Last week, we compiled information for iOSs and OSs in terms of photostability, permeability, and photoreactivity. Like I said in that post, everything that what was done was in preparation for the analysis and discussion of the “toxicity” characteristic. In this post, “toxicity” will refer to what long-term damages occur with the use of sunscreens.
***In this series, I will refer to inorganic sunscreens as iOSs (not Apple, mind you) and organic sunscreens as OSs. While there are many individual compounds in each group—particularly OSs, for the purposes of this post, I will only refer to individual iOSs and OSs as parts of their respective groups. Complete and comparative ingredient profiles will not be seen in this series. Furthermore, I will attempt to discuss technologies that are more relevant and reflect the sunscreen technologies and tendencies of the current market. For example, while para-aminobenzoic acid (PABA) has many documented negativities, it will be ignored in our discussion, due to the fact that it is hardly used nowadays in sunscreen formulations.
For OSs, their toxicity can be determined by the two main pathways that most of the (potential) negative effects manifest from: the generation of radical species and the ability to act as endocrine disruptors.
“I’m not Radical, I’m Conservative!”
Okay admittedly, the title is a bit misleading. As previously discussed when considering the photoreactivity profile of OSs last week, when exposed to UV radiation, OSs will degrade and form reactive oxygen species (ROS) (1). Some, like avobenzone, are more prone to this than others. For those who are curious, this occurs in-part because avobenzone has a relatively high triplet energy, meaning that it can stay for a long time in an “excited” triplet state. If there are no suitable quenchers (such as octocrylene) to receive the energy from this triplet state, avobenzone will just pass it along to ANY “quencher” such as the lipid bilayers of the cellular membrane, or the thiol groups on important antioxidant enzymes such as thioredoxin reductase (2). This can lead to lipid peroxidation, inflammation, and over time, other undesirable effects. And even in combination with these “quenchers,” irreversible reconfigurations (discussed last week), such as 2 +2 addition of cinnamates and alkenes as well as ROS generation, are inevitable.
However, please remember that this deleterious effect is only relevant when the OSs are in contact with viable or living keratinocytes. So now we have to bring in what we learned in our discussion of permeability. Due to the lipophilic nature of OSs, they evidently can penetrate past the stratum corneum, with oxybenzone as the most potent penetrator (3). However, avobenzone is the OS most prone to ROS generation (not oxybenzone), and its permeability profile is not as bad (as that of oxybenzone). Furthermore, oxybenzone is known to stabilize avobenzone; together they form the “Helioplex” system. Then what happens? What about when combined with octinoxate, or homosalate? And what are the individual photostability, permeability, and photoreactivity profiles of those individual OSs? As you can see, there is an overwhelming amount of aspects and angles to consider. It’s impractical for the average end-user to calculate these characteristics.
Ultimately, the overall heterogeneity and diversity of the various profiles of OSs, in conjunction with a lack of conclusive documentation, mean that we don’t know what long-term effects the accumulation of ROS (and their consequent reactions), and in the amount reasonably seen with regular OS use, will have on the body. That is why antioxidants are absolutely necessary for more wholesome protection, since they directly and indirectly combat ROS, in addition to working synergistically with the sunscreen to inhibit the dangers of UV light!
“Mom, Can I Go Bother Mr. and Mrs. Endocrine?”
The term “endocrine disruptor” refers to a compound that can interfere with the endocrine or hormone system. These things can lead to everything from malignant tumors and cognitive disorders, to feminizing men and masculinizing women.
OSs have stirred up some controversy in the past few years because of misinformation and fear, many of which were perpetrated by those quacks over at the Environmental Working Group (EWG). Gah, I can’t even believe I’m giving them their own acronym; they certainly don’t deserve one! But anyways, let’s look at the data ourselves to see if their claim—that OSs such as oxybenzone, are endocrine disruptors—has any validity.
In vitro, many OSs such as oxybenzone, homosalate, and octinoxate have been shown to bind to estrogen receptors, as evidenced by their induction of estrogen-regulated pS2 protein and the increase of uterine weight in immature rats (4). Overall, five of the six tested OSs had significant estrogenic activity in vitro. However, even in that study, when taken orally in rats (in vivo), only three of the six OSs had any activity, indicating the disparity between in vitro and in vivo results. When applied on the skin, 4-MBC (which is not approved for use in the US and Japan) was shown to also increase uterine weight. However, the study acknowledged that the doses used cannot be compared to actual exposure levels; the high doses were only to establish in vivo activity. Finally, the study concluded that until more studies were done to investigate skin penetration (permeability) and kinetic influences, the toxicity of these OSs cannot be disregarded. Note that this study was published in 2001.
As the study (and many, MANY others) recommended, further studies were done to elucidate the mysteries presented above. This study (5) indicated that all five of the tested OSs, in a mineral oil base, were present in the stratum corneum and the viable epidermis underneath. The study indicated that the amounts penetrated were significantly lower (5-fold) than the minimum level necessary to achieve localized toxicity. However, this study only referred to toxicity in the skin. What about the effects that the “amounts penetrated” have on the human body as a whole?
In a 2004 survey (which was published in 2008), it was shown, by analyzing a random one-third subset of a sample population of 9,282 people who were greater than 6 years of age, that oxybenzone and its conjugated forms were detected in 96.8% in the urine of the randomly chosen subset (6). While that number is alarmingly high, alone it doesn’t tell me how MUCH oxybenzone was detected in the skin nor what happens to the oxybenzone before it reaches the kidneys. Fortunately, later in that study, and along with this one (7), it was shown that the volunteers excreted approximately 1.2%-8.7% of the total amount of oxybenzone applied. Keep in mind that the distribution was not uniform; the means was 3.7%, and the median was not discussed.
As for what happens to the oxybenzone before it reaches the kidneys, that study (7), along with this one (8), remarked that when absorbed systemically, the body rapidly glycosylates oxybenzone with glucuronic acid. This conjugation drastically reduces oxybenzone’s toxic potential, while also increasing its water solubility, allowing it to be easy excreted by the kidneys (via urine). Furthermore, the study suggests that some of the (hydroxylated) intermediates, which were present in trace amounts, are actually more “estrogenic” than oxybenzone itself. Keep in mind that most of these intermediates are also conjugated to glucuronides and safely excreted via urine.
So, are the above indicated amounts (of oxybenzone and its intermediates) high enough to elicit a hormonal response? According to this study (9), which tested oxybenzone in addition to octinoxate and 4-MBC, it was shown that the three (which were believed to work additively or even synergistically) did not seem to affect the levels of endogenous reproductive hormones in young men and postmenopausal women, nor induce a hypothalamic, pituitary, or gonadal response. And while there were slight variances in hormonal levels, the differences were attributed to the normal hormonal fluctuations that occur naturally, in addition to mass significance (it’s related in-part to quantifying margins of error).
Therefore, it would appear that overall, and in agreeing with the FDA, EU, and Japanese authorities, it can be said that OSs do not elicit a hormonal response; they do not act as “endocrine disruptors.” However, note that it may be prudent to not allow very young children (say younger than six years of age), to come into regular contact with OSs, just because they are more sensitive to reproductive hormones. Not to mention that they have less developed mechanisms to eliminate drugs (such as via the glucuronidation pathway detailed above), thinner layers of skin, and a larger surface area per body weight count than adults. All this allows for possibly higher uptake and bioaccumulation of OSs. There just haven’t been any studies to document chronic OS use in very young children; so it’s just not worth the risk.
Unlike OSs, the toxicity of iOSs, whether they occur in the skin or throughout the body, are from the same group of negative effects. They include: oxidative stress, inflammation, as well as DNA and cellular damage. However, I reiterate that all of these consequences can occur in the skin, or anywhere else in the body. There are no differing “pathways” as with OSs. Therefore, we will first briefly discuss what negative effects iOSs can have in general, before deciding which of those is relevant in terms of dermal and systemic exposure.
GENERAL TOXICITY OF iOSs
With the advent of nanotechnology, iOSs like titanium dioxide (TiO2) and zinc oxide (ZnO) are readily available at <100 nanometers in particle size. Because these iOS nanoparticles no longer exhibit the same properties as their larger counterparts (10), they can cause a multitude of problems including:
Oxidative Stress: iOSs increases ROS generation and consequently their byproducts such as lipid peroxidation, as well as depleting the levels of cellular antioxidants such as glutathione and superoxide dismutase (11).
Inflammation: iOSs stimulate the release of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-alpha. For those curious, this inflammation occurs due to oxidative stress. These pro-inflammatory cytokines are “activated” by signaling cascades that are sensitive to ROS, such as the mitogen-activated protein kinases (MAPKs) (11).
DNA and Cellular Damage: iOSs has been shown to damage DNA on a chromosomal level, as indicated by the formulation of micronuclei, in addition to internucleosomal cleavage and chromatin compaction; all of which are well-known indicators for apoptosis, or programmed cell-death (12). iOSs can also interfere with mitochondrial function, which coupled with caspase activation, will also lead to apoptosis (13).
HETEROGENEITY OF NANOPARTICLES
Now, as iOS nanoparticles can vary greatly in terms of size, clumping tendencies (agglomeration and aggregation), morphology, crystallinity, doping, and coating, we must discuss the potential influences these characteristics can have on toxicity.
Size: As mentioned above, smaller particles in general exhibit higher toxicities than larger ones.
Clumping Tendencies: This is directly linked to the original particle size, as in solution, the original smaller compound will “clump” together with neighboring ones to form larger “agglomerates” and “aggregates.” Smaller (original) compounds will group together more densely and will be more difficult to separate due to stronger electrostatic interactions, than clumps that are equal in mass, but are composed of larger and more loosely-linked (original) compounds. The former and more densely-packed clump is generally more toxic (14).
Morphology: iOSs can be manufactured into many shapes, ranging from spheres to sheets. Spheres tend to penetrate more deeply than sheets. However, they appear to have similar toxicity profiles, probably due to their similar surface areas (in this study) (15).
Crystallinity: In this category, TiO2 cannot be grouped together with ZnO, since their crystalline structures are very different. The former exists primarily as rutile or anatase, while the latter exists primarily as zincblende or wurtzite. Partially because of this difference, ZnO tends to be less photoreactive and toxic than TiO2. The anatase form is by far the more reactive of the two TiO2 variants (16).
Doping: This is when a very pure compound is intentionally mixed with another in order to achieve a certain goal; in sunscreens it’s usually done to reduce photoreactivity, which in turn, reduces the toxicity. For example, iron (Fe) is added to ZnO to reduce the levels of free zinc ions that form via dissolution (17), which are thought to interfere with cellular homeostasis that eventually leads to apoptosis (18).
Coating: Most people think that the use of coatings will reduce or even eliminate any and all photoreactivity as well as toxicity. Surprisingly however, while that may generally be true, studies have shown that certain materials used for coating can actually increase photoreactivity and toxicity for both TiO2 (19) and ZnO (20), when compared to their uncoated variants. And one also has to consider the thickness, purity, and longevity of the coating used!
As you can see, these characteristics, which can differ vastly between products, only contribute to the overall confusion and uncertainty when evaluating the safety of iOS nanoparticles. But don’t give up just yet. Keep reading! Because after going through all of that, we can finally discuss its relevancy to the dermal and systemic exposures to iOSs.
So how many of these apply when it comes to applying iOSs on to the skin? Fortunately, like we discussed last week, the stratum corneum (SC) of intact skin appears to be an adequate shield that prevents the iOSs from coming into contact with the viable keratinocytes of the epidermis, where the above deleterious effects can occur. As for damaged skin, this study (21) demonstrated that even with UVB-damaged skin, both TiO2 and ZnO did not penetrate into the epidermis; TiO2 did penetrate more deeply though.
However, because permeability tests were not done on all the varying morphologies, coatings, etc… SC penetration can’t conclusively be ruled out. Not to mention that this study (22), shows that iOSs can penetrate into the hair follicle. And since the SC is more disorganized at those locations, the risk of penetration is higher than on the surface of the skin. However, the study does note that sebum flow typically prevents that from happening.
And interestingly enough, this study which tested beryllium as well as titanium dioxide, demonstrated that with repeated rubbing and/or motion (stretching/twisting), these compounds could reach the epidermis and occasionally the dermis (23). Theoretically, this can cause translation to lymph, blood, macrophage, and dendritic cells, which may or may not trigger an immune response and/or translocation to other parts of the body.
However, keep in mind that the many negative effects described above, occurred when excessively high amounts of iOSs were applied to the skin, or were otherwise delivered systemically via injection, inhalation, etc. So the relevancy of these negative effects is still in question.
Another thing to note is that, because the inorganic UV filters are applied to the skin (as sunscreen), they are exposed to constant UVA irradiation. In their nano-forms, iOSs have been shown absorb UV light and act as a photocatalyst; basically that UVA light drastically intensifies any negative effect. Therefore, while the amount of iOSs that penetrate into the epidermis seems negligible, those that do will react more violently than non-irradiated iOSs.
However, except in perhaps extreme scenarios (that involve constant motion, prolonged UV exposure, damaged skin, and high concentrations of iOSs) penetration and negative effects will most likely not occur via dermal exposure.
Because very little if any iOSs get past the stratum corneum, the only other reasonable routes of systemic exposure would occur from sunscreen sprays, and lip products that contain iOSs.
I’ve never liked sunscreen sprays. There’s no rule-of-thumb of how much to apply because of the spray applicator; Furthermore, it’s difficult to achieve a thick and uniform coating of protection; and you can inhale the UV filters. From there, they can go either to your lungs or your brain, which can cause pulmonary neutrophilia (24) or even neurological lesions (25), respectively. Admittedly, while iOS sprays are difficult to find, they do exist. For example, the Kiss My Face Sun Spray Lotion SPF 30 contains 2.20% ZnO. No thank you! Lip products are… a necessary evil I suppose; just avoid licking the lips.
And while the amounts ingested/inhaled are quite low or even negligible, the long-term (like decades) effects have not been elucidated. Considering the ability for iOSs to linger and bioaccumulate in the body, I’d be wise to avoid situations when inhalation and digestion can occur. But otherwise, systemic exposure from iOSs appears to be minimal.
***Oh, and if you're wondering why I bothered to go through all the variations in terms of the nature of the iOSs nanoparticle, in addition to the potential negative effects, when most of them won't occur for the average sunscreen user, the fact that it it might occur compelled me to include that information! And really, like I said, we really don't know the long-term (decades) effects that regular iOS nanoparticles use can have on the body, especially for those scenarios listed above.
iOSs = 5; OSs = 1
While iOS nanoparticles are radically more varied than OSs, they appear to have a safer toxicity profile that I would have to give my vote to iOSs, bringing the score from (4-1) to (5-1). While neither is anywhere near perfect or even known, the fact that iOSs don’t significantly penetrate the stratum corneum and OSs do, makes me more inclined to use sunscreens with inorganic filters, and to consider the former less toxic.
Please let me know what you think about this down below! I spent probably 25+ hours reading (about 1,000+ Pubmed and PMC articles), comprehending, analyzing, brainstorming, writing, and editing this article! Did I miss anything? I'd also love to hear everyone's opinion on a piece I did that answered FAQs about retinol, such as use with acid products like hydroxy acids, strength vs tretinoin, and many others! Find it HERE!
And as you may have noticed, due to the length of this post, I decided to extend this series by one week, so now this will be a FIVE-PART SERIES! Yay!