Hyperbaric 2% prilocaine is increasingly used for spinal anesthesia. It is the only local anesthetic metabolized to o-toluidine, a human bladder carcinogen. Increase of o-toluidine hemoglobin adducts, a marker of o-toluidine ability to modify the DNA structure, was described following subcutaneous injection. In this prospective cohort study we aimed to assess and quantify o-toluidine hemoglobin adducts and urinary o-toluidine after a single intrathecal dose of hyperbaric prilocaine.
10 patients undergoing surgery received 50 mg of hyperbaric prilocaine intrathecally. Blood and urine samples were collected before injection and up to 24 h later (Hospital Braine l’Alleud-Waterloo, Braine l'Alleud, Belgium). Urinary o-toluidine and o-toluidine hemoglobin adducts were measured by tandem mass-spectrometry after gas-chromatographic separation (Institute of the Ruhr-Universität, Bochum Germany). The trial was registered to ClinicalTrials.gov (NCT03642301; 22-08-2018)
Intrathecal administration of 50 mg of hyperbaric prilocaine leads to a significant increase of o-toluidine hemoglobin adducts (0.1 ± 0.02–11.9 ± 1.9 ng/g Hb after 24 h, p = 0.001). Peak of urinary o-toluidine was observed after 8 h (0.1 ± 0.1–460.5 ± 352.8 µg/L, p = 0.001) and declined to 98 ± 66.8 µg/L after 24 h (mean ± SD)
Single intrathecal administration of hyperbaric prilocaine leads to a systemic burden with o-toluidine and o-toluidine hemoglobin adducts. O-toluidine-induced modifications of DNA should be examined and intrathecal hyperbaric prilocaine should not be proposed to patients chronically exposed to o-toluidine.
Clinical trial number and registry URL NCT03642301.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
ACGIH: booklet, TLV and BEI Edition (1996) ISBN: 1–882417–13–5.
Åkerman B, Åström A, Ross S, Telc A (1966) Studies on the absorption, distribution and metabolism of labelled prilocaine and lidocaine in some animal species. Acta Pharmacol Toxicol 24:389–403
Bader M, Wrbitzky R (2006) Follow-up biomonitoring after accidental exposure to acrylonitrile: implications for protein adducts as a dose monitor for short-term exposures. Toxicol Lett 162(2–3):125–131
Barr DB, Wilder LC, Caudill SP, Gonzalez AJ, Needham LL, Pirkle JL (2005) Urinary creatinine in the U.S. population: implication for urinary biologic monitoring measurements. Eviron Health Perspect 113:192–200
Bartsch H, Caporaso N, Coda M, Kadlubar F, Malaveille C, Skipper P, Talaska G, Tannenbaum SR, Vineis P (1990) Carcinogen hemoglobin adducts, urinary mutagenicity, and metabolic phenotype in active and passive cigarette smokers. J Natl Cancer Inst 82:1826–1831
Böhm F, Schmid D, Denzinger S, Wieland WF, Richter E (2011) DNA adducts of ortho-toluidine in human bladder. Biomarkers 16:120–128
Carreón T, Hein MJ, Hanley KW, Viet SM, Ruder AM (2014) Bladder cancer incidence among workers exposed to o- toluidine, aniline and nitrobenzene at a rubber chemical manufacturing plant. Occup Environ Med 73:175–182
Crankshaw TP (1965) Citanest (prilocaine) in spinal analgesia. Acta Anaesth Scand Suppl 16:287–290
DFG (Deutsche Forschungsgemeinschaft Senatskommission zur Prüfung gesundheitsschädlicher Arbeitsstoffe) (2000) Biomonitoring Methods. Haemoglobin adducts of aromatic amines: aniline, o‐, m‐ and p‐toluidine, o‐anisidine, p‐chloroaniline, α‐and β‐naphthylamine, 4‐aminodiphenyl, benzidine, 4,4′‐diaminodiphenylmethane, 3,3′‐dichlorobenzidine. Wiley-VCH. Vol. 7
DFG (Deutsche Forschungsgemeinschaft Senatskommission zur Prüfung gesundheitsschädlicher Arbeitsstoffe) (2007) MAK Value Documentation. o-Toluidine. Wiley-VCH. Supplement:1–9
Ehrenberg L, Hiesche KD, Osterman G, Olkar S, Wennberg I (1974) Evaluation of genetic risks of alkylating agents: tissue doses in the mouse from air contaminated with ethylene oxide. Mutat Res 24:83–103
Gaber K, Harréus UA, Matthias C, Kleinsasser NH, Richter E (2007) Hemoglobin adducts of the human bladder carcinogen o-toluidine after treatment with the local anesthetic prilocaine. Toxicology 229:157–164
Gebhardt V, Herold A, Weiss C, Samakas A, Schmittner MD (2013) Dosage finding for low-dose spinal anaesthesia using hyperbaric prilocaine in patients undergoing perianal outpatient surgery. Acta Anaesthesiol Scand 57:249–256
Gebhardt V, Beilstein B, Herold A, Weiss C, Fanelli G, Dusch M, Schmittner MD (2014) Spinal hyperbaric prilocaine vs. mepivacaine in perianal outpatient surgery. Central Eur J Med 9:754–761
Guntz E, Latrech B, Tsiberidis C, Gouwy J, Kapessidou Y (2014) ED 50 and ED 90 of intrathecal hyperbaric 2% prilocaine in ambulatory knee arthroscopy. Can J Anesth 61:801–807
Higuchi R, Fukami T, Nakajima M, Yokoi T (2013) Prilocaine and lidocaine-induced methemoglobinemia is caused by human carboxylesterase, CYP2E1, and CYP3A4 mediated metabolic activation. Drug Metab Dispos 41:1220–1230
Hillmann KM (1978) Spinal prilocaine. Anaesthesia 33:68–69
Hjelm M, Ragnarsson B, Wistrand P (1972) Biochemical effects of aromatic compounds. III Ferrihaemoglobinaemia and the presence of p-hydroxy-o-toluidine in human blood after the administration of prilocaine. Biochem Pharmacol 21:2825–2834
IARC (International Agency for Research on Cancer) (2010) Monographs on the evaluation of the carcinogenic risks to humans. Some Aromatic Amines, Organic Dyes, and Related Exposures 99:407–451
Kaban OG, Yazicioglu D, Akkaya T, Sayin MM, Seker D, Gumus H (2014) Spinal anaesthesia with hyperbaric prilocaine in day-case perianal surgery: randomised controlled trial. Sci World J 2014:608372
Käfferlein HU, Broding HC, Bünger J, Jettkant B, Koslitz S, Lehnert M, Marek EM, Blaszkewicz M, Monsé C, Weiss T, Brüning T (2014) Human exposure to airborne aniline and formation of methemoglobin: a contribution to occupational exposure limits. Arch Toxicol 88:1419–1426
Klein J, Fernandes D, Gazarian M, Kent G, Koren G (1994) Simultaneous determination of lidocaine, prilocaine and the prilocaine metabolite o-toluidine in plasma by high performance liquid chromatography. J Chromatogr B Biomed Appl 655:83–88
Korinth G, Weiss T, Penkert S, Schaller KH, Angerer J, Drexler H (2007) Percutaneous absorption of aromatic amines in rubber industry workers: impact of impaired skin and skin barrier creams. Occup Environ Med 64:366–372
Kulkarni B, Fiala ES, Weisburger JH (1983) Estimation of N-hydroxy-o-toluidine, a urinary metabolite of o-toluidine and o-nitrosotoluene, by high performance liquid chromatography with electrochemical detection. Carcinogenesis 4:1275–1279
Kütting B, Göen T, Schwegler U, Fromme H, Uter W, Angerer J, Drexler H (2009) Monoarylamines in the general population–a cross-sectional population-based study including 1004 Bavarian subjects. Int J Hyg Environ Health 212:298–309
Larsen K (1972) Creatinine assay by a reaction-kinetic principle. Clin Chim Acta 41:209–217
Lewalter J, Gries W (2001) Haemoglobin adducts of aromatic amines. Analysis of hazardous substances in biological materials. Edited by Angerer J, Schaller K-H vol 7., Weinheim, Wiley-VCH pp 191–219
Markowitz SB, Levin K (2004) Continued epidemic of bladder cancer in workers exposed to ortho-toluidine in a chemical factory. J Occup Environ Med 46:154–160
Markowitz SB (2005) Corrections to: Markowitz SB, Levin K. Continued epidemic of bladder cancer in workers exposed to ortho-toluidine in a chemical factory. J Occup Environ Med 2004;46:154–60. J Occup Environ Med 47:875–877
Microsoft Corporation (2010) Microsoft Excel. Available at: https://office.microsoft.com/excel
Neumann HG, Birner G, Kowallik P, Schütze D, Zwirner-Baier I (1993) Hemoglobin adducts of N-substituted aryl compounds in exposure control and risk assessment. Environ Health Perspect 99:65–69
Neumann HG, Aromatic Amines in Experimental Cancer Research (2007) Tissue-specific Effects, an Old Problem and New Solutions. Crit Rev Toxicol 37(211):236
Richter E, Branner B (2002) Biomonitoring of exposure to aromatic amines: haemoglobin adducts in humans. J Chromatogr 778:49–62
Ringe D, Turesky RJ, Skipper PL, Tannenbaum SR (1988) Structure of the single stable hemoglobin adduct formed by 4-Aminodiphenyl in vivo. Chem Res Toxicol 1:22–24
Robertson DH (1978) Spinal Prilocaine. Anaesthesia 33:647–648
Skipper PL, Tannenbaum SR (1990) Protein adducts in the molecular dosimetry of chemical carcinogens. Carcinogenesis 11:507–518
Son OS, Everett DW, Fiala ES (1980) Metabolism of o-[methyl-14C]toluidine in the F344 rat. Xenobiotica 10:457–468
European Chemicals Agency (2008) Support document for identification of o-toluidine as a substance of very high concern because of its CMR1 properties
Ward EM, Sabbioni G, DeBord DG, Teass AW, Brown KK, Talaska GG, Roberts DR, Ruder AM, Streicher RP (1996) Monitoring of aromatic amine exposures in workers at a chemical plant with a known bladder cancer excess. J Natl Cancer Inst 88:1046–1052
Weiß T (2005) Entwicklung and Anwendung analytischer Methoden zum Biologischen Monitoring & Biochemischen Effektmonitoring von aromatischen Aminen im Rahmen arbeits-& umweltmedizinischer Fragestellungen. Dissertation Universität Erlangen-Nürnberg
Weiß T, Flieger A, Ewers U, Angerer J (2000) Innere Belastung der Allgemeinbevölkerung mit amino- und nitroaromatischen Verbindungen. Umweltmed Forsch Prax 5:101–106
Weiss T, Angerer J (2002) Simultaneous determination of various aromatic amines and metabolites of aromatic nitro compounds in urine for low level exposure using gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 778:179–192
Weiss T, Bolt HM, Schlüter G, Koslitz S, Taeger D, Welge P, Brüning T (2013) Metabolic dephenylation of the rubber antioxidant N-phenyl-2-naphthylamine to carcinogenic 2-naphthylamine in rats. Arch Toxicol 87:1265–1272
This study received fundings from BARA, the Belgian association for Regional Anesthesia, BARA vzw, UZ Leuven – Departement Anesthesie, Herestraat 49, 3000 Leuven (BE), and Association Vésale, Maison des Infirmières – CHU St. Pierre – 322 Rue Haute – Bruxelles (BE).
Conflict of Interest
Ethics committee registration number: EC 332, OM 157; B076201836443. This study was presented as a poster at the 38th annual ESRA Congress in Bilbao, Spain, 11–14 September 2019.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Guntz, E., Carini, A., Koslitz, S. et al. Quantification of systemic o-toluidine after intrathecal administration of hyperbaric prilocaine in humans: a prospective cohort study. Arch Toxicol 95, 925–934 (2021). https://doi.org/10.1007/s00204-021-02973-w
- Local anesthetic
- Hyperbaric prilocaine
- Hemoglobin adducts
- Spinal anesthesia