I have a 10 yo female with hx of intermittent allergic asthma and seasonal allergies. She recently developed acute hives without other associated systemic symptoms. The only new exposure was starting a 1mg fluoride chew 36hrs prior to onset of hives. The hives persisted for 4 days. No associated viral illness or other new exposures. She has previously tolerated fluoride varnish on teeth (5 mo ago), regular toothpaste and fluoride containing mouth wash.

My questions are: Is there any data/protocol for skin testing to fluoride? How often do you see a true IgE mediated allergy to fluoride? Is there any concern for drinking fluoridated water (currently lives in a town that does not have fluoridated water)? As this was the only new exposure, do you think a challenge with the fluoride supplement (if non-standardized skin testing was negative) would be unreasonable?


Flouride is an ion of insufficient molecular size to serve as an allergen. Flouride is highly reaction and could react with proteins or other larger molecules to create an allergen but I would doubt the fluoride itself would serve as an epitope (antigen binding site) for antibody. Thus, IgE response to fluoride is not biologically feasible. Flouride varnishes may contain pine nut but I could not find any evidence that pine nut is in fluoride chews. The latter may contain xylitol, cellulose, sucralose and flavoring. “Severe allergic reactions” are described but I could not find any description of a mechanism. Reactions to xylitol are usually gastrointestinal but urticaria, angioedema, vomting and chest tightness have been reported as well as positive patch tests. Likewise, sucralose may result in gatrointestinal symptoms but not allergic reactions. Cellulose products also would not likely cause an immunologic reaction but gum acacia may be found in cellulose products and may bind to specific-IgE. Evidence of allergy to cellulose is based primarily on testimonials but there is some evidence that cellulose can serve as an allergen (Leemann; van Toorenenbergn; Meyer).

I do not think fluoride in water would be of sufficient concentration or complexed with larger molecules. Therefore, I would not have concerns about drinking water containing added fluoride. I do not know how to suggest a fluoride allergy test should be performed. I would challenge with an alternative fluoride produce. If the fluoride chew contains pine nut, I would test for IgE to pine nut.

In summary, I doubt fluoride is responsible for the symptoms and signs. I am not aware of any skin testing with fluoride. I would challenge in clinic with an alternative fluoride product, ideally without the same flavoring and without pine nuts. I would use products with xylitol, sucralose and cellulose.

I hope this information is of some help to you and your patient.
All my best.

Dennis K. Ledford, MD, FAAAAI

1. Leemann, W., A. L. De Weck, and C. H. Schneider. "Hypersensitivity to carboxymethyl-cellulose as a cause of anaphylactic reactions to drugs in cattle." (1969): 621-623.

2. van Toorenenbergen, A. W., et al. "Irrelevant IgE binding to cellulose discs in RAST." International Archives of Allergy and Immunology 83.4 (1987): 436-439.

3. Meyer, M. W., C. Zachariae, and L. H. Garvey. "[Anaphylactic shock after intradermal injection of corticosteroid.]." Ugeskrift for laeger 177.4 (2015).

Pine nut and flouride dental treatment
Q: 1/26/2015
Fluoride varnish contains pine nuts. Is it safe to give to kids that have nut allergies?

A: There is very little information with respect to cross reactivity among pine nuts and other nuts, seeds or legumes. I have attached a prior question from Ask The Expert and mentions a case report of a patient with peanut and pine nut allergy and almond and pine nut allergy. The review in Molecular Nutrition and Food Allergy in 2012 indicates that the great majority of pine nut allergic subjects do not have tree nut allergy. There are more than 30 products on the market but I am not sure which of these is approved in the United States and if all contain pine nuts. I reviewed the package material and no specific mention was made of pine nuts with the 3M product or Enamel Pro varnish.

In summary, the risk would be extremely low with the use of a fluoride varnish in a patient with “nut allergies”. However, cross reactivity or simultaneous allergy has been described with almond and peanut. If the tree nut allergy is severe, I would suggest testing with pine nut if pine nut is in the product to be used. If the test were positive, I would recommend searching for another fluoride varnish without pine nuts or advise the patient of risk.

Pine nut allergy: possible cross-reactivity with nuts
Q: 9/18/2013
I'm often asked whether pine nuts should be avoided in other tree nut allergic patients. Pine nuts are generally considered a seed. Are there any studies evaluating cross-reactivity between pine nuts and either tree nuts or seeds?

A: You are correct that pine nuts are actually seeds. We do not know, unfortunately, the major allergen of pine nuts, but there are several studies which have isolated components which were allergenic in the particular patients evaluated.

However, there is very little information on potential crossreactivity between pine nuts and other foods, including nuts. There is one study which showed crossreactivity with peanuts (1), and another with almonds (2).

In addition, there are patients who have had anaphylactic episodes to pine nuts who have demonstrated allergy to other nuts as well (3), but there are also patients who were only mono-sensitized to the pine nut (4). Thus, unfortunately, we cannot give you a definitive answer as to which nuts or other foods might be cross-reactive in your patient except to say that crossreactivity evidently does occur and has been demonstrated to almonds and peanuts. It is not known whether patients who have shown anaphylactic sensitivity to pine nuts as well as other nuts or seeds do so because of cross-reacting antigens or the fact that they simply are reacting separately because of their highly atopic nature.

The issue, therefore, of whether pine nuts should be avoided in patients who are allergic to nuts and seeds can only be decided by clinical judgment. However, in most instances, we advise that patients who are allergic to nuts to avoid all nuts, including pine "nuts".

1. A MA, Maselli JP, Sanz Mf ML, Fernandez-Benitez M. Allergy to pine nut. Allergol Immunopathol (Madr) 2002; 30(2):104-8.

2. de las Marinas D, Vila L, Sanz ML. Allergy to pine nuts. Allergy 1998; 53(2):220-2.

3. Rubira N, Botey J, Eseverri JL, Marin A. Allergy to pine nuts in children. Allerg Immunol (Paris) 1998; 30(7):212-6.

4. Ibanez MD, Lombardero M, San Ireneo MM, Munoz MC. Anaphylaxis induced by pine nuts in two young girls. Pediatr Allergy Immunol 2003; 14(4):317-9.

Phil Lieberman, M.D.

Addendum from Dr. Lieberman:
We have heard from one of our readers and one of our AAAAI members, Dr. Beatriz Cabanillas, who sent us some very helpful additional information to our original response. Her letter is copied below:

Letter from Dr. Cabanillas:
I am writing concerning the following question posted on 9/18/2013:
I'm often asked whether pine nuts should be avoided in other tree nut allergic patients. Pine nuts are generally considered a seed. Are there any studies evaluating cross-reactivity between pine nuts and either tree nuts or seeds?

There is a study published in Molecular Nutrition & Food Research in 2012 regarding pine nut allergy (clinical features and major allergens characterization).

In this article, 80% of allergic reactions to pine nut in the ten patients included were severe. Most patients (70%) were monosensitized to this nut. Two major allergens with molecular weights of 6 and 50 kDa were purified and identified as albumin and vicilin, respectively.

All my best.
Dennis K. Ledford, MD, FAAAAI

Close-up of pine tree branches in Winter Close-up of pine tree branches in Winter