TESTING FOB INHALATION TOXICITY 291 Propellant Toxicity Possibly the most sensitive problem currently concerning aerosols and their safety is the question of propellant toxicity. An attempt will be made here to briefly recap some of the inhalation toxicity testing that has been done on the propellants, and then to discuss the recent reports which charge that they are unsafe. More than 30 years ago, the Underwriters Laboratories designed inhalation studies using guinea pigs which exposed them to the Freon©* propellants for different lengths of time. The result was a classification, based on the relative inhalation toxicity of these and other materials, that was divided into 8 groups. For purposes of this discussion, the most significant facts to come out of this rating were that Propellant 11 was put into the same category as car- bon dioxide, and that Propellants 12 and 114 were two categories removed from this and classified as less toxic than CO,.. More recent animal studies (28) have reported that when a concentration of 0.08% dichlorodifiuoromethane (Propellant 12) is breathed for 8 hours a day, 5 days a week, for a total of 30 exposures, or when it is breathed continu- ously around the clock for 90 days, some liver damage appears to result in guinea pigs, but not in rats, rabbits, dogs, or monkeys. To put this into per- spective, this is approximately the level of P-12 that would be present in an 8 x 8 x 8-foot bathroom if the entire contents of a standard can of aerosol deo- dorant were discharged in that room (an effort requiring about 4V4 minutes of continuous spraying). Similar experiments (29) using trichlorofiuoromethane (P-11) at 0.1% for a continuous 90-day exposure, or at 1.0% for the 8-hour a day, 30-day regimen, demonstrated no organ changes, and only very minor deviations in certain biochemical parameters in dogs no effects were seen in rats, guinea pigs, or monkeys. Several other investigators support these findings (2, 30-32). It can be concluded, therefore, that these compounds are practically inert with re- gard to toxicity when they are dispensed in an aerosol product in a normal fashion, or even when used to excess, for the purpose for which they were designed. During the late 1960's, however, it began to become apparent that products containing these propellants were being used for something other than their intended purpose. In 1970, Bass (33) reported on this phenomenon increas- ing numbers of young people were inhaling volatile hydrocarbons for the sen- sation of 'q•igh" that they produced. Between 1966 and 1969 a tremendous up- surge in this unique form .of abuse was noted. The mechanism is rather sim- ple: the contents of an aerosol are discharged into a plastic or paper bag, and the volatilized, concentrated propellants are then inhaled. Bass also noted, *E. I. du Pont de Nemours & Co., Inc., Wilmington, Del. 19898.

292 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS however, a large increase in the number of sudden deaths immediately fol- lowing inhalation in many of these cases, some exertion or stress had directly preceded the death. Reasoning that most of these people were oxygen-defi- cient as a result of confining their breathing to the contents of the bag, and realizing that, as has been known for many years, halogenated hydrocarbons will sensitize the heart to the effects of epinephrine, he hypothesized that the stressful activity had resulted in the endogenous release of epinephrine in the victim, and that sensitization by the fluorinated hydrocarbon propellants had resulted in a fatal cardiac arrhythmia. Also during the 1960's, an epidemic of sudden deaths among asthma-suffer- ers who used acrosolized bronchodilators was noted (34). This large increase in the death rate seemed to be confined, however, to England and Wales, Ire- land, Scotland, New Zealand, and Australia and reached a peak around 1967, after which the rate declined. Putting these two phenomena together, Taylor and Harris published a pa- per (35) in 1970 in which they presented experiments that purported to sup- port their theory that the asthma deaths had resulted from cardiac toxicity induced by the propellants in the victims' nebulizers. Since its publication, debate has continued on the errors in design and conclusions of this study, but unfortunately, the damage has been done to the confidence of the asthma pa- tient in his medication and to the general confidence of the consumer in aerosolized products. One major fault in these experiments was that the mice that were used were administered one puff from an antiasthma nebulizer, dis- charged directly into their nose and mouth. The normal volume of air inspired by a mouse varies from 0.20-0.25 ml, so that the 6.5 ml of propellant gas de- livered by the nebulizer assured that the animal would breathe 100% propel- lant for the three inspirations which it was allowed. The normal volume of air inspired by a human is about 450 ml, approximately 1800 times that of the mouse, so that the propellants would normally be inhaled by a human at a concentration of about 1% of the inspired air in the initial breath. In addition to this, the head of the animal was thrust into a tightly-fitting plastic bag after exposure to the nebulizer until cardiac abnormalities ap- peared on the electrocardiograph. The purpose of this bag was to simulate the lack of air which asthmatics may suffer before using the nebulizer. Taylor and Harris reported serious cardiac arrhythmias following propellant plus asphyx- ia, but none following asphyxia alone of up to 4 minutes. Investigations by 5 different laboratories (36-40) have been unable to duplicate these results and have found that the asphyxia component alone is sufficient to induce se- rious changes in cardiac rhythm. In a recent answer to his critics, Harris (41) now contends that the asphyxia originally described as being induced by "... a form-fitting plastic bag wrapped tightly around the nostrils and mouth ß . ." (35) was actually only partial asphyxia. It is for this reason, he states, that his asphyxia alone did not result in arrhythmias.