Elsevier

Toxicology Letters

Volume 225, Issue 1, 10 February 2014, Pages 102-109
Toxicology Letters

Blood and exhaled air can be used for biomonitoring of hydrofluorocarbon exposure

https://doi.org/10.1016/j.toxlet.2013.11.026Get rights and content

Highlights

  • We compared data on blood and exhaled air from a series of experiments of HFCs.

  • All four HFCs had similar toxicokinetic profiles in blood, breath and urine.

  • The observed time courses in blood and breath were well described by PBPK modeling.

  • Blood and exhaled air can be used for biological exposure monitoring of HFCs.

Abstract

Various hydrofluorocarbons (HFCs) have replaced the ozone-depleting chlorofluorocarbons and hydrochlorofluorocarbons during the last decades. The objective of this study was to examine the usefulness of blood and breath for exposure biomonitoring of HFCs. We compared data on blood and exhaled air from a series of experiments where healthy volunteers were exposed to vapors of four commonly used HFCs; 1,1-difluoroethane, 1,1,1-trifluoroethane, 1,1,1,2-tetrafluoroethane, and 1,1,1,3,3-pentafluoropropane. All four HFCs had similar toxicokinetic profiles in blood with a rapid initial increase and an apparent steady-state reached within a few minutes. For all HFCs, the inhalation uptake during exposure was low (less than 6%), most of which was exhaled post-exposure. No metabolism could be detected and only minor amounts were excreted unchanged in urine. The observed time courses in blood and breath were well described by physiologically-based pharmacokinetic (PBPK) modeling. Simulations of 8-h exposures show that the HFC levels in both blood and breath drop rapidly during the first minutes post-exposure, whereafter the decline is considerably slower and mainly reflects washout from fat tissues. We conclude that blood and exhaled air can be used for biological exposure monitoring. Samples should not be taken immediately at the end of shift but rather 20–30 min later.

Introduction

Hydrofluorocarbons (HFCs) were introduced as substitutes to chlorofluorocarbons (CFCs) in refrigeration and air-condition installations. The CFCs contributed to the depletion of stratospheric ozone and in an international agreement, the Montreal Protocol (UNEP, 1987) restrictions of CFCs use were developed. Hydrofluorocarbons are now the main refrigerants (Blowers and Lownsbury, 2010) and tetraflouroethane (HFC134a) is the most world-widely used (Tsai, 2005). The four studied HFCs, 1,1-difluoroethane (HFC152a), 1,1,1-trifluoroethane (HFC143a), 1,1,1,2-tetrafluoroethane (HFC134a), and 1,1,1,3,3-pentafluoropropane (HFC245fa) are all commonly used colorless gases with faint, ethereal smells and are low-or non-flammable at atmospheric pressure and room temperature. Except for being used as refrigerants, HFCs are also used as blowing agents, in aerosol inhalers and as dry etching agents (Tsai, 2005). HFCs have no potential to deplete the ozone layer. They have short atmospheric lifetimes and their global warming potentials are rather low (Table 1) (Tsai, 2005, Restrepo et al., 2008).

Human exposure to HFCs may occur via inhalation from accidental leaks or spills from refrigeration systems, recycling systems, electronic appliances, degreasing processes for precision cleaning, gas delivery pipelines in semiconductor manufacturing, or medical delivery systems for the treatment of asthma (Tsai, 2005). Levels up to 1444 ppm HFC143a and 340 ppm HFC134a were reported during repair work of a refrigeration installation (Gjolstad et al., 2003).

The adverse effects associated with exposure to HFCs is central nervous system (CNS) depression and cardiac sensitization related to the anesthetic properties of HFCs (Tsai, 2005). Previously, there are very few data on health effects and toxicokinetics in humans. No effects on pulse rate, blood pressure, cardiac rhythm or lung function were seen in humans after one hour exposure at up to 8000 ppm HFC134a (Emmen et al., 2000) or after up to four single inhalations of 40 000 ppm HFC134a (Denyer et al., 1994). No in vivo studies on the disposition of HFC152a, HFC143a and HFC245fa in humans were found.

The acute and chronic toxicity of HFCs in animal studies is low. HFCs are not mutagenic and do not cause developmental toxicity. LC50 (the lethal concentration to 50% of a rat population by 4 h inhalation) of HFC152a, HFC143a, HFC134a, and HFC245fa were 38, 54, 50, and 20 v/v%, respectively (Tsai, 2005). In a study by Keller et al. (1996) inhalation exposure to 3000 ppm HFC152a for 4 h showed no effect in rats. The substance may, however, induce cardiac sensitization at higher exposure levels (150 000 ppm, 405 000 mg/m3). At exposure concentrations below 50 000 ppm of HFC143a, no effects were seen in animal studies. However, cardiac arrhythmia can be induced in dogs given adrenaline at exposure levels of 300 000 ppm (Brock et al., 1996). A NOAEL has been estimated to 49 500 ppm of HFC134a and its critical effect, based on animal data, is cardiac sensitization in dogs (Lundberg, 1995). In inhalation studies of HFC245fa in mice and rats only mild signs of acute toxicity were found. Effects up to 50 000 ppm are mild, exposure below 5000 ppm gives no clear signs of toxicity and 2000 ppm represents a NOAEL for diffuse myocarditis (Rusch et al., 1999). No other data are available of NOAEL or LOAEL of any of the four studied HFCs.

Regarding metabolism of HFCs, it has been shown that oxidation or reduction reactions are catalyzed by cytochrome P450. Acyl halides are formed and further hydrolyzed to trifluoroacetic acid and excreted in urine (Monte et al., 1994, Dekant, 1996). However, very low metabolic rates of the present HFCs are reported in humans, in vivo, Monte and colleagues (1994) found less than 0.0004% of an inhaled single dose of 1200 mg HFC134a excreted as trifluoroacetic acid. In vitro, in human liver microsomes, HFC245fa was metabolized to trifluoroacetic acid and 3,3,3-trifluoropropionic acid (Monte et al., 1994, Bayer et al., 2002).

Some of the HFCs have become substances of abuse due to its accessibility. Fatal cardiac arrhythmias due to intoxication with HFC152a have been reported (Avella et al., 2006). This intoxication has been associated with sudden death involving cardiac arrhythmias termed “sudden sniffing death syndrome” (Bass, 1970, Groppi et al., 1994, Xiong et al., 2004).

The present Swedish 8 h time weighted occupational exposure limit (OEL) of HFC134a is 500 ppm (2000 mg/m3) (SWEA, 2011). No OELs for the other three studied HFCs are available in Sweden. The American Industrial Hygiene Association (AIHA) have established a workplace environmental exposure limit (WEEL) based on 8 h time-weighted average values of 1000 ppm (2700 mg/m3) for HFC152a, 1000 ppm (3500 mg/m3) for HFC143a, 1000 ppm (4200 mg/m3) for HFC134a, and 300 ppm (1500 mg/m3) for HFC245fa. In Germany (MAK value) and United Kingdom the OEL (8 h) for HFC 134a is 1000 ppm.

Exposure to HFCs, e.g. during installation or repair of refrigeration or air-condition systems, is likely to occur as short peaks and to be locally distributed. Air monitoring, including personal monitoring in the breathing zone, may then be misleading. In such cases, biological exposure monitoring may be advantageous as it more closely reflects the internal exposure.

The objective of this paper was to study the possibility to use blood and exhaled air for biomonitoring of HFCs. We compare the uptake, distribution and elimination of four HFCs studied in humans during and after short-term inhalation exposure (Gunnare et al., 2006, Gunnare et al., 2007, Ernstgård et al., 2010a, Ernstgård et al., 2012). The observed time courses in blood and exhaled air is described with a physiologically-based pharmacokinetic (PBPK) model. In additional PBPK simulations, the experimental 2-h exposures were extended to 8-h exposures to better capture occupational conditions. In these simulations, not only the four experimentally studied HFCs but also a fifth one, HFC125a (1,1,1,2,2-pentafluoroethane), were included.

Section snippets

Experimental data

In this study, we compare experimental data from previously published human inhalation studies of four different HFCs (Gunnare et al., 2006, Ernstgård et al., 2010a, Ernstgård et al., 2012) by PBPK modeling. In the experimentally studies, we exposed healthy volunteers to vapors of the four HFCs for 2 h during light physical exercise (50 W) in an exposure chamber. In the studies of HFC143a and HFC134a only male volunteers, occupationally exposed to HFCs, participated. The participants in the

Results

All HFCs had similar toxicokinetic profiles in blood with a rapid initial increase of HFC and an apparent steady-state reached within a few minutes. The first phase of the post-exposure decrease in blood was fast as well; this was followed by a slower phase (Fig. 2A). The blood concentrations were below the detection limit 22 h after exposure. The AUC corrected for the difference in exposure levels was highest for HFC152a and lowest for HFC143a (Table 3).

The inhalation uptake could not be

Discussion

This paper describes and compares data from four experimental studies of HFCs in order to study the possibility to use blood and exhaled air for biomonitoring of HFC exposure. The data is analysed with a PBPK model which would also be appropriate for other HFCs. The PBPK model is necessary for two reasons. First, the concentrations of HFCs were almost identical in inhaled and exhaled air in the human volunteer experiments, therefore the respiratory uptake could not be experimentally determined.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgement

The study was partly funded by a grant from the Swedish Research Council for Health, Working Life and Welfare (Forte, grant No. 2010-0702). We are grateful to Mr. Birger Lind for skillful technical assistance at the chamber exposures of HFC152a and HFC245fa.

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