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FDA’s Proposed Ruling on Sunscreen Protection Products

Neha U. Sheth, PharmD
University of Maryland, School of Pharmacy
Baltimore, Maryland

4/18/2008

US Pharm. 2008;33(4):53-61.

Although the first sunscreen product was developed in 1928, it was not until the 1940s that the FDA began to regulate these products.1 On November 21, 1997, Congress mandated that the FDA, in accordance with the Food and Drug Administration Modernization Act of 1997 (FDAMA), regulate the prevention and treatment of sunburn as it does with all other OTC medications. Since then, regulations for testing and labeling have been set forth by the FDA for ultraviolet B (UVB) protection in sunscreen products. Only recently has the FDA proposed rules and regulations about ultraviolet A (UVA) protection in sunscreen products.

It is commonly known that the sun's ultraviolet radiation causes complications ranging from skin aging, photodermatoses, photosensitivity, and erythema to, most importantly, skin cancer.1-4 The sun radiates UVA, UVB, and ultraviolet C (UVC) rays. The ultraviolet wavelengths differ among A, B, and C with lengths of 320-400, 290-320, and 200-290 nanometers, respectively.5,6 Darkening of the skin or tanning is caused by both UVA and UVB radiation. The longer wavelengths associated with UVA penetrate the dermis more deeply, causing skin aging and prolonged pigmentation. Recently, UVA radiation has been further classified as UVAI (340-400 nm) and UVAII (320-340 nm). Ultraviolet B does not penetrate the dermis as deeply as UVA due to its shorter wavelengths; however, it does cause significant sunburn.2,6 Shorter-wavelength UVAII radiation has also been shown to cause sunburn like UVB. Longer-wavelength UVAI has been known to cause skin damage as well as increase the risk of skin tumors.7-9 The ozone absorbs 100% of short-wave radiation, such as UVC, so the effects of UVC on the skin are negligible. The ozone also absorbs a high portion of UVB, whereas it absorbs very little of UVA due to the longer wavelengths.2,6

The three most common forms of skin cancer include basal cell carcinoma, squamous cell carcinoma, and melanoma. Basal cell and squamous cell carcinoma are responsible for close to 90% to 95 % of all forms of skin cancer. These types of cancer mostly involve only the epidermis and dermis layer with rare metastasis to other organs. Melanoma, although rare, may result in metastasis to other organs and is much more fatal compared to nonmelanoma cancers.2,3 Risk factors for developing skin cancer include light natural skin color, family and personal history of skin cancer, blue or green eyes, blond or red hair, certain types and large number of moles, and exposure to the sun. Damage to DNA causing different forms of skin cancer has been linked primarily to UVB radiation; however, UVA has also been shown to cause DNA damage as well as immunosuppression leading to forms of skin cancer such as melanoma.2,3,10

Current Sun Protection Recommendations
The FDA and the American Academy of Dermatology (AAD) recommend nonpharmacologic and pharmacologic interventions to protect the skin from the sun. Wearing protective clothing such as wide-brimmed hats, long-sleeved shirts, and dark-colored clothing, in addition to sunscreen, has been the gold standard to prevent sun-induced complications. There are currently two classes of sunscreen agents: inorganic and organic. Inorganic agents are also referred to as physical blockers. These agents include zinc oxide, titanium dioxide, and red petrolatum. The physical blockers scatter and reflect radiation. Though these agents are very well tolerated, due to the opaqueness of the topical agent they are very unpleasant aesthetically, leaving a white-colored residue layer. Micronized forms of inorganic agents helped reduce the whitish residue; however, they also caused less scattering of light. Prior to micronization, inorganic agents were able to block long wavelengths such as UVA. After micronization, only shorter wavelengths such as UVB could be reflected.2,6 Organic agents differ from inorganic agents in that they do not reflect radiation but rather absorb it. They absorb the UV radiation and convert it to heat energy by means of electron excitation. The organic agents can further be classified by whether they protect against UVA or UVB. TABLE 1 lists the FDA-approved agents for both the inorganic the organic agents and their spectrum of activity against UV radiation.11




Though there are a number of sunscreen agents that protect against UVA in addition to UVB, consumers would only be aware of this if they knew the ingredients listed inTABLE 1. On each sunscreen bottle, the FDA has regulated that a sunburn protection factor (SPF) be labeled.11,12 The SPF is tested in humans by exposing a small portion of unprotected skin to short wavelengths for up to 24 hours or until sunburn occurs. Later, the same radiation is exposed to the same individual; however, this time the subject wears sunscreen. If it took 50 seconds for a subject to acquire sunburn with no sun protection and 500 seconds with the sunscreen applied, the SPF would be 500 divided by 50, equaling an SPF of 10. Since sunburn is mostly caused by short-wavelength UVB radiation, the SPF test is primarily testing for protection against UVB. Ultraviolet A causes more long-term effects such as wrinkles and skin aging. Compared to UVB endpoints, such as sunburn used in SPF testing, there are no acute end points associated with UVA exposure. This makes testing for protection against this type of radiation rather difficult.13,14

Currently, consumers are accustomed to seeing an SPF factor on all sunscreen products (FIGURE 1 ). The higher the SPF value, the more protection against sunburn is expected. As stated earlier, the SPF test only measures UVB radiation, not UVA radiation. On August 27, 2007, the FDA proposed regulations on how to test for UVA radiation and how to label sunscreen products to familiarize consumers with the effectiveness of these products.



Verifying Sunscreen Effectiveness
The FDA is requiring sunscreen manufacturers to undergo in vitro and in vivo studies to test the amount of UVA protection of their products. The in vitro study determines the ratio of UVAI absorbance to the total of UVB and UVA absorbance. The in vivo method uses a test similar to the SPF test known as the Persistent Pigment Darkening (PPD) test.15,16 As opposed to using sunburn as the end point, which is done in the SPF test, pigment darkening is used in the PPD test. Since pigment darkening is not the only clinical outcome associated with UVA radiation, using this end point is not the only reliable test to accurately identify protection from UVA radiation. The FDA recognizes this limitation and therefore suggests using both the in vivo and in vitro tests to assess the protection against UVA radiation in sunscreen products. The ratings of UVA protection will not be based solely on a ratio as with UVB protection. After compiling the data from the in vivo and in vitro data, the FDA will classify sunscreen products as offering Low, Medium, High, and Highest protection against UVA radiation. One star will be given for the Low, two stars for the Medium, three stars for the High, and four stars for the Highest UVA protection categories. FIGURE 1 shows the current labeling of sunscreen products and the new FDA-proposed labeling. 12,17

Although no standardized test for UVA protection has been widely accepted, other regulatory boards, such as the Japanese Cosmetic Industry Association and the European Union Commission, have endorsed the PPD testing method. The AAD also supports the PPD test. 18 Nash et al showed many of the disadvantages to this test in in vivo testing.14 The PPD test exposes the human subject to only UVA radiation, as opposed to the entire UV spectrum. They showed that filtering the radiation so that the subjectÜ was exposed to only UVA altered the absorption of the radiation. This makes the PPD test very inapplicable to a consumer who will go out in the sun exposed not only to UVA radiation but to other types of radiation. In addition to the PPD test's inaccuracies, its high cost and the expertise required to administer it makes the test must less desirable for sunscreen manufacturers.14 The FDA estimates a one-time cost of $2,200 per sunscreen product to test for UVA protection. In addition to testing, manufacturers must also comply with labeling requirements, as seen in FIGURE 1. The estimated costs for relabeling sunscreen products are $7,600 per product. The total estimated costs for relabeling and testing for all sunscreen products is estimated by the FDA to total $53 million.12

Although UVA testing and relabeling is one of the biggest changes the FDA is currently proposing, the agency is also proposing some changes to UVB labeling. Currently, the maximum SPF value assigned to a sunscreen product is 30+. The FDA is proposing to increase that number to 50+ for sun-sensitive individuals requiring more protection. In addition, the FDA is proposing to change the term SPF or " sun protection factor" to "sunburn protection factor."12 TABLE 2 shows a summary of the FDA-proposed changes to OTC sunscreen products.11,12



The Pharmacist's Role
With all of the changes to sunscreen labeling and testing being proposed, it is especially important for pharmacists to understand how this impacts medications that commonly cause photosensitivity. Although it is not all-inclusive, a list of common medications that cause photosensitivity reactions are listed in TABLE 3.19-23 Photosensitivity reactions can be classified as phototoxic or photoallergic. Phototoxic reactions cause an increase of UV radiation absorption in the skin. Photoallergic reactions are immune mediated and cause changes to the drug, causing a hypersensitivity-like reaction to the medications.20 These medications are affected by all types of UV radiation to which the skin is exposed, including UVA and UVB. To prevent many of these photosensitivity reactions, it is important for consumers to use broad-spectrum sunscreen products. The proposed ruling by the FDA will help consumers identify which sunscreen products are optimal for preventing drug-induced photosensitivity reactions when using offending medications.

Though the accuracy of the testing for UVA protection is still under scrutiny, the proposed labeling will help consumers identify sunscreen products that more effectively protect them against UV radiation complications. This may also entice researchers to further evaluate more accurate testing methods for UVA radiation in human subjects. The AAD has supported many of the changes proposed by the FDA, which reiterates the importance of compliance to sunscreen use in addition to picking the right sunscreen product. Pharmacists will be key players in helping consumers identify the appropriate sunscreen products needed when the changes in labeling do occur sometime later this year.



REFERENCES

1. Lowe NJ. An overview of ultraviolet radiation, sunscreens, and photo-induced dermatoses. Dermatol Clin. 2006;24:9-17.

2. Lautenschlager S, Wulf HC, Pittelkow MR. Photoprotection. Lancet. 2007;370:528-537.

3. Epstein FH. The pathogenesis of melanoma induced by ultraviolet radiation. N Engl J Med. 1999;340:1341-1348.

4. Fisher GJ, Wang ZQ, Datta SC, et al. Pathophysiology of premature skin aging induced by ultraviolet light. N Engl J Med.1997;337:1419-1428.

5. Matts PJ. Solar ultraviolet radiation: definitions and terminology. Dermatol Clin. 2006;24:1-8.

6. Palm MD, O'Donoghue MN. Update on photoprotection. Dermatol Ther. 2007;20:360-376.

7. Lavker RM, Veres DA, Irwin CJ, et al. Quantitative assessment of cumulative damage from repetitive exposures to suberythemogenic doses of UVA in human skin. Photochem Photobiol. 1995;62:348-352.

8. Lowe NJ, Meyers DP, Wieder JM, et al. Low does of repetitive ultraviolet A induced morphologic changes in human skin. J Invest Dermatol. 1995;105:739-743.

9. Sterenborg HJ, van der Leun JC. Tumorigenesis by a long wavelength UV-A source. Photochem Photobiol. 1990;51:325-330.

10. Hanneman KK, Copper KD, Baron ED. Ultraviolet immunosuppression: mechanisms and consequences. Dermatol Clin. 2006;24:19-25.

11. Code of Federal Regulation-21 CFR 352.

12. Federal Register Part III: DHHS CFR 21 347 and 352. Proposed Amendment of Final Monograph.

13. Nash JF. Human safety and efficacy of ultraviolet filters and sunscreen products. Dermatol Clin. 2006;24:35-51.

14. Nash JF, Tanner PR, Matts PJ. Ultraviolet A radiation: testing and labeling for sunscreen products. Dermatol Clin.2006;24:63-74.

15. Moyal D, Chardon A, Kolias N. UVA protection efficacy of sunscreens can be determined by the persistent pigment darkening (PPD) method (Part 2). Photodermatol Photoimmunol Photomed. 2000;16:250-255.

16. Moyal D, Wichrowski K, Tricaud C. In vivo persistent pigment darkening method: a demonstration of the reproducibility of the UVA protection factors results at several testing laboratories. Photodermatol Photoimmunol Photomed. 2006;22:124-128.

17. Food and Drug Administration. FDA aims to upgrade sunscreen labeling. Consumer Update. 2007. FDA. 23 Aug 2007. www.fda.gov/consumer/updates/sunscreeen082307.html.

18. Baker DR. Letter to the Commissioner of Food and Drugs at the FDA in regards to the proposed ruling of CFR 21: 352. www.aad.org/pm/temp/_doc/ResponseToFDA.pdf.

19. Morison WL. Photosensitivity. N Engl J Med.2004;350:1111-1117.

20. Tisdale JE, Miller DA. Drug-Induced Diseases: Prevention, Detection, and Management. Bethesda, MD: American Society of Health-System Pharmacists; 2005:69-77.

21. Moore DE. Drug-induced cutaneous photosensitivity. Drug Saf. 2002;25:345-372.

22. Valeyrie-Allanore L, Sassolas B, Roujeau JC. Drug-induced skin, nail, and hair disorders. Drug Saf. 2007;30:1011-1030.

23. McKenna JK, Leiferman KM. Dermatologic drug reactions. Immunol Allergy Clin N Am. 2004;24:399-423.

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