Exposure Assessment, Biological Monitoring, and Liver Function Tests of Operating Room Personnel Exposed to Halothane in Hamedan Hospitals, West of Iran.

BACKGROUND: Occupational exposure to halogenated hydrocarbons has been associated with halothane hepatitis, an increase of liver enzymes, and congenital malformations. The objectives of this study were to investigate whether bromide, a urinary metabolite of halothane, could be used as a biological marker of exposure to this anesthetic gas and assessment of associated exposure to halothane with any significant changes in conventional parameters of liver function (serum aminotransferase activities). STUDY DESIGN: A cross-sectional study. METHODS: Seventy-five anesthesiologists, anesthesia nurses, operating room nurses, and surgeons (exposed group) and 75 matched unexposed individuals (reference group) were selected randomly from two public hospitals in Hamadan City, western Iran.  Atmospheric concentrations of halothane in the breathing zone of the exposed subjects and urinary bromide levels were measured by headspace gas chromatography. Similarly, serum activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured by the enzymatic method using an automatic Prestige instrument. RESULTS: Mean atmospheric concentrations of halothane and urinary bromide levels for exposed subjects were 1.49 ±1.36 ppm and 0.83 ±0.29 mM, respectively. A relatively good correlation was found between exposure to halothane and urinary bromide levels (r=0.38). The chi-squared test results showed that the proportions of the subjects with abnormal ALT and AST among the women exposed were significantly higher than those of reference individuals (P<0.05). CONCLUSIONS: Urinary bromide can be used as a potential biomarker of exposure to halothane, although additional studies are necessary to further validate these initial findings.

Estudio piloto para la evaluación de la exposición ocupacional a halotano en dos hospitales de la ciudad de La Habana / Pilot study to evaluate occupational exposure to halothane in two hospitals of Havana City

Se realizó un estudio analítico de corte transversal al personal expuesto a gases anestésicos de halotano en los salones quirúrgicos ubicados en dos hospitales pediátricos docentes de la ciudad de La Habana. Se analizaron muestras de orina a 80 trabajadores con ocupaciones de cirujanos, anestesistas, técnicos anestesistas, enfermeras y auxiliares generales que laboraban en estos salones operatorios, después de una exposición de más de 4 horas de forma continuada; de éstos fueron excluidos 13 sujetos por no presentar halotano en orina, por lo que se consideró solamente el 83,7 por ciento del total de trabajadores. La evaluación individual reflejó niveles de halotano en orina, hubo diferencias significativas entre los resultados de ambos hospitales, no siendo así entre las ocupaciones y los años de trabajo(AU)

Biomonitoring of exposure to nitrous oxide, sevoflurane, isoflurane and halothane by automated GC/MS headspace urinalysis.

OBJECTIVES: The goal of the present study was to develop an automated method to assess by biological monitoring, the volatile-anaesthetic exposure (nitrous oxide, sevoflurane, isoflurane and halothane) in operating theatre personnel. METHODS: Post-shift urine samples were analysed by gas chromatography-mass spectrometry coupled with static headspace sampling (GC-MS/ HSS); intra-assay %-RSD (n= 10) was less than 5% for nitrous oxide and less than 7% for each halogenated vapour. The biomonitoring method was validated with air monitoring data, obtained by personal samplers and a similar GC-MS method. The sensitivity achieved by single ion monitoring (SIM) was sufficient to reveal low biological and environmental exposure averages down to 1 microg/l(urine) and 0.5 ppm for nitrous oxide and 0.1 microg/l(urine) and 50 ppb for halogenated compounds, respectively. RESULTS: In 1998 we collected and analysed 714 post-shift urine samples for the biological monitoring of volatile anaesthetics in the urine of the operating-theatre personnel of Sant'Orsola-Malpighi Hospital (Bologna, Italy). Our data showed that nitrous oxide (N20), the anaesthetic most largely used in general anaesthesia, is still the decisive factor in operating-theatre pollution. Moreover, on the basis of our results, working in close contact with anaesthetics seems to be the main determinant of risk: surgical nurses and anaesthesiologists are the most-exposed professional categories (mean post-shift urinary N2O approximately 65 microg/l(urine)) while general theatre staff, surgeons, and auxiliary personnel have significantly lower exposure. CONCLUSIONS: The biological monitoring of post-shift unmodified urinary volatile anaesthetics was confirmed to be a useful tool for evaluating individual exposure to these chemicals. The urinary concentrations of N2O and of halogenated vapours might reflect, to a certain extent, the external exposure to these compounds, and respiratory air-monitoring data support the validity of biological monitoring. Furthermore, the good relationship between air and urinary concentration of anaesthetics in people working in closer contact with these chemicals may be a good indirect means of revealing the bad air conditions of operating rooms, and may contribute to the highlighting and correction of service defects in anaesthesiology equipment and of human errors.

Solid-phase microextraction gas chromatographic-mass spectrometric method for the determination of inhalation anesthetics in urine.

Solid-phase microextraction (SPME) has been applied to the headspace sampling of inhalation anesthetics (i.e. nitrous oxide, isoflurane and halothane) in human urine. Analysis was carried out by gas chromatography-mass spectrometry using a capillary column with a divinylbenzene porous polymeric stationary phase. A SPME divinylbenzene-Carboxen-polydimethylsiloxane coated fiber, 2 cm long, was used, and its performances were compared with those of a Carboxen-PDMS in terms of sensitivity, extraction efficiency, extraction time, fiber coating-urine distribution coefficient. For both fibers, linearity was established over four orders of magnitude, limits of detection were below 100 ng/l for nitrous oxide and below 30 ng/l for halogenated. Precision calculated as %RSD was within 3-13% for all intra- and inter-day determinations. The method was applied to the quantitative analysis of anesthetics in the urine of occupationally exposed people (operating room personnel).

The biological monitoring of inhalation anaesthetics.

The biological monitoring of inhalation anaesthetics. Occupational exposure to inhalation anaesthetics is an undesired consequence of the work in the operating theatre. Anaesthesia is currently practised using nitrous oxide associated with one or more potent anaesthetics (halothane, enflurane, isoflurane). In the present study we evaluated the occupational exposure to inhalation anaesthetics during anaesthesia in 190 operating theatres of 41 hospitals in Italy. Nitrous oxide, halothane, enflurane, isoflurane were detected in the urine of 1521 exposed subjects (anaesthetists, surgeons and nurses). Significant correlations were found between the anaesthetic concentrations in urine produced during the shift (Cu) and anaesthetic environmental concentrations (CI). The results show that the urinary anaesthetic concentration can be used as an appropriate biological exposure index. The biological threshold values (urinary concentration values) proposed are the following: nitrous oxide, 15, 28 and 57 micrograms/L for an environmental exposure of 25, 50 and 100 ppm respectively; halothane, 97 micrograms/L (for an environmental exposure of 50 ppm), 6.1 micrograms/L (for an environmental exposure of 2 ppm) and 3.3 micrograms/L (for an environmental exposure of 0.5 ppm); enflurane, 145 micrograms/L (for an environmental exposure of 50 ppm), 22.7 micrograms/L (for an environmental exposure of 10 ppm), 3.7 micrograms/L (for an environmental exposure of 1 ppm); isoflurane, 5.3 micrograms/L (for an environmental exposure of 2 ppm) and 1.8 micrograms/L (for an environmental exposure of 0.5 ppm). These values apply to urine samples collected at the end of 4-hours' exposure to the anaesthetics.

Physiologically based pharmacokinetic analysis of the concentration-dependent metabolism of halothane.

1. Previous studies with the halothane analogue and chlorofluorocarbon replacement 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) have shown that there are concentration-dependent, sex-specific differences in the rate of uptake during inhalation exposure in rat. Since it is well established that there are sex-specific differences in the control of enzyme activity in drug metabolism, male and female rats were exposed by inhalation to halothane concentrations ranging from 500 to 4000 ppm. 2. A physiologically based pharmacokinetic model describing the concentration-dependent reduction in uptake and metabolism of halothane in male and female rats was developed. The in vivo metabolic rate constants obtained were: for male rats, Km = 0.4 mg litre-1 (2.03 mumol litre-1) and Vmaxc = 9.2 mg kg1 h-1 (46.6 mumol kg1 h-1); for female rats, Km = 0.4 mg litre-1 (2.03 mumol litre-1) and Vmaxc = 10.2 mg kg-1 h-1 (51.7 mumol kg-1 h-1). 3. An equation describing the concentration-dependent decrease of hepatic metabolism of halothane successfully simulated the gas-uptake data. Simulation of cumulative urinary excretion of the major metabolite, trifluoroacetic acid, required introduction of a proportionality constant to limit the extent of reduction of halothane metabolism to 20% of the amount of enzyme activity. Good simulation of urinary excretion data was achieved, which was interpreted to indicate that, when only 20% of the enzyme is inactivated, the rate of enzyme resynthesis was adequate to replenish enzyme activity within 24 h. 4. A rapidly reversible, non-biological inactivation mechanism called "physical toxicity' is discussed as a possible explanation of concentration-dependent gas uptake.

Identification and quantification of fluorine-containing metabolites of 1-chloro-2,2,2-trifluoroethane (HCFC133A) in the rat by 19F-NMR spectroscopy.

1-Chloro-2,2,2-trifluorethane (HCFC133a) causes a reduction in testis weight and germinal epithelial cell atrophy in the rat following exposure by inhalation at concentrations of 10,000 ppm and above. Following administration by gavage, an increased incidence of Leydig cell tumors of the testis was seen. The metabolism of HCFC133a has been investigated in respect to the known toxicity of this compound. Male rats were exposed by inhalation to an atmosphere of 50,000 ppm HCFC133a for a period of 6 hr. Analysis of urine, collected during the exposure period and up to 48 hr following exposure, by 19F-NMR spectroscopy identified 2,2,2-trifluoroethanol (TFE; and its beta-glucuronide), trifluoroacetaldehyde (TFAA; as its hydrate and urea adduct), and trifluoroacetic acid (TFA) as fluorine-containing metabolites of HCFC133a. Of the total amount of metabolite eliminated in urine, 83% was excreted within 24 hr postdose, establishing a rapid elimination of metabolites by this route. TFAA, an established testicular toxicant, was the major metabolite accounting for 57% of the total fluorinated metabolites eliminated in urine, whereas TFA and TFE accounted for 29% and 14%, respectively. The presence of these metabolites in urine is consistent with an oxidative route of metabolism of this fluorocarbon.

[The biological monitoring of occupational exposure to anesthetic gas and vapors: the determination of nitrogen protoxide, halothane and isoflurane in the urine]. / Monitoraggio biologico dell'esposizione professionale a gas e vapori anestetici: determinazione di protossido d'azoto, alotano e isofluorano nell'urina.

A gas-chromatographic method has been developed for measuring urinary nitrous oxide, halothane and isoflurane concentrations. A volume of head-space gases obtained from biological samples is analyzed by ECD-GC on a steel column (2 mm ID) serially packed with Porapak Q (1.2 m) and MS-5A (0.30 m), operated at 160 degrees C. The detection limit (ranging from 0.03 micrograms/l for halothane to 1 microgram/l for nitrous oxide), between-day precision (CV < 6%) and working linear range (up to 100 micrograms/l for halothane and 2000 micrograms/l for nitrous oxide) were determined. A two-year experience in biological monitoring of occupationally exposed surgical staff with the proposed method is reported and confounding factors are discussed. The method is easy to perform, free from interferences and suitable for use in routine analysis in toxicological laboratories.

[Evaluation of several neuropsychological parameters in subjects occupationally exposed to anesthetics]. / Valutazione di alcuni parametri neuropsicologici in soggetti professionalmente esposti ad anestetici.

51 workers, occupationally exposed to anaesthetic gases and vapours (nitrous oxide, halothane, and isoflurane), were studied monitoring their environmental and biological exposure. Moreover, they were tested for visual reaction times and neurobehavioural batteries. There was no evidence of important neurotoxic effects nor of neurobehavioural problems with low concentrations of anaesthetics.

Urinary and biliary excretion of metabolites of halothane in dogs.

To determine the urinary and biliary excretion of metabolites of halothane in dogs, 12 beagles were anesthetized with halothane either at 0.5 MAC (minimum alveolar concentration) for 1 hr or at 1.4 MAC for 4 hr. Urine and bile were then collected for 11 days following the anesthesia. The concentrations of inorganic fluoride in the urine and bile were measured with a fluoride electrode and an ion meter. The concentration of total fluoride containing organic fluoride also was measured in the same manner after conversion of the organic fluoride to an inorganic form by combustion. The concentration of trifluoroacetic acid (TFA) in the urine was measured by ion chromatography and that in the bile by gas chromatography. Over 80% of all the fluoride was excreted in the urine as organic fluoride in both groups. While the fraction of TFA in the organic fluoride in the bile was about 30% in both groups, that in the urine was 40% in the 0.5 MAC group and 65% in the 1.4 MAC group. Therefore, it was concluded that the organic fluoride compounds, the metabolites of halothane, and in particular TFA, were excreted mostly into the urine. The extent of metabolism of halothane decreased from 7.6% in the 0.5 MAC group to 4.9% in the 1.4 MAC group. The urinary excretion rate of TFA, however, was not affected by the concentration of inspired halothane.

Biological monitoring of the occupational exposure to halothane (fluothane) in operating room personnel.

The concentration of halothane (fluothane) in the ambient atmosphere was determined in five operating theaters of two hospitals in Italy. The concentrations of halothane in the ambient air exceeded the NIOSH recommended time-weighted average exposure levels (median value: 10.38 mg/m3). Halothane was detected in the urine of 58 exposed subjects (anesthetists, surgeons, and nurses). A significant correlation was found between the halothane concentration in urine produced during the shift (Cu, micrograms/L) and halothane environmental concentration (CI, mg/m3) (Cu = 0.242 x CI + 3.51) (N = 58; r = 0.92; p less than 0.0001). The results show that the urinary halothane concentration can be used as an appropriate biological exposure index. The biological values proposed are: 92 micrograms/L, corresponding to a 50 ppm of environmental exposure; 6.5 micrograms/L, corresponding to 2 ppm of environmental exposure and 3.9 micrograms/L, corresponding to a 0.5 ppm of environmental exposure.

Interaction between prostaglandins of the E-type with a urinary component from halothane anesthetized rats.

Prostaglandins of the E-type (PGE's) were found to react or combine with a urinary metabolite of Halothane yielding products which were left unrecovered during the purification procedure preceding specific radioimmunoassay of PGE2. The products were retained on sephadex LH-20 columns, and showed on thin layer silica gel plates (TLC) Rf values lower than those of the parent PGE-compounds. The product formation is supposed to involve the beta-hydroxyketone system of PGE, since PG's of the F and A type were unaffected. The product formation could be avoided by inducing anaesthesia with Hexobarbitone and maintaining the anaesthesia with Halothane-nitrous oxide or it could be reversed by adding barbiturates to urine samples obtained from animals anaesthetized with Halothane-nitrous oxide alone. The barbiturates effectively competed with PGE for the metabolite leaving PGE to behave normally on sephadex LH-20 and TLC, thus enabling us to evaluate correctly the PGE2 content by RIA.

Detection of fluorinated anesthetic metabolities by sodium fusion.

A method is reported which utilizes a sodium fusion reaction to decompose organofluorine compounds and yield ionic fluoride which may then be quantified with a specific ion electrode. The method is simple, quick, sensitive, and applicable to fluorinated anesthetic metabolities.

[Adverse effects of modern inhalation anesthetics. 2. Control of amounts and elimination of escaping anesthesia gases]. / Gesundheitsschäden durch moderne Inhalationsnarkotika. Teil 2: Beschränkung der Menge und Eliminierung überschüssiger Narkosegase.

This paper presents a review on the pathological effects caused by acute or chronic exposure to the inhalation anesthetics halothane, methoxyflurane, or enflurane. Methoxyflurane has a dose-related nephrotoxicity due to its metabolic degradation with release of fluoride ions whereas suggested pathological renal effects of halothane or enflurane are still under discussion. As to the syndrome of halothane- (or enflurane-, methoxyflurane-) associated hepatitis no dose-dependent hepatotoxicity has been proven but interactions with hypoxia, hypotension, drug-pretreatment, and perhaps genetic abnormalities should be kept in mind. Severe hematologic alterations are effected by prolonged exposure to N2O or halothane and alterations of tumor immunity caused by anesthetic agents are reported, too. From clinical studies and observations of pregnant animals, a correlation between the incidence of miscarriages or malformations and chronic exposure to low doses of inhalation agents may be stated. Nevertheless, an inhalation agent is easy to control because it can be eliminated quickly in the case of complications. Therefore, one would not like to miss these inhalation agents in clinical practice but the immission into the operating room should be limited. Moreover, the best way to keep the operating room clean from waste anesthetic gases is the installation of a scavenging system which is connected to suction.

Mutagenicity of volatile anesthetics: halothane.

The mutagenicity of halothane was tested in an in-vitro microbial assay system employing two histidine-dependent mutants of Salmonella typhimurium, TA98 and TA100, Halothane in concentrations ranging from 0.1 to 30 per cent was incubated with bacteria in the presence or absence of a metabolic activation system prepared from either rat liver treated with Aroclor 1254 or human liver. Trifluoroacetic acid, a major metabolite of halothane, and urine from patients anesthetized with halothane also were tested. Halothane, trifluoroacetic acid, and patients' urines were not mutagenic.