Hepatotoxic and neuroendocrine effects in physicians occupationally exposed to most modern halogenated anesthetics and nitrous oxide

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Highlights

  • Physicians occupationally exposed to modern inhalational anesthetics were evaluated.

  • Hepatotoxic and neuroendocrine biomarkers were assessed for the first time.

  • Anesthetic concentrations were detected in the workplace.

  • The anesthetic exposure is not associated with changes in liver enzymes and hs-CRP.

  • ACTH, cortisol and prolactin are not significantly affected by the exposure.

Abstract

The lack of data on hepatic and hormonal markers for occupational exposure to most modern halogenated anesthetics has stimulated our research, which assessed liver enzymes, high-sensitivity C-reactive protein (hs-CRP) and neuroendocrine response. The study investigated 106 physicians who were categorized in an exposed group (primarily exposed to isoflurane and sevoflurane and less to desflurane and nitrous oxide) as well as as a control group. Anesthetic air monitoring was performed, and biological samples were analyzed for the most important liver enzymes, hs-CRP, adrenocorticotrophic hormone, cortisol and prolactin. No biomarkers were significantly different between the groups. Exposed males showed significant increases in cortisol and prolactin compared to unexposed males. However, values were within the reference ranges, and 22 % of exposed males versus 5 % of unexposed males exhibited higher prolactin values above the reference range. This study suggests that occupational exposure to the most commonly used inhalational anesthetics is not associated with hepatotoxicity or neurohormonal changes.

Introduction

Annually, millions of people worldwide undergo a surgical procedure under general anesthesia with inhalation anesthetics. Concomitantly, a large number of healthcare professionals who work in surgical theaters are occupationally exposed to trace amounts of anesthetic gases because inhalational anesthetics inevitably generate waste concentrations of these gases in the workplace. Patients are highly exposed to anesthetics during surgical procedures, although professionals have much lower exposure. However, this exposure may extend over several years.

There are recommendations to minimize occupational exposure to inhalational anesthetics, such as that of the National Institute for Occupational Safety and Health (National Institute for Occupational Safety and Health (NIOSH, 2007) in the US, which recommends 2 parts per million (ppm) for halogenated anesthetics and 25 ppm for nitrous oxide, and the UK, which recommends 50 ppm and 100 ppm for halogenated isoflurane and nitrous oxide gas, respectively (Health and Safety Executive (HSE, 2002). However, exposure to anesthetic gases is inevitable in the surgical theater milieu (Braz et al., 2018; Chandrasekhar et al., 2006; Lucio et al., 2018), especially in rooms that are not equipped with an exhaust/scavenging system (Herzog-Niescery et al., 2019; Sharma et al., 2019; Wiesner et al., 2001).

Therefore, anesthesiologists, surgeons, nurses, technicians, trainees and students in both human and veterinary surgical theaters as well as some dentists must face chronic exposure to waste anesthetic gases (Chessor et al., 2005; Van der Kooy et al., 2012). The scientific literature has not to date established a strong causal link between adverse health effects and occupational exposure to anesthetic gases. However, long-term exposure to a mixture of older and more modern inhalational anesthetics is associated with hematopoietic changes (Casale et al., 2014; Weimann, 2003), immune deficiency (Bargellini et al., 2001; Goto et al., 2000), inflammation (Braz et al., 2020; Chaoul et al., 2015) and genetic damage (Braz et al., 2018; Costa Paes et al., 2014; Souza et al., 2016; Vodicka et al., 2016; Wrońska-Nofer et al., 2012).

The advantages of modern and commonly used inhalational halogenated anesthetics, such as sevoflurane, desflurane and isoflurane, include potency, rapid anesthetic induction and recovery, low rates of metabolism, and low solubility in blood and fat (Jakobsson, 2012; Prielipp, 2010). However, despite low solubility and rapid elimination, halogenated inhalational anesthetics are degraded into potentially toxic products (Obata et al., 2000) that may be linked to possible hepatotoxicity (Kharasch et al., 2001). Nitrous oxide, known colloquially as ‘laughing gas’, has anesthetic and analgesic properties, and it is commonly used in conjunction with other inhalational or intravenous anesthetics.

Abnormal liver biochemistry is characterized by a transient increase in enzymes, such as alanine-aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyltransferase (GGT) and alkaline phosphatase (ALKP), and the production of C-reactive protein (CRP), which is an important mediator of the inflammatory response (Desborough, 2000). Contradictory findings liver enzyme levels in professionals working in operating rooms exposed to inhalational anesthetics have been described (Bakhshaei et al., 2017; Caciari et al., 2013; Casale et al., 2014; De Zotti et al., 1983; Franco, 1989; Franco et al., 1993; Nunn et al., 1982; Safari et al., 2014). However, it is noteworthy that most of the aforementioned studies assessed only older halogenated anesthetics and did not evaluate anesthetic exposure in the current work environment. One study reported increased autoantibodies associated with volatile anesthetic hepatitis in pediatric anesthesiologists (Njoku et al., 2002), but these authors stated that most of these individuals do not develop hepatitis, which suggests that the autoantibodies may not have a pathological role in volatile anesthetic-induced hepatitis. Therefore, there is a lack of literature concordance on the potential risks of possible hepatotoxicity in professionals who are occupationally exposed to modern and frequently used inhalational halogenated anesthetics.

An increased level of CRP is related to a concomitant increase in the concentration of cytokines (Kurosawa and Kato, 2008), which are important in signaling the inflammatory response. During this response, other mediators, such as the adrenocorticotrophic hormone (ACTH) and cortisol, are released via the hypothalamic-pituitary-adrenal axis (HPA) axis. Therefore, the production of proteins, immune cells and hormones characterizes inflammatory response. However, the changes in the neuroendocrine system caused by occupational exposure to inhalational anesthetics are unknown, and there are scarce and controversial studies on this occupational exposure to the neurobehavioral system in exposed professionals (Isolani et al., 1999; Lucchini et al., 1995, 1997; Scapellato et al., 2008).

Considering the importance and relevance of evaluating the possible toxic effects of occupational exposure to inhalational anesthetics and the lack of studies that assessed the effects on liver and neurohormones in professionals exposed to the most modern halogenated anesthetics (sevoflurane, isoflurane and desflurane) and nitrous oxide, our study investigated the hepatotoxic and neuroendocrine effects in physicians with known anesthetic exposure to better understand the impact of current occupational exposure.

Section snippets

Ethics and study design

The institutional review board approved this study (Research ethics committee from “Faculdade de Medicina de Botucatu”, n. 1.602.015/2.261.832) prior to its initiation, and it was carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki).

This cross-sectional study included 106 physicians who worked in the same university tertiary hospital. The exposed group included 53 physicians (anesthesiologists and surgeons) of both sexes who worked in the

Results

There was similarity between the assessed groups because the unexposed group was matched by age, sex and lifestyle to the exposed group (Table 1). The anesthesiologists and surgeons (exposed group) worked 40 h per week in the surgical theater on average and were primarily exposed (90 %) to sevoflurane and isoflurane (6 ppm) and, to a lesser degree, desflurane (15 ppm) and nitrous oxide gas (100 ppm). The average exposure was 10 years.

Comparison of the exposed and unexposed groups (no missing

Discussion

Our study showed that occupational exposure to most modern halogenated anesthetics and nitrous oxide was not associated with abnormal liver biochemistry (hepatic enzymes and hs-CRP) or hormonal changes. Male anesthesiologists and surgeons showed slightly increased values of cortisol and prolactin when compared with unexposed male physicians, but these values were within the reference range. In addition, 22 % of exposed males versus 5 % of unexposed males exhibited higher prolactin values above

Funding

This study was supported by the São Paulo Research Foundation - FAPESP [grant numbers 2016/15559-1 and 2018/20143-4]. A.G.A. received a scholarship from the Coordination for the Improvement of Higher Education Personnel (CAPES), and K.M.S. and J.L.G. received a scholarship from FAPESP [grant numbers 2016/23902-8 and 2017/21504-8]. MGB is a recipient of a fellowship from the CNPq (#304107/2018-2).

Conflict of Interest

The authors declare no conflict of interest.

CRediT authorship contribution statement

Aline G. Aun: Conceptualization, Investigation, Project administration, Visualization, Writing - original draft. Kátina M. Souza: Investigation, Project administration, Visualization. Júlia L. Guedes: Conceptualization, Visualization. Drielle B.S. Figueiredo: Validation. Juliana R. Lara: Validation. Mariane A.P. Silva: Validation. Leandro G. Braz: Methodology, Supervision, Project administration, Funding acquisition, Writing - review & editing. Mariana G. Braz: Conceptualization, Visualization,

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgements

The authors would like to thank Prof. Lídia R. de Carvalho (Department of Bioestatistics, Institute of Biosciences, São Paulo State University - UNESP, Botucatu, Brazil) for providing statistical analyses.

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