ORIGINAL ARTICLE Antonio Accorsi Æ Simona Valenti Æ Anna Barbieri Giovanni Battista Raffi Æ Francesco Saverio Violante Proposal for single and mixture biological exposure limits for sevoflurane and nitrous oxide at low occupational exposure levels Received: 17 December 2001 / Accepted: 15 July 2002 / Published online: 24 September 2002 Ó Springer-Verlag 2002 Abstract Objectives: Assessment of individual expo- sures to sevoflurane plus nitrous oxide (N 2 O) by bio- logical monitoring of unmodified analytes in post-shift urine of exposed personnel. Methods: Anaesthetics in urine and breathing area were monitored in 124 subjects in 11 operating theatres. Passive samplers were collected after 2.5–7 h of exposure, at the same time as post-shift urinary samples, to evaluate the individual time- weighted average (TWA) exposures to sevoflurane and N 2 O. A static headspace sampler coupled with a gas chromatograph mass spectrometer was used for analyt- ical determinations (sensitivity sufficient to reveal bio- logical/environmental exposures of 0.1 lg/l urine and 50 ppb for sevoflurane, and 1 lg/l urine and 80 ppb for N 2 O). Results: Median (range) post-shift urinary and environmental values were 1.2 lg/l urine (0.1–5.0) and 0.4 ppm (0.05–3.0) for sevoflurane (n=107) and 10.9 lg/ l urine (0.5–74.9) and 8.6 ppm (0.2–123.4) for N 2 O (n=121) (all low-exposure range). At log–log regression, urinary levels closely correlated with environmental data (sevoflurane, r 2 =0.7538; N 2 O, r 2 =0.8749). Biological equivalent limits (BELs) based on National Institute for Occupational Safety and Health (NIOSH) TWA expo- sure limits, calculated as means of regression slope and y-intercept, were 3.6 lg/l urine for sevoflurane (corre- sponding to 2 ppm) and 22.3 lg/l urine for N 2 O (corre- sponding to 25 ppm). Individual ‘‘mixture BELs’’, which we calculated by applying the American Confer- ence of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV)mix formula to biomarker values and using the obtained NIOSH-based BELs as a reference, closely correlated with mixture TLVs (q=0.816, Lin’s concordance test). Conclusions: We propose urinary sevoflurane as a new, specific, internal dose biomarker for routine biological monitoring of personal exposures among operating-theatre personnel, and use of reliable ‘‘mixture BELs’’ to provide safer levels of internal exposure for workers exposed to mix- tures of sevoflurane and N 2 O, and conceivably also to other mixtures of toxicants with possible additive effects. Keywords Sevoflurane Æ Nitrous oxide Æ Biological monitoring Æ Biological exposure limit Introduction All modern anaesthetic drugs, whether inhalational ha- lides such as desflurane (C 3 H 2 F 6 O; molecular weight (MW), 168) and sevoflurane (C 4 H 3 F 7 O; MW, 200) or intravenous anaesthetic agents such as alkylphenols or fentanyl-type opioids, allow rapid recovery and early postoperative mobilisation. Nitrous oxide (N 2 O; MW, 44) is a mild anaesthetic that has been safely used in combination with oxygen for over 150 years. Sevoflu- rane is a halogenated agent which is increasingly being used in anaesthesiology because of its pharmacokinetic properties (low blood/gas distribution coefficient, fast metabolism, rapid recovery time). Combined use of N 2 O and sevoflurane is today very common (O’Shea et al. 2001). Anaesthetic exposure levels in operating theatres de- pend primarily on the efficiency of the active scavenging system, as well as on multiple factors such as the chosen types of anaesthesiological equipment (close/open systems) and the techniques used for induction and maintenance of anaesthesia (high/low flow rate, use of face masks or laryngeal mask airways, use of uncuffed tracheal tubes, etc.) (Lauwerys 1983; Imbriani et al. 1988a; Accorsi et al. 2001). N 2 O may produce heavy pollution in a very short time when leaks occur in high- pressure circuits, especially in rooms with insufficient air Int Arch Occup Environ Health (2003) 76: 129–136 DOI 10.1007/s00420-002-0379-4 A. Accorsi (&) Æ S. Valenti Æ A. Barbieri Æ G.B. Raffi F.S. Violante Laboratorio di Tossicologia, Servizio di Sicurezza, Igiene e Medicina del Lavoro, Universita` degli Studi di Bologna, Via Palagi 9, 40138 Bologna, Italy E-mail: accorsi@orsola-malpighi.med.unibo.it Tel.: +39-051-4290216 Fax: +39-051-301968