If you follow the medical literature and the unfolding story of a specific type of hair loss known as frontal fibrosing alopecia (FFA), you’ve probably come to appreciate that an environmental factor is proposed to somehow be relevant in the mechanisms that lead to frontal fibrosing alopecia (or simply called “FFA”). This environmental factor (if the assumption is indeed correct), became a part of the lives of humans somewhere in the 1970s or perhaps 1980s. FFA was non-existent for the most part up until the early 1990s when it first was reported by Dr Kossard from Australia. If we assume that if an environmental factor is indeed responsible, we’d probably need a decade or two of exposure (i.e. lead time) before any sort of disease manifests. Since its first reports in 1994, the rates of FFA have been increasing around the world. Some have even termed the increases an “epidemic.“
Everything and everything in the environment and in our foods and cosmetics is now being investigated as a cause of FFA. Foods, cosmetics, pills, pollution, pesticides – they are (or at least should be) all on the radar.
It was 2016 that Dr Messenger and his colleagues in the UK proposed that sunscreens could be a culprit. The actual study was a study that compared 105 women with FFA and 100 women without FFA. Everyone filled out a detailed survey. Surprisingly, a much greater proportion of women with FFA reported using sunscreens (at least twice weekly) compared to women without FFA. Specifically, 48 % of FFA patients reported such sunscreen use compared to just 24 % of women without FFA.
Other studies have suggested that patients with FFA are using more moisturizers and sunscreens than the general population. Since that study, the world has gone about figuring out what sunscreens to use and which to avoid. Titanium has been implicated in some studies but yet not thought to play a role in other studies. Some hair loss clinics and hair loss physicians are routinely recommending sunscreen avoidance – again without a whole lot of great evidence to back up the recommendations. Some physicians are taking the view to scream at anyone who recommends sunscreen avoidance given that this may lead to reduced sun protection and an increased risk of skin cancer. One study by Cranwell and colleagues did find that a patient with FFA markedly improved her disease by avoiding sunscreen use on the forehead. This too has fuelled an interest to limit sunscreens. Unfortunately, the authors of the paper (and editors of the journal) did not let us know what actual sunscreen was avoided so we can’t make further inferences on what ingredients in sunscreens might be bad. The mystery and search continues.
A New Report Suggests Sunscreen Allergy is Probably not Relevant in FFA
There has been interest by some authors in investigating whether “allergy” to sunscreen ingredients could be causative. A new report in the British Journal of Dermatology provides an opinion that even though it’s possible for anyone to develop a sunscreen allergy – this probably has nothing to do with how FFA actually comes about. Felmingham and colleagues point out that the mechanisms leading to FFA are unlikely to be an allergic one.
The authors also point out that we don’t really know if titanium dioxide in sunscreens is a problem, despite the suggestion that it could be. The authors remind us all that allergy to titanium dioxide is uncommon and so it is not likely to be causing problems through a mechanism of allergy. Furthermore than authors more boldly state that a previously published study by Thompson and colleagues that “identified titanium dioxide along hair shafts of both patients with FFA and controls” is …. well…. “meaningless.”
Meaingless data, I must say, has fueled a revolution among dermatologists treating FFA. Some think sunscreens have no role. Some think sunscreen has a role and some clinicians simply have or offer no opinion about the whole thing.
There has been ongoing debate in the “FFA research community” as to whether allergy to sunscreen ingredients has any role. Some authors, namely Aldoori and colleagues, found that women with FFA had a greater likelihood of having patch test positive reactions to fragrance ingredients and Balsam of Peru than controls. The point that Felmingham and colleagues make in their British Journal of Dermatology article is that what we choose as our “controls” makes all the difference in the world. When the data we have so far in 2019 is looked at another way, it appears that women with FFA probably have no difference in their rates of allergies than women in the general population who are of similar age. But this is a ‘probably’ – more good studies are needed.
Overall, Felmingham and colleagues are careful not to say that sunscreens have no role in FFA. Rather they authors emphasize their main message that sunscreen probably don’t have a role via an “allergic” mechanism.
Sunscreens and Moisturizers: Are we barking up the wrong tree?
There are those among us who treat lots and lots of patients with FFA who feel that the whole sunscreen issue is a ‘red herring’ and we’re all ‘barking up the wrong tree’ (…as the expression goes). It’s true that there are limitations in the types of survey-based studies that were initially done showing that women with FFA were more likely to be using sunscreens than those without FFA. Furthermore, it’s important to note that many patients with FFA in these various studies that have been done DO NOT use much in the way of sunscreens or facial moisturizers at all. So if sunscreens and facial moisturizers are relevant, it’s probably NOT that only mechanism leading to FFA.
But frankly, I don’t think we have enough evidence yet to know if we’re barking up the wrong tree or not. For now, it seems there’s at least something logical to pursue in this line of thing that leads researchers to study the role of sunscreens and moisturizers in FFA. I’m not surprised by the opinion of the authors in the paper discussed above – namely that sunscreen allergy probably does not play a role in FFA.
How many trees are there anyways?
The race is on to find out what causes FFA. We don’t really know if we’re barking up the right tree or the wrong tree by continuing to pursue the sunscreen story. It sure seems reasonable to keep going with this approach given we have little else to go on right now and also the remarkable improvement that one (yes, just one) patient had with her FFA disease by stopping her sunscreen. But the report is impressive. Unless you yourself have treated a lot of patients with FFA, you can’t come to realize how much of an impact this publication carries. It’s impressive.
It could be a coincidence. But it could be real.
FFA could possible be a heterogenous condition
It seems to me that FFA is quite a heterogenous condition. There are many presentations of the disease, and many different responses to treatment. Some patients are young, some are older. Some are female and some (a small proportion) are male. Some have only eyebrow loss. Some have forehead hair loss before the eyebrows and some of body hair loss before anything. That a sunscreen or moisturizer would explain EVERYTHING about FFA just doesn’t make a lot of sense to me. It may be relevant to how some people’s FFA develops (perhaps) – but the sunscreen story is likely not going to apply to everyone.
I don’t think we’re barking up the wrong tree necessarily – but I do think there are a lot of trees that we need to be sitting at the base of barking up at. In other words, I think that we need to keep an open mind that there may actually be ‘many triggers’ in FFA that do a similar thing – namely that they disrupt the normal hormonal milieu in the scalp and/or activate the immune system in a manner that it should not have been activated.
So back to our main tree – sunscreens and moisturizers.
What we (think we) know about sunscreens and moisturizers and what we don’t know we don’t know.
1. Some sunscreen ingredients get absorbed into the body.
The skin is viewed as a pretty good barrier. It protects us. In fact, the argument for most topical cosmetic products (and much of the cosmetics industry) is that most chemicals don’t get absorbed into the body. The skin blocks this. Surprisingly, that view changed somewhat with a a 2019 study by Matta and colleagues which showed just how much sunscreen gets absorbed in to the blood when we put in on our skin. The Matta study was surprising to me.
The Matta Study
The Matta study was a randomized study of 24 patients (12 men and 12 women) who applied sunscreens 4 times a day to 75 % of their body surface area for four days. 6 patients use a lotion, 6 used a cream, 6 used a spray and 6 used a second type of sunscreen spray. These sunscreens contained ingredients avobenzone, oxybenzone, octocrylene, and ecamsule. The sunscreen was applied at the current recommend amount – namely 2 mg per square cm. The study researchers collected 30 blood samples from study subjects not only for the 4 days that the sunscreen was applied but also 3 additional days as well. The study was conducted indoors in a somewhat artificial setting without exposure to heat, sunlight, or moisture.
Matta and colleagues found that after 4 applications on day 1, 23 of 24 subjects had systemic concentrations greater than 0.5 ng/mL for all active ingredients in the formulation applied. This concentration is important because 0.5 ng/mL is the so called “Threshold of Toxicological Concern (TTC)” that the FDA adopted to approximate the highest plasma level below which the carcinogenic risk of any unknown compound would be less than 1 in 100,000 after a single dose. The average levels of avobenzone was 4.0 and 3.4 ng/mL in the 2 sunscreen sprays studied, 4.3 ng/mL in the lotion. Interestingly, the avobenzone concentration in the blood in those using the cream was lower at 1.8 ng/mL.
The numbers for the other sunscreen ingredients were also higher than the 0.5 ng/mL cut off. For oxybenzone, the corresponding values were 209.6 ng/mL for spray 1, 194.9 ng/mL for spray 2, and 169.3 ng/mL for lotion. The the ingredient octocrylene, the concentrations were 2.9 ng/mL for spray 1, 7.8 ng/mL for spray 2, 5.7 ng/mL for lotion, and 5.7 ng/mL for the cream cream. Finally for ecamsule, the systemic concentration was 1.5 ng/mL for the one product that contained it (cream).
The researchers showed that the blood levels above this “0.5 ng/mL” level were reached quickly: within 6 hours after the first application of avobenzone, 2 hours after application of oxybenzone, and 6 hours after application of octocrylene. In addition, there was evidence that these drugs accumulated in the blood after more and more exposure.
The Matta study is important to me because it reminds us that these chemicals are in fact being absorbed into the body. Many of these ingredients have been shown to affect hormones in various animal studies (so called “endocrine disrupting chemicals”). Clearly, we need to understand these ‘organic’ sunscreen ingredients a whole lot better. The FDA, in fact, has called upon the sunscreen industry to provide more data on these ‘organic’ ingredients, including how they get absorbed, and whether they affect cancer risk or reproductive health in any way. We’ll soon be learning more about these sunscreen chemicals including avobenzone, homosalate, octinoxate, octisalate, octocrylene, and oxybenzone.
FFA is a partly a hormonal disease so we need to understand what affects hormones. There’s no doubt that these sunscreen chemicals have the potential to affect hormones in various animal models. Whether they have the potential to affect hormones in humans – and whether they have the potential to alter hormones in the right manner in patients with a predisposition to developing the hormonal disease FFA is still unknown.
My own view is that until we figure out what’s causing FFA, it makes sense for patients with FFA to limit intense sun exposure, wear hats and sunglasses and long sleeve shirts. If they are going to be out in the sun, I encourage my patients to reach for a ‘non-nano’ particle mineral sunscreen (containing zinc oxide and possible titanium dioxide too). We’ll get in that later.
2. Zinc oxide (ZnO) and titanium dioxide (TiO2) do not appear to be absorbed through the skin.
Zinc oxide and titanium dioxide have been deemed less concerning by the FDA than the organic ingredients like avobenzone, homosalate, octinoxate, octisalate, octocrylene, and oxybenzone. In fact, the FDA and others have terms these so called ‘inorganic’ sunscreen ingredients as “GRASE” sunscreen ingredients. The term “GRASE” stands for generally regarded as safe and effective. The compounds are thought to not cause harm in humans unless inhaled or swallowed. For now, we don’t often inhale these sorts of ingredients – but clearly as they pollute our waters more and more we are going to be swallowing more and more of these compounds.
There is however, a body of experimental research that needs clarifying in the skin of patients predisposed to FFA and that is whether the generation of reactive oxygen species following UV exposure to titanium and zinc oxide have relevance or not. Titanium dioxide is “more reactive” than zinc oxide meaning that when ultraviolet radiation strikes it, more reactive oxygen species get produced. At present, it would appear that the formation of reactive oxygen species is a minor issue compared to just how much reactive species and inflammation can form from the UV radiation itself. Studies to date have suggested that if zinc oxide or titanium oxide particles are somehow activated by ultraviolet radiation itself and generate reactive oxygen species – the inherent antioxidant ability of our resilient skin quenches any sort of problem whatsoever. We don’t really know if the skin of different people has different ability to do this. Clearly more study of this is needed. It would appear that the generation of these types of harmful reactive oxygen species is higher with titanium dioxide than zinc oxide – but whether this has any relevance at all for sunscreens is not clear. Whether it has any relevance for patents with FFA is also unclear. The skin of FFA is different than the skin of patients without FFA – so we got to start thinking this way if we’re going to move things forward.
As we think about sunscreens, it’s important to understand that the size of the titanium oxide and zinc oxide particles has changed in recent recent years. In much of the modern world, bigger is better. But that’s not true for how the cosmetic industry has changed the size of zinc and titanium particles. We are now in a whole new era of titanium dioxide nanoparticles (or what is simply called TiO2-NPs). Traditional or old fashioned titanium dioxide particles are bigger than 100 nm. The newer TiO2-NPs are well under 100 nm – about 1000 times smaller than the diameter of a hair shaft. They are aesthetically much nicer to use as they make sunscreen products much smoother and easy to apply. People like applying nanoparticle containing sunscreens – and in turn like buying them. The concern is whether or not these tiny particles make their way down the hair pore and incite any sort of inflammation or immune reaction. That we don’t really know yet.
The traditional sized titanium dioxide particles are classified as being “biologically inert” in both humans and animals and therefore, they have been extensively used in a wide range of products such as cosmetics and pharmaceuticals. The use of TiO2-NPs is growing exponentially and it’s hard to keep up with just how many products now have them. TiO2-NPs can be found not only in sunscreen products, but toothpaste, sugar, paints, printing ink, rubber, paper, cement, film, bio-medical ceramic and implanted biomaterials, antimicrobial plastic packaging and self-cleaning sanitary ceramics.
TiO2-NP have also been reported to elicit changes in gene expression pathways, including apoptosis-related genes and inflammatory genes, and to promote oxidative stress and DNA damage responses. Some investigators have suggested that nanoparticles may be more toxic than larger particles of the same material because of their larger surface area, enhanced chemical reactivity and easier cellular penetration. Whether this truly means anything in the skin of a sunscreen wearer is not completely clear. Whether this truly means anything in the skin of an FFA patient wearing sunscreen is not completely clear either.
Most products we use in North America are not required to be labelled as having regular titanium dioxide particle size or nanoparticle sized titanium dioxide. That regulation is different in different countries.
UV attenuation properties of these two particles are complementary; TiO2 being primarily a UVB absorbing compound, while ZnO is more efficient in UVA absorption.
We still don’t really know if zinc and titanium nanoparticles are a problem or not. The United States FDA is not formally pursuing the issue so we’re not going to get any more helpful information there. Some companies are addressing the lack of information by producing sunscreens that lack nanoparticles. I’ll discuss more of this below.
We must not forget that in addition to thinking about our safety, we need to think about the environment as well. It’s clear that even the inorganic ingredients have potential to affect the environment. Titanium dioxide and zinc oxide are continuing to be studied in terms of their effects on many biological and eco systems. The release of these chemicals into the environment has the potential to affect aquatic life as well as nonliving structures too. Many sunscreen manufacturers are marketing themselves as ‘reef friendly.” It is likely that non-nano titanium sunscreens are safer for many aspects of the environmental than “nano’ sunscreens but again further study and confirmation awaits. Finally, we need to keep in mind that while zinc and titanium nano particles could turn out to be safe for sunscreens, their release into the environment may ultimately find their way back into humans – where the ingestion of such particles is known to have health consequences. You and me eating a good amount of titanium dioxide nanoparticles is not going to be good for us. Likely these particles will plug up or somehow affect the delicate intestinal system we have and cause problems. Animals studies show ingestion of these particles lead to their deposition in many organs of the body. Whether this is ever to be an issue for humans is not clear. That’s another different issue.
3. The organic filters are still being studied and I await the FDA’s final ruling.
I’m eager to see what the FDA will say about many of the “organic” filters currently used in sunscreens. As mentioned above, the FDA has had a bit of a crackdown on sunscreen ingredients and is back to reviewing their safety. We’ll soon be learning more about these sunscreen chemicals including avobenzone, homosalate, octinoxate, octisalate, octocrylene, and oxybenzone.
Even if the FDA rules on their safety in humans, we need to always consider the environmental impact of these products. Oxybenzone (also called benzophenone-3) was banned in Hawaii because it was shown to cause harm to coral reefs. Octinoxate (also called methoxycinnamate) was also banned in Hawaii as well. studies in animals have shown effects of the thyroid gland and reproductive systems.
Given that we have many options to recommend to our patients in terms of sun protection (hats, clothing, sun glasses) and zinc and titanium based mineral based sunscreens.
4. Facial moisturizers contain an array of ingredients.
We need to also remember in this FFA story, that many studies have showed another consistent finding: specifically that women and men with FFA are more likely to be be using facial moisturizers than men and women without FFA. We still don’t really know what this all means… and if it really means anything. But just like the sunscreen story, it’s something we have to go on.
Facial moisturizers contain a lot of different ingredients. Just pick up any moisturizer the next time you are in the store or pharmacy and you’ll see a good 10-20 ingredients listed on the back. And the ingredients in one moisturizer and not quite the same as the next – even though many moisturizers can look and smell fairly similar.
Some of these ingredients have caught the attention of people who study the safety of products. The David Suzuki Foundation for example has put forth a ‘dirty dozen’ list of chemicals that we as consumers should consider avoiding. Most of the top 10 facial moisturizers on the market contain one or more chemicals from the dirty dozen list. What this all means is again not so clear. If there’s any problem with these chemicals (and again that’s open to at least some debate) – it seems that patients with FFA are using more of them.
Let’s consider a theoretical example. Again, so little is know about the cause of FFA that we can only theorize at this point. But here goes. Paraben ingredients are one of the Suzuki Foundations dirty dozen chemicals. A compound on that list known as methyl paraben is thought to be a xenoestrogen and is found in one moisturizer I picked up on the shelf today. Xenoestrogens are chemicals that have a molecule structure somewhat similar to the hormone estrogen itself and can even bind estrogen receptors. Xenoestrogen are found in plastics, pesticides, chemicals, and water systems. We know that there are several genes that seem relevant to FFA. One of these is the P450 1B1 microsomal enzyme (which goes by the second name “xenobiotic mono-oxygenase and aryl hydrocarbon hydroxylase).. This gene is responsible for how estrogen gets metabolized in the body. One wonders if patients with FFA are somehow differentially sensitive to the effects of xenoestrogens that plague our ever changing world.
It’s a bit of a mess when it comes down to how we should as consumers choose sunscreens and moisturizers and even more challenging for those with FFA. Does the sunscreen issue even matter? We have so many different interest groups and so many conflicts of interests that it makes anyone a bit dizzy. Who to trust is becoming more and more difficult. If you trust zinc oxide, use zinc oxide sunscreens. If you trust the data on organic filters, use anything sunscreen product you want. If you trust the data on titanium dioxide, use any mineral sunscreen with either zinc or titanium. If you feel the nano particle issue is still unsettling for you, buy nano-free titanium dioxide and zinc oxide products from the lists above.
We have a lot of learn when it comes to understanding FFA. For now, simplicity in ingredients probably makes some sense. As we learn more, we can revamp these recommendations. But regardless of what we ultimately come to learn about FFA, there are important lessons for us all to be aware of when it comes to the products on our shelves and in our world.
REFERENCES OF INTEREST
Brezova et al. Reactive oxygen species produced upon photoexcitation of sunscreens containing titanium dioxide (an EPR study).J Photochem Photobiol B. 2005 May 13;79(2):121-34.
Felmingham et al. Allergy to sunscreen and leave‐on facial products is not a likely causative mechanism in frontal fibrosing alopecia: perspective from contact allergy experts. British Journal of Dermatology Aug 2019
Ghazipura M et al. Exposure to benzophenone-3 and reproductive toxicity: A systematic review of human and animal studies. Reprod Toxicol. 2017 Oct;73:175-183. doi: 10.1016/j.reprotox.2017.08.015. Epub 2017 Aug 24.
Matta et al. Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients. A Randomized Clinical Trial. JAMA. 2019;321(21):2082-2091. doi:10.1001/jama.2019.5586
Smiles et al. Titanium dioxide and zinc oxide nanoparticles in sunscreens: focus on their safety and effectiveness. Nanotechnol Sci Appl. 2011; 4: 95–112.
Thompson et al, British Journal of Dermatology 2019.
Article orginally posted at donovanmedical.com