MAY 1986
Mariposa Education & Research Foundation
MARIPOSA OCCASIONAL PAPER #6
IN A SERIES OF ONGOING PROJECTS FOR EDUCATING THE PUBLIC ABOUT "MAKING SEX SAFE" AND "SENSIBLE SEX."
ARE "POPPERS" SAFE?
By BRUCE VOELLER, Ph.D.
When mediocre or even plain bad scientific research is politically exploited by AIDS institutions eager to appear to be earning their keep, or by the media -- ever keen to fan any spark of controversy, or zealots riding their favorite hypothesis saddled up as fact, the public is in danger.
Basing public policy on inadequate science is particularly inappropriate.
All this appears to be fueling the hysteria surrounding the use of volatile nitrites or "poppers", especially the issue of whether "poppers" are a factor in causing AIDS or in suppressing the immune system.
As a scientist current with AIDS research and who has reviewed the extensive literature on nitrite use, I can not assure you that "poppers" are harmless, any more than I can assure you aspirin is; but neither have I found grounds to tell you "poppers" are harmful. I can assure you, however, that the existing scientific studies on this topic do not justify the widespread belief that “poppers" have been shown to help cause AIDS, or cause anything else for that matter. My viewpoint is shared by other preeminent and qualified persons, including the prominent cardiologist John 0. Parker, M.D., and James Mosley, M.D., the University of Southern California Medical School professor who heads the federal government's largest, multi-million dollar program studying the AIDS virus and the nation's blood supply. Each of these physicians has provided public testimony in recent months at governmental hearings considering the banning of “poppers". Each had reviewed the evidence and stated under oath that he regards the claims of danger to be ill founded.
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"When mediocre or even plain bad scientific research is politically exploited by AIDS institutions eager to appear to be earning their keep, or by the media -- ever keen to fan any spark of controversy, or zealots riding their favorite hypothesis saddled up as fact, the public is in danger."
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I can also tell you that the intense campaigns against use of volatile nitrites conducted by Hank Wilson in San Francisco, Neil Schram and his Los Angeles City/County Aids Task Force, and John Lauritsen in New York, are slim in scientific merit.
Space limits for this article do not allow reviewing each of the many published papers on "poppers". However, a critical look at three of the most frequently cited ones may whet your awareness of the need for a more substantial weighing of the evidence than has been provided by the "popper"-ban advocates. A look at these three papers is representative, in my view, of the best of what has been published.
Hersh and Newell and their colleagues(1) at M.D. Anderson Hospital in Houston, studied the effect of butyl nitrite (“poppers") on laboratory (in vitro) cultures of white blood cells --cell types important in the body's immune response to infection.
They reported that many of these cells were killed when left for 24 hours in the presence of one percent added butyl nitrite, whereas at 1/2 that concentration (i.e., 0.5 percent) or less the "cell count and viability were unaffected." [emphasis added] In other words, a small change in concentration dramatically eliminated the toxic effect. They also wrote that at 0.5 percent several of the cells' immunological responses were inhibited. However, again only a generally small inhibition could be detected at slightly lower concentration (0.01 percent).
The authors warned of the need for caution in evaluation of the significance of their results in real life application(2): "The data suggest but do not prove that the agents may be immunosuppressive in vivo [in living animals]." Despite their own sound advice, a paragraph later in their text, they ignore their advice stating: "these in vitro studies strongly suggest that the inhalant nitrites may indeed be dangerous, and their use should be condemned by those physicians who treat patients who use these drugs regularly." [Note that they use the term "condemned”, a judgmental, non-scientific word, rather than one such as it cautioned about."]
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"In other words, a small change in concentration dramatically eliminated the toxic effect."
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Although it is true that instructive information about the effect of use of a drug on people is sometimes gained by in vitro (test tube) studies, more often than not such work proves non relevant. Most people are aware, for instance, of the large numbers of “promising" drugs discovered in the lab and reported in the press but which then prove unworkable when tested on live patients. This drug failure, in moving from the test tube to actual people, is often because very high or very low concentrations of drugs were used in the laboratory phase of the study and have little relevance to "real life" testing.
Clearly a small reduction in nitrite concentration dramatically changed the responses Newell and Hersh found. The question logically follows: how relevant is the use of their concentration of poppers to real life"?
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"The authors warned of the need for caution in evaluation of the
significance of their results in real life applications"
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One estimate is to calculate what Newell's one percent nitrite concentration means for an average adult male with 6 liters of blood for even transiently establishing a one percent blood level, never mind for a 24-hour one. CALCULATION: one percent of 6 liters equals 0.06 liters, or 60 milliliters (ml.) of butyl nitrite. A representative bottle contains 10 to 12 ml. of “poppers"; that is to say, about 5 or 6 bottles of "poppers" would have to be injected into a person's blood to briefly attain a one percent level ... a staggering amount of butyl nitrite!
And that's attained only if all the nitrite gets into the person's blood. Unlike adding butyl nitrite directly into Hersh and Newell's laboratory dish where the "poppers" can saturate the culture medium, only a fraction of the chemical will be absorbed at the lungs through inhalation, the common way poppers are used. As with cigarette smoke, most of what is inhaled is immediately exhaled out of the user, thus, many more bottles of butyl nitrite would be needed to achieve an inhalation level comparable to that in the laboratory study, making the bearing of Newell and Hersh's data still more remote in human relevance.
Also, the authors' laboratory results are based on 24-72 hour continuous exposure to butyl nitrite, a condition utterly without parallel in common human usage, even though some might wish that disco-ing or sex lasted that long.
I think it is instructive to consider all this information with regard to a far less politicized compound, such as aspirin. It would not be surprising to find that common household aspirin, used by generations of average Americans, would have had similar inhibitory laboratory effects if Newell and Hersh had tested one percent levels of it, too. In fact, for a rough and ready comparison, as little as 0.325 grams (gm.) of aspirin taken by some persons can cause changes in blood chemistry leading to bleeding for several days, as well as other effects. 0.3 gm. of aspirin in 6 liters of blood represents a concentration of 0.005 percent, even less than the percentage of butyl nitrite needed for an effect.
To conclude, yes, if enough "poppers" are used an effect can be forced... just as household aspirin can be forced to lethal levels.
In another study, the M.D. Anderson Hospital group(3) injected mice with "Rush", a commercial brand of “poppers", in order to see "real life” effects of nitrites. They inoculated the mice twice, each time with 1/4 ml. of a “poppers" solution of about 5.6 percent nitrite. That calculates to about 0.028 ml. of butyl nitrite per mouse.
How does that compare to a man? The average mouse weights about 80 gm., the average man 80,000 gm.; the weight ratio is about 1000 to 1.
Scaling up the nitrite dose used in the mice to a comparable one for a man, would thus require injecting him twice with 14 ml. of "Rush" -- that is a total of 28 ml., or nearly three bottles of "Rush". Adult humans have died from similar amounts (10 to 30 gm.) of aspirin(4). Such a massive dose of aspirin is highly toxic compared to ordinary usage. With this parallel in mind I fail to see what significance a similarly massive dose of butyl nitrite has for comparison to ordinary “popper" use.
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“ ... about 5 or 6 bottles of "poppers" would have to be injected into a person's blood to briefly attain a one percent level ... a staggering amount of butyl nitrite!
Also, the authors' laboratory results are based on 24-72 hour continuous exposure to butyl nitrite, a condition utterly without parallel in common human usage, even though some might wish that disco-ing or sex lasted that long.
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The third research study is one of rare restraint and high integrity. The study by Haverkos et al.(5) has been widely used by "popper"-ban lobbyists to claim a link between "poppers" and AIDS, even though the authors avoid that link. In fact, they argue that of those persons who have already developed immunodeficiency, those who have a history of using substantial amounts of “poppers" more frequently succumb to Kaposi's sarcoma (KS), whereas those with lower or no nitrite use, succumb to pneumocystis pneumonia (PCP). Ironically, the AIDS patients with KS (higher nitrite use) have a considerably longer life expectancy after diagnosis than do those with PCP (lower use).
However, in comparing a rather small sample of 47 men with KS and 20 with PCP, Haverkos found a long list of other statistically significant differences too: Men with KS were more likely to earn over $20,000 per year (!); to have had hepatitis B; use amphetamines, barbiturates, cocaine, ethyl chloride, LSD, marijuana, methaqualone; had more sexual partners. This is a formidable list of statistically significant differences.
Unable to draw any clear conclusions from these direct correlations, the authors resorted to 'multivariate analysis’, a sophisticated, but treacherous technique. It is especially tricky with small numbers of subjects, as in this study. Indeed, Haverkos and his associates themselves state that multivariate analysis only “suggests the relative importance of differences." [emphasis added]
Haverkos et al. cautiously report "Total days of nitrite use more significantly differentiated between the disease groups than any other variable," and "interpreting the results of these analyses requires caution. The numbers of patients enrolled are small," and as the final statement in the 'discussion' section of their paper: "The association of KS with nitrites in this study may only represent correlation. In other words, nitrites may be merely a marker for other behaviors or exposures associated with their use."
Indeed, other published multivariate studies do not confirm Haverkos et al. As the authors forthrightly and candidly admit, Marmor et al.(6) initially reported a KS-“poppers" link, "However, they [Marmor et al.] reanalyzed their data, entering additional factors, and found that still other variables appear to
differentiate KS patients from controls by multivariate analysis," and Jaffe et al., at the Centers for Disease Control.(7) also reported using multivariate analysis and found that nitrite use was NOT significant.
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"In short, the much vaunted body of research supposedly demonstrating a link between "poppers" and AIDS does not withstand close scrutiny. If a link exists it still remains to be proven."
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Elsewhere, in the lead chapter of one of the finest new AIDS research and therapy books(8), J.J. Goedert and W.A. Blattner at the National Cancer Institute draw a very interesting conclusion from their research and that of others. While noting that in one study, "helper T-cell counts were slightly lower with frequent nitrite inhalant use; this suggests the possibility that nitrite use may be a co-factor" for AIDS or for KS, "Neither of these possibilities has been completely evaluated," and, "However, it now appears that frequent use of nitrite inhalants simply may be a surrogate marker of frequent receptive anal intercourse. This sexual activity was associated very clearly with Kaposi's sarcoma in a case-control study of homosexual men and with HTLV-III seropositivity in the cohort studies of homosexual
men in Denmark and New York City, even after statistically adjusting for the number of homosexual partners and the frequencies of nitrite inhalant use and seven other sexual practices.”
In short, the much vaunted body of research supposedly demonstrating a link between “poppers” and AIDS does not withstand close scrutiny. If a link exists it still remains to be proven.
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“…it now appears that frequent use of nitrite inhalants simply may be a surrogate marker of frequent receptive anal intercourse.”
J.J. Goedert, M.D.
W. A. Blattner, M.D.
National Cancer Institute, NIH
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IN analyses of diverse other published works, Goedert et al., Jacobs et al., Gerblish et al., Mathur-Wage et al., and unpublished work by Gangadharam et al., for example, fare even less well than those I have addressed here.
Do I advocate “popper” use? No. Am I paid by the “popper” industry? No. Why do I press the issue?
1) Because I think some of us have to tell the truth with as much objectivity as possible – some of us with the scientific research training to evaluate the data at more than its face value (thus, leaving out most physicians and nearly all journalists and advocate-lobbyists).
2) I feel that the liberties with fact taken by some who act as medical spokespeople in the AIDS crisis can only serve to undermine public trust in the scientific process.
3) I fear the damage which will be done if people are boldly told, as they have been, that “poppers” are ‘the drug linked with AIDS.’ Too many will give up “poppers”, but continue with (or move on to) cocaine, heroin, crystal meth, and other amphetamines, etc. These are drugs more likely in my view to be among the AIDS-cofactors.
In the New York Native(9) a Gay doctor in San Francisco was quoted as saying, “Unfortunately, most of my patients and friends appear to be engaged in an elaborate ritual of denial that there is even a problem here. They make some token sacrifice, such as giving up a drug or sexual practice that they never really liked anyway, and they convince themselves that this sacrifice will get them through the Lenten period for another 40 days or so until the AIDS problem is solved.”
I’m fearful that illegalizing “poppers”, coupled with the media blitz which already exists, makes “poppers” the “token sacrifice”, and “legitimizes” clearly dangerous drugs.
4) I’ve seen gas chromatographic profiles of the purity of street “poppers” and of the largest ‘legitimate’ manufacturer’s. The latter is pure, while the street form is like bathtub gin. Illegalizing “poppers” will knock out the pure forms and make dirty street “poppers” the standard item.
5) We either need to put the issue of “poppers” behind us, or make a valid case against them through better science, so that we can turn our attention to other drugs and other and other cofactors. We’ve been too preoccupied with “poppers” to the exclusion of everything else. By continuing up a wrong path, we lose time finding the right one.
On the AIDS clock, time is measured in deaths.
1 1983 Cancer Research 43; 1365
2 ibid pg. 1371
3 1984 Lotzova, Hersh et al., Cancer Iaununol. Itnmunother. 17; 130-134
4 1985 'Goodman and Gillman', THE PHARMACOLOGICAL BASIS OF TYIERAPEUTICS, 7th ed.
5 1985 Sexually Transm. Dis. 12(4:203-220)
6 1982 Lancet, 1:1083-7
7 1983 Ann. Int Med. 99:145-151
8 Goedert, JJ. and Blattner, W.A. The epidemiology of AIDS and related conditions. IN: AIDS: ETIOLOGY, DIAGNOSIS, TREATMENT, AND PREVENTION. eds.: DeVita, V.T., Hellman, S. and Rosenberg, S.A. 1985 J.B. Lippincott Company. New York
9 No. 102, p. 16
This reprint is provided by the Mariposa Education & Research Foundation as a public service and is #6 in a continuing series on “Making Sex Safe”.
©1986 Bruce Voeller, Ph.D./Mariposa Education & Research Foundation
Much of Dr. Voeller's life work has been archieved for future generations of researhers in the "Human Sexuality Collection" of the 'Rare & Manuscript Collections' at Cornell University Library.
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