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Review of Organic Chemical UV Filter Safety

Updated: Apr 1

Dalia Mizikovsky

Bachelor of Advanced Science, Honours student


Sunscreen is often used as the primary defense against sun damage, and its associated maladies. Despite the extensive use of sunscreen, the majority of the active ingredients lack the necessary safety data. In fact, toxicity studies for organic UV filters have not been conducted under the assumption that these chemicals did not have systemic absorption [1-2]. A Maximum Usage trial (MUst) conducted by the Food and Drug Administration (FDA) recently overturned this assumption, finding that every single chemical UV filter tested showed systemic absorption [2]. These findings led the FDA to re-evaluate the GRASE status of active ingredients in sunscreen. In a proposed rule, published on 02/26/2019, the FDA declared Zinc Oxide and Titanium Dioxide, the two inorganic UV filters as GRASE, and Trolamine Salicytate and Aminobenzoic acid (PABA) as not GRASE, stating that the harm outweighed the benefit of their use [1]. For the remaining 12 active ingredients, there was insufficient safety information to conclusively determine the GRASE status (Table 1) [1]. In this report, we will review the results of the MUst, in addition to other literature which has investigated the safety of organic UV filters.


Plasma concentration of a topically applied substance must be below 0.5ng/ml in order to forego toxicology testing. The MUst found that every organic UV filter tested exceeded this threshold after a single application (Table 2) [2]. Furthermore, the concentration of the organic UV filters accumulated with subsequent application and remained above 0.5ng/ml in at half of the participants for at least 3 days after ceasing application [2]. Two of the UV filters, octocrylene and homosalate were still above the threshold on day 21 of the study, 17 days after ceasing application [2]. Octocrylene had plasma concentrations that were 33-fold and 25-fold higher than the other UV filters tested at day 1 and day 4 respectively [2]. Previous studies have also identified the presence of organic UV filters in other relevant biological samples, such as urine, breast milk, the placenta and cord blood [3-7]. It should be noted that physiological concentrations vary depending on the demographic sampled. For instance, concentrations up to 13000ng/ml of oxybenzone were found in the urine of California females [8].


Table 1. Active sunscreen ingredients (UV filters) and their GRASE status as established in the proposed rule by the Food and Drug Administration on 02/26/2019.


Table 2. Maximum Usage trial conducted by the Food and Drug Administration for six chemical UV filters. Sunscreen was applied once on day 1, and 4 times a day for the subsequent 3 days. Blood samples were collected multiple times per day for days 1 to 4, and then on day 5, day 6, day 7, day 10, day 14 and day 21.



Dermal absorption is not the only relevant route of exposure to chemical UV filters. UV filters also accumulate in bodies of water, at concentrations of 300ng/ml in rivers, and at lower levels in sea and lake water [9-10]. Furthermore, small amounts of chemical UV filters were found in tap and groundwater, suggesting ingestion as an additional route of exposure [10]. Swimming pools are another zone of major concern. They act as ‘sinks’ for chemical UV filters, and their chlorine byproducts, with concentrations ranging from 2.85g/l to 0.95g/l (2850000ng/ml to 950000ng/ml) for the 4 UV filters tested [10-11].


The exposure to organic UV filters is almost ubiquitous and unavoidable, and there is no doubt that organic UV filters have systemic absorption. We must now evaluate whether organic UV filters are harmful at physiological concentrations.


Endocrine disruption by organic UV filters has been characterized in a range of in vitro and in vivo animal and human studies. Many organic UV filters have been found to possess some endocrine activity. In animal and in vitro studies, benzophenones, camphor derivatives, and cinnamate derivatives, three of the major classes of chemical UV filters, have all been shown to possess estrogenic and androgenic disruptive effects, and to interact with the progesterone receptor [15-18]. Additionally, benzophenones and cinnamate derivatives have been found to disturb the thyroid hormone receptor, and benzophenones the thyroid peroxidase enzyme [18-20]. These findings are reinforced by human studies, where small but significant changes in the relevant hormones were observed after topical application of sunscreen [21] . The low amplitude of the changes was partially attributed to robustness against endocrine changes in adults [21].


Minor endocrine changes are unlikely to be of detriment to adults. However, children, whose key developmental milestones are dependent on the correct endocrine signaling, are far more vulnerable to endocrine disruption. Exposure to organic UV filters can begin as early as in utero with maternal use of sunscreen [7]. Maternal exposure to endocrine disrupting chemicals can affect the fetus via direct action if the fetus is exposed via placental transfer, or indirectly by the disruption of maternal hormones [7]. Placental transfer is likely, due to the lipophilic nature of many organic UV filters [22]. Indeed, organic UV filters have been detected in the placenta, amniotic fluid, and cord blood [5,7].


A human study which investigated the effect of maternal urine concentration of oxybenzone on maternal hormones and birth outcomes found that the presence of oxybenzone was positively associated with birthweight in boys, and negatively associated with birthweight in girls [23]. Sex-specific effects are consistent with a endocrine mode of action. Two other studies which investigated the effect of oxybenzone on birthweight did not find an association to birthweight, however, the concentration of oxybenzone was 3-fold lower in those studies, suggesting a dose-dependent effect [24,25]. A more recent study found a significant association between maternal urine and serum concentration of 4-hydroxybenzophenone (4-HBP), and decreased birth weight, head circumference and abdomen circumference [7]. Additionally, urine concentration of 4-HBP was positively correlated with maternal triiodothyronine (T3), thyroxine (T4) and insulin-like growth factor 1(IGF-1) [7]. 4-HBP is one of the known metabolites of benzophenones, in addition to a commercially used UV filter, so a proportion of the serum and urine concentration may originate from other benzophenone filters [7].


Unfortunately, these human studies have major limitations, which do not enable us to accurately capture any developmental effects of organic UV filters. As with most observational studies, neither the independent variable, nor any confounding variables are controlled effectively. To justify more in-depth human studies, we have to rely on animal models to determine the physiological, cellular, and molecular mechanisms through which organic UV filters impact in utero development and growth. In one rat model, organic UV filters 4-methylbenzylidene camphor and 3-benzylidene camphor was administered in food to the parent generation pre-mating, during pregnancy, and during lactation and then to the offspring until adulthood [26]. It was found that exposure to the UV filters was associated with delayed puberty and enhanced prostate growth in males, and with altered uterine gene expression in females [26]. Adult organ weights were altered in both sexes [26]. There are numerous other animal model studies of developmental toxicity of organic UV filters which report significant effects from UV filter exposure.


In addition to exposure to organic UV filters in utero, young children are also exposed through frequent topical application in a bid to prevent sun damage. The serum concentration of organic UV filters, although not tested, can be predicted to be higher in children than adults, as children have a greater skin surface area to volume ratio. In the MUst conducted by the FDA, it was proposed that the limiting factor for serum concentration of organic UV factors was skin absorption, rather than elimination or breakdown of the compounds [2]. As such, it is reasonable to posit that the greater surface area to volume ratio would culminate in a higher serum concentration.


Children are the most at-risk group to the endocrine disruptive effects of organic UV filters, yet there is very little safety data regarding maternal and childhood use of sunscreen. There is also a startling lack of research into non-endocrine effects of organic UV filters. Moreover, recent evidence has shown that the breakdown products of organic UV filters may be hazardous, opening up another avenue that requires investigation [27].


Organic UV Filters have been shown to impact birth outcomes and hormone levels in humans, so it’s undeniable that they have physiologically meaningful activity. Further safety testing must be conducted, including thorough toxicology studies on all organic UV filters, and their prominent breakdown products. Without this comprehensive safety information a decision regarding their safety for further use cannot be made.



References

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2. Matta, M. K. et al. Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial. JAMA 323, 256–267 (2020).

3. Janjua, N., Kongshoj, B., Andersson, A.-M. & Wulf, H. Sunscreens in human plasma and urine after repeated whole-body topical application. J. Eur. Acad. Dermatology Venereol. 22, 456–461 (2008).

4. Rodriguez, J. & Maibach, H. I. Percutaneous penetration and pharmacodynamics: Wash-in and wash-off of sunscreen and insect repellent. J. Dermatolog. Treat. 27, 11–18 (2016).

5. Valle-Sistac, J. et al. Determination of parabens and benzophenone-type UV filters in human placenta: First description of the existence of benzyl paraben and benzophenone-4. Environ. Int. 88,243–249 (2016).

6. Schlumpf, M. et al. Exposure patterns of UV filters, fragrances, parabens, phthalates, organochlor pesticides, PBDEs, and PCBs in human milk: Correlation of UV filters with use of cosmetics. Chemosphere 81, 1171–1183 (2010).

7. Krause, M. et al. Maternal exposure to UV filters: Associations with maternal thyroid hormones, IGF-I/IGFBP3 and birth outcomes. Endocr. Connect. 7, 334–346 (2018).

8. Philippat, C., Bennett, D., Calafat, A. M. & Picciotto, I. H. Exposure to select phthalates and phenols through use of personal care products among Californian adults and their children. Environ. Res. 140,369–376 (2015).

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12. Wang, J. et al. Recent advances on endocrine disrupting effects of UV filters. Int. J. Environ. Res. Public Health 13,1–11 (2016).

13. Schlumpf, M. et al. In vitro and in vivo estrogenicity of UV screens. Environ. Health Perspect. 109, 239–244 (2001).

14. Kunz, P. Y. & Fent, K. Multiple hormonal activities of UV filters and comparison of in vivo and in vitro estrogenic activity of ethyl-4-aminobenzoate in fish. Aquat. Toxicol. 79, 305–324 (2006).

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18. Axelstad, M. et al. Effects of pre- and postnatal exposure to the UV-filter octyl methoxycinnamate (OMC) on the reproductive, auditory and neurological development of rat offspring. Toxicol. Appl. Pharmacol. 250, 278–290 (2011).

19. Schmutzler, C. et al. The ultraviolet filter benzophenone 2 interferes with the thyroid hormone axis in rats and is a potent in vitro inhibitor of human recombinant thyroid peroxidase. Endocrinology 148, 2835–2844 (2007).

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21. Janjua, N. R. et al. Systemic Absorption of the Sunscreens Benzophenone-3, Octyl-Methoxycinnamate, and 3-(4-Methyl-Benzylidene) Camphor After Whole-Body Topical Application and Reproductive Hormone Levels in Humans. J. Invest. Dermatol. 123, 57–61 (2004).

22. Hiller, J. et al. Systemic availability of lipophilic organic UV filters through dermal sunscreen exposure. Environ. Int. 132,105068 (2019).

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27. Wang, C. et al. Stability and removal of selected avobenzone’s chlorination products. Chemosphere 182, 238–244 (2017).

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