Topical retinoids, compounds that are metabolites, analogues, or derivatives of retinol and possess biological vitamin A activity, are among the most used adjunctive agents for the mitigation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of photodamaged and chronically aged skin. Retinoic acid (RA) is the most active biological form of vitamin A and remains the medical treatment of choice for photoaged skin. Retinyl palmitate (RP) is the major storage form of vitamin A in the skin and, because RP is also the most stable of available vitamin A esters, it is readily incorporated into the oil phase of cosmetic creams or lotions. Therefore, the topical application of RP is a practical strategy for increasing the levels of vitamin A in the skin. Usual cosmetic product concentrations of RA range from 0.025% to 0.1% and those of RP range from 0.1% to 5%.
With a maximum absorbance around 325 nm, RA and RP absorb both ultraviolet A and B radiation (UVA and UVB) in incident sunlight. A 1-year study was conducted in mice to determine whether RA and RP would alter the photocarcinogenicity of broad-UV spectrum light generated by xenon arc lamps, termed simulated solar light (SSL), or narrow spectrum UV light generated by UVA and UVB lamps.
One-year study
Groups of 36 male and 36 female Crl:SKH-1 (hr–/hr–) hairless mice were irradiated 5 days per week (Monday through Friday) in the morning for 40 weeks with SSL at levels of 0.00, 6.85, or 13.70 mJ•CIE/cm2 that were emitted from glass-filtered 6.5 kW xenon arc lamps. The mice received topical applications of control cream or creams containing 0.001% (w/w) RA or 0.1%, 0.5%, 1.0%, or 2.0% RP to the dorsal skin region in the afternoon of the same days of irradiance exposures. Separate groups of 36 female Crl:SKH-1 (hr–/hr–) hairless mice were irradiated with UV light emitted from fluorescent UVA or UVB lamps at a single level that was equivalent to the amount of UVA or UVB generated by SSL at a level of 13.70 mJ•CIE/cm2 SSL and received topical application of control cream or creams containing 1.0% RP or 0.001% RA. A 12-week observation period followed the 40-week treatment/exposure period. Additional groups of 36 male and 36 female mice received no cream and were exposed to 0.00, 6.85, 13.70, or 20.55 mJ•CIE/cm2 SSL or to a single level of either UVA or UVB light (females only), equivalent to the amount of UVA or UVB generated by SSL at a level of 13.70 mJ•CIE/cm2.
Mice that received no cream treatment and were exposed to increasing levels of SSL showed significant SSL exposure-dependent decreases in survival, earlier in-life onset of skin lesions, and significant SSL exposure-dependent increases in the incidences and multiplicities of in-life skin lesions, as well as in the incidences and multiplicities of histopathology determined squamous cell nonneoplastic skin lesions (hyperplasia and focal atypical hyperplasia) and neoplastic skin lesions (papilloma, carcinoma in situ, and/or carcinoma). Female mice that received no cream treatment and were exposed to UVA showed significant increases in survival, later onset of in-life skin lesions, and significantly decreased incidences and multiplicities of in-life skin lesions when compared to female mice that received SSL at a level of 13.70 mJ•CIE/cm2. Female mice that received no cream treatment and were exposed to UVB demonstrated significant decreases in survival and significant increases in the multiplicities of in-life skin lesions when compared to female mice that received SSL at a level of 13.70 mJ•CIE/cm2.
The control cream was composed of a base cream (85%, w/w) and diisopropyl adipate (15%, w/w). The control cream was formulated specifically to blend with the RA and RP test articles; although the ingredients listed as components of the control cream were found as common ingredients in many, if not most, cosmetic creams or lotions. Diisopropyl adipate, another ingredient common to a variety cosmetic and skin care products, was used as a carrier for the RA and RP in order to incorporate them into the control cream. The topical treatment of mice with the control cream imparted significant effects when compared with comparable measurements in mice that received no cream treatment and were exposed to the same level of SSL. Specifically, the exposure of mice to control cream resulted in decreased survival rates, earlier times to the onset of skin lesions, and increased incidences and multiplicities of in-life skin lesions and squamous cell neoplasms in both the absence and presence of SSL exposure and increased incidences and multiplicities of in-life skin lesions in female mice exposed to UVA.
The application of RA (0.001%, w/w) creams to mice significantly decreased survival, even in the absence of SSL exposure in male mice, when compared to mice that received the control cream and the same level of SSL. Significantly earlier in-life skin lesion onset and significantly increased multiplicities of skin lesions were observed at each SSL level, including 0.00 mJ•CIE/cm2, in male mice and in female mice exposed to 6.85 mJ•CIE/cm2 SSL, UVA, or UVB. No histopathology was conducted on the RA cream treated mice.
Significant dose trend effects and earlier in-life skin lesion onsets were observed in mice that received the RP cream treatments in the presence of SSL, UVA, or UVB compared with mice that received control cream treatment and the same level of irradiation. In mice exposed to SSL, there were significantly increased multiplicities of in-life skin lesions at RP doses of 0.1% to 1.0%. Significant dose-related trends were observed in the incidences of squamous cell carcinoma and/or squamous cell carcinoma in situ in female mice exposed to 6.85 mJ•CIE/cm2 SSL. Significant RP dose-related increases were also observed in the multiplicities of squamous cell papilloma and in the combination of all squamous cell neoplasms.
Conclusions
These experiments investigated the effect of topical applications of creams containing RA or RP on the photocarcinogenic activity of SSL in male and female SKH-1 hairless mice. Skin lesions were assessed during the in-life phase and/or by histopathologic evaluation at necropsy.
Control cream
Under the conditions of these studies, the topical treatment of SKH-1 mice with the control cream resulted in earlier onsets of in-life skin lesions and higher incidences and multiplicities of in-life skin lesions, when compared to untreated controls, in the absence and presence of SSL.
The topical treatment of SKH-1 mice with control cream resulted in higher incidences and multiplicities of squamous cell neoplasms of the skin when compared to untreated controls in the absence and presence of SSL.
Retinoic acid
Compared to the control cream, RA further enhanced the effects of SSL in SKH-1 mice based upon earlier onsets and increased multiplicities of in-life skin lesions.
Retinyl palmitate
Compared to the control cream, RP enhanced the photocarcinogenicity activity of SSL and UVB in SKH-1 mice based upon earlier onsets and increased multiplicities of in-life skin lesions and increased incidences and multiplicities of squamous cell neoplasms.
Compared to the control cream, RP further enhanced the photocarcinogenic activity of SSL in SKH-1 mice based upon increased incidences and multiplicities of squamous cell neoplasms of the skin.