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Fluorocarbon Aerosol Propellants" THE development of pressurised self-propelled

aerosol products using liquified-gas propellants hascentred around the fluorocarbon compounds. Thecharacteristic stability, non-inflammability, low de-gree of toxicity, and lack of odour provide a uniquecombination of properties especially desirable for thepropelling force in this rapidly expanding industry."This quotation from a manufacturer’s technicalbulletin on applications of fluorocarbons illustrates

why they have become so widely used. Whippedcream, hair-spray, insecticides, and asthma remediesare only a few of the products that come hissingout of a pressurised aerosol canister. However, onseveral occasions in the past few years, questions havebeen raised about their safety. BASS 1 in 1970 re-

ported an epidemic of 110 sudden " sniffi4g "deaths in American youths. The substances mostoften involved were trichloroethane and fluorocarbonaerosol propellants. - This paper led to suggestionsthat the epidemic of asthma deaths which occurred inthe United Kingdom and some other countries from1960 to 1967 might have been caused by sensitisationof the heart to cardiac arrhythmias by the fluoro-carbons used to propel bronchodilator aerosols.2Now SPEIZER et al. suggest that use by surgical-pathology residents of an aerosol preparation contain-ing monochlorodifluoromethane to accelerate pre-paration of frozen sections was associated with a riskof palpitations 3-6 times higher than in those notexposed.

Since the evidence of toxicity of the fluorocarbonsin man is mainly indirect, much work has been carriedout in animals. The general toxicology of fluorocar-bons was assessed many years ago when they were firstintroduced as refrigerants.4,5 Exposure of animals toconcentrations of 20% dichlorodifluoromethane

(fluorocarbon-12) and dichlorotetrafluoroethane(fluorocarbon-114) causes sluggishness, drowsiness,and tremor. In the case of fluorocarbon-114 this leads

eventually to convulsions. Some animals exposed to20% fluorocarbon-114 died, although 15% was tolera-ted for 21 consecutive daily exposures of 8 hours.

1. Bass, M. J. Am. med. Ass. 1970, 112, 2075.2. Speizer, F. E., Doll, R., Heaf, P. Br. med. J. 1968, i, 335.3. Speizer, F. E., Wegman, D. H., Ramirez, A. New Engl. J. Med.

1975, 292, 624.4. Nuckolls, A. H. Underwriters’ Laboratories’ Report on the Com-

parative Life, Fire and Explosion Hazards of Common Refriger-ants. National Board of Fire Underwriters, Chicago, 1933.

5. von Oettingen, W. F. J. ind. Hyg. Toxicol. 1937, 19, 3375.

Histologically there was no important abnormality.6Later work in rabbits showed that fluorocarbon-11,which has a lower boiling-point and a higher blood-gaspartition coefficient, produced unconsciousness at aconcentration of 9% and death at 10%.7 Repeated orcontinuous exposure of rats, dogs, monkeys, andguineapigs to fluorocarbon-12 at high concentrationshowed interstitial inflammatory changes in the lung,with fatty infiltration and focal or submassive hepaticnecrosis.8 These changes occurred at concentrationsof about 4 (1.g. per ml. in the inhaled air, similar to thealveolar gas concentration found after use of asthmainhalers,9 although in the latter case the exposurewas very brief. Studies with fluorocarbon-11 at

concentrations of 1% revealed no toxic effects apartfrom mild inflammatory changes in the lungs andmild vacuolar changes in the livers of guineapigs.10One monkey died on the 78th day of exposure andno specific cause was found at necropsy, althoughthere were haemorrhagic lesions on the surface of thelung. Most workers concluded from these experi-ments that, apart from the general-anaesthetic andconvulsive activity seen at high concentrations, thefluorocarbons could be regarded as safe.

After the epidemic of asthma deaths, further

investigations were done in animals to try to replil-cate the circumstances found in the patients whodied. Deaths from bradyarrhythmia 11 in mice seemto have been due principally to anoxia rather thanto the aerosol propellants 12; but later studiesshowed conclusively that ventricular arrhythmiascould be provoked by aerosol propellants in consciousanimals that were challenged with intravenousadrenaline in doses of 8 (1.g. per kg. Inhaled concentra-tions as low as 1% of fluorocarbon-11 and 5% offluorocarbon-114 could cause ventricular arrhythmiasunder these circumstances.13,14 Further workshowed that ventricular arrhythmia could be pro-voked without adrenaline challenge, but only at muchhigher concentrations. Monkeys developed ventri-cular arrhythmias when they breathed a gas mixturecontaining 30% fluorocarbon-12 and 9% fluorocarbon114.15 Some trained beagle dogs breathing fluoro-carbons while running on a treadmill developedventricular arrhythmias at inhaled concentrations of10% of fluorocarbon-12 and 5% and 10% of fluoro-carbon-114. None of these animals died and none

6. Yant, W. P. Am. J. publ. Hlth, 1933, 23, 3384.7. Lester, D., Greenberg, L. A. Archs ind. Hyg. occup. Med. 1950, 2,

335.8. Prendergast, J. A., Jones, R. A., Jenkins, L. J., Siegel, J. Toxicol.

appl. Pharmacol. 1967, 10, 270.9. Draffan, G. H., Dollery, C. T., Williams, F. M., Clare, R. A.

Thorax, 1974, 29, 95.10. Jenkins, L. J., Jones, R. A., Coon, R. A., Siegel, J. Toxicol. appl.

Pharmacol. 1970, 16, 133.11. Taylor, G. J., Harris, W. S. J. Am. med. Ass. 1970, 214, 81.12. Azar, A., Zapp, J. A., Reinhardt, C. F., Stopps, G. J. ibid. 1971, 215,

1501.13. Reinhardt, C. F., Azar, A., Maxfield, M. E., Smith, P. E., Mullin,

L. S. Archs environ. Hlth, 1961, 22, 265.14. Clarke, D. G., Tinston, D. J. Ann. Allergy, 1972, 30, 536.15. Taylor, G. J., Harris, W. S., Bogdonoff, M. D. J. clin. Invest. 1971

50, 1546.

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developed arrhythmias with fluorocarbon-ll.16 It is

noteworthy that one dog seemed to be much moresensitive to this effect than the others. These in-

vestigations disclosed a range of concentrations thatprovoke arrhythmias in the normal hearts of animalssuch as monkeys and dogs with or without adrenalinechallenge. As with most other aspects of toxicology,the effect must depend both upon individual sus-ceptibility and on the concentration to which thesensitive tissue is exposed.17 Application of thesedata to man has involved measurement of concentra-tions in alveolar gas and in arterial blood after use ofasthma inhalers, and calculations of myocardialconcentrations which occur during normal or exces-sive use of aerosol preparations.

Deliberate inhalation of very high concentrationsof fluorocarbons is undoubtedly dangerous. Thusthe glue-sniffers described by BASS almost certainlydied of a ventricular arrhythmia. However, there is

. a great difference between breathing an undilutedmixture from a plastic bag and breathing the contentsof a room in which an aerosol canister has been dis-

charged. Even if the whole of a domestic aerosolcanister was discharged into a small unventilatedroom, the average concentration in the air would beless than that needed to sensitise the dog heart in thepresence of large challenge doses of adrenaline,although the local concentration for short periodsmight be much higher. The concentrations measurednear the cryostats used by the American pathologyresidents were low (0-33%). The greatest hazardseems likely to arise when patients deliberately inhalefluorocarbons and sympathomimetic substances, as

they do in the treatment of asthma. Fluorocarbonconcentrations up to 5 tg. per ml. are found in arterialblood after one or two puffs from an inhaler .18 Theconcentrations required to sensitise conscious, dogschallenged with adrenaline were higher (20-35 p.g.per m1.).14,19 Furthermore, adrenaline seems muchmore apt to produce arrhythmias than other broncho-dilator drugs like isoprenaline. Calculation of theconcentration in myocardium after use of an aerosolinhaler twice within a minute gave a maximum

figure of 6-8 g. per g. compared with an estimated35-40 pug. per g. required to sensitise the dog heart.However, under conditions of grossly excessive use,such as firing an aerosol canister on every breath forone or two minutes, the concentrations in the humanmyocardium could approach, or even exceed, thosethat sensitise the dog heart. The provisional con-clusion from such calculations is that pressurisedaerosol cans are safe if used in the recommendedmanner. It is reassuring that the asthma-deaths

16. Mullin, L. S., Azar, A., Reinhardt, C. F., Smith, P. E., Fabryka,E. F. Am. ind. Hyg. Ass. J. 1972, 33, 390.

17. Williams, F. M., Draffan, G. H., Dollery, C. T., Clark, J. C.,Palmer, A. J., Vernon, P. Thorax, 1974, 29, 99.

18. Dollery, C. T., Williams, F. M., Draffan, G. H., Wise, G., Sahyoun,H., Paterson, J. W., Walker, S. R. Clin. Pharm. Ther. 1974, 15, 59.

19. Azar, A., Trochimowicz, H. J., Terrill, J. B., Mullin, L. S. Am.ind. Hyg. Ass. J. 1973, 34, 102.

rate in the U.K. has declined since 1967 almost backto the pre-1960 figure 20 although use of asthmainhalers has continued albeit with many warningsabout overdose. However, because of the difficultyof making extrapolations from animals to man andbecause of the individual variability that has beennoted in animals,21 research to discover safer methodsof dispensing inhaled drugs and other substancesshould go on.

Why Does Peptic Ulcer Happen?GASTRIC and duodenal ulcers are common diseases

which vary strikingly in frequency, yet little isknown of the causes. Since the mid-nineteenth

century, gastric ulcer (then a disease of young women)has been replaced by duodenal ulcer as the commonervariety, and both are increasingly becoming diseasesof the elderly. The tide of duodenal ulcer probablyreached its peak some ten years ago,22 and it nowseems to have become less frequent both in theUnited Kingdom and in the U.S.A.23,24 Gastric ulcerhas declined even more sharply-at least if hospital-admission rates can be accepted as criteria, in theabsence of satisfactory estimates of true populationfrequency. 25 Associated with these changes in ulcerfrequency and in age patterns there has been a

tendency for duodenal ulcer to join gastric ulcer as adisease of the socially underprivileged. Mortalitytables can be a poor guide to disease frequency,but the evidence that fifty years ago duodenal-ulcermortality was greater in those of social classes I and IIthan in poorer people is difficult to explain exceptby postulating that the disease was commoner (ormore prone to complications) in the well-off.26 Thistrend has now been reversed, and duodenal ulcerseems well established as a disease of poorer people,from the evidence of both mortality and morbiditystatistics.27,28

Patterns of this sort are not seen everywhere;thus, gastric ulcer seems to be relatively infrequent inpeople living in India and Africa. By contrast,duodenal ulcer is common in those areas, and theclinical characteristics may be unusual, stenosingulcer presenting a special problem. 29-32 The greatvariations in ulcer frequency between one tropicalarea and another need much better definition. In

20. Standing Medical Advisory Committee for the Central Health Ser-vices Council, Secretary of State for Social Services, and theSecretary of State for Wales. Deaths from Asthma. Department ofHealth and Social Security, 1973.

21. Roslaw, M., Belej, A., Smith, D. G., Aviado, D. M. Toxicology,1974, 2, 381.

22. Susser, M. J. chron. Dis. 1967, 20, 435.23. Meade, T. W., Arie, T. H. D., Brewis, M. Br. med. J. 1968, iii, 70124. Mendeloff, A. I. Gastroenterology, 1974, 67, 1020.25. Brown, R. C., Langman, M. J. S. Gut, 1974, 15, 335.26. Morris, J. N., Titmuss, R. M. Lancet, 1944, ii, 841.27. Litton, A., Murdoch, W. E. Gut, 1963, 4, 360.28. Registrar General’s decennial supplement on occupational mortality

for 1961. H.M. Stationery Office, 1971.29. Tovey, F. I. Trop. geogr. Med. 1972, 24, 107.30. Malhotra, S. L. Gut, 1964, 5, 412.31. Madanagopalan, N., Subramaniam, R., Krishnan, M. N. ibid.

1968, 9, 69.32. Konstam, P. G. Lancet, 1954, ii, 1039.