The following is a review of much of the literature on
the toxicology of PFIB. Although listed in Schedule 2 of
the CWC, there is relatively little written in the usual
military chemical books about PFIB, compared to the
"classic" CW agents. Much of the literature
discussion appeared in occupational medicine journals in
the 1960s and 1970s. In the interests of better
understanding of common medical issues in CBW, ASA is
happy to present this article by Drs. Bajgar and Patocka.
Toxicology of Perfluoroisobutene
by Jiri Patocka and Jiri Bajgar
The Department of Toxicology, Military Medical Academy 500 01 Hradec Krlov, Czech Republic. E-mail: firstname.lastname@example.org and email@example.com
Perfluoroisobutene (PFIB, 1,1,1,3,3-penta fluoro-2-trifluoro methylpropene, CAS No. 3812-21-8) is a fluoro-olefin produced by thermal decomposition of polytetrafluoroethylene (PTFE), e.g., Teflon .
Overheating of PTFE generates fumes of highly toxic PFIB and poses a serious health hazard to the human respiratory tract. PFIB is approximately ten times as toxic as phosgene . Inhalation of this gas can cause pulmonary edema, which can lead to death. PFIB is included in Schedule 2 of the Chemical Weapons Convention (CWC), as a result of the prompting by one delegation to the Conference on Disarmament . The aim of the inclusion of chemicals, such as PFIB was to cover those chemicals, which would pose a high risk to the CWC. Subsequently PFIB, specifically, was included in the final text of the CWC.
PFIB is a strong electrophile, which reacts with all nucleophiles . The high electrophilicity of PFIB is a result of the strong electron-attracting effects of the fluorine atoms of the trifluoromethyl groups and the conjugation of the fluorines p electrons with the double bond of the vinyl group. Several reactive intermediate species were identified in the reaction of PFIB with nitrone and nitroso spin trap agents, and, some of the expected reactive nucleophiles in vivo include amines, alcohols and especially thiols .
PFIB decomposes rapidly when dissolved in water, forming various reactive intermediates and fluorophosgene, which then decomposes into carbon dioxide, a radical anion and hydrogen fluoride . PFIB is a gas with a boiling point of 7.0çC at one atm and a gas density of 8.2 g/L . The synthesis of PFIB from fluorodichloromethane is given in Fig. 1.
The toxicity of PFIB may be correlated with its susceptibility to nucleophilic attack and the generation of reactive intermediates . This is similar to the toxicity of other fluoro-olefins; their toxicity is directly proportional to the reactivity of that olefin with nucleophiles [7, 8].
The median lethal concentration (LC50) in single exposures of rats was 0.5 ppm. The intoxicated rats either died with gross pathological signs of pulmonary congestion or recovered with no apparent residual effects. The 15-second LC50 was 361 ppm and the 10-minute LC50 was 17 ppm . Similar high acute toxicity following inhalation was seen in other species with a two hour LC50 in mice reported to be either 1.6 ppm  or 0.98 ppm , in rabbits either 4.3 ppm  or 1.2 ppm , in guinea-pigs 1.05 ppm  and in cats 3.1 ppm . In experiments in which rats were exposed to a concentration of 12.2 ppm for 10 min, an unusual postexposure latency period of approximately 8 hours was observed prior to the occurrence of pulmonary edema .
Repeated Dose Toxicity
The information on repeated dose inhalation studies of PFIB are not generally available. According to Kennedy , rats exposed to 0.1 ppm, six hours per day, five days per week for two weeks showed no compound-related pathological changes and only mild respiratory impairment and restlessness during their exposure. A repeat study using the same experimental conditions (0.1 ppm) found no effects in rats .
Pyrolytic products of PTFE heated below 500çC may be dangerous .[Editors note: this has been called "polymer fume fever."] Five workers accidentally exposed to a gas containing 2 percent PFIB reported irritation of the respiratory tract within 24 h of exposure. The lung irritation was manifested by cough in all cases. The patients developed headache, cough, substernal pain, dyspnoea and fever within the first hour following exposure. The symptoms became worse at six to eight hours after exposure. Also choking or shortness of breath was observed in a majority of the patients. The condition of the patients began to improve on the fifth day and they were discharged from the hospital after two to three weeks. One patient developed a respiratory infection, which required his stay in hospital to be extended to about eight weeks. All the patients were shown to have pulmonary edema and this was confirmed at post mortem on two patients died. One died after 11 days after exposure, the other died after 13 days [16, 17]. According to Kennedy , one worker exposed to PFIB for three minutes reported strong subjective symptoms of bad odor, bad taste in the mouth, nausea and weakness. On returning to fresh air, the worker recovered and had no further symptoms. Half an hour later, a concentration of 0.04 ppm of PFIB was measured in the exposure area.
The latency period for PFIB injury is one to four hours until pulmonary edema symptoms appear. In many cases, pulmonary edema clears up in about 72 hours, with little long-term damage .
Genetic Toxicity and Carcinogenicity
No information of either genetic toxicity or carcinogenicity was found.
No officially available studies on the environmental effects of PFIB have been found. The concentration of PFIB in air can be determined  and probably 0.1 ppm is the maximum air concentration (cont. p. 16 "PFIB") ("PFIB" from p. 15) below which nearly all individuals could be exposed for up to one hour without serious adverse health effects or symptoms .
The histopathology of rat lung has been studied after an acute exposure to PFIB at a concentration of 78 ppm for 1.5 min. Within 5 min of exposure, changes to the bronchioles and peribronchial alveoli were observed which took the form of alterations to cilial structure, increased pinocytosis with occasional vesicle formation of type I alveolar epithelial cells. The gradual development of pulmonary edema was visible histologically two to three hours post exposure, with death occurring from seven hours onwards. Animals sacrificed at 24 hours post exposure showed evidence of widespread pulmonary edema and alveolar interstitial infiltration by lympho mononuclear cells and macrophages . In other experiments, PFIB induced pulmonary edema involving a translocation of blood compartment proteins into the lungs alveolar compartment. By high-performance capillary electrophoresis of proteins from the fluid lining of the lungs of rats exposed to PFIB was estimated that albumin, transferrin and IgG are three major proteins translocated into the alveolar space .
Pretreatment and Treatment
The PFIB exposure caused an immediate depletion of intracellular lung cysteine and glutathione. Therefore several cysteine esters and N-acetylcysteine were used as thiol pretreatment to increase the level of intracellular thiols and have been shown to protect against a lethal exposure of PFIB . Oral N-acetylcysteine , which is used as a mucolytic in chronic obstructive pulmonary disease, as well as in diseases which are complicated by the production of viscous mucus [22, 23], has shown protection against inhalation of PFIB in rats . Protection against the lethal effect of inhaled PFIB has been shown when N-acetylcysteine has been orally administered 4, 6 or 8 hours before gas exposure and the duration of protection has been related to the duration of increased levels of cysteine, glutathione and N-acetylcysteine in the plasma .
The treatment of PFIB intoxication is based on edema reduction by administration of diuretics. In experiments on rats, the diuretics furosemide and torasemide reduced the lung edema and the pattern and severity of the pathological changes associated with inhalation of PFIB and delayed the time to death .
Perfluoroisobutene (PFIB) is a hydrophobic reactive gas produced by pyrolysis of polytetrafluoroethane that induces pulmonary edema similar to that induced by phosgene when inhaled. PFIB is highly toxic, approximately ten times as toxic as phosgene and can be very dangerous for humans. Oral administration of N-acetylcysteine appears to be a good protective drug against the lethal effect of inhaled PFIB.
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