title: Photocarcinogenesis study of glycolic acid and salicylic acid (CAS Nos. 79-14-1 and 69-72-7) in SKH-1 mice (simulated solar light and topical application study).
abstract: Acidic solutions have been used for decades to treat a variety of skin conditions. Many of these solutions consist of organic acids with a hydroxy group on a carbon adjacent to the carbonyl carbon and are referred to as alpha-hydroxy acids (AHA). Organic acids with hydroxy groups on the second carbon from the carbonyl carbon are referred to as beta-hydroxy acids (BHA). Both AHA and BHA are used to treat various skin conditions. One of the most widely used AHA is glycolic acid, while salicylic acid is a commonly used BHA. Chemical peels containing 20% to 70% glycolic acid have been used by dermatologists to treat ichthyosis, acne, xerosis, actinic keratosis, seborrheic keratoses, warts, and psoriasis. AHA have recently been used to treat photoaged skin and are now included in many commercially available cosmetic skin treatments. When used in a formulation for a chemical peel, topical treatment of skin with AHA and BHA can result in removal of the stratum corneum, alteration of the skin's histology, and increased cell proliferation in the basal layer of the epidermis. Since AHA and BHA are used to correct photoaged skin, and since exposure to sunlight of skin treated with AHA or BHA is likely, studies were designed to determine the effects of topical application of creams containing AHA (0%, 4%, or 10% glycolic acid, pH 3.5) or BHA (0%, 2%, or 4% salicylic acid, pH 4.0) on the photocarcinogenesis of simulated solar radiation using a filtered 6.5 kW xenon arc light source [simulated solar light (SSL)]. Male and female Crl:SKH-1 (hr-/hr-) hairless mice were exposed to glycolic acid or salicylic acid alone or in combination with SSL for 40 weeks, and the mice were followed for an additional 12 weeks. 1-YEAR STUDY IN MICE: Groups of 36 male and 36 female mice were exposed to 0.0, 0.3, 0.6, or 0.9 minimal erythema dose (MED) of SSL during the afternoon (1200 to 1600 hours) 5 days per week for 40 weeks. Groups of 18 male and 18 female mice were treated in the morning (0800 to 1100 hours) with 2 mg/cm2 control cream, 4% glycolic acid cream, 10% glycolic acid cream, 2% salicylic acid cream, or 4% salicylic acid cream on the dorsal skin, and in the afternoon (1200 to 1600 hours) with 0.3 MED of SSL 5 days per week for 40 weeks. Additional groups of 18 male and 18 female mice were treated in the morning (0800 to 1100 hours) with 2 mg/cm2 control cream, 4% glycolic acid cream, 10% glycolic acid cream, 2% salicylic acid cream, or 4% salicylic acid cream on the dorsal skin, and in the afternoon (1200 to 1600 hours) with 0.6 MED of SSL 5 days per week for 40 weeks. All mice were held an additional 12 weeks following the end of treatment. There were no effects of SSL exposure or topical treatment on the body weights of the mice. Increasing doses of SSL resulted in an SSL-dose trend in survival, with the greatest dose of SSL causing the earliest removal. This effect was present in both the untreated and control cream treated mice. The only consistent effect of glycolic acid on survival was a dose-dependent increase in survival of females at 0.3 MED SSL. Survival was increased in mice exposed to 0.6 MED of SSL and treated with 2% and 4% salicylic acid compared to mice treated with 0.6 MED and treated only with the vehicle. This effect was not observed in the mice treated with 0.0 and 0.3 MED of SSL and salicylic acid compared to the control groups. The mean or median time to first skin tumor of at least 1 mm decreased with increasing SSL exposure concentration in mice that were not treated with cream. Addition of the control cream resulted in a decrease in the time to tumor at 0.3 and 0.6 MED of SSL in male and female mice. The addition of glycolic acid (4% or 10%) did not affect the time to tumor in male or female mice at either SSL dose when compared to mice receiving the control cream. When compared to mice receiving control cream, the inclusion of 4% salicylic acid in the cream increased the time to tumor for male mice receiving 0.3 or 0.6 MED of SSL and female mice receiving 0.3 MED of SSL. The results indicate that inclusion of glycolic acid in the topical cream had no effect on the time required to induce tumors by SSL; however, inclusion of salicylic acid at 4% in the cream was photoprotective, increasing the time required to achieve median tumor incidence at a corresponding dose of SSL and control cream. The skin tumors induced by SSL in mice were squamous cell papilloma, carcinoma in situ, and squamous cell carcinoma. Except for papilloma in male mice, the tumors were induced in a dose-dependent manner by SSL in male and female mice. In male and female mice treated with control cream, the exposure to SSL caused significant increases in the incidences of carcinoma in situ, squamous cell carcinoma, and the combined incidence of carcinoma in situ and squamous cell carcinoma. When male or female mice were exposed to 0.3 or 0.6 MED SSL, the inclusion of 4% or 10% glycolic acid did not affect the induction of skin neoplasms over the incidence detected when the control cream was used, with the single exception of a glycolic acid dose-trend in squamous cell carcinoma incidence in male mice receiving 0.3 MED SSL. The inclusion of salicylic acid in the cream that was topically applied to female mice did not affect squamous cell papilloma formation at either SSL dose. The incidence of carcinoma in situ was decreased in male and female mice at 0.3 MED SSL when treated with 4% salicylic acid. A salicylic acid dose-trend was also observed in both sexes at 0.3 MED SSL.
  
  
  CONCLUSIONS
  These experiments investigated the impact of topical application of a cosmetic formulation containing 4% or 10% glycolic acid (pH 3.5) or 2% or 4% salicylic acid (pH 4) on the photocarcinogenesis of filtered 6.5 kW xenon arc simulated solar light (SSL) in SKH-1 hairless mice. Taking into consideration the survival data, time to tumor data, and the pathology results, glycolic acid did not alter the photocarcinogenesis of SSL, and salicylic acid was photoprotective, reducing the carcinogenicity of 0.3 MED SSL.
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D015197:Carcinogenicity Tests; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006016:Glycolates / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D010212:Papilloma / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D020156:Salicylic Acid / Q000008:administration & dosage / Q000633:toxicity*; D012867:Skin / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000139:chemically induced / Q000209:etiology / Q000473:pathology; D013472:Sunlight / Q000009:adverse effects*; D014466:Ultraviolet Rays
chemical_list: D006016:Glycolates; C031149:glycolic acid; D020156:Salicylic Acid