That’s the question Dr. Bruce Jafek is attempting to answer in this deposition.
Q. Okay. And is it your opinion to a reasonable degree of scientific probability that zinc gluconate in Zicam is the chemical equivalent to the zinc sulfate which was used in the 1930's in the polio experiments?
A. It's my opinion that the zinc ions contained in the zinc gluconate are the same as the zinc ions contained in the zinc sulfate and the zinc chloride and the other zinc salts that were used throughout the years to study loss of olfaction.
Q. That wasn't my question. My question is, is it your opinion to a reasonable degree of scientific probability that the zinc gluconate in Zicam is the chemical equivalent to the zinc sulfate which was used in the 1930's in the polio experiments?
A. And my answer is that zinc chloride or zinc sulfate and zinc gluconate of course are different compounds. What makes them similar is the presence of the zinc ions when placed in solutions. It is my testimony that the zinc ions are the same.
Q. I appreciate that they both have zinc. Lots of things in the world have zinc. My question is different though.
A. Yes.
Q. My question is, is it your opinion to a reasonable degree of scientific probability that the zinc gluconate in Zicam is the chemical equivalent to the zinc sulfate that was used in the polio experiments?
A. It is my opinion that the zinc ion in the two substances is equivalent. The two substances of
Q. How much zinc does a human receive when Zicam is used in accordance with the package directions?
A. I don't know.
Q. How much zinc does a person receive upon administration of the zinc sulfate in the polio experiment?
A. There is no standard answer to that question, nor is there in the Zicam.
Q. Is the apparatus shown in Exhibit Jafek which was used in the polio experiments the same, in your opinion, to a reasonable degree of medical probability, as the container which is used to administer Zicam?
A. Both are designed to squirt a substance in the nose. In that sense, they're equivalent. In terms of the structure, they are different.
Q. In terms of structure they're very different, aren't they, doctor?
A. I said that they were different. I'm not sure how you would define very.
Q. Well, doctor, the polio apparatus has a long skinny needle or cylinder that's inserted in a nose way back up to the olfactory cleft and the Zicam is a plastic tip that's designed to be inserted angled one-eighth of an inch into the nose. Correct?
A. The atomizer that you gave me the picture of is designed to try to insert into the olfactory cleft. Whether that actually happened in all the patients is open to question. In terms of the atomizer, it is designed to be inserted into the nose and it has its own self-contained propellent which is different from the bulb that's on that particular apparatus. The two are equivalent in the sense that they are designed to deliver a substance into the nose.
Q. Now, the children and the -- strike that. The people in the polio experiments were put in a very special position to have the zinc sulfate administered to them, correct?
A. Some of them they tried to put into a special position. I can't comment on the varying degrees of success. All I can say is that some of the children had permanent loss of the sense of smell.
Q. Were you familiar with the Shaninian paper?
A. I am familiar with the Shaninian position and his description of how he would like to have tried to put kids. Having had children and grandchildren, I'm not sure that I could ever get one of my children into that particular position for a prolonged period of time in order to spray a painful substance into their nose, so I don't know how successful he was. That's what they were trying though.
Q. You don't treat children, do you, doctor?
A. I do.
Q. Okay. And do you remember when someone from the Riscassi and Davis firm first contacted you?
A. No. I think it probably would have been either -- well, it would have been by telephone in November of '03, roughly, to say would you review a case and I said yes, I would.
Q. Okay. Did they tell you how they got your name?
A. No.
Q. Now, going back to the patients -- strike that.
Going back to the people you have examined who contend that they have smell loss as a result of the use of Zicam, did you conclude in any of those cases that their -- that first of all, that they didn't really have smell loss?
A. No. I don't -- no.
Q. Did you conclude in any of those cases that the smell loss was related to something other than the use of Zicam?
A. I don't remember specifically. I think that there are some cases that are much clearer than others. When there is association of the severe burning and the immediate loss of smell, then I think it's quite clear that it was the zinc in the Zicam that caused the problem. I remember a case I saw two weeks ago in which the woman spent five hours in the emergency room getting her nose lavaged and receiving pain medicine because of the severe burning with the use of the Zicam. She reported loss of sense of smell afterward and I would conclude in that particular case that it was due to the Zicam.
Q. When did you first form your hypothesis that the use of Zicam causes smell dysfunction?
A. Probably it became clearer and clearer throughout 2002 and early 2003 as we saw more and more patients, did more and more review of the scientific literature. But I was aware quite early that zinc causes smell loss. We had done studies in the eighties on other heavy metal ions, particularly copper, and there is a large group of heavy metal cations, divalent cations that all produce loss of the sense of smell. But zinc is the most specific in terms of its olfactory toxicity.
Q. Doctor, my question is when did you first form your hypothesis that the use of Zicam causes smell dysfunction?
A. Probably in late 2002 when I found out that Zicam contained zinc as I did my research in that area.
Q. Have you done any experiments or studies to prove or disprove or test your hypothesis that the use of Zicam causes smell dysfunction?
A. There are a number of tests available in the literature. I have done specific tests with Zicam on ciliary beat frequency and will probably do some additional ones in the future. But the fact that zinc ion causes smell loss has been known for over 60 years and is not particularly innovative type research.
Q. Now, you said that there are a number of tests available in the literature. To what are you referring to?
A. I'm referring specifically or particularly to the work of Schultz in the late 1930's and early 1940's in which intranasal zinc sulfate was used in a large population of children. Following that it was noted that they had lost their sense of smell in probably 15 to 25 percent of cases.
Following my presentation, a colleague came to me and said that his mother was a part of the
A. That was in the report from the Matrixx company with regard to the follow-up of their scientific advisory committee.
Q. When did you see that?
A. In, I think that that was in about December of 2004. I think that report came out.
Q. And how did it come to pass that you saw that report?
A. Somebody suggested it to me and I looked it up on the internet.
Q. Who was the somebody who suggested it to you?
A. I don't remember. I talk to a number of people.
Q. Are you somebody who spends any amount of time on the internet?
A. I don't think so, no.
Q. Do you get involved in any way with internet posting with regard to stock investments?
A. I don't. No. I do not. The answer is no, I do not.
Q. Have you ever?
A. No.
Q. Do you own any stock in Matrixx?
A. No, I don't.
Q. Have you ever owned stock in Matrixx?
A. I don't think so.
Q. Have you ever owned -- do you now or have you ever owned stock in the Quigley Company or any other company with a zinc product?
A. I don't think so. The reason I ask for that qualification is the majority of my savings is in mutual funds primarily through the university, and the TIAA CREF fund has a very large investment of which I confess I don't specifically look at it at all. I don't pay attention to it. Whether they own stock in either company or not or ever have, I have no idea. But I don't personally own stock in Matrixx or Quigley. I never have personally owned stock in Matrixx or Quigley or anything else that has to do with zinc manufacture or anything else that I know of.
Q. How about any members of your immediate family?
A. I don't know the specific details with regard to my family, what they have and what they don't have. I think some members of my family probably don't have any investments at all. Other members in my family probably have more.
Q. But you don't know whether anyone in your
Q. Now, you wrote a paper and you published a paper in 1983 in the journal Laryngoscope on the ultrastructure of the human nasal mucosa, correct?
A. Yes. And I received an award from the Triologic Society for that scientific study.
Q. Are the observations you made in that prize-winning paper still valid?
A. I don't remember them specifically. I think that they are. I'm not aware of specific contradictions in the literature. I don't know exactly what you have reference to though.
Q. Let's go over a couple of them.
A. Okay.
Q. The purpose of your paper was to present a comprehensive description of the ultrastructure of the mucosa or epithelium of the human nose, correct?
A. That's correct.
Q. You said in the paper that, quote, “the olfactory mucosa is almost anatomically inaccessible in living humans,” close quote. Is that true?
A. That's -- that's an exact quote in the paper, that is -- that was a correct quotation. It is an incorrect observation, however.
Q. What do you mean it's an incorrect observation?
A. Based upon subsequent studies in which in fact we show that you could obtain biopsies in that particular area relatively repetitively. I'll have to rely upon your quotation out of context, however.
Q. Well, you published in 1983 that the olfactory mucosa is almost anatomically inaccessible in living humans. You're saying that that statement is no longer true and accurate?
A. I don't know the context out of which you took it. I don't know the sentence before or the sentence after. Therefore, I have no opinion with regard to the accuracy of that statement in the context in which it was presented.
MR. WENZEL: Why don't we give a little more context.
MS. SHARKO: I'll take care of it.
MR. WENZEL: Okay. I mean I want him to give you all the information you want, Susan. I don't want there to be quarrels where there need not be.
MS. SHARKO: I know. It's okay.
(Deposition Exhibit No. 7 was marked for identification.)
Q. BY MS. SHARKO: Doctor, I show you Exhibit Jafek 7 for identification. Is that the paper that we've just been talking about?
A. Yes, thank you. I would have brought a copy had I known that you were going to be interested in this particular study on the ultrastructure.
Q. Take a look at the first page of the paper, the second paragraph.
A. Okay.
Q. And you state there in the third line, do you not, that the olfactory mucosa is almost anatomically inaccessible in living humans, correct?
A. That was an observation at that time, yes.
Q. Is it your testimony here today that the olfactory mucosa in living humans is not almost anatomically inaccessible?
A. That's correct. It is my testimony that it is not anatomically inaccessible.
Q. Can you show me where you've published a retraction of this statement in this 1983 paper?
A. If we go down further in that paragraph, it says the olfactory mucosa in microsmatic man is a smaller target and, in fact, I talk about the biopsy that I obtained in human beings in this particular paper and I presented my observations on biopsies that I had personally obtained and therefore the statement that is inaccessible is incorrect.
Q. Where have you published that the statement that the olfactory mucosa is almost anatomically inaccessible is incorrect?
A. Within the context of this paper, I presented the results of my biopsies which refutes the statement that you made.
Q. Well, you state in the paper that the olfactory mucosa is sheltered, correct?
A. That is correct.
Q. And is that a true and accurate statement?
A. It's in the nose, yes, it's sheltered.
Q. Now, you state in this paper that to reach the olfactory mucosa, the biopsy instrument must pass approximately 7 centimeters deep to the nostril, the terminal portion blindly into a 1.0 millimeter crevice between adjacent nasal bones. Correct?
A. That is correct and that also implies therefore that the biopsy instrument did pass into that area, therefore, it is almost anatomically inaccessible which was the word that we used in that sentence that you presented previously. Therefore, what I'm saying is that it is difficult to obtain the biopsy, but not impossible, and it is not inaccessible. And that was the basis of the award, was that I proved for the first time that you could obtain smell tissue from the intact living human being without causing damage.
Q. Is the description of the journey that the biopsy instrument must take through the nose to get up to the olfactory mucosa as described in your 1983 paper still an accurate one?
A. It's a straight shot from the sill, the opening of the nose up into the olfactory region and it's a distance of approximately three inches as indicated in the measurements that I presented.
Q. Where do you say in this paper that it is a quote, “straight shot,” close quote?
A. The instrument is a straight instrument. I imply therefore that it's a straight shot. I did not use that word; however, I used a straight biopsy instrument as shown in the pictures in the paper.
Q. You state in your paper that “direct visualization with even the smallest telescope is impossible.” Is that still a true statement?
A. No, it isn't. With improved telescopes, we can see that area quite nicely and do so, and I think Terry Davidson, for example, has published very excellent views of the human olfactory mucosa.
A. They are possible depending upon the, how this all evolves and so on. As I said, the knowledge that zinc ions produce olfactory damage is 60 years old. There is very little innovative stuff that you need to do in that particular area. That's a known fact that was the basis of the literature that was done through the seventies, eighties and nineties.
Q. Well, what specific literature are you referring to?
A. Literature, for example, by Slotnick. There are a number of citations in my paper. Schultz's observations in the thirties are pertinent. Margolis, Matulionis; there are a number of different specific studies in terms of the effects of loss of the sense of smell. For these studies, zinc ions were used to destroy the sense of smell. That's a known fact.
Q. What specifically was used in the research of Margolis and Slotnick and Schultz to destroy the sense of smell as you put it? What specifically?
A. I'd have to go back and look at theirs. I believe that they were using the zinc sulfate preparation. Cancalon used zinc sulfate and zinc chloride. Schultz used zinc chloride, zinc bromide, ??
use the exact millimolar concentration of zinc chloride and zinc sulfate.
Q. If you don't use the exact millimolar concentration of the two substances, doctor, how can you fairly and accurately draw a conclusion that it is the zinc as opposed to the sulfate or the chloride which is causing the temporary damage?
A. The zinc chloride had no sulfate in it, it produced damage as he pointed out and I also alluded to studies by Schultz in which he used the bromide, the iodide and other zinc compounds. The literature, since Alberts' study in 1971, has focused upon zinc as a means of killing olfactory tissue. I think the literature including this article is replete with references to the fact that the zinc ion is specifically toxic to olfactory tissue which was the point of Schultz's original studies.
Q. All of the literature you just cited, doctor, from Alberts forward, talks about zinc sulfate, doesn't it? It doesn't talk about the zinc ion. It talks about zinc sulfate. Isn't that true?
A. No.
Q. Okay. What paper talks about the zinc ion being the causative factor as opposed to the zinc ??
children in an effort to prevent polio in Canada in the 1930's?
A. That was an atomizer that was used in some children in the 1930's to administer the zinc sulfate. I don't know that that was the atomizer that was used in all people because as you are aware there were a number of studies in terms of the way to deliver the zinc to the nose. The fact that the zinc was toxic to the smell tissue is a fact. The fact that they couldn't get it into all the kids is the problem that they worked on with the atomizers.
Q. One of the key things in the polio studies in Canada in the 1930's was that you had to get the zinc sulfate in, up high in the nose directly in contact with the olfactory epithelium in order to even hope to have an effect. Correct?
A. That was absolutely correct. And once you did, then you destroyed the smell tissue which was the goal of putting that stuff up high into the nose. Very well said. Thank you.
Q. And in fact, are you familiar with Dr. Peet's paper?
A. I'm aware that Peet wrote a paper. I don't know that I know exactly which one you're referring to because he had a number of publications.
Q. Dr. Peet found in his research, didn't he, that unless you got the zinc sulfate in direct contact with the olfactory epithelium, you couldn't harm the sense of smell. Correct?
A. I think that's a valid statement. Unless you get the zinc onto the olfactory epithelium, you can't harm it and, when you do, you will harm it.
Q. And that harm was in most children temporary, correct?
A. I will take that as a statement off an article that you're referring to that I didn't see the title on. In many children it was reversible. In some children it was permanent; the same is true in the animal studies. It depends upon dosage, where you get it, how many times you put it in there. But there is no doubt about the fact that the zinc ion is toxic to smell tissue. That's the point of the research that's pertinent to this case.
Q. Take a look at page 45 of the Schultz paper that we were discussing if you would, please.
A. Okay.
Q. On the left-hand side, read along with me. Quote, “Dr. Bergheim reported the following based on his own observations, quote, “it was impossible for me to ascertain what percentage of anosmia resulted ??
Q. All right. That was a long answer. Let's try and break that down.
A. It was a long question and I tried to respond.
Q. The CBF studies, that's the lab study where you took cells from the trachea of cows, right?
A. It is the scientific study in which we looked at cultured respiratory cells from a cow in the microscope.
Q. Okay. And is it your opinion to a reasonable degree of scientific probability that zinc gluconate in Zicam is the chemical equivalent to the zinc sulfate which was used in the 1930's in the polio experiments?
A. It's my opinion that the zinc ions contained in the zinc gluconate are the same as the zinc ions contained in the zinc sulfate and the zinc chloride and the other zinc salts that were used throughout the years to study loss of olfaction.
Q. That wasn't my question. My question is, is it your opinion to a reasonable degree of scientific probability that the zinc gluconate in Zicam is the chemical equivalent to the zinc sulfate which was used in the 1930's in the polio experiments?
A. And my answer is that zinc chloride or zinc sulfate and zinc gluconate of course are different compounds. What makes them similar is the presence of the zinc ions when placed in solutions. It is my testimony that the zinc ions are the same.
Q. I appreciate that they both have zinc. Lots of things in the world have zinc. My question is different though.
A. Yes.
Q. My question is, is it your opinion to a reasonable degree of scientific probability that the zinc gluconate in Zicam is the chemical equivalent to the zinc sulfate that was used in the polio experiments?
A. It is my opinion that the zinc ion in the two substances is equivalent. The two substances of
Q. How much zinc does a human receive when Zicam is used in accordance with the package directions?
A. I don't know.
Q. How much zinc does a person receive upon administration of the zinc sulfate in the polio experiment?
A. There is no standard answer to that question, nor is there in the Zicam.
Q. Is the apparatus shown in Exhibit Jafek which was used in the polio experiments the same, in your opinion, to a reasonable degree of medical probability, as the container which is used to administer Zicam?
A. Both are designed to squirt a substance in the nose. In that sense, they're equivalent. In terms of the structure, they are different.
Q. In terms of structure they're very different, aren't they, doctor?
A. I said that they were different. I'm not sure how you would define very.
Q. Well, doctor, the polio apparatus has a long skinny needle or cylinder that's inserted in a nose way back up to the olfactory cleft and the Zicam is a plastic tip that's designed to be inserted angled one-eighth of an inch into the nose. Correct?
A. The atomizer that you gave me the picture of is designed to try to insert into the olfactory cleft. Whether that actually happened in all the patients is open to question. In terms of the atomizer, it is designed to be inserted into the nose and it has its own self-contained propellent which is different from the bulb that's on that particular apparatus. The two are equivalent in the sense that they are designed to deliver a substance into the nose.
Q. Now, the children and the -- strike that. The people in the polio experiments were put in a very special position to have the zinc sulfate administered to them, correct?
A. Some of them they tried to put into a special position. I can't comment on the varying degrees of success. All I can say is that some of the children had permanent loss of the sense of smell.
Q. Were you familiar with the Shaninian paper?
A. I am familiar with the Shaninian position and his description of how he would like to have tried to put kids. Having had children and grandchildren, I'm not sure that I could ever get one of my children into that particular position for a prolonged period of time in order to spray a painful substance into their nose, so I don't know how successful he was. That's what they were trying though.
Q. You don't treat children, do you, doctor?
A. I do.
?? get the zinc into the nose to kill the olfactory tissue.
Q. How do you know that the man shown in figure 3 on Exhibit 11 is using a different apparatus from that shown in Exhibit 10A?
A. I'm looking at your diagram figure two and if you'll notice at the upper part of the nose, to me that looks like a dropper. That doesn't look at all like the atomizer that you gave me previously. That's the basis of my conclusion those are different application techniques.
Q. How does the use of the position shown in figure 3 on Exhibit 11 affect the ability of the zinc sulfate to get to the olfactory cleft?
A. According to Dr. Shaninian, the goal of that was to irrigate, not spray with an atomizer. What he wanted to do was to bathe the tissue, to prolong the dose contact of the zinc sulfate in the olfactory region. As we mentioned before, the sprayer was somewhat less successful than the irrigation, but the irrigation was very, very difficult to accomplish in little kids. I notice that nobody has their hand on that child's head and I doubt very much that he would hold his head still while spraying that stuff or dropping that stuff
?? you use pontocaine?
A. I use it occasionally for the anesthesia of the nose.
Q. Now, let's go back to the Cancalon paper if we could.
A. Okay.
Q. You have that there?
A. Yes.
Q. Here it is, Exhibit 8. How does the nasal anatomy of a catfish differ from the nasal anatomy of a human?
A. Catfish in general, and I don't have a whole lot of knowledge in that area, but like other fish have rosettes inside their gill clefts that have arrangements of smell tissue on the surface so it's somewhat more concentrated. In addition, catfish probably have better smellers than humans because they depend upon the sense of smell to locate their prey.
MR. LAZARUS: Before you ask your next question, I wonder if I could get the stack back if you're not using it. Thank you.
Q. BY MS. SHARKO: What experience do you have in catfish research?
A. I have no experience in catfish research.
Q. Is it fair to draw conclusions with regard to humans based on a study in catfish?
A. I believe so, yes.
Q. Why?
A. Because catfish have olfactory tissue that is exposed to the surface just like in humans. I don't think that catfish are absolutely equivalent to humans. But ethical constraints require you to use some sort of experimental animal and Cancalon selected the catfish. We used trout because we had them more available.
Q. What Cancalon found is that the damage caused by zinc sulfate to catfish was temporary and that the animals recover. Isn't that true?
A. If you read me and point me out exactly to your statement because Cancalon, of course, used a whole variety of solutions, and what I found of interest in his article is the fact that his approximate break point in terms of the activity of the zinc was at about 30 millimoles, and that is very similar to the 33 millimolar concentration of the zinc in the Zicam preparation.
So Cancalon found a whole variety of effects depending upon the concentration of the zinc sulfate that he used.
Q. Well, the zinc sulfate that Cancalon used which you say is similar to the zinc in Zicam, first of all, how was that administered to the catfish?
A. They swam around it so it was put into their nose just as Zicam is put into human noses. People don't tend to swim in it. I would agree that that's correct.
Q. How long were the catfish exposed to it?
A. For a variety of different periods of time depending upon the nature of the experiment that Cancalon was doing.
Q. Did any of the catfish have permanent loss of smell from zinc sulfate?
A. I don't know. I don't think that the catfish were maintained. I'm not sure that we can draw an exact association between humans and catfish, but the regeneration when it occurred was prolonged and we would have to speculate in terms of permanent. He didn't keep the catfish that long.
Q. In fact, the catfish olfactory cells were regenerating after the administration of zinc sulfate, correct?
A. I think that's a fair statement. They were regenerating. Now whether they came back to normal or not is speculative. But there certainly was ??
depiction of what happens to Zicam when you apply it to your nose following the package instructions, wouldn't you?
A. No.
Q. Why not?
A. Squirting Zicam is squirting Zicam. And I don't know that either one of us could define a, quote, “standard squirt.” When you aim the bottle at your nose, the potential is that if your nose weren't there, you could reach ten feet or at least four, in my evaluation with that. That is sufficient to get the Zicam into the olfactory cleft area and maintain it for the reasons that I cited.
Q. Well, the instructions on the box -- you have seen the instructions on the box, haven't you, doctor?
A. I have brought that with me per your instructions, yes.
Q. The box instructions tell the user to place the tip of the nozzle just past the nasal opening approximately one-eighth of an inch?
A. Yes.
Q. Correct?
A. Yes.
Q. And then while inside the nasal opening, one-eighth of an inch, slightly angle the nozzle outward and pump once into each nostril, correct?
A. Those are the directions on the box, yes.
Q. And then the directions go on to say to avoid possible irritation, do not sniff up the gel. Correct?
A. That's on the box.
Q. And then they tell the user to press lightly on the outside of each nostril for about five seconds and to wait at least 30 seconds before blowing the nose again. Correct?
A. That's on the box, yes.
Q. And following those directions that we just reviewed, you wouldn't expect the Zicam to go straight up to the olfactory epithelium, would you?
A. It depends upon what the word means, slightly in a patient's knowledge, let alone outside or inside or things like that. What I'm saying is if you put the nostril [sic] into the nose and spray it, the material has the capable of reaching the olfactory cleft. In addition to that, as you squeeze the bottle, your hand actually changes position, so where that stuff goes in the nose, neither of us have any idea, but we know that that's a long squirt and a very small target and it is my opinion that in some patients, that goes directly into the olfactory cleft producing the damage with the zinc ions that I mentioned.
Q. You haven't studied that though, have you?
A. I've sprayed it, as I mentioned to you. I'm not going to spray it in my nose, no.
Q. So you have no experience and no data as to what happens when it's sprayed into the nose in terms of where it goes? Correct?
A. Throughout the over 35 years of my professional career, I have sprayed many, many, many, many noses. I know where sprays go into noses. When you start with a spray on the front of the nose, I know that it can go a whole variety of places, let alone septal deflections and things that direct it into different ways. It is my opinion that that spray is capable of reaching the olfactory tissue in many patients, then the zinc ion does its damage.
Q. That opinion though is based only on your squeezing the bottle out in the open air, correct?
A. No. As I mentioned, it's based upon 35 years of looking into noses, spraying noses, examining noses and that experience.
Q. Have you ever sprayed Zicam into anybody's ??
very clearly. As I mentioned, there would be a difficulty in interpreting a uniform following of those directions.
Q. What is so hard to interpret in them?
A. As I mentioned to you, we don't know what slightly means in common language. And also, the position of a person's hand as they execute the squeezing maneuver changes the position of the nozzle in the nose.
Q. You don't know what slightly means, doctor?
A. I think slightly means very different things to many different people. I've actually had patients report that they have injured their nose with the use of the applicator because it bumped their septum.
Q. What do you know about Mrs. Nelson's nasal anatomy?
A. I would have to rely upon the observations of Dr. Henkin and Dr. Castro. I think that Dr. Castro described some septal deviations. I don't think that Dr. Henkin described those in quite the same way. Those were not characterized however on the CT scans that Dr. Castro ordered.
Q. Do you know Dr. Henkin?
A. I have heard him speak. I don't know him well personally. I don't think I would even recognize him if he came through the door, I would confess.
Q. Do you recognize him as an authority in the area of taste and smell?
A. Yes.
Q. Do you refer patients to him?
A. Not very often. He's located in Washington DC. I'm in Denver. I have taken care of patients who have gone on to see him. I have seen patients that he has seen.
But I don't refer patients to him and I don't think he refers them to me because the distance involved.
Q. Why were you seeing patients who had been seen by Dr. Henkin?
A. They came to see me after they saw him. I'm sure that some of my patients go on to see him. You've got to understand that loss of smell is a very frustrating problem.
Q. Were they satisfied with the treatment they got by Dr. Henkin?
A. I think probably if they were entirely satisfied, they wouldn't come to see me. On the other hand, the reason that they came to see me, and ??
Q. Now, the non-ciliated anterior portion of the nose on the right-hand side of the drawing --
A. Okay.
Q. -- how far up into the nose does that extend?
A. It varies from patient to patient.
Q. In the average patient?
A. I would say less than a centimeter. It's on the lateral aspect of the nose primarily, on the medial aspect of course you run into the septum. And some of that respiratory epithelium has undergone metoplasia to squamous epithelium because of its exposure to air over a period of time. So as I say, it's an individual thing, but about a centimeter I suppose it's not a bad suggestion.
Q. A centimeter is about half an inch?
A. Half an inch, yes.
Q. So the first half inch or so of the nose in the average person is non-ciliated?
A. That's correct as a generality. As I say, we're all a little different.
Q. How often do olfactory epithelial cells turn over?
A. The literature suggests about every 40 days they regenerate, turn over.
Q. Do you agree with that?
A. I think that's generally accepted. I haven't done any specific research in that area.
Q. Now, have you actually seen yourself cells from the nasal epithelium which have been destroyed by zinc sulfate in a human?
A. Only in the pictures. I haven't done that myself.
Q. Have you seen for yourself cells which have been destroyed by viruses or colds?
A. Yes, in pictures.
Q. And how about cells destroyed by Zicam?
A. I have not seen microscopic sections of them. I have not taken biopsies of those patients. I certainly have looked into those noses. So I suppose I've seen the cells. But I've not seen microscopic views of them.
Q. Do the insides of the noses of patients who have used Zicam and complained of smell loss look different to you in any way from the noses of people who complain of smell loss who have not used Zicam?
A. No. I don't -- I can't see any consistent differences at all. Terry Davidson describes some changes that he observes, but I can't see them myself.
A. Never heard that name.
Q. John Fiero, F-I-E-R-O?
A. I have not heard that name.
Q. Timothy Mulligan?
A. No. I have not heard that name.
Q. Have you had any involvement at all with an investor publication called the Eye Shade Report?
A. No.
Q. Do you know who James Siracusano is?
A. No. Even if you pronounced it correctly, then I don't know who that person is. Could you spell it for me? But I don't know anybody like that.
Q. S-I-R-A-C-U-S-A-N-O. Of Aurora, Colorado?
A. No.
Q. You wrote a paper, you published a paper in the American Journal of Rhinology in 1990 on Postviral Olfactory Dysfunction?
A. That's correct.
Q. That was a peer reviewed paper?
A. Yes.
Q. Are your observations, conclusions and opinions expressed in that paper still valid?
A. I don't remember independently exactly what I said in that paper. I assume that they are, but if you could give me some specific references, I'll be happy to go over them.
Q. Okay. In that paper, you said that an estimated two million adult North Americans suffer from taste or smell disorder primarily smell.
A. That's correct. That was based upon the National Geographic test.
Q. Okay. Is that still a fair estimate of the prevalence of smell and taste dysfunction in America?
A. I think probably it is. The test has never been repeated and there are more Americans now than there were then so the numbers I suspect are a little bit higher.
Q. You wrote in that paper that “the most common cause of prolonged olfactory dysfunction other than nasal polyps or an obstructive abnormality was an influenza like upper respiratory infection.” Is that still true?
A. I think that's valid, yes.
Q. You called that entity postviral olfactory dysfunction, PVOD, correct?
A. Yes. I think that some people put in chronic sinusitis, but inflammation of the nose is the most common cause of the problem, I think. ??
question.
Q. Well, do people complain to you from time to time about burning in the nose?
A. Yes.
Q. And what percentage of those people do not have smell loss?
A. Most of them do not have smell loss.
Q. Now, when you say the known toxicity of the zinc ion, you are relying on the polio literature which we discussed a little this morning?
A. Yes.
Q. You are relying on the Cancalon paper?
A. Yes.
Q. Are you relying on anything else?
A. There is accumulated literature from Slotnick, from a number of other authors that were partially contained in that list of materials that I presented and cited in my paper, my publication; Margolis, Alberts and so on.
Q. Do scientists generally accept temporal association as a basis for drawing opinions as to causation?
A. As a general statement, the temporal association is very important in terms of arriving at a proper diagnosis.
Q. Now, in formulating your hypothesis about Zicam and the sense of smell, you're making some assumptions, aren't you?
A. I'm sorry. That's a broad general question. Could you be more specific?
Q. Well, in formulating your hypothesis that Zicam causes damage to the sense of smell, you are assuming, No. 1, that zinc sulfate has the same effect as zinc gluconate in humans, correct?
A. I'm assuming that the effect is due to zinc ions regardless of their source as validated by the literature that I've cited.
Q. Have you done any research at all using zinc gluconate?
A. Yes.
Q. What?
A. The animal studies on the mouse that I previously suggested to you, the animal studies on the ciliary beat frequency as well as the comprehensive review of the literature. As I mentioned, the toxicity of zinc ions is not particularly innovative. It's been there for over 60 years.
Q. What literature have you found that talks about the use of zinc gluconate in humans or ??
the first to open and calcium goes in. Since calcium is a divalent cation and zinc is a divalent cation and we know that other divalent cations, selenium, copper, led, silver and so on, also cause inhibition of smell, that's where I think I would start and that's purely speculation, however. That's a hypothesis.
Q. In formulating your hypothesis that zinc gluconate causes anosmia, you're also assuming, are you not, that Zicam gets up to the neuroepithelium?
A. My hypothesis is that the zinc ions cause the anosmia. I assume that in some patients the zinc ion containing Zicam gets up into the olfactory tissue area.
Q. What experiments would need to be done, in your opinion, to a reasonable degree of medical and scientific probability to prove your hypothesis that Zicam harms the sense of smell?
A. I've not thought that through so I would be speculating. As I mentioned, zinc ions are known to be toxic and it's not particularly innovative to try and pursue that approach.
Q. But you agree that some experiment or study, whatever it is, would have to be done to prove or disprove the hypothesis that zinc gluconate causes anosmia?
A. I think that the experiment that should be done is to prove that zinc gluconate does not cause anosmia because based upon our observations and the studies in the past, we are firmly convinced that zinc does cause loss of smell. Now Slotnick did some nice experiments to show that the rat is not affected nearly so much as the mouse, and so we know that there are interspecies variation. We can accept that probably there are dosage requirements and things of that sort. I think that we probably know that there are inter-individual variations particularly with the elegant work of Axel and Buck in terms of showing that humans have different kinds of receptors.
But I think that the research should have been done to prove this is a safe product before it was released on the market given the impression that zinc ions, and I believe it to be a fact, is toxic to olfactory tissue. I don't think those were ever done.
Q. Would Slotnick be the logical person to do this experiment you've described?
A. I don't know. Slotnick certainly has done some very nice work in terms of mice and rats. Whether he could offer a definitive answer, I don't know. I'd have to re-review his experimental protocol and a number of other things in order to decide whether it was the answer or not the answer.
Q. But you as you sit here today, you can't tell me what the answer would be, what experiment would need to be done to prove or disprove your hypothesis?
MR. WENZEL: Objection; mischaracterizes his testimony.
THE WITNESS: As I sit here today, I offered some proposals and things like that. As I said, it's more of a null hypothesis that would have to be done given the overwhelming body of literature that suggests that the zinc ion is toxic.
Q. BY MS. SHARKO: What do respiratory viruses do to nasal membranes?
A. I'm not particularly an expert in that area. I think they damage them, but beyond that, I can't offer an opinion.
Q. What do respiratory viruses do to cilia in the nose?
A. I don't know for sure. I'd be speculating.
Q. Well, you wrote in your postviral olfactory dysfunction paper that respiratory viruses cause ??
Q. What do you mean taken out of context?
A. I don't know exactly what she wrote. I don't know what kind of series she reviewed. I don't know what kind of analysis she undertook. Dr. Murphy is a very respected scientist. I would tend at first blush to believe exactly what she said but I'd have to review the material that she wrote in order to offer an opinion.
Q. Do you disagree with the proposition that men have a higher prevalence of smell dysfunction at all ages?
A. I don't offer an opinion in that particular area.
Q. Okay. You wrote a paper on evaluation and treatment of anosmia in the year 2000. Do you recall that paper?
A. I don't remember the details of it specifically.
Q. It was published in the Current Opinions of Otolaryngology, Head and Neck Surgery?
A. That's correct.
Q. You said in that paper that head trauma, sino-nasal disease and postviral account for approximately 60 percent of cases of smell loss. Is that still your opinion?
A. I think that's a commonly accepted conclusion, yes.
Q. Okay. And later you wrote there that if you combine post-traumatic postviral nasal sinus disease and idiopathic, you have 70 to 85 percent of reported cases of olfactory loss. Do you still agree with that?
A. Yes, I do. And we do the best we can to sort out the idiopathic things and once we found Zicam, we were able to peel off a certain group of patients who previously might have been identified as idiopathic.
Q. What do you mean they previously might have been identified as idiopathic?
A. If it weren't known what the patients were using and they simply presented de novo to somebody with loss of smell, one might assume that it was idiopathic by going back and inquiring carefully into the history and then going into the additional history of the specific loss. The history is the most important part of smell loss diagnosis. By going back into that additional history, one could then eliminate a patient from idiopathic and move him over into known causes as, say, Susan Schiffman has done, S-C-H-I-F-F-M-A-N.
?? if it's the same in Medline as it was in Matulionis' paper, then that's one thing. I cited Matulionis which is what the Medline citation is to.
Q. Do you have any explanation for why your published paper is word for word the same as Medline?
A. No. Other than the fact that they both refer to the same paper by Matulionis, the citation is there.
(Deposition Exhibit No. 16 was marked for identification.)
Q. BY MS. SHARKO: I show you Exhibit Jafek 16 for identification. Have you ever seen that before?
A. Yes, I have.
Q. Okay. What is Exhibit 16?
A. Guidelines for Authors, American Journal of Rhinology.
Q. Did you fill out a form like this when you submitted your paper for publication?
A. I'm sure that I did, yes.
Q. Okay. And did you disclose in this form when you submitted it that you were consulting with plaintiff's lawyers in litigation against Zicam, against Matrixx regarding Zicam?
A. No. I didn't, I don't think.
Q. Why not?
A. It's not apparent to me that that's important in terms of the presentation.
Q. Why?
A. Well, it doesn't seem to be important to me in terms of consulting with lawyers. I had been asked by lawyers to review cases. That's what I did.
Q. Have you ever reviewed a case involving a patient who had used Zicam or a person who had used Zicam and come to the conclusion that Zicam had nothing to do with their smell loss?
A. I think you asked that question previously this morning.
Q. And your answer is?
A. There are a number of patients who have used Zicam in which I pointed out that I didn't think it was likely that that was the source of their loss. I don't have an independent recollection of any of them.
Q. You don't know --how many patients was that?
A. I just said.
Q. You just said what?
Q. Was it more than five or less than five?
A. I suspect it was less than five. But I don't have an independent recollection. I would be speculating.
Q. Now, looking at Exhibit 15 on the Matulionis paper, you end your discussion with the phrase “most advanced neural degeneration from 24 to 72 hours after treatment,” correct, in your paper?
A. Okay.
Q. That's the last sentence?
A. Yes.
Q. You don't, however, mention the fact in your paper that Matulionis reported regeneration of the olfactory epithelium, do you?
A. I didn't entirely include all of Matulionis' paper. That's a brief summary.
Q. Well, one of the purposes of Matulionis' paper was to show not only degeneration, but early regeneration of the olfactory epithelium in the mouse, correct?
A. I will accept your explanation. I didn't review that specifically in terms of his purpose and I can't speak to his purpose.
Q. Can you explain why you didn't mention in your paper that the Matulionis study in fact showed regeneration of the olfactory epithelium?
A. You remember that I said I didn't include all of Matulionis' observations. I tried to summarize it briefly as I could the nature of the olfactory changes that occurred. Regeneration probably did occur in some animals. I didn't make an independent recollection of that.
Q. Does the fact that Matulionis and many other scientists have observed regeneration in the olfactory epithelium after the administration of zinc sulfate conflict with your theory?
A. Not at all.
Q. Okay. Why not?
A. Because I think that there is some inter-individual and interspecies variations in terms of the reaction. The point is that the zinc ion is toxic. It does destroy olfactory tissue. It was designed to destroy olfactory tissue. It does its job. It doesn't do it in all people. It doesn't do it in all rats. It doesn't do it in all mice. It doesn't do it in all ferrets, but it does do it in some.
Q. How much is necessary to do it in a human?
A. I don't know.
Q. Would you agree that if Zicam in a human does not reach the olfactory epithelium then it therefore does not and cannot cause smell loss in that person?
A. I don't think that that reflects the facts to a reasonable likelihood in Ms. Nelson's case.
Q. Well, I'm not talking about Ms. Nelson yet. My question is, if somebody uses Zicam and it does not get up to the olfactory epithelium, would you agree that it therefore cannot cause smell loss in that person?
A. Yes.
Q. Now, what is the basis for your statement that -- strike that. It's your opinion, I gather, that Zicam reached Ms. Nelson's olfactory epithelium?
A. Yes.
Q. What is the basis for that opinion?
A. She used the product. She had immediate burning, it was followed by immediate loss of smell. Based upon that, I conclude that this known toxic product reached the olfactory tissue and caused her to lose it, lose the sense of smell.
Q. Now, looking at page -- the first page of your paper on the right side, you state “this toxicity is thought to be caused by the direct ??
A. Because you've interchanged the word zinc and zinc sulfate. If zinc sulfate is used, it is the source of zinc ion. When zinc sulfate goes into solution, it produces zinc ions and sulfate ions. Zinc ions has been described by many other investigators, but if Harding failed to use that particular word, I don't think it would rule out the zinc as the source of the problem. Certainly, Harding showed that the olfactory tissue was damaged with the use of zinc sulfate.
Q. What effect does the sulfate have on the olfactory tissue?
A. It appears to have much less effect than the zinc. Any other answer would be speculative other than to show that others have used it. Sodium sulfate has no effect on zinc -- on the smell tissue. I therefore conclude that sulfate is a minor player, if at all, and I don't think it's a player at all in terms of the olfactory damage.
Q. What research has been done to support or reject that opinion?
A. We've discussed that also this morning. And there are a number of uses of different zinc salts, zinc sulfate, zinc chloride, zinc iodide --
Q. I'm going to interrupt you because that is not my question. My question now is directed to sulfate. Has anybody studied the effect of sulfate on the olfactory issue?
A. Sodium sulfate does not produce the damage. Zinc sulfate does. Sodium chloride does not produce the damage. Zinc chloride does. That's the research and on down the line.
Q. Where is this sodium sulfate research published? What paper is that in?
A. I'm sorry, I don't have an independent recollection of that.
Q. What was Ms. Nelson's taste and smell like before she used Zicam?
A. Historically, it was normal.
Q. What is the basis for that statement?
A. Her history is obtained by Dr. Castro and particularly Dr. Henkin.
Q. Had she ever experienced smell loss in the past?
A. Yes.
Q. When?
A. Briefly in 1994.
Q. What is the significance of that?
A. I have experienced loss of smell, too, when I had a cold. She had a cold. She had three days ??
A. I don't believe the combination with zinc and sulfate enhances the toxicity. Zinc in a variety of different preparations has been used by a variety of different researchers with the same conclusion, that it's the zinc that is toxic, not the related N ion.
Q. Now, looking at your paper, the 55-year-old man who is the case report, is he represented by counsel?
A. I don't know.
Q. Has he had any discussions with you about litigation?
A. No.
Q. What is the basis for your statement that he previously had normal smell and taste?
A. The materials provided to me by Dr. Linschoten.
Q. Which are somewhere in that stack?
A. Yes.
Q. Okay. Was an endoscopy done of him?
A. I don't know.
Q. What effect, if any, did his rheumatoid arthritis medications have on his sense of smell?
A. We would be speculating in that area.
Q. Well, did you do any research on that?
A. I think some of the medications for rheumatoid arthritis have been described as causing problems. In this particular case, his history was relatively clean in terms of the use and the immediate discomfort and so on. He was using his rheumatoid medications before he used the Zicam and he had normal smell. He was using them afterward and he didn't have normal smell. Therefore, I have to assume the temporal relationship of the use of the Zicam along with the burning, along with the known toxicity of the zinc was the, therefore the probable source of his anosmia.
Q. Did the Zicam get up to the olfactory epithelium in this 55-year-old man?
A. It would certainly appear so.
Q. And that's an assumption on your part though, isn't it?
A. I didn't watch him spray at the time. Based upon the fact that he did use Zicam, that he did report burning, he did lose his sense of smell, it is a conclusion that I reached and an opinion.
Q. Where in the nose do these complaints of burning come from?
A. I'm not exactly sure. There are sensory receptors in the nose.
Q. Throughout the nose, correct?
A. Probably so.
Q. Were you able to rule out preexisting sinusitis as a cause of the 55-year-old man's smell loss?
A. One has to take the totality of the history, the physical examination and the findings and reach a reasonable conclusion. A reasonable conclusion in his case was that the Zicam caused his loss of sense of smell.
Q. Can you -- DP1MR. LAZARUS: Move to strike as nonresponsive.
Q. BY MS. SHARKO: Can you rule out sinusitis as a cause of his smell loss?
A. To a degree of medical probability, yes.
Q. On what basis?
A. The fact that he had normal sense of smell prior to the use of Zicam independent of his previous sinusitis -- and we've all had sinusitis -- and didn't have it afterward.
Q. Well, sinusitis is one of the major causes of smell loss, isn't it? You've written that?
A. In people with sinusitis, it is. But many of those people have not used Zicam. And in that case, I would certainly rule out Zicam as the source of their loss of smell. If there is a strong history of recurrent sinusitis, then I have to consider that probably the loss of smell was because of the recurrent sinusitis; the scarring, the inflammation, the damage that has occurred over time. But with sinusitis, the loss is slowly progressive over a period of time.
With zinc toxicity, it is acutely present and permanent.
Q. What is the basis for that opinion?
A. The basis for that opinion is the observation of patients over a period of time and the study over 30 years.
Q. No. Your opinion that with zinc, the loss is immediate?
A. Yes.
Q. What's the basis for that opinion?
A. A number of animal studies have shown that within the first 6 to 24 hours there are cellular changes. You have to assume that there were physiologic changes even before the cellular changes become apparent. The loss is acute.
Q. What about a patient with sinusitis who has a cold who uses Zicam, how do you rule out sinusitis ??
Q. So that's within the documents you produced?
A. Yes.
Q. What is the difference, if any, in the disassociation of zinc ions and zinc gluconate versus zinc sulfate?
A. Zinc sulfate tends to disassociate better than zinc gluconate.
Q. What does that mean in plain English?
A. It means that when you put a substance such as salt into water, sodium chloride, the sodium comes apart from the chloride. When you put zinc and sulfate -- zinc sulfate in the water, the zinc and the sulfate come apart. Same thing for the zinc gluconate but they tend to come apart a little less well than the zinc sulfate.
Q. So if you have equal amounts of zinc sulfate and zinc gluconate, with zinc sulfate, the zinc ions are going to come apart better and faster and in a higher volume than with the zinc gluconate?
A. I would need more information to draw a conclusion there.
Q. What more information do you need?
A. I need to know the molar strength of each. We discussed that this morning.
Q. Assume equal molar strength.
A. Okay. I need to know the temperatures. I assume that the temperatures are the same.
Q. Right. Assume everything is equal?
A. Then the zinc gluconate probably will come apart just a little bit less well than the zinc sulfate.
Q. How much more zinc is there in zinc sulfate than zinc gluconate?
A. I would need a lot more information before I could answer that question without speculating.
Q. Well, what else do you need to know?
A. I need to know their molar strengths.
Q. Why?
A. Because you need to have equal molar strengths to predict the amount -- you need to know the molar strength in order to predict the disassociation.
Q. What is the molar strength of Zicam?
A. It's 33 millimolars according to the patent and published information.
Q. How much Zicam is released in one squeeze of the bottle?
A. A squirt.
Q. And how much -- what is the volume of a squirt?
A. It depends on how hard you squeeze and a number of other things. A squirt is released.
Q. Why were you -- you said you were doing this mouse cadaver research preparatory to something else. What was it preparatory for?
A. What we had thought of doing was to put some Zicam into one side of a mouse and no Zicam into the other side of the mouse and look for the olfactory degeneration on the two sides.
Q. Why were you thinking of doing that?
A. To work with the issue of zinc gluconate. As I said, it's not particularly innovative and we didn't pursue it.
Q. Why didn't you pursue it?
A. As I just mentioned, it's not particularly innovative or helpful. Therefore, we didn't pursue it.
Q. Well, wouldn't that be helpful in trying to determine whether your hypothesis that zinc gluconate causes anosmia is correct?
A. We know in this human being that she used the product. We know that zinc is toxic. We know that she lost her sense of smell. We know that she experienced burning. I think that that ??
Q. What effect does cigar smoking have on the olfactory epithelium and the sense of smell?
A. I haven't reviewed that either. Mrs. Nelson didn't smoke cigars, I don't believe.
Q. Is the hypothesis that zinc gluconate causes damage to the sense of smell generally accepted in the medical and scientific community?
A. I believe so, yes.
Q. What is the basis for that opinion?
A. The acceptance with peer review of my article as presented in the American Journal of Rhinology along with presentations or discussions with colleagues at scientific meetings.
Q. Has any colleague expressed skepticism about your conclusions or the basis for your opinions?
A. They may have. I don't remember specific discussions. And again, I would point out it's the zinc ion. It's not the gluconate part that does the damage.
Q. And your opinion that it's the zinc ion is based on the catfish paper and the polio papers?
A. No. As I mentioned, there are a whole bunch of other papers in terms of --
Q. And the animal zinc sulfate papers?
