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A study of the cardiac effects of bromochlorodifluoromethane (halon 1211) exposure during exercise.

Bromochlorodifluoromethane (halon 1211, a fire extinguisher), like other fluorocarbons, has been linked with ventricular arrhythmias and myocardial depression. Ten healthy firefighters, aged 40-50, were exposed to 1,000 ppm halon while exercising, in a double-blind, placebo-controlled crossover experiment, and were monitored during and after exposure. Complex ectopy (ventricular couplets and idioventricular rhythm) occurred in two subjects with halon, but none with placebo. One subject had 49.5 ventricular premature beats (VPB)/hour during the period of halon exposure and subsequent 8 hours and only 8.7 VPB/hour during the same period of placebo. In addition, 8 of the 10 subjects had a smaller systolic blood pressure rise during exercise with halon than with placebo. None of the observed differences was statistically significant. These results are consistent with findings in other investigations, suggesting that occupational fluorocarbon exposures may be cardiotoxic in certain individuals, although the small sample sizes used in this and other studies have resulted in limited statistical power to demonstrate this effect.

Adult↗

Toxicokinetics of inhaled bromotrifluoromethane (Halon 1301) in human subjects.

Bromotrifluoromethane (CBrF3), commonly known as Halon 1301, is used as a fire extinguishant in the Space Shuttle. Several scenarios, such as a fire or a faulty alarm, could lead to its discharge resulting in a Halon 1301 concentration of up to 1% in the spacecraft cabin atmosphere. To examine the effects of Halon 1301 on mental performance and physiologic function, the National Aeronautics and Space Administration sponsored a human inhalation study. Four pairs of adult male subjects were each exposed in a double-blind fashion for 24 hr to 1% (10,000 ppm or 60,875 mg/m3) Halon 1301 and to air in two separate exposures approximately 1 week apart. Mental performance and physiologic function were assessed and the results are reported in a companion paper (D. S. Calkins, J. J. Degioanni, M. N. Tan, J. R. Davis, and D. L. Pierson. Fundam. Appl. Toxicol. 20, in press). Blood and breath samples from the exposed subjects were also collected to provide dosimetric and toxicokinetic information, which is presented here. Blood Halon 1301 levels increased rapidly and approached a steady state within 2 hr of beginning the exposure; the steady-state concentration was approximately 3-4.5 micrograms/ml. Breath samples collected during exposures closely reflected chamber concentrations. Analysis of postexposure blood samples revealed that Halon 1301 was eliminated biphasically with an average t1/2 alpha and t1/2 beta of 4.5 min (range 2.5-8.1 min) and 200 min (range 131-347 min), respectively. Halon 1301 concentrations in fat and soft tissues were also estimated. Subsequently, the end-tidal breath/blood/tissue/fat partition coefficients were calculated to be 17/1/0.5/33.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

Human performance and physiological function during a 24-hr exposure to 1% bromotrifluoromethane (Halon 1301).

Performance and physiological measurements were obtained from four pairs of men exposed for 24 hr to 1% (10,000 ppm) Halon 1301 (bromotrifluoromethane, CBrF3) and to air with order counterbalanced using a double-blind protocol. Cognitive and motor performance was assessed before, during, and after the exposures using seven scales of the Automated Portable Testing System, which produced 13 measures of performance. Halon inhalation induced decrements in 2 of the 13 measures, but actual and estimated magnitudes of the decrements were no greater than 5% of baseline values. Physiological data were obtained before, during, and after the exposures from clinical chemistry analyses of blood and urine samples, pulmonary function tests, and monitoring of vital signs. Significant change during Halon inhalation was observed for 6 of the 52 variables assessed; however, all physiological values remained within clinically acceptable limits. No cardiovascular effects were noted. This study demonstrated that exposure to 1% Halon 1301 for 24 hr can produce minor disturbance of central nervous system function as assessed by cognitive tasks.

Administration, Inhalation↗

Activity of bromochlorodifluoromethane (BCF) in three mutation tests.

The halocarbon BCF was tested in 3 assays to assess its mutagenicity and clastogenicity. It produced a positive response in Salmonella typhimurium strain TA1535 but was negative in TA1537, TA1538, TA98 and TA100. In an L5178Y mouse lymphoma microwell assay (TK locus), BCF was negative. BCF was administered at 5000 and 50 000 ppm in air for 6 h to groups of C57B1/6J mice of both sexes. Animals were killed at 24, 48 and 72 h after cessation of exposure and the incidence of bone marrow micronuclei per 1000 PCEs determined. There was no significant difference in the incidences of micronuclei between untreated animals and those exposed to either concentration of BCF at any of the sampling times. These results suggest that BCF is mutagenic in vitro in only one strain of Salmonella; in mammalian cells the compound induced no gene mutation in vitro nor clastogenic activity in vivo at doses that also produced clear evidence of toxicity.

Animals↗

Metabolism and pharmacokinetics of selected halon replacement candidates.

Metabolism studies were conducted using Fischer 344 and Sprague-Dawley rats following inhalation exposure to 1.0% (v/v) air atmospheres of 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123), 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124), 1-chloro-1,1-difluoroethane (HCFC-142b), bromochlorodifluoromethane (Halon 1211), and perfluorohexane (PFH) for 2 h. There were no remarkable differences in results between the two strains of rats. Animals exposed to HCFC-123 or HCFC-124 excreted trifluoroacetic acid in their urine. Urinary fluoride concentrations were increased in rats exposed to HCFC-124, and urinary bromide levels were increased in rats exposed to Halon 1211. Small quantities of volatile metabolites 2-chloro-1,1,1-trifluoroethane (HCFC-133a) and 2-chloro-1,1-difluoroethylene were observed in the livers of rats exposed to HCFC-123. Rats exposed to HCFC-142b excreted chlorodifluoroacetic acid in their urine; no volatile metabolites were detected in tissue samples. For PFH studies, no metabolites were detected in the urine or tissues of exposed animals. These results are consistent with proposed oxidative and reductive pathways of metabolism for these chemicals. Pharmacokinetic studies were carried out in rats exposed by inhalation to 1.0%, 0.1%, or 0.01% of HCFC-123. Following exposure, blood concentrations of HCFC-123 fell sharply, whereas trifluoroacetic acid levels rose for approx. 5 h and then declined gradually. Using a physiologically based pharmacokinetic model, saturation of HCFC-123 metabolism was estimated to occur at approx. 0.2% (2000 ppm) HCFC-123.

Animals↗

A possible mechanism of halocarbon-induced cardiac sensitization arrhythmias.

Cardiac sensitization is the term used for malignant ventricular arrhythmias associated with exposure to inhaled halocarbons in the presence of catecholamines. We investigated the electrophysiological changes associated with cardiomyocyte exposure to epinephrine and a halocarbon known to be associated with cardiac sensitization (halon 1301, CF3Br). Cardiomyocytes (CMs) were isolated from neonatal rats and grown on multielectrode arrays (MEAs). Upon exposure to epinephrine, the CM inter-spike interval (ISI) was decreased 14% at 10 microg/L (P<0.05) and 27% at 100 microg/L (P<0.05) as compared to baseline. Halon alone (50 mg/L) mildly prolonged the field potential (FP) duration (7%). CMs exposed to combinations of epinephrine (100 microg/L) and halon (50 mg/L) for 15 min showed a blunted increase in the ISI (35+/-12%) and a 38% decrease in conduction velocity (P<0.05) when compared to epinephrine alone. There was no change in field potential properties, but dephosphorylated connexin 43 (Cx43) was increased 60+/-16% with the combination as compared to epinephrine alone (P<0.05). Treatment with okadaic acid, a phosphatase inhibitor, prevented the Cx43 dephosphorylation and the reduction in conduction velocity upon exposure to halon and epinephrine. Moreover, the electrophysiological changes induced by epinephrine and halon were indistinguishable from those seen with the gap junction inhibitor heptanol. In conclusion, the combination of a halocarbon and epinephrine results in a unique electrophysiological signature including slow conduction that may explain, in part, the basis for cardiac sensitization. The slowing of conduction is most likely related to changes in the phosphorylation state of Cx43.

Action Potentials↗

Effects of halone 1301 on Lepidium sativum, Petunia hybrida and Phaseolus vulgaris.

Halone 1301 belongs to a group of widely used fire repellants. Although banned in several countries, the production has still not been discontinued, and thus hazards due to use or spill can be expected. The study reports on effects of the halone 1301 on three plant species frequently used for bioindication studies: Lepidium sativum (mouse-ear cress), Phaseolus vulgaris (bush bean) and Petunia hybrida. Plants were exposed to 1 ppbv of the gas in ambient air under controlled conditions for 18 days (L. sativum), and 45 days (P. vulgaris, P. hybrida), respectively. None of the plants showed visible stress symptoms. Chlorophylls in cress and petunia were unaffected whereas in beans significant changes of the photosynthetic pigments were observed. Photosynthesis and gas exchange of bean plants were monitored during the experiment, and a lowering of transpiration was noticed. In all investigated plants, protein contents declined significantly, but despite this reduction, activity of the glutathione S-transferases (GST) increased strongly in bean and petunia. The significance of this reaction as detoxification step is discussed.

Bromochlorofluorocarbons↗

Experimental and computational studies of the gas-phase reaction of halon 1211 with hydrogen.

The gas-phase reaction of halon 1211 (CBrClF2) with hydrogen has been studied experimentally at atmospheric pressure in a plug flow, isothermal reactor over the temperature range of 673 to 973 K, at residence times ranging from 0.5 to 2.5 s with an input ratio of N2:H2:halon 1211 of 19:10:1. The major carbon containing products include CHClF2, CHBrF2, CH2F2, and CH4. Gas-phase reactions of CHClF2, CCl2F2, and CH2F2 with hydrogen are also investigated under the conditions similar to those for halon 1211 hydrodehalogenation, and the results are used to assist in understanding the mechanism of the reaction of halon 1211 with hydrogen. A kinetic reaction scheme involving 90 species and 430 reaction steps is developed and used to model the halon 1211 hydrodehalogenation reaction. Generally, satisfactory agreement between experimental and computational results is obtained for the production of major species. Using the software package AURORA, the reaction pathways leading to the formation of major products are elucidated. It has been found that the reaction steps involving CF2 are responsible for the formation of CH4.

Atmosphere↗

Reactive airways dysfunction syndrome following exposure to a fluorocarbon.

This report describes the case of a 43-yr-old male who developed reactive airways dysfunction syndrome after exposure to a high level of bromotrifluoromethane (CF3Br, Halon 1301), a fluorocarbon widely used in automatic fire extinguishing systems. The patient was a previously healthy, nonatopic male, who developed wheezing and intermittent and reversible obstructive ventilatory impairment starting immediately after a large accidental nonfire-related release of CF3Br in a confined space.

Accidents, Occupational↗

Setting safe acute exposure limits for halon replacement chemicals using physiologically based pharmacokinetic modeling.

Most proposed replacements for Halon 1301 as a fire suppressant are halogenated hydrocarbons. The acute toxic endpoint of concern for these agents is cardiac sensitization. An approach is described that links the cardiac endpoint as assessed in dogs to a target arterial concentration in humans. Linkage was made using a physiologically based pharmacokinetic (PBPK) model. Monte Carlo simulations, which account for population variability, were used to establish safe exposure times at different exposure concentrations for Halon 1301 (bromotrifluoromethane), CF(3)I (trifluoroiodomethane), HFC-125 (pentafluoroethane), HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane), and HFC-236fa (1,1,1,3,3,3-hexafluoropropane). Application of the modeling technique described here not only makes use of the conservative cardiac sensitization endpoint, but also uses an understanding of the pharmacokinetics of the chemical agents to better establish standards for safe exposure. The combined application of cardiac sensitization data and physiologically based modeling provides a quantitative approach, which can facilitate the selection and effective use of halon replacement candidates.

Animals↗

An accidental discharge of a Halon 1301 total flooding fire extinguishing system.

An accidental discharge of a total flooding Halon 1301 fire extinguishing system is described. The release of the Halon was accompanied by a sudden very loud noise, considerable air turbulence and a dense fog, resulting in worker anxiety and loss of visibility. The workers in the area at the time of the discharge reported higher frequencies of lightheadedness, headache, nasal complaints and disorientation than those entering the area later. Halon 1301 usually is regarded as having a low toxicity, although at concentrations above those used in occupied spaces, effects on consciousness and cardiac rhythm have been reported. In the present report no significant illness or injury due to the Halon exposure was found. A fine oily deposit found on horizontal surfaces in the area subsequent to the discharge consisted of mineral oil and iron, suggesting that this material was scoured out of the piping as the Halon discharged. The disorientation and anxiety produced by an accidental discharge can be minimized through education programs designed to ensure that personnel know what to expect and how to abort the discharge if it results from a false alarm. Situations leading to triggering of fire detectors by events other than fires should be investigated and reduced.

Accidents, Occupational↗

A xenon ionization detector for scanned projection radiography: Xenon/Freon 13B1 comparison.

In a companion paper, we reported on the construction and testing of a xenon gas ionization detector for use in line scanned projection radiography. Experimental results indicate that the detector has sufficient resolution for chest radiography, but higher resolution is required for mammography. Theoretical analysis suggested that a detector pressurized with Freon 13B1 would have better resolution and higher x-ray energy efficiency than a xenon-filled detector for energies below 60 keV. In this paper we compared, theoretically and experimentally, Freon 13B1 to xenon as the detector gas. For a 120-kVp x-ray spectrum, the detector filled with 2.0 MPa of xenon had less channel-to-channel crosstalk, a higher quantum efficiency (QE), and twice the output signal than the detector filled with 1.4 MPa of Freon (highest possible pressure at room temperature), while for a 60-kVp spectrum, crosstalk is the same, but the detector has slightly higher QE and 1.4 times the energy efficiency when filled with Freon instead of xenon. We conclude that xenon is better for high-kVp imaging, while Freon at a lower pressure is slightly better for low-kVp imaging.

Bromochlorofluorocarbons↗

Reactive airways dysfunction syndrome caused by bromochlorodifluoromethane from fire extinguishers.

Although the neurological and cardiovascular effects of Freons have been extensively described, the respiratory effects have been less well documented. We report four cases of occupational asthma following accidental exposure to bromochlorodifluoromethane (Halon 1211) due to release of the contents of a fire extinguisher. All subjects developed an irritative reaction of the upper airways and lower respiratory symptoms immediately after exposure. Non-specific bronchial hyperreactivity was present for at least two months in all subjects and was still present more than two years after exposure in one case. The diagnosis of reactive airways dysfunction syndrome can be adopted in at least three of these four cases.

Adult↗