Zinc oxide, part 2

Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.

Zinc oxide (ZnO) and titanium dioxide (TiO₂) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.

Elevated risk

Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).

In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).

Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).

In a 2010 in vitro study of the toxicity of ZnO and TiO₂ on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO₂, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO₂ exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO₂ nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO₂. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO₂ nanoparticles poses a possible health risk (Small 2010;6:1908-17).

In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).

Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).

In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).

Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).

Weight of evidence

However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO₂ do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).

In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO₂-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO₂ nanoparticles and two commercially available formulations containing TiO₂ alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO₂ nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO₂ nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).

According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO₂ nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).

Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO₂ in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).

In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO₂ nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).

Conclusion

Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.

Zinc oxide (ZnO) and titanium dioxide (TiO₂) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.

Elevated risk

Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).

In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).

Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).

In a 2010 in vitro study of the toxicity of ZnO and TiO₂ on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO₂, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO₂ exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO₂ nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO₂. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO₂ nanoparticles poses a possible health risk (Small 2010;6:1908-17).

In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).

Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).

In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).

Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).

Weight of evidence

However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO₂ do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).

In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO₂-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO₂ nanoparticles and two commercially available formulations containing TiO₂ alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO₂ nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO₂ nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).

According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO₂ nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).

Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO₂ in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).

In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO₂ nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).

Conclusion

Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.

Nanotechnology, which applies gathered knowledge on the characteristics of matter to design new products on the nanoscale (<1,000 nm), emerged in the 1980s and has made great strides since then. Dermatology is a prime area of interest for nanotech applications, as numerous products using nanotechnology have been marketed. In fact, the sixth-largest U.S. patent holder in nanotechnology is a cosmetics company (Skin Therapy Lett. 2010;15:1-4). The newest generation of skin products is characterized by improved skin penetration (Arch. Dermatol. Res. 2011;303:533-50), and these products may have a role in enhancing the treatment of several skin disorders; however, toxicological studies must establish the safety of formulations increasingly likely to penetrate multiple skin layers.

Zinc oxide (ZnO) and titanium dioxide (TiO₂) are two of the most prominent ingredients in the dermatologic armamentarium that are used in micro- and nanoparticle forms. Efficacy has been well established for these ingredients as inorganic sunscreens, but their relative safety has been debated and remains somewhat controversial. This column discusses findings regarding the safety of ZnO nanoparticles.

Elevated risk

Absorption and effects of zinc ions. In a small study (n = 20) in humans conducted in 2010, Gulson et al. found that small amounts of zinc from ZnO in sunscreens applied for five consecutive days outdoors were absorbed in the skin, with levels of the stable isotope tracer (68)Zn in blood and urine from females receiving the nano sunscreen higher than in males receiving the same sunscreen and higher than in all participants who received the bulk sunscreen (Toxicol. Sci. 2010;118:140-9).

In 2010, Martorano et al. examined the separation of zinc ions from ZnO in commercial sunscreens under UVB exposure and studied the effects of zinc ion accumulation in human epidermal keratinocytes. They noted that UVB light exposure led to a significant concentration-dependent and radiation intensity–dependent rise in zinc ion levels. In turn, a late- or delayed-type cytotoxicity in human epidermal keratinocytes was observed, as was the induction of reactive oxygen species (ROS) in the keratinocytes. The investigators concluded that UVB exposure leads to an elevation in zinc ion dissociation in ZnO sunscreen, yielding cytotoxic effects and oxidative stress (J. Cosmet. Dermatol. 2010;9:276-86).

Genotoxic potential. As Wang and Tooley aptly noted, the concerns regarding the safety of nanoparticles in sunscreens pertain to potential toxicity and capacity to penetrate the skin (Sem. Cutan. Med. Surg. 2011;30:210-13).

In a 2010 in vitro study of the toxicity of ZnO and TiO₂ on keratinocytes over short- and long-term application periods, Kocbek et al. found that ZnO nanoparticles conferred more adverse effects than TiO₂, with ZnO inhibiting cell viability above 15 mcg/mL after brief exposure while TiO₂ exerted no effect up to 100 mcg/mL. Prolonged exposure to ZnO nanoparticles at 10 mcg/mL yielded diminished mitochondrial activity as well as changes in cell morphology and cell-cycle distribution; no such changes were associated with TiO₂ nanoparticles. The researchers also reported more nanotubular intercellular structures in keratinocytes exposed to either nanoparticle type as compared to unexposed cells and nanoparticles present in vesicles within the cell cytoplasm. Finally, they observed that partially soluble ZnO spurred the synthesis of ROS, as opposed to insoluble TiO₂. They concluded that their findings of an adverse effect on human keratinocytes suggest that long-term exposure to ZnO and TiO₂ nanoparticles poses a possible health risk (Small 2010;6:1908-17).

In early 2011, Sharma et al. studied the cytotoxic and genotoxic potential of ZnO nanoparticles in the human liver carcinoma cell line HepG2, given what they argued was the pervasiveness of ZnO in consumer products and industrial applications and the concomitant likelihood of transmission to the liver. Their various assays revealed a significant concentration- and time-dependent toxicity after 12 and 24 hours at 14 and 20 mcg/mL, as well as a significant surge in DNA damage in cells exposed to ZnO nanoparticles for 6 hours (J. Biomed. Nanotechnol. 2011;7:98-9).

Previously, in 2009, Sharma et al. had investigated the potential genotoxicity of ZnO nanoparticles in the human epidermal cell line A431. They found concentration- and time-dependent decreases in cell viability as well as DNA damage potential, as revealed by Comet assay results. In addition, oxidative stress was provoked by ZnO nanoparticles, as evidenced by significant reductions in glutathione, catalase, and superoxide dismutase. The investigators urged caution related to dermatologic formulations containing ZnO nanoparticles, suggesting that their findings indicate a genotoxic potential in human epidermal cells, possibly mediated via lipid peroxidation and oxidative stress (Toxicol. Lett. 2009;185:211-8).

In May 2011, Sharma et al. investigated the biological interactions of ZnO nanoparticles in human epidermal keratinocytes, where electron microscopy showed the internalization of the nanoparticles after 6 hours of exposure at a concentration of 14 mcg/mL. Various assays revealed a time- and concentration-dependent suppression of mitochondrial activity as well as DNA damage in cells, compared with controls. The investigators concluded that ZnO nanoparticles are internalized by human epidermal keratinocytes and provoke a cytotoxic and genotoxic response, providing reason for caution when using consumer products containing nanoparticles. Specifically, they warned that any disruptions in the stratum corneum (SC) could allow the exposure of internal cells to nanoparticles (J. Nanosci. Nanotechnol. 2011;11:3782-8).

Also, in a recent study of the interactions of ZnO nanoparticles with the tumor suppressor p53, Ng et al. found that the p53 pathway was activated in BJ cells (skin fibroblasts) upon treatment with ZnO nanoparticles, leading to a reduction in cell numbers. One implication of this response, the researchers concluded, was that in cells lacking robust p53, the protective response can be turned toward carcinogenesis due to exposure to DNA damage–inducing agents like ZnO nanoparticles (Biomaterials 2011;32:8218-25).

Weight of evidence

However, several researchers contend that current data strongly suggest that nanosized ZnO and TiO₂ do not, in fact, pose such risks (Photodermatol. Photoimmunol. Photomed. 2011;27:58-67; Int. J. Dermatol. 2011;50:247-54; Sem. Cutan. Med. Surg. 2011;30:210-13).

In 2009, in response to increasing concerns about the potential adverse effects of ZnO- and TiO₂-coated nanoparticles used in physical sunblocks, Filipe et al. evaluated the localization and possible skin penetration of these nanoparticles in three sunscreen formulations under realistic in vivo conditions in normal and altered skin. They tested a hydrophobic formulation containing coated 20-nm TiO₂ nanoparticles and two commercially available formulations containing TiO₂ alone or in combination with ZnO. The goal was to assess how consumers actually use sunscreens in comparison to the recommended standard condition for the sun protection factor test. Traces of the physical blockers could only be detected at the skin surface and uppermost area of the SC in normal human skin after a 2-hour exposure. No ZnO or TiO₂ nanoparticles could be detected in layers deeper than the SC after 48 hours of exposure. The investigators concluded that significant penetration by ZnO or TiO₂ nanoparticles into keratinocytes is unlikely (Skin Pharmacol. Physiol. 2009;22:266-75).

According to a safety review by Schilling et al., the current evidence implies that there are minimal risks to human health posed from the use of ZnO or TiO₂ nanoparticles at concentrations of up to 25% in cosmetic preparations or sunscreens, regardless of coatings or crystalline structure. The researchers observed that these nanoparticles incorporated in topical products occur as aggregates of primary particles 30-150 nm in size that bond in a way that leaves them impervious to the force of product application. Consequently, their structure is unaffected, and no primary particles are released (Photochem. Photobiol. Sci. 2010;9:495-509).

Newman et al. reviewed studies and position statements from 1980 to 2008 in order to characterize the safety, use, and regulatory conditions related to nanosized ZnO and TiO₂ in sunscreens. They reported that, while no data suggested significant penetration of the particles beyond the SC, there is a need for additional studies simulating real-world conditions, especially related to UV exposure and sunburned skin (J. Am. Acad. Dermatol. 2009;61:685-92).

In 2011, Monteiro-Riviere et al. performed in vitro and in vivo studies in which pigs received moderate sunburn from UVB exposure. The researchers found that UVB-damaged skin slightly mediated ZnO or TiO₂ nanoparticle penetration in multiple tested sunscreen formulations, but they observed no transdermal absorption (Toxicol. Sci. 2011;123:264-80).

Conclusion

Zinc oxide has long been used as one of the two primary inorganic physical sunscreens. Its use in nanoparticle form has appeared effective, but the different physicochemical qualities of the metal oxide in nanosized form have prompted questions regarding safety. Current data suggest minimal risk to intact skin, but additional studies are needed.

Dr. Baumann is chief executive officer of the Baumann Cosmetic & Research Institute in Miami Beach. She founded the cosmetic dermatology center at the University of Miami in 1997. Dr. Baumann wrote the textbook "Cosmetic Dermatology: Principles and Practice" (McGraw-Hill, April 2002), and a book for consumers, "The Skin Type Solution" (Bantam, 2006). She has contributed to the Cosmeceutical Critique column in Skin & Allergy News since January 2001 and joined the editorial advisory board in 2004. Dr. Baumann has received funding for clinical grants from Allergan, Aveeno, Avon Products, Galderma, Mary Kay, Medicis Pharmaceuticals, Neutrogena, Philosophy, Stiefel, Topix Pharmaceuticals, and Unilever.