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Home , Amyl nitrite, Butyl nitrite

- - I - I- I M : History, Epidemiology, and Nitrite 'in'alat's have been commonly :abused sR e&insla the nIted tates. Possible Links to AIDS Nitre ixa m s a npopular topic in the early 1980sX tecu of Harry W Haverkos, Andrea N. Kopstein,1 Hank Wilson, and Peter Drotman3 AIDSWas not k Wn.Withthe discovery of 1National Institute on Abuse, Rockville, MD 20857, USA; 2Committee to Monitor HIV, concern about nitrite use in the USA , San Francisco, CA 94102 USA; and 3National Center for Infectious Diseases, waned. However nitrite use is Centers for Disease Control and Prevention, Atlanta, GA 30333 USA asoiae wit baaiorl reaaeadt.t.n.mX.g...... w...`n ad.`HgaZ..HWnWl t dKcre£'.L''p te. cn. an natural Nitrite inhalants are commonly abused the package insert is pectoris (17). killer cel activity in a few labitory stud- substances in the United States, primarily is used experimentally to treat ies, d t:r a c ec tor in by homosexual men and others who use poisoning. The drug produces the patdge-nesis of AIbS-rele Kaposi's to facilitate sexual intercourse , which has a high affinity sarcomia. Discourap g ir :continues and/or produce (1-4). Scientific for cyanide, and leads to the production of to be a wordiwhll&pubiic healthjI.il Key in o.rd: AD5 HI infection' Inimunosup- interest nitrites increased in the 1980s cyanomethemoglobin, releasing cyanide pressio.... Kpoi's. sarcoma, nitrite due to their possible links to AIDS (5-11). from cell mitochondrial cytochrome oxidase ;$ ir behaor. Envmn Health In this paper we review the history, appli- sites, where it is otherwise destructive (18). Perspect 102:858-861 (1994) cations, and prevalence of use of nitrite When amyl nitrite became difficult to inhalants. We present the hypotheses link- procure for nonmedical or recreational pur- ing their use to AIDS. We provide sugges- poses during the 1970s, there was a prolif- mia, intoxication, and, rarely, death (15). tions to physicians, community leaders, eration of products by non- Other effects include development of policymakers, and researchers on what they pharmaceutical manufacturers (15). Butyl habitual use patterns, tolerance, and burns can do to limit the use of nitrites. nitrites were marketed as "liquid incense" resulting from inadvertent ignition of the or "room odorizers." Because the labels on vapor. The National Toxicology Program History and Clinical Uses bottles containing butyl nitrites stated that of the National Institute of Environmental The nitrites (e.g., amyl, butyl, iso- they were not to be inhaled and no health Health Sciences evaluated mice and rats propyl) are colorless or yellow liquids at claim was made, the FDA never had juris- exposed short term (6 hr/day for 14 days room temperature and are highly volatile. diction over this product as it does medi- and 13 weeks) to inhaled at They are of that have a cine and many foods. concentrations ranging from 0 to 800 ppm fruity odor (often described as unpleasant) The legal status of some key nitrite and noted several adverse effects. Rats and have been nicknamed "poppers" because preparations has changed in the past few exposed to greater than 600 ppm died dur- of the sound made when glass capsules con- years. One development prompting this ing the 14-day studies. At lower exposure taining amyl nitrite are crushed (12). change has been the description of several levels, the most striking lesion seen in mice The vasodilatory effect following acute and chronic adverse effects attributed was hyperplasia of the nasal mucosa and inhalation of amyl nitrite vapor was to the abuse of nitrite inhalants (15). In bronchial and bronchiolar tree. described in 1859 and led to the first response to those reports, the U.S. Methemoglobinemia was confirmed. report of its clinical application to provide Congress enacted a ban on the manufac- Other adversely affected organs included relief for angina pectoris in 1867 (13,14). ture and retail sale of butyl nitrites (except the liver, spleen, thymus, and bone mar- In the 1880s, butyl nitrites were found to when used in specified chemical commer- row (19). have similar vasodilatory qualities, but cial processes) in the Anti-Drug Abuse Act these compounds were never developed for of 1988 (Public Law 100-690, Section Prevalence ofNonmedical Nitrite Use clinical use (12). 2404). The law specified that the Con- are among the most com- Amyl nitrite was initially marketed as a sumer Product Safety Commission (not the monly used inhalants in the United States. prescription drug in the United States in FDA) would enforce the ban. However, to Other commonly abused inhalants are 1937 and remained a prescription drug circumvent the clear intent of the law, , , glues, and , until September 1960, when the Food and nitrite manufacturers began to sell other such as paint thinners. The National Drug Administration (FDA) eliminated nitrite alkyl congeners, such as isopropyl Institute on Drug Abuse has collected the prescription requirement. In the 1960s, nitrite, as "new and improved" room odor- information concerning nitrite inhalant sublingual tablets, dermally izers. In 1990, Congress outlawed manu- use among high school seniors since 1979. applied ointments, and, later, transdermal facture and sale of alkyl nitrites in the Eleven percent of high school seniors patches began to replace amyl nitrite as the Omnibus Crime Bill (Public Law 101-647, interviewed in 1979 reported ever using preferred treatment for angina pectoris. In Section 3202). Since then, at least one nitrites. Use has decreased consistently the late 1960s, pharmacists and drug man- manufacturer has developed a cyclohexyl among seniors since 1980, to 1.5% for the ufacturers noticed widespread purchases of nitrite inhalant and marketed it diversely. class of 1992 (20). amyl nitrite by apparently healthy young According to chemical nomenclature, According to national surveys, self- men. These over-the-counter purchases cyclohexyl nitrites are not in the same class reported amyl and butyl nitrite use varies became the impetus for the FDA to rein- as alkyl nitrites and therefore may not be by gender, region, and race. Male high state the prescription requirement in 1968. banned under current federal law. school seniors reported higher rates of Since then an underground market for Underground manufacturers and importers amyl nitrite has emerged (15). For the last continue to market butyl and isopropyl few years, there has been no medical adver- nitrites illegally. Address correspondence to H. W. Haverkos, tising for pharmaceutical-grade amyl nitrite, The acute toxicity of inhaled and Room 1OA-38, NIDA, 5600 Fishers Lane, Rockville, MD 20857 USA. and it is no longer listed in the Physician's ingested nitrites in humans includes skin We thank Peter Delany, William Grace, and Desk Reference (16). irritations (especially around the nose and Vincent Smeriglio for reviewing the paper and Amyl nitrite remains available by pre- lips), tracheobronchial irritation, headache, providing helpful comments. scription. The clinical indication listed in , cyanosis, methemoglobine- Received 2 June 1994; accepted 25 July 1994.

858 Environmental Health Perspectives I ...... s i 1i 1ifi S M M Mfi&EF1diJIl1&-fj- A g-. inhalant use and nitrite use than females. heterosexual men and women who did not day for 3 or 18 days on the immune sys- The proportion of males who used nitrites consistently report using nitrites. In 1983 tems of 18 male volunteers. One inhala- at least once was typically twice the per- and 1984, human immunodeficiency virus tion of amyl nitrite (0.18, 0.36, or 0.48 centage of females reporting lifetime use (HIV) was discovered and reported as the ml) was administered from a closed 4-1 (20). The highest rate of nitrite use report- cause of AIDS (31,32). Subsequently, flask at 3-hr intervals each day of study. ed by high school seniors in 1979 was in three other hypotheses suggesting nitrites After full exhalation, the subject inhaled the Northeast, and the lowest rate was as promoting factors in AIDS have been from the flask through the mouthpiece reported in the West. Rates have decreased proposed. First, nitrites have been pro- with the nose "clipped" and held at full markedly in all regions, with the highest posed to enhance HIV transmission by inspiration for 5 sec before exhalation. rates in 1992 reported in the North- their association with risky sexual behaviors Blood was drawn for immune profile Central United States and the lowest rates and HIV infection among gay men. immediately after the last inhalation and 1, in the Northeast (21). Second, nitrite use has been associated 4, and 7 days later. Modest of Nitrite use varies by race/ethnicity as with immune suppression and thus might T-lymphocyte counts and natural killer cell well as geographic area. Although hasten the onset of symptomatic disease. activity were noted with a rebound to at racial/ethnic data are not available for high Third, nitrite inhalant use has been associ- least baseline levels several days after the school seniors, the Public Health Service- ated with the development ofAIDS-related last inhalations. Cell proliferation respons- sponsored National Household Survey Kaposi's sarcoma. es to phytohemagglutinin (PHA), con- provides limited population-based esti- Nitrites and Sexual Behavior/HIV canavalin A (Con A), and pokeweed mito- mates. Self-reported nitrite use in 1991 was Transmission. Several studies have linked gen (PWM) were unaffected by amyl highest for white males in each of six nitrite use with risky sexual behavior nitrite inhalation (36). selected metropolitan areas for which data and/or HIV infection among gay men. Ross and Drew (37) interviewed 97 gay were analyzable. National estimates of use Ostrow et al. found these associations in men in Australia and measured T-cell counts by females was 1.3% for white females in the Multicenter AIDS Cohort Study and mitogenesis responses to PHA, Con A, 1991, 0.7% for black females, and 0.8% (29,30). A similar correlation was not and PWM. T-lymphocyte counts did not for Hispanic females (22). found for other substances of abuse, differ between nitrite users and nonusers. Nitrite use has been commonly reported including (30). Stall et al. (33) Mitogenesis in response to the three antigens among homosexual men for several linked nitrite, alcohol, marijuana, and was significantly higher in users compared decades, but less so for self-identified het- other drug use during sex with increased with nonusers after cells were incubated for erosexual adolescents and adults. In 1981, likelihood of "risky" sexual behavior for 72 hr, but the differences disappeared for Centers for Disease Control and Pre- HIV infection among gay men in San PHA and Con A by 96 hr (37). vention (CDC) investigators surveyed 420 Francisco. They did not identify a unique Studies of the immune system of mice men attending sexually transmitted disease risk for nitrites independent of several following nitrite challenge are even less clinics in New York, San Francisco, and other studied (33). In a longitudinal consistent than those among humans. Atlanta and found that 242 of 279 (86%) study of 249 gay men in Toronto, Studies evaluating nitrites' effects on homosexual/bisexual men compared with Calzavara et al. (28) found a significant immune parameters have been hampered 21 of 141 (15%) heterosexual men report- decline in sexual activities associated with because formulations and dosages vary ed any use of nitrite inhalants within the HIV infection and that nitrites and other greatly, and routes of administration and previous 5 years (6). Almost all gay men drug use during sex are strong predictors of immunologic outcome measures have not enrolled in an AIDS case-control study continuation of high-risk behaviors for been standardized. conducted by CDC in 1981 reported use HIV infection. Among all the variables CDC investigators evaluated the effects of nitrites (23). Other studies of gay men tested, Penkower et al. (34) found that of isobutyl nitrite on the immune system in the United States, Canada, and Europe nitrite inhalant use was the most strongly of BALB/c mice (38,39). The mice were found high rates of nitrite use (24-29). A associated with HIV seropositivity among exposed to either 50 or 300 ppm isobutyl multisite study demonstrated a marked a cohort of 1045 gay men. nitrite for 6.5 hr/day, 5 days/week for up decrease of nitrite use among gay men Nitrites and the Immune System. The to 18 weeks. Mice were sacrificed at vari- from 66% to about 35% between 1984 hypothesis that nitrite inhalants might ous times and antibody-producing cells and 1989 (L. Jacobson, personal commu- induce immune suppression was first were enumerated; mitogenesis responses nication). Possible explanations for this advanced by Goedert et al. in 1982 (8). T- were evaluated to PHA, Con A, PWM, trend include increased awareness of lymphocyte abnormalities were reported in 9 and lipopolysaccharide and skin test reac- adverse effects, including concern about of 10 gay men who reported regular nitrite tions to purified protein derivative of nitrites' possible links to AIDS, and use compared to 1 of 7 who did not use immunized mice were observed. No decreased availability after nitrites were nitrites (8). This study came under criticism immunotoxic effects were discerned, banned as consumer products (30). because of its small numbers and lack of although decreased thymic weights were evaluation for many potentially confounding noted for female mice at the highest dose Hypotheses Linking Nitrites and AIDS variables, including HIV infection. levels (38,39). At least four separate hypotheses have been Several other investigators have evaluat- Other investigators have noted decreases proposed that suggest a role for nitrites in ed the effects of nitrites on human in natural killer cell activity, helper the pathogenesis of AIDS. When AIDS immune function. Hersh et al. (35) cul- lymphocyte counts, and/or body weight in cases were first recognized in 1981, nitrites tured venous blood with up to 1% isobutyl mice exposed to nitrites. Lotzova et al. were proposed as a possible cause of the nitrite in alcohol and, after 24 hr, observed (40) injected mice with 0.50 ml isobutyl new syndrome (5,6). Nitrite abuse was irreversible effects on various lymphocyte nitrite and noted significant depression of virtually universal among the gay men functions, including blastogenesis, cell- natural killer cell activity in female diagnosed with AIDS in 1980-1983. mediated cytotoxicity, and monocyte C57BL/6 x DBA/2 mice. Administration However, this hypothesis was dismissed adherence. Dax et al. (36) at the Addiction of isobutyl nitrite by inhalation (2- to 3- when the disease was recognized among Research Center studied the effects of three min exposures twice daily) also suppressed drug injectors, hemophiliacs, and other inhalations at various concentrations per natural killer cell function in mice (40).

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Ortiz and Rivera (41) exposed CD-I mice but not all, epidemiologic studies have nitrite inhalants should be pursued. to increasing amounts of amyl nitrite by shown a statistical association between the The possible links of nitrites with nasal administration for up to 21 weeks. development of KS among gay men with AIDS and the other known adverse effects The total T-cell and suppressor cell counts AIDS and the use of large quantities of of these inhaled substances suggest that did not differ from mice exposed to saline nitrite inhalants when compared with gay more attention to these products by clini- solutions. However, helper cell counts, men with AIDS, but without KS cians and researchers is warranted. body weight, and weight gain rates were (11,51-56). Third, anecdotal reports of Clinicians and community leaders should significantly decreased in nitrite-exposed increased frequency ofAIDS-related KS on discourage the use of nitrite inhalants. versus control mice (41). Soderberg and the chest and face, especially the nose, and Researchers should study further the asso- Barnett (42) exposed female C57BL/6N in the lungs are consistent with the body ciations between nitrite use and HIV infec- mice to 900 ppm isobutyl nitrite by inhala- areas most heavily exposed to nitrite vapors tion and AIDS. tion chamber for 45 min per day for 14 when inhaled. Finally, plausible mecha- days. Body weight was reduced 4%, nisms of action have been proposed for REFERENCES mixed-lymphocyte reaction (MLR) was nitrites and their metabolites, such as cho- reduced 50-60%, and mitogen response to lesteryl nitrite and , to be car- 1. Louria DB. Sexual use of amyl nitrite. Med Con A was reduced was reduced 33% (42). cinogenic, and mutagenesis has been Aspects Hum Sex 4:89 (1970). Although much laboratory work has demonstrated in the Ames test (7,57,58). 2. Pearlman JT, Adams GL. Amyl nitrite inhalation been done to evaluate nitrites and the Nitrites are known to affect small blood fad (letter). J Am Med Assoc 212:160 (1970). immune system, it remains unclear vessels, the anatomic site presumed to give 3. Sigell LT, Kapp FT, Fusaro GA, Nelson ED, nitrite HIV- rise to KS (12). Falck RS. Popping and snorting volatile nitrites: a whether continued use by current fad for getting high. Am J Psychiatry infected or uninfected individuals is Nitrite inhalants are one of several fac- 135:1216-1218 (1978). immunotoxic. tors proposed as KS promoters in HIV- 4. Schwartz RH, Peary P. Abuse of isobutyl nitrite Nitrites and AIDS-related Kaposi's infected individuals. Other KS cofactors inhalation (Rush) by adolescents. Clin Pediatrics Sarcoma. The epidemiology of Kaposi's proposed include a second sexually trans- 25:308-310 (1986). sarcoma (KS), the most commonly report- mitted agent and/or genetic factors 5. Durack DT. Opportunistic infections and Kaposi's sarcoma in homosexual men. N Engl J ed cancer among AIDS patients, differs (48,59465). Med 305:1465-1467 (1981). markedly from the other opportunistic dis- 6. Centers for Disease Control. Epidemiologic eases that have characterized the AIDS epi- Conclusions aspects of the current outbreak of Kaposi's sarco- demic. KS has occurred much more fre- In summary, nitrite inhalants are common- ma and opportunistic infections. N Engl J Med quently among gay men with AIDS and ly abused substances in the United States. 306:248-252 (1982). much less frequently among other AIDS Nitrite inhalants are associated with behav- 7. Jorgensen KA, Lawesson S-O. Amyl nitrite and Kaposi's sarcoma in homosexual men. N Engl J patients. Furthermore, the rate of increase ioral relapse and HIV transmission among Med 307:893-894 (1982). in KS cases has been lower than that of gay men, with decreased lymphocyte 8. Goedert JJ, Neuland CY, Wallen WC, Greene other AIDS indicator diseases (43-46). KS counts and natural killer cell activity in a MH, Mann DL, Murray C, Strong DM, was almost never seen in HIV-infected few laboratory studies, and they remain a Fraumeni JF Jr, Blattner WA. Amyl nitrite may blood-transfusion recipients, even when candidate cofactor in the pathogenesis of alter T lymphocytes in homosexual men. Lancet the presumed HIV donor developed KS AIDS-related KS. i:412-415 (1982). in nitrite 9. Marmor M, Friedman-Kien AE, Laubenstein L, (47,48). KS was reported about twice as Encouraging the decline Byrum RD, William DC, D'Onofrio S, Dubin often among white gay men with AIDS abuse appears to be a worthwhile public N. Risk factors for Kaposi's sarcoma in homosex- than among black gay men with AIDS, health goal. The most effective ways to ual men. Lancet i: 1083-1087 (1982). suggesting an association with increased accomplish this goal are not clear. In the 10. Newell GR, Mansell PWA, Spitz MR, Reuben socioeconomic status or some other factor United States, laws banning nitrite manu- JM, Hersh EM. Volatile nitrites: use and adverse (49). Women linked sexually to gay men facture and sale were enacted in 1988 and effects related to the current epidemic of the of inhalants acquired immune deficiency syndrome. Am J were reported with AIDS-related KS more 1990. However, use nitrite Med 78:811-815 (1985). often than women infected with HIV by had started to decrease even before the laws 11. Haverkos HW, Pinsky PF, Drotman DP, heterosexual contact with intravenous drug were implemented. What impact did dis- Bregman D. Disease manifestation among homo- users (50). Wide geographic variations of cussions of scientific findings suggesting a sexual men with acquired immunodeficiency syn- KS rates were reported among gay men link between nitrites and AIDS, particular- drome: a possible role of nitrites in Kaposi's sarco- with AIDS in the United States (50). ly as reported in the predominantly gay ma. Sex Trans Dis 12:203(1985). nitrite 12. Nickerson M. Vasodilator drugs. In: The pharma- These observations suggested that some press, have on sales and use? What cologic basis of therapeutics, 5th ed (Goodman cofactor highly associated with gay lifestyle impact did grass-roots organizations dis- LS, Gilman AG, eds). New York:Macmillan, was operating in conjunction with HIV in couraging nitrite use have? What alterna- 1975;727-743. the pathogenesis of AIDS-related KS. tive drugs of abuse will take the place of 13. Brunton TL. On the use of nitrite of amyl in Nitrite inhalants were suggested as one nitrites by those who discontinue use? angina pectoris. Lancet ii:97-98 (1867). possible factor (10,11,51-56). The search for cofactors in AIDS-relat- 14. Brunton TL. Lectures on the actions of medi- KS an scientific chal- cines. New York:Macmillan, 1897;332-341. There are several reasons to consider ed remains important 15. Haverkos HW, Dougherty JA, eds. Health haz- nitrite inhalants as a KS cofactor. First, the lenge. If the KS cofactor(s) can be identi- ards of nitrite inhalants. NIDA research mono- epidemiology of nitrite use in the United fied, it may provide important insights into graph 83. Washington DC:U.S. Government States parallels that of HIV-related KS. the pathogenesis of AIDS and possibly Printing Office, 1988. Nitrite inhalants are used more commonly some forms of cancer. Nitrite use is consis- 16. Physician's desk reference, 47th ed. Montvale, by gay men than others (6); use has been tent with much of the epidemiology of NewJersey-.Medical Economics Data, 1993. AIDS was AIDS-related KS. Further studies of nitrite 17. Newton brand of amyl nitrite inhalant, USP, declining since first reported February 1989, package insert. Newton, (30) and has roughly paralleled the pattern use and other potential cofactors among NJ:Newton Industries. of reported KS cases, and use among gay men with KS as well as women and 18. Ellenhorn MJ, Barceloux DG. Medical toxicolo- whites is greater than among blacks, as is others with KS should be encouraged. gy: diagnosis and treatment of human poisoning. the incidence of KS (22). Second, some, Animal models exposed to retroviruses and NewYork:Elsevier, 1988;833.

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