Many halogenated hydrocarbons and other compounds are stratospheric ozone depleters, and the Montreal Protocol on Substances That Deplete the Ozone Layer proposed a ban on them in 1987. In response, the U.S. chemical industry ceased their production and has been phasing out their use ever since. Among the chemicals that were scheduled to be phased out were the chlorofluorobromines (halons). The U.S. military uses halons for fire suppression and extinguishment in electronic equipment, crew compartments in such combat vehicles as aircraft and armored vehicles, machinery spaces in military ships, and high-bay rooms in flight simulators. The U.S. Army is actively engaged in identifying effective, efficient, and safe substitutes for halons in those applications. Among the contenders as a replacement is iodotrifluoromethane (CF3I).
CF3I is an odorless, colorless gas with slight solubility in water. It was approved as a substitute for Halon 1301, a common fire extinguisher in total flooding systems under the U.S. Environmental Protection Agency (EPA) Significant New Alternatives Policy (SNAP), in 1997. However, EPA stipulated that any personnel that could possibly be in an area of exposure to CF3I should be able to escape within 30 seconds (sec), that the employer ensure that no unprotected employees enter the area during CF3I discharge and that the use of CF3I be in accordance with the safety guidelines in the latest edition of the National Fire Protection Association (NFPA) standard. The 2001 Standard on Clean Agent Fire Extinguishing Systems states that a human may be safely exposed to CF3I at concentrations above the no-observed-adverse-effect level (NOAEL) of 0.2% (2,000 parts per million [ppm]) up to 0.3% (3,000 ppm) for as long as 5 minutes (min). Brief exposure at concentrations above 3,000 ppm is permissible in occupied and
unoccupied spaces (where exposure might occur as a result of an accidental release), but the time for “safe” exposure decreases. NFPA used a NOAEL of 2,000 ppm and a lowest-observed-adverse-effect level (LOAEL) of 4,000 ppm derived from experiments in dogs for a pharmacokinetic model on which it based its determinations of the toxicity of CF3I.
In May 1999, the U. S. Army Center for Health Promotion and Preventive Medicine at Aberdeen Proving Ground, Maryland, prepared a report that reviewed the toxicity of CF3I, which it updated in 2002. Those reports did not accept the NFPA 2001 Standard “safe” exposure limit of 2,000 ppm for CF3I but instead indicated that any use at a design concentration greater than 2,000 ppm must conform to the EPA SNAP guidelines as published in 1995. The Office of the Surgeon General of the U.S. Army then requested that the National Research Council Committee on Toxicology (COT) independently review the Army’s assessment and evaluate the scientific basis of its recommended exposure limit.
THE CHARGE TO THE SUBCOMMITTEE
In response to the Army’s request, the National Research Council formed the Subcommittee on Iodotrifluoromethane under COT. Members were chosen for their expertise in toxicology, pharmacology, occupational health, chemistry, biostatistics, physiologically based pharmacokinetic modeling, and risk assessment. The subcommittee was asked to review the toxicologic, toxicokinetic, and related data on CF3I and to evaluate the scientific basis of the Army’s recommended exposure limit of 2,000 ppm in air. It was also asked to identify relevant database deficiencies and to make recommendations for future research need.
THE SUBCOMMITTEE’S APPROACH
To meet its charge, the subcommittee held two public sessions; reviewed materials submitted by the Army and others, including the Army’s 1999 and 2002 toxicity review of CF3I; and assessed current literature relevant to the toxicity of CF3I, such as the NFPA Standard 2001. The subcommittee also conducted a literature search to identify any new materials published since the Army’s 2002 report.
THE SUBCOMMITTEE’S FINDINGS AND RECOMMENDATIONS
The subcommittee found that the acute toxicity (continuous exposure for less than 24 hours [h]) of CF3I is low; adverse effects are seen in rats at concentrations of 10.0% (100,000 ppm) or greater in inhalation studies. For subacute exposures (repeated exposures for less than 1 month), changes in some thyroid measures were seen in rats at 2.0% (20,000 ppm), hematologic effects and decreased body weights were seen at 4.0% (40,000 ppm) at 4 weeks. For subchronic exposures (repeat exposure for more than 1 month but less than 3 months), hematologic effects were seen at 2.0%, at 13 weeks.
On the basis of those results at high concentrations, the subcommittee found no need for further acute, subacute, or subchronic testing of CF3I.
The subcommittee found that the conclusions reached by the Army on most of the genotoxicity data are scientifically appropriate. However, one reproductive study with a micronuclei-induction component had a weakness. Although it had negative results for micronuclei induction, the highest concentration (2.0% or 20,000 ppm) used in this negative study was below the lowest concentrations used in earlier micronuclei-induction studies (5.0% and 4.0% for mouse and rat, respectively), which had positive results. The ratio of polychromatic erythrocytes to normochromatic erythrocytes was the same in all concentration groups, including the control group; that suggests that the concentrations could have been higher. The subcommittee finds that the negative study should not be viewed as having as much weight as the other micronucleus studies. Five gene-mutation assays also had equivocal results: two were weakly positive for gene mutations, two strongly positive for gene mutations, and one negative for gene mutations and chromosomal aberrations.
Given the varied genotoxicity results, the subcommittee suggests that it would be prudent to verify the micronucleus results in a mouse or rat bone marrow chromosomal-aberration study that focuses on structural aberrations, as opposed to micronuclei induction. This recommendation
is based on the positive results in two species (rat and mouse) in previous micronucleus assays and the potential for chronic exposure to CF3I.
No published studies on the carcinogenicity of CF3I in animals were found by the Army in its toxicity review or by the subcommittee. However, studies suggest that CF3I may be a mutagen, so it may also be a carcinogen.
On the basis of the positive genotoxicity findings, the subcommittee recommends that short-term testing for carcinogenicity be conducted. Studies of in vitro cellular transformation, as in the Syrian hamster embryo cell-culture assay, and transgenic animals should be considered. The subcommittee finds that if any of the recommended short-term carcinogenicity tests are positive, the Army must consider whether, given its proposed use and exposure scenarios, a 2-year, in vivo, inhalation bioassay for carcinogenicity should be conducted.
The subcommittee and the Army found only one reproductive-toxicity study of CF3I. It was negative for all reproductive indexes, and the subcommittee concurs with the Army’s conclusion that CF3I is not likely to have reproductive toxicity in the rat. However, in a subchronic inhalation study with rats via nose-only exposure, degeneration of the testes and a relative decrease in testicular weight were seen in the highest-exposure group. Review of the literature suggests that those effects may be due to heat stress associated with nose-only exposure. The subcommittee concluded that the effects seen in the subchronic study were most likely due to heat stress, not to CF3I exposure.
In light of the negative findings in the reproductive-toxicity study, the subcommittee does not recommend further testing of CF3I for reproductive or developmental effects.
Primary among the toxic effects associated with halogenated hydrocarbons, such as CF3I, is cardiac sensitization. Cardiac sensitization is
typically manifest as an arrhythmia followed by ventricular fibrillation that may result in death. In the cardiac-sensitization protocol, dogs receive a dose of epinephrine, are exposed to the test chemical, and shortly thereafter receive a challenge dose of epinephrine while continuing to inhale the test chemical. Changes in a dog’s electrocardiogram are taken as evidence of cardiac sensitization. Not all halocarbons induce cardiac sensitization; effects of those which do induce it depend on the blood concentrations of both epinephrine and halocarbon. That elevated endogenous concentrations of epinephrine, such as those achieved through exercise or by fright, can also result in fatal cardiac arrhythmia is of particular concern for human exposure. Halocarbon concentrations required to induce cardiac sensitization with endogenous epinephrine are 2-20 times higher than those required with exogenous epinephrine. Thus, the typical cardiac-sensitization protocol that uses exogenous epinephrine yields a conservative measure of toxicity. In addition, the subcommittee recognizes the lack of studies of cardiac response to CF3I with endogenous epinephrine stimulation and suggests that such studies be conducted in the future. Although one study shows that dogs exposed to CF3I at up to 2.5% with administration of exogenous epinephrine do not develop cardiac arrhythmias, additional studies of exposures to CF3I with endogenous epinephrine may provide useful information.
Inhalation studies of CF3I with exogenous epinephrine indicated that cardiac sensitization occurred in dogs at 0.4% (4,000 ppm)—the LOAEL, or greater; the NOAEL was 0.2% (2,000 ppm). The subcommittee concluded that the dog cardiac-sensitization studies that used exogenous epinephrine are appropriate for estimating the NOAEL in humans without any additional uncertainty factors to account for dog-to-human extrapolation or for endogenous epinephrine in humans, because of the high exogenous concentrations of epinephrine used in the studies. The subcommittee suggests, however, that further research could be conducted to investigate the mechanisms of induction of cardiac arrhythmia in dogs. Critical to the determination of the LOAEL for halocarbons is a measure of the blood concentration of the compound. Blood concentrations of halocarbons typically reach a steady state after about 5 min of exposure and do not increase substantially with longer exposures. The subcommittee concluded that cardiac sensitization is correlated with the peak blood concentration of the halocarbon before an epinephrine challenge. Prolonged exposure to an airborne concentration of halocarbon that does not achieve this peak blood concentration does not appear to increase the risk of cardiac sensitization.
Physiologically Based Pharmacokinetic Modeling
Physiologically based pharmacokinetic (PBPK) models can provide an estimate of the internal concentration of a chemical at a target tissue, such as blood, on the basis of exposure concentrations. For cardiac-sensitizing agents, such as some halocarbons, the model must account for short exposure periods—0-5 min—with airborne concentrations at the NOAEL or LOAEL.
The subcommittee finds that the use of a validated, EPA-approved PBPK model is a reasonable scientifically based approach to determine safe egress times for exposure to CF3I. The PBPK model depends on the determination of the critical blood concentration that would result in a cardiac event in epinephrine-challenged dogs, typically resulting from exposure to the LOAEL. Use of arterial CF3I concentrations measured in dogs in the absence of exogenous or elevated endogenous epinephrine is a reasonable approach to estimate the critical arterial blood concentration. The NOAEL and LOAEL for CF3I as determined with the dog cardiac-sensitization model are 0.2% and 0.4%, respectively. According to the PBPK model, people could be safely exposed to 0.4% for about 51 sec before the critical CF3I blood concentration for cardiac sensitization is achieved. Furthermore, people could be exposed to concentrations as high as 0.3% 5 min or more without achieving the critical blood concentration. The Army’s decision to use an exposure limit of 0.2% (2,000 ppm) in normally unoccupied areas is a conservative policy decision to protect military personnel from health effects of CF3I exposure in undefined Army applications.
The two Army toxicity reviews provide few specific exposure data on CF3I. Two studies were performed: one to assess exposures that might result from the use of CF3I in hand-held fire extinguishers, and one to assess exposures resulting from the intentional release of CF3I from Air Force F-15 aircraft engine nacelles which encase the engine compressor, combustor, and turbine. There is also some anecdotal information on the inhalation of CF3I by two salesmen.
Of primary concern to the subcommittee is the decomposition of CF3I to highly toxic substances, such as hydrogen fluoride, hydrogen iodide, and carbonyl fluoride. The subcommittee recommends that the Army collect and evaluate information on types of exposure (such as acute, chronic, and
intermittent) and exposure concentrations to CF3I and its decomposition products in Army uses and that such information be considered in its assessment of the adverse health effects of CF3I.
CF3I has been approved for use in unoccupied spaces by Germany and Australia. No exposure or toxicity data were found on such use. Because the proposed military applications of CF3I might result in high concentrations in the event of an accidental discharge, particularly when used in Air Force F-15 aircraft, the subcommittee recommends that personnel who might be potentially exposed be trained in standard operating procedures and the use of appropriate personal protective equipment. The subcommittee concurs with NFPA that uses of CF3I that may involve acute exposures should be restricted to normally unoccupied areas. The Army is encouraged to monitor international exposure and toxicity data on CF3I as they become available.