FLUOROCARBON TOXICITY 347 For the evaluation of the inhalation hazard peculiar to life in a nuclear submarine which may operate continuously submerged, Siegel (12) conducted continuous exposures of rats, guinea pigs, rabbits, monkeys, and dogs for a ninety-two-day period to 810 ppm of dichloro- difluoromethane. Some liver changes were observed, but there was no clinical intoxication, and hematological values were within normal limits. BIOLOGICAL ACTIVITY What emerges from these chronic studies is evidence of a low degree of biologic activity of the fluoroalkanes investigated. Furthermore, it is apparent that each of the studies was specially designed for a particular need. There are, of course, decided advantages to this approach, which answers specific questions. However, there remains the question of the mechanism of action of the fluoroalkanes. Generally these com- pounds act on the central nervous system with a mild effect, if any, on the liver. Each of these actions is dependent largely on the number of fluorine atoms in the molecule--a higher complement being associated with lower activity. This is usually related to the strength of the C-F bond. Assurance of low toxicity is therefore to be inferred from these observations, and this is of great practical importance to the manufac- turer and consumer. On the other hand, with the increasing penetration of fluoroalkanes in the marketplace, there is a growing need to study the body's handling of this class of fluorochemicals to elucidate modes o[ biological action. Some insight into the biologic activity of the fluorocarbons may be gained by considering a few of the salient features of the biology and chemistry of the halogenated hydrocarbons and comparing them with those of the fluorocarbons. Dehalogenation in aliphatic systems is well established for many compounds, and it is the basis of the mechanism of action of a number of halogenated compounds (13). Both enzymatic and nonenzymatic processes have been observed in this regard. It is noteworthy that the biologic activity is not related to the halogen moiety but rather to the halogen-free part of the molecule. As pre- viously cited, the dehalogenation of CHsBr to form the methylating residue CHs. is typical of this concept. It is the methyl radical which can react with sulfur-containing compounds in vivo, thus producing a biologically active compound. CHsC1 is not as active as CHsBr, and CHsF is even less active than CH3C1. The labile halogens of COC12, which gives rise to an active --C=O group, are another example. The I

348 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS corresponding fluorocompounds CH3F and COF2 exhibit much lower activity than the chlorocompounds, largely due to a firm C-F bond. Further addition of F to the molecule tends to stabilize carbon- halogen bonds. It is known that di- and tri-halogenated compounds differ markedly from the monosubstituted analogues owing to shortened interatomic distance and increase in steric effects from the added bulk in the former compounds. These kinds of molecular changes result from increasing fluorination and are probably the basis for the low toxicity of the highly fluorinated anesthetics, i.e., CF3--CHBrC1 (halo- thane), CHamO--CF2--CHCI•, CFamCHBrF (teflurane), HCFe--CF• --CH2C1, and HCF2--CF•--CH•Br (14). Although dehalogenation of these may occur it would appear to be of minor significance. The anesthetic activity of these materials may be best explained by the formation of "physical adducts" according to Chenoweth and McCarty (13) and is comparable to the action of nitrogen and xenon. These inert materials may become part of in vivo "crystal" formations in accord with Pauling's hypothesis (14). Another aspect of these postulated in vivo actions is the requirement of binding forces and a dipole moment. Completely halogenated molecules or partially halogenated, symmetrical compounds, because of the lack of the requisite dipole function, would not readily form "crystals" and therefore in most cases would be poor anesthetics. CC14 is a notable exception, although CF4 certainly is not. Hexafluoroethane and monochloropentafluoroethane are poor anesthet- ics, possibly because of their symmetrical morphology. Hydrogen situated at the end of a three-carbon chain enhances chemical stability and anesthetic potency, whereas a centrally placed hydrogen exerts the opposite effect (15). Although highly fluorinated compounds may be poor anesthetics, they are active in sufficiently high concentration. The mechanism of action in these instances may be akin to the physical adducts alluded to above however, this remains speculative until relevant studies are conducted. The mild hepatotoxic action of some of the chlorofluoro- carbons falls into the same category. The idea that lipophilic properties of halogenated compounds influence biologic activity, as in the preceding hypotheses, must be regarded as a chance correlation. Any relation between this physical property and biological effects is uncertain. FUTURE RESEARCH It is evident at the present stage of knowledge of the toxicology of the fluorocarbons that experiments to elucidate biologic mechanisms