotoxic carcinogens: methods and their limitations. J. Cancer Res. Clin. Oncol. 117 (1991), 6– 12 2Becker, R. A., Barrows, L. R., Shank, R.: Methylation of liver DNA guanine in hydrazine hepatoxicity: dose-response and kinetic characteristics of 7-methylguanine and O6-methylguanine formation and persistence in rats. Carcinogenesis 2 (1981), 1181– 1188 3Bolt, H. M., Peter, H., Föst, U.: Analysis of macromolecular ethylene oxide adducts. Int. Arch. Occup. Environ. Health 60 (1988), 141– 144 4Bosan, W. S., Lambert, C. E., Shank, R. C.: The role of formaldehyde in hydrazine-induced methylation of liver DNA guanine. Carcinogenesis 1 (1986), 413– 418 5Degan, P., Montesano, R., Wild, Ch. P.: Antibodies against 7-methyldesoxyguanosine: Its detection in rat peripheral blood lymphocyte DNA and potential applications to molecular epidemiology. Cancer research 48 (1988), 5065– 5070 6 ECETOC: DNA and protein adducts: Evaluation of their use in exposure monitoring and risk assessment. ECETOC Monograph Nr. 13, Brüssel 1989 7Doerjer, G., Bedell, M. A., Oesch, F.: DNA adducts and their biological relevance. In: G Obe. (ed.): Mutation in man (1984), 20– 34 8Eberle, G., Glusenkamp, K.-H., Drosdziok, W., Rajewsky, M. F.: Monoclonal antibodies for the specific detection of 3-alkyladenines in nucleic acids and body fluids. Carcinogenesis 11 (1990), 1753– 1759 9 Environmental Health Criteria 68: Hydrazine. WHO, Geneva 1987 10Gustavson, S., Proper, J. A., Bowie, W. E., Sommer, St. S.: Parameters affecting the yield of DNA from human blood. Anal. Biochem. 165 (1987), 294– 299 11 D Henschler. (ed.): Gesundheitsschädliche Arbeitsstoffe. Toxikologisch-arbeitsmedizinische Begründung von MAK-Werten. VCH Verlagsgesellschaft, Weinheim (1972, 1986) 12 International Agency for Research on Cancer (IARC): The evaluation of the carcinogenic risk of chemicals to humans. IARC Monograph No. 7. IARC, Lyon 1974, pp. 37– 72 13Kaneo, Y., Iguchi, S., Kubo, H., Iwagird, N., Matsuyama, K.: Tissue distribution of hydrazine and its metabolites in rats. J. Pharm. Dyn. 7 (1984), 556– 562 14Kimball, R. E: The mutagenicity of hydrazine and some of its derivatives. Mutat. Res. 39 (1977), 111– 126 15Lambert, C. E., Shank, R. C.: Role of formaldehyde hydrazone and catalase in hydrazine-induced methylation of DNA guanine. Carcinogenesis 9 (1988), 65– 70 16Lewalter, J.: Personal experience during the biological monitoring of persons exposed to hydrazine (1978–1990) 17 D. Henschler (ed.): Analytische Methoden zur Prüfung gesundheitsschädlicher Arbeitsstoffe, Bd. 2: Analysen in biologischem Material, Hydrazin-Bestimmung per Kapillargas-chromatographie und ECD. In preparation. VCH Verlagsgesellschaft, Weinheim 18Lutz, W. K.: Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens. J. Cancer Res. Clin. Oncol. 112 (1986), 85– 91 19Lutz, W. K.: Structural characteristics of compounds that can be activated to chemically reactive metabolites: use for a prediction of a carcinogenic potential. Arch. Toxicol. Suppl. 7 (1984), 194– 207 20Parodi, S., De Flora, S., Gavanna, M., Pino, A., Robbiani, L., Bennicelli, C., Brambilla, G.: DNA-damaging activity in vivo and bacterial mutagenicity of sixteen hydrazine derivates as related quantitatively to their carcinogenicity. Cancer Res. 41 (1981), 1469– 1482 21Perry, T. L., Kish, S. J., Hansen, S., Wright, J. M., Wall, R. A., Dunn, W. L., Bellward, G. D.: Elevation of brain GABA content by chronic low-dosage administration of hydrazine, a metabolite of isoniazid. J. Neurochem. 37 (1981), 32– 39 22Prevost, V., Shuker, D. E. G., Bartsch, H., Pastorelli, R., Stillwell, W. G., Trudel, L.J., Tannenbaum, S. R.: The determination of urinary 3-methyladenine by immunoaffinity chromatography – monoclonal antibody-based ELISA: use in human biomonitoring studies. Carcinogenesis 11 (1990), 1747– 1751 23Roggers, K. J., Pegg, A. E.: Formation of O6-methylguanine by alkylation of rat liver, colon and kidney DNA following administration of 1,2-dimethylhydrazine. Cancer Res. 37 (1977), 4082– 4087 24Rüdiger, H. W., Lehnert, G.: Toxicogenetic: Grundlagen, Methoden und Bedeutung fur die Arbeitsmedizin. ASP-Sonderheft 11 (1988), 4– 16 25Schmidt, E. W.: Hydrazine and its derivatives, preparation, properties, applications. Wiley & Sons, New York 1984 26Shank, R. C., Bosan, W. S., Lambert, C. E.: Studies on the mechanism of action of hydrazine-induced methylation of DNA guanine. National Technical Information Service, AFAMRL-TR-85–057, Springfield, USA, 1984 27Shank, R. C., Bosan, W. S., Lambert, C. E.: Role of formaldehyde in hydrazine-induced methylation of liver DNA guanine. National Technical Information Service, AAMRL-TR-85–052, Springfield, USA, 1985 28Shank, R. C.: Evidence for indirect genetic damage as methylation of DNA guanine in response to cytotoxicity. Dev. Toxicol. Environ. Sci. 11 (1983), 145– 152 29Shuker, D. E. G., Bailey, E., Gorf, S. M., Lamb, J., Farmer, P. B.: Determination of N-7-(2 H3)methyl-guanine in fat urine by gas chromatography-mass spectrometry following administration of trideuteromethylating agents or precursors. Anal. Biochem. 140 (1984), 270– 275 30Shuker, D. E. G., Bailey, E., Parry, A., Lamb, J., Farmer, P. B.: The determination of urinary 3-methyladenine in humans as a potential monitor of exposure to methylating agents. Carcinogenesis 8 (1987), 959– 962 31Sina, J. E., Bean, C. L., Dysart, G. R., Taylor, V. I., Bradley, M. O.: Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of carcinogenic/mutagenic potential. Mutat. Res. 113 (1983), 357– 391 32Topal, M. D.: DNA repair, oncogenes and carcinogenesis. Carcinogenesis 9 (1988), 691– 696 33Vernot, E. H., Macewen, J. D., Bruner, R. H., Haun, C. C., Kinkead, E. R., Prentice, D. E., Hall, A., Schmidt, R. E., Eason, R. L., Hubbard, G. B., Young, J. T: Long-term inhalation toxicity of hydrazine. Fundam. Appl. Toxicol. 5 (1985), 1050– 1064 34Wild, Ch. P.: Antibodies to DNA alkylation adducts as analytical tools in chemical carcinogenesis. Mutat. Res. 233 (1990), 219– 233 35Wright, J. M., Timbrell, J. A.: Factors affecting the metabolism of 14C-acetylhydrazine in rats. Drug Metab. Dispos. 6 (1978), 561– 556 The MAK-Collection for Occupational Health and Safety: Annual Thresholds and Classifications for the WorkplaceBrowse other articles of this reference work:BROWSE TABLE OF CONTENTSBROWSE BY TOPIC ReferencesRelatedInformation" @default.
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