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Figure.
TiO2 Nanoparticle Application and Maximal Dermal Presentation
TiO2 Nanoparticle Application and Maximal Dermal Presentation

A, Image made with light microscopy of a thick section. B, Images made with transmission electron microscopy (TEM) of thin sections from a study participant treated with titanium dioxide (TiO2)–containing sunscreen and showing maximal dermal presentation of TiO2 nanoparticles. Each boxed area in the image correlates with a TEM micrograph of a grid hole. Each grid hole is approximately 220 x 220 μm. The dotted pink line in the montage of TEM micrographs shows the division between epidermis and dermis. Grid holes 12 and 14 seen on TEM contain the epidermal layer and part of the dermal layer, whereas grid holes 13 and 15 contain only the dermal layer. A hair follicle structure was observed with TEM in this sample in grid holes 10 and 11. Electron-dense regions of the appropriate size and morphology to be TiO2 particles are indicated with dotted blue circles in the TEM micrographs. All particles were confirmed to contain TiO2 using scanning electron microscopy and energy dispersive X-ray spectroscopy as previously described.2

1.
Miller  SA, Coelho  SG, Miller  SW, Yamaguchi  Y, Hearing  VJ, Beer  JZ.  Evidence for a new paradigm for ultraviolet exposure: a universal schedule that is skin phototype independent.  Photodermatol Photoimmunol Photomed. 2012;28(4):187-195.PubMedGoogle ScholarCrossref
2.
Sadrieh  N, Wokovich  AM, Gopee  NV,  et al.  Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles.  Toxicol Sci. 2010;115(1):156-166.PubMedGoogle ScholarCrossref
3.
Kornhauser  A, Wei  RR, Yamaguchi  Y,  et al.  The effects of topically applied glycolic acid and salicylic acid on ultraviolet radiation-induced erythema, DNA damage and sunburn cell formation in human skin.  J Dermatol Sci. 2009;55(1):10-17.PubMedGoogle ScholarCrossref
4.
Bennat  C, Müller-Goymann  CC.  Skin penetration and stabilization of formulations containing microfine titanium dioxide as physical UV filter.  Int J Cosmet Sci. 2000;22(4):271-283.PubMedGoogle ScholarCrossref
5.
Mavon  A, Miquel  C, Lejeune  O, Payre  B, Moretto  P.  In vitro percutaneous absorption and in vivo stratum corneum distribution of an organic and a mineral sunscreen.  Skin Pharmacol Physiol. 2007;20(1):10-20.PubMedGoogle ScholarCrossref
6.
Filipe  P, Silva  JN, Silva  R,  et al.  Stratum corneum is an effective barrier to TiO2 and ZnO nanoparticle percutaneous absorption.  Skin Pharmacol Physiol. 2009;22(5):266-275.PubMedGoogle ScholarCrossref
Research Letter
April 2016

Repetitive Application of Sunscreen Containing Titanium Dioxide Nanoparticles on Human Skin

Author Affiliations
  • 1Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
  • 2Nanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, Maryland
  • 3Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, St Louis, Missouri
  • 4National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas
  • 5Division of Radiological Health, Office of In Vitro Diagnostics and Radiological Health, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland
JAMA Dermatol. 2016;152(4):470-472. doi:10.1001/jamadermatol.2015.5944

Titanium dioxide (TiO2) has for decades been approved for use in sunscreens as a physical sunblock. It is not known whether reducing the size of TiO2 particles in sunscreens creates new issues of safety and/or effectiveness. A study was therefore conducted to investigate the relative risk of skin penetration by TiO2 nanoparticles in healthy fair-skinned individuals.

Methods

The protocol for the study was approved by the Research Involving Human Subjects Committee of the US Food and Drug Administration, and informed written consent was obtained from each of the study participants. The participants were 6 fair-skinned individuals with phototypes II and III skin as defined by a UV-sensitivity questionnaire 1 and dermatological evaluation, who were recruited from the Washington, DC area. Daily applications of sunscreen with and without TiO2 nanoparticles at a concentration of 2 mg/cm2 were made to 2 test sites (5 x 5 cm) on the lower back of each participant, with a separate site as an untreated control. Except for the absence of tocopheryl acetate, the 2 custom-prepared sunscreen formulations used in the study (sunscreen with uncoated TiO2 nanoparticles [sunscreen plus TiO2] and [sunscreen only]) were identical to previously reported formulations.2 The sunscreens were applied once daily for 3 days to 2 of the participants. To further detect penetration of TiO2 nanoparticles, sunscreen was applied once-daily for 8 days to the 4 other participants. One day after the final sunscreen application, 5 shave biopsy specimens were acquired from each participant (2 from the sunscreen plus TiO2 site, 2 from the sunscreen-only site; and 1 from the control site). Details of the procedures for biopsy and tissue specimen processing, and of the biomarkers for immunohistochemistry, have been described,3 as have details of the biopsy-sample preparation for electron microscopy.2 Transmission electron microscopy was used to assess the penetration of TiO2 particles through epidermal-dermal skin layers. Confirmatory identification was done with scanning electron microscopy and energy dispersive X-ray spectroscopy (SEM-EDX) analysis as previously described.2

Results

The study participants (4 female and 2 male) were healthy individuals with a mean age of 37 years and did not present with skin irritation or other adverse effects. All skin specimens contained TiO2 particles in the stratum corneum layer, probably caused by normal rubbing of clothing and resulting in cross-contamination of the study preparations to other sites. The TiO2 nanoparticles in the specimens appeared agglomerated and ranged from 20 to 100 nm in diameter, as found previously.2 Generally, the skin sites receiving sunscreen plus TiO2 contained more TiO2 particles than those treated with sunscreen only, as would be expected, and therefore were sites of greater scrutiny for dermal penetration. The deep epidermis and dermis of the control sites and at the sunscreen-only sites were not examined because the level of TiO2 in the stratum corneum of these samples was much lower than in the sunscreen plus TiO2 skin samples. The TiO2 nanoparticles were confirmed with SEM-EDX as present mainly in the dermis surrounding hair follicles but at very low qualitative levels and with no obviously decreasing gradient with skin depth.

Discussion

Fewer than 30 confirmed TiO2 nanoparticles or their aggregates were detected in all of the sunscreen plus TiO2 skin specimens, mainly in the dermis surrounding the hair follicle. The detectable numbers of TiO2 nanoparticles were several orders of magnitude lower than those in the applied doses of sunscreen plus TiO2 in the area with maximal dermal presentation (Figure), or about 0.00014% of the total applied dose of uncoated TiO2 on the basis of the assumptions previously described.2 These results are in accord with previous findings in minipigs and corroborate findings for nanoparticles surrounding the hair follicles in humans.2,4-6 Our findings depend on selected “regions of interest,” which does not allow a detailed quantitative assessment of dermal penetration of TiO2 nanoparticles. Notwithstanding its limitations, however, the study described here provides valuable data on the dermal penetration of TiO2 nanoparticles and the parameters for informing the design of future clinical studies.

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Article Information

Corresponding Author: Sergio Coelho, PhD, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bldg 37, Room 2132, Bethesda, MD 20892 (sergio.coelho@fda.hhs.gov).

Accepted for Publication: December 1, 2015.

Published Online: February 24, 2016. doi:10.1001/jamadermatol.2015.5944.

Author Contributions: Drs Coelho and Miller had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wokovich, Howard, Miller.

Acquisition, analysis, or interpretation of data: Coelho, Patri, McNeil, Miller.

Drafting of the manuscript: Coelho, Wokovich, Howard.

Critical revision of the manuscript for important intellectual content: Coelho, Patri, McNeil, Howard, Miller.

Statistical analysis: Patri.

Obtained funding: McNeil, Miller.

Administrative, technical, or material support: Coelho, Patri, Wokovich, McNeil, Howard.

Study supervision: Patri, McNeil, Miller.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported in part by the Office of Science and the Center for Devices and Radiological Health, US Food and Drug Administration (FDA), and in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (under contract HHSN261200800001E).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. This article reflects the views of the authors and should not be construed to represent FDA’s views or policies. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the US Department of Health and Human Services.

Additional Contributions: We are indebted to our colleague, Janusz Beer, PhD, DSc, Center for Devices and Radiological Health, FDA, who created the clinical facility in which this work could be completed and is survived scientifically through the collaborations he nurtured. In addition, we thank Lucinda Buhse, PhD, Center for Drug Evaluation and Research, FDA, for helping to design and create the cream formulation. Nakissa Sadrieh, PhD, Center for Drug Evaluation and Research, FDA, published the seminal paper on which this work is based and reviewed the clinical protocol. We would also like to extend special thanks to Boris Lushniak, MD, MPH, who at the time of the study was Rear Admiral and Assistant Surgeon General, US Public Health Service (and now is retired Acting Surgeon General) for review of the study design, and Barbara Zmudzka, PhD, Center for Devices and Radiological Health, FDA, and Vincent Hearing, PhD, National Cancer Institute, National Institutes of Health, for their help during the clinical study. None of these individuals received additional compensation for their work in the study.

References
1.
Miller  SA, Coelho  SG, Miller  SW, Yamaguchi  Y, Hearing  VJ, Beer  JZ.  Evidence for a new paradigm for ultraviolet exposure: a universal schedule that is skin phototype independent.  Photodermatol Photoimmunol Photomed. 2012;28(4):187-195.PubMedGoogle ScholarCrossref
2.
Sadrieh  N, Wokovich  AM, Gopee  NV,  et al.  Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles.  Toxicol Sci. 2010;115(1):156-166.PubMedGoogle ScholarCrossref
3.
Kornhauser  A, Wei  RR, Yamaguchi  Y,  et al.  The effects of topically applied glycolic acid and salicylic acid on ultraviolet radiation-induced erythema, DNA damage and sunburn cell formation in human skin.  J Dermatol Sci. 2009;55(1):10-17.PubMedGoogle ScholarCrossref
4.
Bennat  C, Müller-Goymann  CC.  Skin penetration and stabilization of formulations containing microfine titanium dioxide as physical UV filter.  Int J Cosmet Sci. 2000;22(4):271-283.PubMedGoogle ScholarCrossref
5.
Mavon  A, Miquel  C, Lejeune  O, Payre  B, Moretto  P.  In vitro percutaneous absorption and in vivo stratum corneum distribution of an organic and a mineral sunscreen.  Skin Pharmacol Physiol. 2007;20(1):10-20.PubMedGoogle ScholarCrossref
6.
Filipe  P, Silva  JN, Silva  R,  et al.  Stratum corneum is an effective barrier to TiO2 and ZnO nanoparticle percutaneous absorption.  Skin Pharmacol Physiol. 2009;22(5):266-275.PubMedGoogle ScholarCrossref
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