I took Zicam a year or so ago when I had a bad cold. It didn’t help at all, so I have to agree with this expert’s opinion that Zicam is no more effective than a placebo. Had I known that there was any risk at all that Zicam would cause me to lose my sense of smell, I never would have taken it. This expert attempts to put the risk into numeric form.
The risk benefit ratio becomes a numbers game. We fly in an airplane knowing the risk of death is 3 or 4 in a million. We take antibiotics for acute sinusitis knowing there is a 1:1000 risk of infection spreading to the brain or eye and knowing there is a 1:100,000 risk of a serious allergic reaction to the antibiotic. We accept these risks for the benefits seem favorable. No one would use nasal zinc knowing that the risk of losing their sense of smell is 1 in 100. Would they use the product knowing the risk is 1 in 1000, 1 in 10,000, 1 in 100,000 or even 1 in 1,000,000. None of us enjoy the common cold and if there were an effective medicine, many would take it. But if we knew the benefit was placebo, few, if any, would risk losing their sense of smell, even if that risk were small.
It is my calculation that if we add up all the zinc induced anosmia cases we know, for example, those in class action suits, individual suits and those who have telephoned Matrixx complaining of olfactory loss after use of Zicam nasal gel products, we easily arrive at an estimate of at least 500 people. If we double that, assuming only half of those injured complained, we conservatively conclude that 1000 people are anosmic secondary to their zinc exposures. Furthermore, if we assume Matrixx has sold 10,000,000 vials of Zicam nasal gels, then the relative risk is 10,000/10,000,000 or 1/10,000 or 0.001%. The risk of being killed driving is 50,000 deaths per year divided by 200 million adults or 0.0025%. This is 21/2 times the risk of anosmia, but I accept that risk for I benefit from driving. I would not accept that risk for a placebo nasal spray, which neither prevents, cures, nor ameliorates the common cold.
Another way to ask this question is whether a human subject committee, called an institutional review board (IRB) would approve a clinical trial with zinc nasal gel such as Zicam Cold Remedy Nasal Gel. I believe they would not. Most sensible people would not knowingly incur this risk of permanent anosmia for so little potential benefit. This opinion is supported in the January 2007 Consumer Report, “Oral Zinc is probably safe if you take less than 40mg a day.” The evidence on its efficacy, however, is also mixed. Consumer Reports' take is that “The possible risk posed by nasal zinc outweighs any benefit. It is not clear whether oral zinc is worth taking for colds.” Eby and Halcomb in Alternative Therapies 2006 conclude, “We contend that it is unethical to introduce any potentially permanent anosmia-inducing agent such as zinc or other heavy metals into the interior of the nose in a manner that could result in contact with the olfactory region to treat a temporary discomfort such as a common cold or allergy. We found no reason to recommend intranasal zinc gluconate or zinc orotate lozenges in treating common colds.” Based on the lack of any verified, demonstrable benefit from the use of zinc gluconate based nasal gels, such as Zicam Cold Remedy Nasal Gel, juxtaposed against the potential for permanent anosmia posed by such products, it is clear that zinc gluconate based nasal gels fail risk benefit analysis.
1. Summary
2. Introduction
3. The common cold
4. Zinc and the common cold
5. 1938 polio experience with nasal zinc and anosmia
6. Human experience with zinc induced anosmia - Bradford Hill Analysis
7. Differential diagnosis of anosmia
8. Chemistry of zinc cations
9. Toxicology
10. Rodents
11. Rodents versus humans
12. Importance of olfaction
13. Risk benefit ratio
14. Opinion
SUMMARY
As a clinician knowledgeable and experienced in rhinology, including olfaction, and having now seen over 25 patients with zinc induced anosmia after using Zicam Cold Remedy Nasal Gel, 15 of whom are reported in a peer reviewed medical journal, it is my opinion, to a reasonable degree of medical certainty, that zinc gluconate nasal gel, squirted and sniffed into the nasal cavity, does, in a small group of patients, reach the olfactory cleft, destroy the olfactory epithelium and receptors, and cause permanent smell loss, a condition called anosmia.
Zicam Cold Remedy Nasal Gel is marketed as a homeopathic remedy for the “common cold” and employs the active ingredient zinc gluconate, the toxicity of which is discussed further in this report. The product uses a pump to deliver the zinc gluconate, suspended in a gel, to the nasal cavity. In some cases, the gel can reach the olfactory cleft and cause injury to the olfactory epithelium. It is my opinion to a reasonable degree of medical and scientific certainty that this product, which employs zinc gluconate, is a toxic substance that is capable of sustained contact with the olfactory epithelium and may thereby cause permanent anosmia.
To be certain that review of relevant sciences support this clinical opinion, I have reviewed the related scientific studies. These include:
• the clinical presentation of zinc induced anosmia;
• the differential diagnoses, primarily post viral anosmia;
• the human clinical experience with zinc sulfate and with zinc gluconate nasal gel;
• the pathophysiology of the common upper respiratory tract viral infection;
• the history and science of zinc in the treatment of the common cold;
• the chemistry of zinc cations;
• the anatomy of the olfactory cleft and olfactory epithelium, both in humans and in animals from a comparative anatomy perspective;
• toxicology;
• animal experience with zinc induced anosmia;
• dose response, as it pertains to zinc induced anosmia;
• Bradford Hill criterion regarding association versus causation; and
• the risk benefit ratio of zinc nasal gels for the common cold.
The common cold affects the average American adult twice annually. It is caused by several different viruses including rhinovirus, corona virus, influenza and parainfluenza viruses, adenoviruses and others. The nose is infected directly by contact with viral laden nasal secretion. The virus enters the nasal mucosal cells, where it replicates and causes symptomatic illness.
Oral zinc has been studied as a homeopathic remedy for the common cold. Some report benefit, others do not. How it might work is theorized, but has not been proven. The limited studies that have been conducted regarding the efficacy of intranasal zinc are also inconclusive as to benefit.
There are currently four published studies reporting anosmia from intranasal zinc. The first involves 5,000 children who were administered zinc sulfate in 1938 to prevent polio infection. There was no protection from the polio virus, but fifty-two were left anosmic as a result of the administration of zinc sulfate. Zinc based nasal gels, such as Zicam Cold Remedy Nasal Gel, with no FDA review, were introduced as a homeopathic cold medicine in 1999. C.A. DeCook reported the first case of zinc gluconate nasal gel induced anosmia in 2000. Bruce Jafek reported ten cases in 2004 and Terence Davidson reported fifteen cases in 2006. The differential diagnosis for anosmia includes head trauma, inflammatory nasal diseases such as allergic rhinitis and sinusitis, post viral anosmia, toxin induced anosmia, congenital anosmia and many others. Post viral anosmia is the only differential potentially confused with zinc induced anosmia. In the 15 patients reported by Davidson, seven (47%) did not have a cold, so no other reasonable explanation other than zinc induced anosmia exists.
Cationic zinc, as opposed to elemental zinc is a proteolytic chemical at physiologic pH and quite capable of causing chemical injury to the olfactory epithelium. There is a large animal experience with nasal zinc. Scientists studying olfactory neuroanatomy and olfactory related behavior have used zinc sulfate in thousands of animals including mice, rats, primates, and others to chemically destroy the olfactory receptors. While there yet exists no consensus as to the permanency of these acute anosmias, there is ample suggestion that they can and do. Furthermore mice, rats, and even monkeys are anatomically and physiologically different than humans, so one cannot reliably extrapolate from the animal experiments with zinc sulfate to the human experience with zinc gluconate gel. The animal experience, like the human experience, clearly shows that zinc is toxic to the olfactory system and should warn us not to use it in the nose.
In looking at the dose response curve, the dose is a function of available zinc cation (concentration) and the time of exposure. Mixing the zinc gluconate in a glycerin based gel extends the potential contact time by one or two orders of magnitude. Hence, dose response considerations support the finding that zinc nasal gel can and does cause anosmia. Analysis employing the Bradford Hill criteria concludes that zinc induced anosmia is by causation, not by association. As there is no confirmed, demonstrable benefit to the use of intranasal zinc gluconate, the risk-benefit ratio for zinc nasal gels is highly unfavorable. Given that there is no benefit other than placebo effect and that there is risk of serious morbidity, namely anosmia, the risk-benefit considerations argue strongly against using the gel as a homeopathic cold medicine.
Based on all of this, it is my opinion to a reasonable degree of medical and scientific certainty that Zinc nasal gels, such as Zicam Cold Remedy Nasal Gel, can and does cause permanent anosmia, a syndrome I have called zinc induced anosmia syndrome.
Introduction
I am the medical director of the University of California - San Diego Nasal Dysfunction Clinic. Over the twenty-five years in which the clinic has been open, it is estimated that the Clinic has evaluated and/or treated approximately 2,000 patients who present with nasal diseases, such as chronic sinusitis, nasal polyposis, allergic rhinitis, nasal tumors and nasal trauma, exclusive of patients with smell loss. This group would increase the number of patients with olfactory complaints to well over 10,000 patients.
A recent publication evaluating a cohort of patients seen in the UCSD Nasal Dysfunction Clinic is attached supporting the volume of smell and taste patients evaluated and treated at the UCSD Nasal Dysfunction Clinic (Harris, 2006). It is titled “Clinical evaluation and symptoms of chemosensory impairment: One thousand consecutive cases from the Nasal Dysfunction Clinic in San Diego”. An earlier paper describing the first sixty-three patients is also attached, which documents the twenty year duration of the clinic experience and the differential diagnosis considered for olfactory impaired patients (Davidson, 1987).
The core of the issue of the potential toxicity of zinc gel to the olfactory epithelium is the clinical diagnosis of anosmia. First, one must make the diagnosis of anosmia, independent of its etiology. Following the diagnosis of anosmia, one must consider the history, physical examination, and laboratory findings in order to make the diagnosis of zinc induced anosmia.
I became aware of the concerns of homeopathic zinc toxicity in humans prior to publication of Dr. Bruce Jafek's original article. (Jafek, 2004). While Dr. Tisdall described zinc sulfate induced anosmia in 1938 (Tisdall, 1938), I became aware of the potential causal link between intranasal zinc gel and anosmia through the work of Dr. C.A. DeCook, who first described zinc gluconate induced anosmia in an abstract in 2000 (DeCook, 2000). The DeCook description is classic:
225. Anosmia due to inhalational zinc: a case report C.A DeCook and A.R. Hirsch 1
Rush Medical College and The Smell and Taste Treatment and Research Foundation, Chicago, IL, USA
A 47-year-old married white male with no past history of chemosensory difficulties experienced the sensation ‘as if a cold were coming on’ and tiredness. No fever, rhinorrhea, nasal congestion, cough or malaise were present. To prevent the development of an upper respiratory tract infection, Zicam nasal inhaler was applied as per the manufacturer's specifications one application per nostril, with delivery of-250 Ilg of zinc per inhalation. He immediately experienced severe right periorbital pain and anosmia. The pain resolved in I day, but the anosmia persisted. Despite treatment with Zithromax and Prednisone, the olfactory ability did not return, precipitating a visit to a chemosensory clinic I month later. At that time, olfactory testing demonstrated anosmia, with an UPSIT score of 20, Alcohol Sniff Test of 6 cm and olfactory threshold to Carbinol at an irritant level of >35 decismels in both nostrils. Isovaleric acid, 2, 3-butanedione, pentadecalactone, phenylethyl alcohol and tetrahydrothiophene were absent at 25 decismels. Isobutyl isobutyrate and L-carvone were intact at 25 decismels. The patient never developed a cold, nor had any underlying illnesses which could account for the chemosensory deficits. Ionic zinc instilled directly on the olfactory epithelium appears to be the pathogen in this patient's smell loss. Given the above, further investigation of the olfactory effects of the Zicam nasal inhaler is warranted.
I was initially dubious about this diagnosis and, while several patients claiming zinc induced anosmia were seen, I was not comfortable differentiating these patients from post-viral anosmia. However in one week, sometime in 2002, two patients presented to the UCSD Nasal Dysfunction Clinic with complaints of zinc induced anosmia following the use of Zicam nasal gel. The two patients presented with nearly identical histories. Both reported believing they were going to catch a cold, spraying the Zicam nasal gel into their nose, sniffing, feeling an intense burning sensation in their nose that persisted for several hours, and, within a twenty-four hour period, realizing that they had lost their sense of smell. In both patients, olfactory testing confirmed a severe loss.
What was interesting is that neither patient developed an upper respiratory tract infection (URI); therefore, viral induced anosmia was unlikely. The difference in the time of the onset of the olfactory loss in these cases and the typical viral induced anosmia was striking. Whereas post viral anosmia patients generally first note their smell loss several weeks after the upper respiratory tract infection, the zinc induced anosmia patients recognize the loss in approximately one day. Based on my examinations of the patients, I came to believe that, in fact, homeopathic nasal zinc did cause smell loss in some patients. Over the ensuing three years, seventeen patients claiming zinc induced anosmia, all having used Zicam nasal gel products, presented to and were evaluated at the UCSD Nasal Dysfunction Clinic. These were ultimately summarized and reported in a peer reviewed medical journal. (Alexander, 2006). The term zinc induced anosmia was thus coined.
The Common Cold
In order to understand the different causes of viral induced anosmia and zinc induced anosmia, one should understand the natural cause and progression of the common cold. The common cold may be caused by various viruses, including rhinovirus, coronavirus, influenza, parainfluenza, adenovirus and other less common viruses. The virus is spread by direct contact with respiratory secretion from an infected host.[FN1] The virus invades the respiratory mucosa of the new host primarily in the nose and throat and, to a lesser degree, in the trachea and lungs. Only a very small number of viral particles are necessary to induce infection. The incubation period is one to four days. The virus replicates in the cells of the respiratory epithelium. Viral particles are shed in the respiratory secretions and can then infect other people. Important to the current matter is that the virus has successfully invaded the respiratory mucosal cells twenty-four or more hours prior to the onset of clinical symptoms. Therefore, placing a chemical on the mucosa after the infection is symptomatic would not provide prophylactic benefit. Furthermore, placing the chemical only in the lower half of the nostril would neither prevent nor ameliorate infection in the upper half of the nose. As the virus is active in the nasal tissues, the idea of a local medicine is attractive. Because of the oral zinc lozenge experience, one can understand how this might seem like a good idea. Unfortunately, there is no scientific evidence that the oral or nasal zinc is locally absorbed or locally active.
FN1. Several different viruses are reported to be responsible for post viral anosmia (Suzuki 2007, Wang, 2007).
The typical cold begins with a sore throat and malaise. Nasal symptoms follow within twenty-four hours and include congestion and rhinorrhea (runny nose). The rhinorrhea is at first clear, but later becomes infected with bacteria and the mucus turns yellow or green in color. The common cold typically resolves without medical treatment.
Antiviral medications have failed to protect against or otherwise treat a URI, and numerous other medications have been proposed to treat a URI. These include topical intranasal decongestants such as Afrin(R) or neosynephrine, oral decongestants such as pseudoephedrine, antihistamines (both sedating and newer generation nonsedating), topical ipratropium bromide (anticholinergic/parasympatholytic), and antibiotics. Complimentary, alternative/homeopathic therapies including Echinacea, vitamin C and zinc have also been used. Some have anecdotal, symptomatic benefit. None have proven measurable, significant, clinical benefit, and, absent nasal zinc, none have had significant side effects.
While S.B. Mossad lists 5 theoretical reasons why zinc salts might have some benefit against the common cold. (Mossad, 2003), to date, none of these activities have been demonstrated to occur at clinically achievable concentrations of zinc. Furthermore each would require systemic zinc, not topical zinc. Therefore, even if they were operant, they still would not apply to topical instillation of zinc in the nose. As will be discussed later, zinc is absorbed into the small intestine by a metalloproteinase enzyme, called Zip4, present primarily in the small intestine and not present in the nose. Hence topical nasal zinc is not absorbed in the nose. It would have to be swallowed and from there absorbed in the small intestine and then via the blood system circulated to the nose.
The zinc rhinovirus story is 50 or more years old. Korant reports in 1976 that zinc inhibits protein cleavage of rhinovirus (Korant, 1976).
The clinical zinc cold saga begins in 1979 when Mr. Eby administered oral zinc lozenges to his leukemic daughter. She was coming down with a cold which appeared to be “bad” she refused several medicaments offered by Mr. Eby, but she agreed to take the oral zinc lozenges (Eby, 2002). The cold virtually vanished in a matter of hours. Mr. Eby was so impressed that he set about studying the effects of zinc on the common cold. His first study, published in 1984, administered cold-infected patients an oral zinc lozenge with 23 mg of Zn (Eby, 1984). They were to take one lozenge every two hours while awake. He measured the duration and severity of the cold symptoms and found that, for those taking the zinc lozenge, the cold had a shorter duration and a lesser severity. This study was repeated by others, with inconclusive results. Some studies showed a benefit; some did not show any benefit.
Zinc and the Common Cold
Several reviews of zinc and the common cold have been written with varying degrees of sophistication -- meaning inclusion and exclusion criteria varied among the multiple reviews. Viewed from a scientific perspective, one cannot conclude that oral zinc is beneficial, measured by either duration or severity. Most studies examined patients who had already acquired a cold and were careful to enroll patients in the first two or three days of the cold. The reported benefit from the positive studies shows that the duration may by reduced by a day or two. Severity, however, is a tougher outcome to measure. The studies in favor of zinc show a small reduction in severity.
Any study of the common cold must bear a caveat, though, due to the multifarious viral causes of the common cold and their respective affect on any particular patient's body. Some colds are mild and of short duration, while others are intermediate to severe, and of longer duration. This is a function of the particular virus, the particular patient's immunity to the infecting virus and to similar viruses, and to the patient's general immunity. The healthy relaxed individual who stays home, rests and drinks ample fluids will resolve a URI faster than those who work long hours and are not healthy, well rested and relaxed. Hence these seemingly conflicting results maybe a function of the cold and host variability and not of the treatment.
Two studies examined the ability of zinc lozenges to reduce the likelihood of “catching a cold.” One of these, in the traditional scientific methodology of studying URI viral prophylaxis, enrolled a group of volunteers. They were sprayed with rhinovirus particles. The experimental group was then given 23 mg of oral, elemental zinc for five or seven days. This study showed no benefit and is probably the best evidence of the ineffectiveness.
The second study enrolled 200 healthy children and randomly divided them into two groups. One group received an oral zinc lozenge daily; the other group received a placebo. The study looked at the number of colds the children had in that year and the number of days of school missed. They found benefit, but the benefit was small. The number of colds was reduced from 1.7 to 1.2 per year and the number of days missed was reduced from 1.3 in the placebo group to 0.9 in the zinc group.
Mossad references 14 controlled studies of zinc and URI. Six showed benefit and eight did not (Mossad, 2003). A number of mild side effects such as nausea, dizziness, lightheadedness, upset stomach, dry mouth, and burning tongue were reported. None were considered serious and all were transient. Smell testing was not performed in any of the studies.
Caruso also reviewed zinc and the common cold in 2007 (Caruso, 2007). Of the 105 published reports he examined, fourteen were randomized controlled studies, four “of which he found scientifically valid. Three of these studies reported no therapeutic effect from the zinc lozenge or nasal spray. One study reported a positive effect from zinc nasal gel. Of the remaining 10 studies, 6 reported a positive effect and 4 reported no effect.”
There are five studies looking at intranasal zinc and the common cold. The most scientifically valid study, published by R.B. Turner in 2001 used intranasal zinc gluconate in a group of patients inoculated with a rhinovirus (Turner, 2001). Half the patients received the study medication, half received a placebo. Turner found that intranasal zinc gluconate was ineffective in preventing the experimental rhinovirus cold. Adverse events judged to be possibly related to the intranasal zinc were nasal burning, throat burning, throat irritation, dry nose, dry mouth, epistaxis (nasal bleeding), and nasal tenderness. Smell loss was not reported and smell was not tested. Mossad in 2003 reported that zinc gluconate nasal gel reduced symptom severity of the common cold (Mossad, 2003). Significant adverse effects were not reported.
Taken as a whole, the science does not show any real benefit to zinc in treating a URI. One could conclude, then, that zinc might be a useful homeopathic medicine. Given the lack of scientifically demonstrated efficacy (benefit) and the risk of anosmia, however, the risk benefit ratio is not favorable. A reasonable physician must conclude that nasal zinc, such as in Zicam Cold Remedy Nasal Gel, is a dangerous homeopathic medication.
1938 Polio experience with nasal zinc and anosmia
The late 1930s polio zinc nasal experience is relevant to the current matter. (Tisdall, 1938; E.W. Schultz, 1938). Polio, like an URI, is a viral infection. It was thought the polio virus entered the brain through the nose,[FN2] and it was further thought that administering nasal zinc in the form of zinc sulfate might reduce infectivity. There was no protective benefit to the topical nasal zinc in the prevention of polio, and the therapy was quickly stopped. According to the 1938 paper by Tisdall, the nasal zinc was reported to cause smell loss in some patients. 4,713 children were sprayed with nasal zinc. At the end of six months, 52 (1%) self reported anosmia.
FN2. This hypothesis as to the causation of polio was later shown to be incorrect.
It would appear that today's zinc nasal gels are a repeat trial of the unsuccessful 1930s polio experiment, as both provide no measurable benefit to any but do cause anosmia in some. Schultz reported the same concerns of olfactory injury associated with intranasal zinc in an editorial to the American Medical Association (JAMA), making interesting comments regarding the differences he noted between the upper nasal cavities, or olfactory cleft, of adults and children (Schultz, 1938). He reports additional work in monkeys using 1% zinc sulfate, demonstrating significant damage, but recovery of most of the olfactory receptor cells (Schultz, 1941, Schultz, 1960).
Tisdall describes acute loss in the 1937 publication (Tisdall 1937). Olfactory testing was made with oil of cloves and oil of spearmint, and they were conducted on three occasions. In two of these a non-odorous control was used. In the first test of 330 children, forty-four (13%) had smell loss. In the second test, now including the control smell, 138 children were tested 48-72 hours after zinc sulfate spraying. Thirteen of 138 (10%) had smell loss 48-72 hours after spraying. In the third testing, performed after the second spraying, using oil of spearmint and a non-odorous control in 391 children ages 6-10, fifty-one of 268 (19%) had lost their sense of smell.
Pentecost describes techniques for applying the zinc sulfate as measured by 100% of the children reporting smell loss (Pentecost 1937).
This cannot be clearer. Zinc cation reaching the olfactory cleft causes anosmia.
Human experience with zinc induced anosmia - Bradford Hill Analysis
Sir Austin Bradford Hill published a paper in 1965 titled, “The environment and disease: association or causation” (Hill, 1965). He describes 9 criteria which can be used to make this distinction: strength of the association; consistency; specificity; temporality; biologic gradient; plausibility; coherence; experiment; and analogy. While generally used for environmental carcinogens, it is easily applied to other medical conditions. Applying the criteria to a homeopathic medicine is perhaps unusual, but in the current matter seemingly appropriate. proteolytic
The first criterion is strength of the association. There currently exist four independent, peer reviewed, scientific reports of zinc induced anosmia in humans. The first is Tisdall with fifty-two cases (Tisdall, 1938). The second is DeCook with a single case (DeCook, 2000). The third is Jafek with ten cases (Jafek, 2004). The fourth is Davidson with fifteen cases (Davidson, 2006). In animals there are thousands of cases reported in peer reviewed scientific journals. Under this criterion, the issue is causation versus association. Association for those with a concomitant URI, excluding preexisting anosmia, is post viral anosmia. This is the primary and only possible differential diagnosis. Differential diagnosis for those who took the zinc nasal gel prophylactically, but never developed a URI, could only be spontaneous or sudden, idiopathic smell loss, a non-existent diagnosis. Post viral anosmia, more common than zinc induced anosmia, is associated with a viral URI, generally severe, and the resultant anosmia is normally noticed weeks after the URI, generally when the URI associated rhinitis and the nasal congestion resolve. Conversely, I personally have never seen post viral anosmia reported by a patient in the early stages or days of the URI, nor have I found a report of onset of anosmia preceding a URI. I have rarely, if ever, seen a mild URI resulting in anosmia. Of the initial fifteen patients with zinc induced anosmia reported by Davidson in the Laryngoscope in 2006, seven (47%) did not suffer a URI. These patients used the Zicam nasal spray prophylactically and never did develop signs or symptoms of a URI. Since they did not have a URI, they could not have had a post viral anosmia. Eight (53%) of the patients did have or develop a URI. For that segment of patients, post viral anosmia is considered in their differential diagnosis, but, based on temporality, this diagnosis was ruled out. Therefore, the Bradford Hill criterion for association is weak; for causation, it is strong.
The next Bradford Hill criterion is consistency. Quoting from the original Bradford Hill publication, this criterion asks the question “Has it been repeatedly observed by different places, circumstances and times?” Zinc induced anosmia is uncommon with an estimated 1,000 cases in the US and an estimated incidence of 1 case per 10,000 bottles of sold zinc spray. Zinc induced anosmia has been observed and reported in peer reviewed medical journals by 4 different observers in 4 different places e.g. Canada, Chicago, Denver and San Diego, under 2 different circumstances i.e. medical application (polio prophylaxis) and self administration (homeopathic cold remedy) and at different times 1938, 2000, 2004 and 2006. To quote Bradford Hill “We have (or certainly had) to make up our minds on a unique event; and there is no difficulty in doing so.” This is the case for zinc induced anosmia. The preponderance of the evidence supports zinc induced anosmia causation.
The third Bradford Hill criterion is specificity. This is clear. Zinc gluconate based nasal spray, such as Zicam Cold Remedy Nasal Gel, is uniquely and specifically capable of causing anosmia. It does not cause sinusitis, blindness, cancer or any other illness. It specifically causes anosmia.
The fourth criterion is temporality. The zinc nasal sprays cause immediate onset burning and the anosmia is generally perceived within twelve to thirty-six hours. I believe the anosmia is immediate. The realization takes anywhere from minutes to thirty-six hours. Bradford Hill is often applied to cancer induction by tobacco smoke or industrial materials. The cancers are generally seen years later so temporality is more obtuse. In zinc nasal spray the onset is immediate and the temporality criterion is clear.
The fifth criterion is biologic gradient. Bradford Hill writes, “Fifth if the association is one which can reveal a biologic gradient, or dose response curve, then we should look most carefully for such evidence.” The dose response curve in zinc induced anosmia is on one hand simple and, on the other, complex. Theoretically, this should be a very simple dose response curve, the greater the zinc concentration the greater the effect i.e. the chemical injury, the greater the damage to the olfactory receptor cells and the greater the anosmia. However, in the current matter dose variation is not so much the zinc cation concentration, for all Zicam has the same molar concentration and no experiments have been conducted looking at concentration vs. effect, but rather the nature and time of the contact between the zinc and the olfactory tissue.
The dose variable is the time and of the contact of the gel with the olfactory cleft. The cleft is variable in location and the distribution of the olfactory receptor cells in the cleft is variable, the nasal anatomy is variable, the direction and spray force are variable, and the presence and strength of the sniff are variable. Therefore how much zinc gel gets to the olfactory cleft is variable. In addition, the time or duration of the exposure is important. Whereas most experimental zinc applications use a watery, low viscosity solution, Zicam Cold Remedy Nasal Gel sprays are mixed in a glycerin material that makes the spray a gel, a high viscosity solution. This viscous gel, when deposited in the olfactory cleft, adheres to the tissue and hence the time of contact and the time of exposure are long. This prolonged exposure extends the time of chemical interaction and increases the proteolytic destruction of the olfactory receptor cells. While there is no information regarding the time of exposure, I estimate this at 15 to 20 minutes, based on my experience placing this gel on my own fingers. It is the sum of all of these variables that creates the variation in “dose” and the variation in effect. Bradford Hill criteria require that a dose response curve exits. Dr. Davidson believes there is a dose response curve and that this fifth criterion is satisfied.
The sixth criterion is plausible. “It will be helpful if the causation we suspect is biologically plausible.” Biochemically, zinc gluconate is a weak acid and at physiologic pH is proteolytic. The animal experiments clearly demonstrate that topical nasal zinc causes an animal to lose its sense of smell. Furthermore if the olfactory clefts are examined at necropsy tissue damage is seen. The clinical experiences show that olfaction is lost. Zinc induced anosmia is plausible.
Coherence is the seventh criterion. “Coherence: On the other hand the cause-and-effect interpretations of our data should not seriously conflict with the generally known facts of the natural history and biology of the disease - in the expression of the Advisory Committee to the Surgeon-General it should have coherence.” Webster defines coherence as “the quality of being logically integrated, consistent and intelligible.” In other words, plausible means possible, and coherence means probable. One should set aside those individuals who used nasal zinc for a URI and consider the two groups who used nasal zinc while they were otherwise healthy. The Canadian children administered nasal zinc to prevent polio had no reason to lose their olfaction from natural cause. The only intervention was the nasal zinc and therefore the probable explanation for their smell loss was the chemical injury of the nasal zinc. The same can be said for those individuals who used Zicam Cold Remedy Nasal Gel prophylactically, thinking they were going to get a cold. These individuals had no natural cause to lose olfaction. The sole intervention was the nasal zinc and therefore the probable explanation for their smell loss was the chemical injury of the nasal zinc. The same is true for the rodent induced anosmia. It is difficult to imagine that a cage of 10 or 30 rats became suddenly and spontaneously anosmic unrelated to the nasal installation of cationic zinc. Therefore, the Bradford Hill criterion of coherence is satisfied.
The eighth criterion is experiment. Putting aside the unfortunate human experiments of polio prophylaxis and homeopathic nasal zinc, the animal experimentation is crisply clean. Zinc cation causes anosmia. The only experiment which has not been conducted is the dose response calculation of zinc gluconate gel. The obvious experiment is to administer the gel in different strengths and because of its propensity to adhere for different periods of time and then measure the degree and duration of olfactory impairment. This experiment has not been conducted, or if it has, has not been reported.
The ninth and final Bradford Hill criterion is analogy. Other topical proteolytic chemicals have caused anosmia. Ammonia, industrial strength cleaning fluid and gasoline have all been seen. Chronic toxin induced anosmia has been seen with formaldehyde and photochemical developing agents.
Applying the Bradford Hill criterion regarding the Environment and Disease; Association or Causation, it appears evident that zinc gluconate based nasal gels, such as Zicam Cold Remedy Nasal Gel, can and do cause anosmia. Bradford Hill eloquently concludes “All scientific work is incomplete - whether it be observations or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time.
Zinc induced anosmia is an acute, topical, toxic injury. Acute toxin anosmia is a known entity. In my own practice I have seen it on several occasions. The first is from ammonia exposure. A young man bit into a store bought sandwich in which someone had placed an ammonia capsule. When the patient bit the capsule and exhaled there was intense burning and acute onset anosmia. His sense of smell did not recover. A second example is a young woman instructed to clean the bathroom of a fast food store. She failed to dilute the industrial strength cleaning solution, and she also failed to properly ventilate the small bathroom. From inhalation of the solution, she burned the inside of her nose and suffered acute onset, permanent anosmia. I have seen two cases of gasoline pump injuries wherein the pump handle popped off the hose, and pressurized gasoline was squirted into the nose. There was intense burning and acute, permanent anosmia.
There is a substantial animal literature regarding topical nasal zinc and anosmia. Scientists interested in the neuroanatomy of olfaction and in the behavioral importance of anosmia create acute toxin induced anosmia by instilling zinc sulfate into the animals' nose. Acute onset anosmia has been successfully created in thousands of animals such as mice, rats, gerbils and even monkeys, and the findings have been reported in hundreds of peer reviewed scientific journals. It is crystal clear that zinc cation is toxic to olfactory receptor system.
It is interesting and important to the current matter that younger brains are more plastic than those of adults. This seems true of olfaction as well. Close examination of the polio experiment shows that long term anosmia was more common in teenagers than in prepubertal children. The UCSD pediatric head trauma study shows a much lower incidence of past traumatic anosmia in children than is generally reported in adults. (Sandford, 2006).
This appears to be a function of youth and brain plasticity and not of simple adaptation. The rodent experience discussed later is predominantly in young animals, and there is little doubt some are rendered permanently anosmic (Harding 1978). I suspect had this been conducted in older animals, permanent anosmia would have been more common. Zinc gluconate induced anosmia in humans, to date, has been seen exclusively in adults.
Differential Diagnosis of anosmia
The next area of clinical importance is the differential diagnosis of smell loss, here called anosmia. As published by ourselves and by others, the differential is long (Feldman, 1991). The most common differential diagnoses of smell loss are inflammatory nasal disease, post viral anosmia and head trauma. Inflammatory disease includes all the nasal rhinitides. The most common are allergy, sinusitis, and nasal polyps. These are all reversible Post viral anosmia is the most important differential for zinc induced anosmia. The typical post viral anosmia is well described in the papers published by Dr. Davidson and noted above. It begins with a URI, typically a particularly severe URI, most commonly in middle aged adults. As the rhinitis dissipates, patients become aware their sense of smell is diminished or gone. This is first noticed several weeks after the URI. In contrast, zinc induced anosmia is a chemical injury to the olfactory receptor cells in the olfactory cleft in the roof of the nose. Post viral anosmia is generally thought to be a viral induced injury to the olfactory receptor cells in the roof of the nose, hence once the injury occurs, the two conditions appear similar. They can be mild, moderate, or severe; they can be temporary or permanent; and the patients may or may not experience parosmia, a distortion of smell wherein the remaining olfactory receptors are stimulated by a “smell” but due to some miswiring between the olfactory receptor cells and the brain, the patient detects a different odor, typically unpleasant. Parosmia is seen in any olfactory receptor cell injury and does not help differentiate post viral anosmia from zinc or other chemical toxin induced anosmia (Bonfils, 2005).
There are other toxins known to cause olfactory injury. Dr. Davidson has seen ammonia exposure, both acute and chronic, cause smell loss. Exposure to formaldehyde and photochemical developing agents can cause anosmia. Gasoline pumped into the nose when a gas pump handle breaks can also cause anosmia. Medicines can also cause smell impairment, some temporary, some permanent. There are many other causes of anosmia. Dementia, particularly Alzheimer's disease, causes anosmia; however, the demented rarely complain.
Patient history easily distinguishes most other possible causes. Zinc induced anosmia is invariably accompanied by an immediate, intense and prolonged nasal burning. Nasal burning from cationic zinc was first described in 1937 when scientists were considering zinc sulfate to prevent polio (Peet, 1937). M.M. Peet observed, “It was found that when zinc sulfate was actually applied to the olfactory area it produced a severe burning or smarting sensation with coryza and in most subjects a severe headache which lasted for several hours. Zinc sulfate introduced into the lower portion of the nose did not produce such symptoms. It is only when it is applied to the olfactory area that this pain results.” Tisdall observed the same pain in his patients. (Tisdall 1937). He wrote, “Most of the children (ages 3-10) suffered temporary discomfort. Some, however, complained of severe pain ‘between the eyes,’ which continued for several hours.” Conversely, post viral anosmia has no nasal burning. Post viral anosmia is accompanied by a URI, typically severe. The olfactory loss of post viral anosmia is typically first noted several weeks after the URI. The olfactory loss of zinc induced anosmia is generally recognized within 12 to 36 hours of the burning application. In both cases, inflammatory nasal disease is excluded by sinus CT scan or by a short course of high dose prednisone.
It should be noted that some of these patients did not have a cold; hence, post viral anosmia is not included in their differential diagnosis. In fact, there are no other possible explanations for their acute onset smell loss. While sudden loss occurs with hearing and vision, it does not occur with olfaction. In the original publication in Laryngoscope 2006, fifteen patients with zinc induced anosmia were reported. Seven (47%) did not have a URI; therefore, there is no other reasonable or plausible causal agent, other than the zinc nasal gel, that would cause these individuals to have lost their sense of smell.
Based on the above distinct differences, the zinc induced anosmia syndrome was described. The syndrome is squirt, sniff, burn, and anosmia.
The application of the zinc nasal gel is a given. In my experience, most if not all, patients sniff. This is a normal way to use most nasal sprays, Afrin and Neosynephrine being the classic examples.
This raises an interesting question whether all patients sniff. Some remember, some are not sure and some don't remember or even think they did not. Unfortunately, sniffing is such a common habit, one may not notice or remember. If you ask people if they did any of the following yesterday and how many times, many would not remember; swallow, sniff, scratch their nose, sneeze, burp, or pass gas.
Patients typically describe an immediate onset severe burning. When asked to define immediate, they typically state 1 to 3 minutes. Zinc cation in the lower half of these causes a mild, tingling sensation. Patients localized this to the lower, anterior regions of their nose.
Zinc cation squirted and sniffed into the upper half of these, specifically the olfactory cleft, describe an intense 10/10 severe burning pain. The pain location is between the eyes or in the glabella (middle brow).
Chemistry of zinc cations
Zinc is a caustic, chemical irritant and causes a sense of burning when applied to nasal mucosa. In most, this is of short duration, often described as a tingling and may be responsible for the placebo benefit of zinc nasal gel. In those who lose their sense of smell, the burning is of longer duration, up to an hour or more. It is also described by most as intense. Whereas the smell loss in post viral anosmia is generally first noted when the cold resolves and typically noted several weeks after the URI, in zinc induced anosmia, it seems to be immediate and noted within 12 to 36 hours of the offending application. Post viral anosmia and zinc induced anosmia are dramatically different and not difficult to separate on a clinical basis.
Certainly not everyone who uses zinc nasal gel develops anosmia. My opinion is that in certain individuals the zinc nasal gel is sniffed or squirted or both into the olfactory cleft, where, because of the gel carrier, it can remain in contact with the olfactory receptor cells for an extended period of time. Whether injury is a function of bad luck, layering the gel in contact with the olfactory receptors, a function of anatomy, a function of the infecting virus (Wang 2007) or a function of individual sensitivity is not known and regardless, is irrelevant, for it clearly causes anosmia in some people.
The chemistry and toxicology of topical, cationic zinc and olfaction are next considered. As there is a potential for permanent anosmia, it is unethical to experiment on humans, so studies are generally performed in the chemistry lab and then in the animal lab. Zinc cations are well known to the chemist and review of standard chemistry books reveals what needs to be known. The argument is made that all of the clinical and laboratory experiences have been made with the zinc sulfate and that zinc gluconate is different. This is bio-chemically misleading. The destructive chemical is the zinc cation and it does not matter whether the zinc is chemically bonded to a sulfate or to a gluconate. Sulfate and gluconate have different molecular weights; therefore, different concentrations by weight have different amounts of cationic zinc. These differences are small and do not affect the zinc cation toxicity.
Basically, zinc cation is proteolytic, meaning it is destructive to proteins, such as mucosa and olfactory receptor cells. It is chemically active against tissue at physiologic pH. It clearly has effect on human nasal tissue or why would it be used as a nasal spray.
Zinc is a naturally occurring element. Elemental zinc has an anatomic number of 30 and a molecular weight of 65.39. Zinc compounds such as zinc sulfate or zinc gluconate are produced by a chemical reaction with elemental zinc. This creates cationic zinc, often written Zn 2*.
Cationic zinc is not inert. It is biochemically active. If swallowed, the zinc is actively absorbed in the small intestine. The zinc is transported by the zinc trans membrane protein, Zip4, and used for numerous important biologic actions (Maverakis, 2007). There is no scientific study supporting local Zn2* absorption in the mouth or nose.
Zinc cation is loosely bonded to the anions sulfate and gluconate. The relative weights and molar and percent solution strengths are shown in the following table.
TABLE
A 5% solution of zinc sulfate contains 50 grams of zinc sulfate per liter of water. This corresponds to 174 mmoles of zinc sulfate heptahydrate, written as 177 milimolar and abbreviated 177 mM. Each molecule of zinc sulfate is bonded to 7 molecules of water. Pure zinc sulfate is not U.S.P. It is strongly irritating and hard to handle. It is also hydroscopic and difficult to obtain pure. A 5% solution of zinc gluconate has 50 grams of zinc gluconate per liter of water. This corresponds to 110 mmoles of zinc gluconate i.e. 110 mM. A 1.5% solution of zinc gluconate contains 15 grams of zinc gluconate per liter of water. This corresponds to 33 mmoles of zinc gluconate, 33 mM.
The strength of the ionic bond is pH dependant as shown in the following graph.
Zicam Cold Remedy Nasal Gel consists of zinc gluconate (33 mM, 1.5%) in an emulsion of benzylkonium chloride, glycerin, hydroxyethyl cellulose, sodium chloride and sodium hydroxide. Its reported pH is 7.2.
TABLEClearly cationic zinc is chemically and biologically active and available at physiologic pH.
At physiologic pH's ranging around 7.2-7.4, the ionic bond is weak and the zinc cation is available and chemically active. It reacts with, denatures and destroys proteins. On the skin this would be called an astringent, but generally this would be described as a proteolytic reaction. The olfactory epithelium and olfactory receptor cells contain proteins and when this protein is denatured, the tissue is destroyed and rendered non-functional. A common English word describing this is burn. The reaction is a chemical burn as opposed to a thermal burn. If the zinc cation burn is mild, the tissues are injured and recover. If the burn is more severe, the cells are more seriously injured and do not recover.
Toxicology
Different specialties have different expertise in toxicology. Those relevant to the current matter are individuals typically interested in the neuroscience of olfaction and for well over 50 years have used zinc sulfate to produce olfactory deficits. The majority of this work has been performed in rodents, typically mice and rats, but other animals have also been used. A second group of individuals with expertise in toxicology are those with an M.D. and the broad specialty of toxicology. These are individuals with special training and experience in toxicology, particularly as it pertains to humans. They are typically employed in Emergency Departments, poison control centers, or are engaged in clinical research.
The third group with expertise in toxicology relevant to the current matter is physicians with specialty training and clinical experience in olfaction. While such specialists may have less general training in toxicology than would a toxicologist, they are the only individuals with sufficient understanding of the subspecialty area, namely clinical olfaction, to be able to make the clinical associations necessary for expert opinion. While the opinions of basic scientists and general toxicologists are valued, it is ultimately the specialist in the area of interest who must make the clinical evaluation of harm or injury.
Rodents
Next in the scientific considerations is the rodent experience. The literature is robust. Zinc sulfate has been used to evaluate rodent behavior and to look at olfactory neuroanatomy and physiology. Zinc sulfate is a proteolytic chemical which causes necrotic changes in the olfactory sensory system. Typically the animals are administered intranasal zinc sulfate and then their ability to smell a buried pellet of food is measured. The time it takes to find the food pellet is a measure of the degree of olfactory injury. They are then autopsied and the olfactory epithelium and its connections to the brain are evaluated.
In most cases the work is short term so long term anosmia is unimportant and rarely measured. Nonetheless, whether the zinc causes long term anosmia seems to be of scientific interest. Schultz asks this question with 1% zinc sulfate in monkeys in 1937 and again in 1960 (Schultz, 1937, Schultz 1960). He found serious damage to the olfactory epithelium. Harding evaluated this in 1978 (Harding, 1978). The following is quoted from his publication in Brain Research, “Intranasal irrigations of mice with 0.17 molar (5%) zinc sulfate solution results in the immediate and total loss of the ability to find a buried pellet.” This anosmia persists for 6 weeks in at least 80% of the treated animals and for 4 months in half of the animals. Slotnick, in 2000, argued that the literature does not support zinc causing permanent smell impairment (Slotnick, 2000). He quotes 83 papers, all producing anosmia and concludes that zinc does not cause permanent anosmia. One of the papers cited is the above work of Harding, which seems to contradict his conclusion. It is hard to imagine why literally hundreds of investigators have used zinc in olfactory experiments to produce anosmia and destruction of the olfactory sensory system if it did not cause anosmia. It is easy to imagine that a chemical that consistently causes “temporary” anosmia by destruction of the olfactory epithelium might in some cases cause a permanent anosmia. Whether or not we can conclude or agree that zinc sulfate in a watery solution causes permanent anosmia is not important. This extensive animal research raises enough concern that we must worry that placing any zinc solution in the human nose could cause permanent injury and anosmia. It should be commented that there are considerable interspecies differences and there are even intra-species differences.
Rodents versus humans
Some have attempted to extrapolate the rodent data to humans; however, this extrapolation is seriously flawed. The key experiment has not been conducted. The proper experiment would be to apply the Zinc nasal gel to a wild mouse or rat in varying concentrations and determine how long it stays in the olfactory cleft and the amount and time necessary to cause permanent anosmia. This could be expressed as an LD1, LD50 or LD99. It really doesn't matter what zinc sulfate does in a non viscous watery solution. What does matter is what zinc gluconate, in a sticky, viscous glycerin solution does to the olfactory epithelium. Slotnick examines zinc gluconate olfactory toxicity in a mouse model (Slotnick, 2007). In the paper he conducts this in response to the publications by Jafek and by Davidson. Basically, he introduced zinc sulfate and gluconate in nasal cavities of mice 10 to 25 weeks old and found the olfactory injury to be mild and short lived. Unfortunately, the zinc compounds were in water and not in gels and therefore contact times were short. Not only is this a poor research design, but also there is a potential conflict of interest, as both of Slotnick studies were supported by Matrixx, the maker of Zicam Cold Remedy Nasal Gel.
All this aside, attempt is still made to extrapolate rodent data to humans. A mouse weighs 30 grams, a laboratory rat, 250 grams or more, and the adult human Caucasian male 70 kg or 70,000 grams. A mouse is therefore, 30/70,000=0.00043 or 0.04% of the human. A rat, therefore, is 250/70,000=0.0036 or 0.4% of the human. Interestingly, a mouse is 30/250=0.12 or 12% of a rat. Rodents, like dogs and cats, are macrosmic meaning they have large olfactory areas. Man is microsmic meaning he has a relatively smaller olfactory area. To better understand this, the Comparative Anatomy of the Nose and Paranasal Sinuses by Victor Negus is recommended (Negus, 1958). He traces the evolution of olfaction from insects to man. He describes the ethmoid turbinal as the anatomic site of olfactory receptors. In man this is the middle and superior turbinate. He also comments that the better an animal can smell, the more area devoted to olfaction. In the animals with sensitive olfaction, the ethmoid turbinal is a complex, folding bone covered with olfactory mucosa. The complex convolutions greatly increase the surface area. Exact surface area numbers are not well known for all animals. He reports the following from M.J. Jamieson in the Ferens Institute of the Middlesex Hospital Medical School.
Total Olfactory Area in square centimeters
Adult Man ... 10 - 12.5
Rabbit ... 7.4
Cat ... 20.8
The rat also has an olfactory area of 2 cm2 (Hinds, 1981, Weiler, 1998).
Negus and others describe the density of olfactory receptors to be variable. In the macrosmic, the density is high and in the microsmic, such as man, it is lower, variable and often patchy. Many report that the numbers of olfactory receptors decrease by as much as 50% with age. As to the exact surface area devoted to olfaction in the human nose, I find the opinions variable. Negus writes, “ According to one observer, the olfactory nerves of Man reach nearly to the free edge of the superior turbinal bone and over almost three-quarters of the length of the lateral wall; also over one-third of the septum. The area covered is said to be almost one square inch, VonBrunn in 1892 described the area of human olfactory epithelium as being on the superior turbinal and of very small size. Parker gives the area in Man as being 2.57 sq.cm. or possibly 2.38 sq.cm. It may be rather more according to some.”(Negus, 1958, pgs 78 & 79) Jafek writes in the Human Sense of Smell, “The precise location and distribution of the olfactory epithelium in humans of different ages is not well documented. In order to find a suitable region to biopsy, serial sections through the putative olfactory region of several cadavers from persons 60 -70 years of age were taken. Examination of these thick sections by light microscopy showed that the olfactory epithelium covers an area of about 1 square centimeter per nostril.”
Furthermore, the internal anatomy of a macrosmic animal's nose is very complex. The ethmoid turbinal containing the olfactory epithelium is complexly folded such that the surface area is increased. In the following figure, (Figure 1) a sagittal section from a cat, this complex folding is clearly seen. The second figure (Figure 2) is a sagittal section of the nose of a cat, again showing the complex folding of the ethmoid turbinal lined by olfactory epithelium. This complex folding provides the surface area for the macrosmic, olfactory epithelium (Negus, page 321). The third figure (Figure 3) is a coronal section from a rabbit and shows the same complex folding of the olfactory cleft. The fourth figure (Figure 4) compares a rabbit and a human, the rabbit showing elaborate scrolling of the ethmoid turbinates. The dark line shows the area covered by olfactory epithelium. The human cross-section shows the limited area in the roof of the nose devoted to olfactory epithelium (Farbman, page 17) This is particularly obvious when compared to the following figures which are CT scans from normosmic, microscomic, adult humans (Figures 5a-e).
TABLE
TABLE
Having examined thousands of noses with endoscopes and having looked at thousands of sinus CT scans, there is variability in the shape and width of the olfactory cleft. Some seem wide open, and some quite narrow. This probably effects which noses are easily coated with the gel and which noses, once coated, might drain a fluid or gel more or less quickly. The first third coronal CT scans show a narrow cleft (Figures 5a,b,c). The next two CT scans show an open cleft (Figures 5d,e).
TABLE
TABLE
If one compares human toxicity by weight, it would require thousands or tens of thousands times more solution to cause injury. If one compared by olfactory epithelium area, rodents and man would be similar. This does not account for the relative sizes of the nasal cavities, how much chemical solution can be placed in the nose, or exactly what direct contact the gel would have with the olfactory receptor cells. Is the olfactory cleft or nasal mucus blanket of the mouse or rat different than that of a human and might it provide more or less protection? We don't know.
Human children are administered different doses of medications than are adults, children often requiring relatively more medication per kilogram body weight. For example, children are generally prescribed amoxicillin 40 mg/kg/day. Adults are generally prescribed 1500 mgs/day. If one used the pediatric dosing this would be 40 mg/kg/day x 70 kg= 2800 mg, almost twice the recommended pediatric dose.
As with humans, animals, even of the same species, have very different sensitivities to medicines and poisons. For example, adult humans bitten by a southern California rattlesnake on average require 20 vials of Wyeth horse serum antivenom. Medium and large dogs generally require no antivenom for the same snake bite. Dogs and cats lack glutathione reductase in the P450 enzyme pathway responsible for metabolizing acetaminophen and ibuprofen. Hence a normal human dose of either medication can kill a dog or cat. These kinds of variations exist throughout the animal kingdom. Experience in adult humans has shown less brain plasticity and less capability for neurologic, injury recovery than is seen in some animals or even in children. Furthermore, as written elsewhere, the animal experience is in young animals with greater ability to regenerate neurologic injury. Perhaps if older adult animals had been used, zinc would have more frequently caused permanent anosmia.
The bottom line is one cannot make exact dose comparisons between rodents and humans. This is why animal research is evidence-based medicine Level V. Science uses animal experimentation to get early, prephase I experience with new drugs. The animal science clearly shows that zinc acids like zinc sulfate and zinc gluconate are chemically toxic to olfactory receptor cells. Ergo, anyone thinking that zinc gluconate can be applied to the nose should be very concerned that the zinc acids might cause olfactory problems.
Importance of olfaction
Olfaction is important. People who lose olfaction risk important dangers, most notably the smell of smoke and the early detection of fire, the smell of gas and the hazard of gas explosion, and, perhaps most importantly, the smell of spoiled or rotten food and the risk of food poisoning, illness or even death. Olfaction is also important in the quality of life. There is the smell of one's environment, the smell of one's loved ones and the joy of eating. In fact, the majority of our appreciation of food comes from olfaction. Hence its loss is a major morbidity. One of the best descriptions of olfaction is in the National Geographic, Vol 70(3) 1986, pp. 324-362. An article from 2007 shows olfaction remains of scientific interest (Li, 2007). Even the Economist took interest in olfaction in the January 12, 2008 edition with an article titled the scent of a woman (and a man). They describe how animals and men, in part, choose a mate by their smell. Apparently women prefer men with certain smells which suggest major histocompatibility complexes different from their own. This favors genetic diversity (Economist, January 12-18, 2008, pg 73). Not only is olfaction important, we continue to study this important sense and learn more of its importance to healthy, enjoyable survival. The article comments “However, as the multi-billion-dollar industry attests, beauty is in the nose of the beholder, too.”
Risk benefit
Ultimately we must address the risk benefit ratio. First and foremost, other than placebo effect, topical nasal zinc, including Zicam Cold Remedy Nasal Gel has shown no demonstrable ability to alter the course of an upper respiratory tract viral infection. Topical zinc's benefit is therefore minimal to none. If there is any clinical concern for olfactory toxicity, this is a risk and becomes critically important.
The risk benefit ratio becomes a numbers game. We fly in an airplane knowing the risk of death is 3 or 4 in a million. We take antibiotics for acute sinusitis knowing there is a 1:1000 risk of infection spreading to the brain or eye and knowing there is a 1:100,000 risk of a serious allergic reaction to the antibiotic. We accept these risks for the benefits seem favorable. No one would use nasal zinc knowing that the risk of losing their sense of smell is 1 in 100. Would they use the product knowing the risk is 1 in 1000, 1 in 10,000, 1 in 100,000 or even 1 in 1,000,000. None of us enjoy the common cold and if there were an effective medicine, many would take it. But if we knew the benefit was placebo, few, if any, would risk losing their sense of smell, even if that risk were small.
It is my calculation that if we add up all the zinc induced anosmia cases we know, for example, those in class action suits, individual suits and those who have telephoned Matrixx complaining of olfactory loss after use of Zicam nasal gel products, we easily arrive at an estimate of at least 500 people. If we double that, assuming only half of those injured complained, we conservatively conclude that 1000 people are anosmic secondary to their zinc exposures. Furthermore, if we assume Matrixx has sold 10,000,000 vials of Zicam nasal gels, then the relative risk is 10,000/10,000,000 or 1/10,000 or 0.001%. The risk of being killed driving is 50,000 deaths per year divided by 200 million adults or 0.0025%. This is 21/2 times the risk of anosmia, but I accept that risk for I benefit from driving. I would not accept that risk for a placebo nasal spray, which neither prevents, cures, nor ameliorates the common cold.
Another way to ask this question is whether a human subject committee, called an institutional review board (IRB) would approve a clinical trial with zinc nasal gel such as Zicam Cold Remedy Nasal Gel. I believe they would not. Most sensible people would not knowingly incur this risk of permanent anosmia for so little potential benefit. This opinion is supported in the January 2007 Consumer Report, “Oral Zinc is probably safe if you take less than 40mg a day.” The evidence on its efficacy, however, is also mixed. Consumer Reports' take is that “The possible risk posed by nasal zinc outweighs any benefit. It is not clear whether oral zinc is worth taking for colds.” Eby and Halcomb in Alternative Therapies 2006 conclude, “We contend that it is unethical to introduce any potentially permanent anosmia-inducing agent such as zinc or other heavy metals into the interior of the nose in a manner that could result in contact with the olfactory region to treat a temporary discomfort such as a common cold or allergy. We found no reason to recommend intranasal zinc gluconate or zinc orotate lozenges in treating common colds.” Based on the lack of any verified, demonstrable benefit from the use of zinc gluconate based nasal gels, such as Zicam Cold Remedy Nasal Gel, juxtaposed against the potential for permanent anosmia posed by such products, it is clear that zinc gluconate based nasal gels fail risk benefit analysis.
Opinion
Through reviewing the relevant scientific studies of zinc and olfaction, employing the Bradford Hill Criteria to analyze the multiple studies conducted on the toxicity of zinc as shown in this report, and based on my substantial experience in nasal dysfunction, it is my opinion to a reasonable degree of medical and scientific certainty that a zinc gluconate based nasal gel, such as Zicam Cold Remedy Nasal Gel, is toxic to the human olfactory epithelium and is capable of rendering a user of any such product permanently anosmic. I have termed this condition “Zinc Induced Anosmia Syndrome.” All opinions stated in this report are to a reasonable degree of medical and scientific certainty.
