Review
Benzoyi Peroxide Carcinogenicity and Aiiergenicity Daniel J. Hogan, M.D.
Benzoyi peroxide does not occur naturally. It has been a standard and effective topical treatment of acne for the past 25 years (Eig. 1).'"^ Benzoyi peroxide is available in varying concentrations in a number of different vehicles for topical use. Preparations containing high concentrations of benzoyi peroxide are no more effective in the treatment of acne than those containing 2.55% benzoyi peroxide.^ By an occlusive method of application, benzoyi peroxide is also used to treat cutaneous ulcers.'*' In 1930, benzoyi peroxide powder was advocated as an ideal treatment of poison ivy dermatitis because it was suggested that benzoyi peroxide would oxidize the Rhus antigen; however, this indication fefl out of favor when an explosion due to ignition of a benzoyi peroxide powder dressing by the lighting of a cigarette caused damage to the skin and muscles of a patient's hands.*-' Eortunately, patients do not have to worry about explosions when applying modern topical formulations of benzoyi peroxide! Pure benzoyi peroxide has caused industrial injuries and fatalities due to its flammability and explosiveness.* Benzoyi peroxide is used in a number of industrial processes because it is a good source of free radicals. It is used in the mining industry, in the manufacture of plastics, automobile putty, and roof-bolting systems, as a curing agent for silicon rubber, as a source of free radicals in resin cements used in dentistry, and as a initiator in the synthesis of poly vinyl chloride. It is used to bleach flour, and its use for bleaehing cheeses has also been approved.* In this article, the two adverse effects of benzoyi peroxide that are of greatest concern—its potential carcinogenicity and its allergenieity—are reviewed.
From the Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida. Address correspondence to: Daniel J. Hogan, M.D., Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, P. O. Box 016250, Miami, FL 33101. Juty 1991, Vol. 30, No. 7
Benzoyi Peroxide as a Tumor Promotor Studies of experimental carcinogenesis classify chemicals according to operational terms as tumor initiators, promoters, and progressors.^ Initiators, the primary inducers of tumors, are believed to induce irreversible damage to DNA. Promoters increase the number of initiated cells, but their damage is reversible. Progressors can induce malignancy in benign tumor cells and their damage is irreversible. Extensive experimental studies demonstrate that benzoyi peroxide has signiflcant tumor promoter aetivity in the mouse skin initiator-promoter tumor model, in the cheek pouch epithelium of the hamster, and in Syrian golden hamster skin after oral administration of a carcinogenic dose of 7,12-dimethylbenz(a) anthracene (DMBA).'°-"*''*-^° In contrast to the classic tumor promoter croton oil, which contains 12-O-tetradencanoylphorbol-13-acetate) (TPA), benzoyi peroxide does not act as a tumor promoter after tumor initiation with ultraviolet light.'"" No co-carcinogenic effect of benzoyi peroxide and ultraviolet light has been observed in these animal studies. Only one of the many studies of the earcinogenic effects of benzoyi peroxide after long-term topical administration to the skin of various strains of mice and Syrian golden hamsters has demonstrated a possible complete carcinogenic effect. This study used a relatively small number of mice that appeared to have an unusually high incidence of spontaneous tumors and a high death rate.'" Tumor promotion by croton oil and some other substances has been demonstrated in mice and occasionally in hamsters and rats. Tumor promotion studies have not been reproduced in higher animals.-" Tumor promoters induce mitoses. It appears that it is easier to destabilize the cellular DNA of rodents through mitogenie stimuli than it is to destabilize the cellular DNA of higher animals and especially humans. The possibility of oncogene activation appears to be considerably higher in rodents than in humans. The epider467
468
International Journal of Dermatology • July 1991
Benzoyi Fferoxide Figure 1. Chemical structure of benzoyi peroxide.
mis is three times and the stratum corneum, which protects the skin from cutaneous irritants and chemical agents, is two times thicker in humans than in mice. The target cells for carcinogenesis are closer to the surface and less well protected in mice than in humans. These factors probably account in large part for the high susceptibility of mouse skin to topically applied carcinogens and the readily seen tumor promotion effect. It has been postulated that benzoyi peroxide stimulates malignant progression because its application as a third-stage agent after the classical two-step chemical carcinogenesis protocol in the mouse skin model gives rise to an increased conversion of papillomas to carcinomas.'* Pretreatment of a mouse squamous cell carcinoma cell line tissue culture with benzoyi peroxide increased the capacity of those cells to migrate through a porous filter coated with matigel.^' Epidemioiogic Studies Only one published study has specifically evaluated benzoyi peroxide therapy as a risk factor for skin cancer .^^ This preliminary study of patients with malignant melanoma and eontrols found no evidence that prior use of benzoyi peroxide was a risk factor for cutaneous malignant melanoma. An hypothesis-generating study based on the Los Angeles County Cancer Surveillance Program noted that chemists with malignant melanoma had worked with more organic chemicals and had greater exposure to multiple chemicals, including benzoyi peroxide, than a group of older, less well-educated chemists.^-' The International Agency for Research on Cancer (IARC) ofthe World Health Association has reviewed benzoyi peroxide. Their expert committee found insufficient evidence to elassify the carcinogenicity of benzoyi peroxide.^'* Zbinden feels it would be ludicrous for the use of benzoyi peroxide to be restricted because ofthe observation of tumor promoter activity in rodent skin while the misuse of ultraviolet light in commercial tanning
Vol. 30
salons and during recreational activity is not curtailed.^° There may be, however, a link between acne, its treatments, and skin cancer—particularly basal cell carcinoma.^' Some toxicologists have recommended that the use of benzoyi peroxide for acne be eurtailed.^* We require more definitive epidemiologic studies regarding benzoyi peroxide treatment of acne as a risk factor for skin cancer before disregarding the numerous animal studies of benzoyi peroxide and skin cancer. Ailergic Contact Dermatitis to Benzoyi Peroxide Allergic contact dermatitis to benzoyi peroxide was reported shortly after this medication became widely available for the treatment of acne.^' Researchers from the Procter and Gamble Company and Leyden and Kligman found that benzoyi peroxide was a potent skin sensitizer in repeat insult pateh tests in humans and guinea pigs.^*'^' The most recent study of the allergic and irritant potential of benzoyi peroxide by Haustein et al. found benzoyi peroxide to be a weak allergen and a strong irritant.^" Only 11 ofthe 155 acne patients in their series had clinical signs of intolerance to benzoyi peroxide; 10 of these 11 patients were able to continue using benzoyi peroxide. Positive Patch Test Reactions to Benzoyi Peroxide Various authors have published their results of patch testing patients with various dermatoses and controls to benzoyi peroxide (Table 1). The reported incidence of positive patch test reactions varies from 0% to 75% t,4,5,t5,27,29-36 jj^g highest reported ineidence was in a group of 41 patients with leg ulcers treated with 20% benzoyi peroxide under occlusion.'* A high incidence of positive patch test reactions to benzoyi peroxide would be expected in this group due to the following: (1) benzoyi peroxide is a sensitizer; (2) occlusion increases the risk of sensitization; (3) a high concentration of benzoyi peroxide was apphed; (4) patients with stasis dermatitis appear to be easily sensitized to topical medications; and (5) the multiple sensitivities present in these patients may increase the risk of nonspecific patch test reactions due to the excited skin syndrome.^^ The incidence of positive patch test reactions to benzoyi peroxide does not appear to increase with the duration of benzoyi peroxide use.^" Most patients with positive patch test reactions to benzoyi peroxide were able to continue using this medication."'^"'^* Contact dermatitis has been reported to rarely interfere with benzoyi peroxide treatment of decubitus and other cutaneous ulcers.' Agathos and Bandmann, who noted a 76% in-
No. 7
Benzoyi Peroxide • Hogan
469
Table 1. Frequency of Positive Patch Test Reactions to Benzoyi Peroxide Among Patients Using Benzoyi Peroxide and Controls Positive Reactions (M/F) Author (year) Eaglstein(1968) Jensen (1980)
Diagnosis of Patients
Miscellaneous Leg ulcer treated with 10%BPgel Lindemayr(1981) Miscellaneous Contact dermatitis Acne treated with BP Rietschel(1982) Acne controls BP X 12 wk for acne Haustein (1985) Acne before BP Acne after 8 wk BP Acne on long-term BP Controls Balato (1984) Acne Agathos (1984) Acne Dermatitis Leg ulcer treated with 20% BP lotioti
Vehicle for Patients Patch Tests
No. of 41 16 94 69 59 32 28 100 93 72 100 50 13 739 41
5% BP
Petrolatum Petrolatum
2.4%
Gel
3.1%(3%/4%) 5.8%(ll%/2%) 5%
BP gel in petrolatum
——
Petrolatum
Petrolatum Petrolatum
19%(12%/29%) 34% (28%/43%) 29% (27%/33%) 29% (29%/29%) 0% —
2% BP
1% BP
_ 50%
_ —
— — 19% — 25% — 2% (0%/5%) — 0% — 0% — 0% 0% — 0% 0% — 4.1% — 76%
0..1% BP _
4% 0% 0% 0% 0% —
BP: benzoyi peroxide.
eidence rate of positive patch test reactions to benzoyi peroxide among leg ulcer patients using 20% benzoyi peroxide under occlusion, observed that only 9% of patients had to discontinue benzoyi peroxide because of severe loeal dermatitis.'* The incidence of positive patch test reactions to benzoyi peroxide used in the treatment of acne is of greater interest because the vast majority of patients treated with benzoyi peroxide use it for this reason. The prevalence of positive patch test reactions to benzoyi peroxide is similar or higher in patients with dermatitis than in patients with acne."*'" Cunliffe found that acne patients rarely have allergic contact dermatitis to benzoyi peroxide.' It has been suggested that patients with acne may be resistant to allergic contact dermat i t i s 30,34,36
Dermatitis at one site lowers the threshold of all the skin to reaet to cutaneous irritants.^^ Lindemayr and Drobil noted that patients with initial positive patch test reactions to benzoyi peroxide, which appeared irritant in nature, had negative patch test reaetions when previously inflamed acne lesions had improved." Irritant contact dermatitis, which occurs frequently in acne patients initiating treatment with topical benzoyi peroxide, probably lowers the threshold of reactivity of the skin to patch tests with materials tested near an irritant concentration, such as 5% benzoyi peroxide gel. Most acne patients appear to have "hardening" or accommodation to the irritant effect of topical benzoyi peroxide.'
Case Reports A number of case reports document patients with allergic contact dermatitis to benzoyi peroxide. Cunliffe obtained a positive patch test reaction in one of six benzoyi peroxide-treated acne patients who were patch tested to 0.1 % benzoyi peroxide.' Eour patients had positive patch test reactions to 1 % benzoyi peroxide. Some patients become sensitized to benzoyi peroxide from its use for rosacea and chronic paronychia.^'* Benzoyi peroxide has also been reported to cause allergic contact dermatitis in individuals exposed to benzoyi peroxide transferred to their skin from the skin of others or from inanimate objects.-'^ Patch Test Concentrations The concentrations of benzoyi peroxide used in patch tests range from 0.1 % to 5% benzoyi peroxide in petrolatum. The incidence rate of positive patch test reactions varies from 0% to 34% in acne patients.''^"'^''^* Haustein et al. found that 29% of acne patients and unexposed controls had a positive patch test reaction to 5% benzoyi peroxide in yeflow, soft paraffin.^" Haustein et al. noted that from 19% to 34% ofthe patients with various dermatologic disorders patch tested to 5% benzoyi peroxide had positive patch test reactions. Almost all had negative reactions to 1% benzoyi peroxide. Agathos and Bandmann noted positive patch test reactions in 76% of their leg ulcer patients patch tested to 1% benzoyi peroxide.'* Haustein et al. recommended
470
International Journal of Dermatology • July 1991
that benzoyi peroxide be patch tested at concentrations of 0.15-1% in petrolatum. The majority of previous studies had patch tested patients to 5% benzoyi peroxide in petrolatum or in a gel base. Some patients in previous studies may have had irritant patch test reactions to 5% benzoyi peroxide rather than true positive (allergic) reactions. The most appropriate concentration for patch testing appears to be 1% benzoyi peroxide. This eoneentration minimizes irritant patch test reactions to benzoyi peroxide, particularly in patients with disorders other than leg ulcers. Conclusion An early study indicated that benzoyi peroxide was a potent cutaneous sensitizer. Eurther studies and clinical experience have demonstrated that benzoyi peroxide used to treat acne is a rare sensitizer. Benzoyi peroxide is clearly a tumor promoter in mice. It may stimulate malignant progression of benign tumors and enhance the invasive ability of skin cancers in mice. Additional epidemiologic studies are needed to support the clinical impression that the regular use of benzoyi peroxide is not a risk factor for skin cancer.
References 1. Cunliffe WJ, Burke B. Benzoyi peroxide: Lack of sensitization. Acta Derm Venereol (Stockh). 1982;62:458-459. 2. Mills OH, Kligman AM, Pochi P, et al. Comparing 2.5%, 5%, and 10% benzoyi peroxide on inflammatory acne vulgaris. Int J Dermatol. 1986;25:654-667. 3. Swinyer LJ, Baker MD, Swinyer TA, et al. A comparative study of benzoyi peroxide and clindamycin phosphate for treating acne vulgaris. Br J Dermatol. I988;l 19:615-622. 4. Agathos M, Bandmann HJ. Benzoyl peroxide contact allergy in leg ulcer patients. Contact Dermatitis. 1984;11:316-317. 5. Morley MH. Decutitus ulcer management: A team approach. Canadian Nurse. 1973;69:41-43. 6. Lamson PD. Benzoyi peroxide in the treatment of poison ivy intoxication. JAMA. 1930;95:663. 7. Lamson PD. Benzoyi peroxide: An apology. JAMA. 1931; 97:1225. 8. NIOSH. Criteria for a Recommended Standard. . . Occupational Exposure to Benzoyi Peroxide. Washington, DC: U.S. Department of Health, Education, and Welfare, 1977. 9. Matula TI, Somers E. The classification of chemical carcinogens. Regul Toxicol Pharmacol. 1989;I0:174-182. 10. Epstein DH. Photocarcinogenesis promotion studies with benzoyi peroxide (BPO) and croton oil. J Invest Dermatol. I988;9I:I14-116. 11. Iversen OH. Carcinogenesis studies with benzoyi peroxide (Panoxyl Gel 5%). J Invest Dermatol. 1986;86:442-448. 12. Iversen OH. Skin tumorigenesis and carcinogenesis studies with 7,I2-dimethylbenz[a]anthracene, ultraviolet light, benzoyi peroxide (Panolxyl gel 5%) and ointment gel. Carcinogenesis. 1988;9:803-809. 13. Klein-Szanto AJP, Slaga TJ. Effects of peroxides on rodent skin: Epidermal hyperplasia and tumor promotion. J Invest Dermatol. 1982;79:30-34.
Vol. 30
14. Kurokawa Y, Takamura N, Matsushima Y, et al. Studies on the promoting and complete carcinogenic activities of some oxidizing chemicals in skin carcinogenesis. Cancer Lett. 1984;24:299304. 15. Lindemayr H, Drobil M. Contact sensitization to benzoyi peroxide. Contact Dermatitis. 1981;7:137-140. 16. O'Connell JF, KJein-Szanto AJP, DiGiovanni DM, et al. Enhanced malignant progression of mouse skin tumors by the freeradical generator benzoyi peroxide. Cancer Res. 1986;46:28632865. 17. Odukoya O, Shklar G. Initiation and promotion in experimental oral carcinogenesis. Oral Surg. 1984;58:315-320. 18. Slaga TJ, Klein-Szanto AJP, Triplett LL. Skin tumor-promoting activity of benzoyi peroxide, a widely used free radical-generating compound. Science. 1981;213:1023-1025. 19. VanDuuren BL, Nelson N, Orris L, et al. Carcinogenicity of epoxides, lactones, and peroxy compounds. J Natl Cancer Inst. 1963;31(l):41-55. 20. Zbinden G. Scientific opinion on the carcinogenic risk due to topical administration of benzoyi peroxide for the treatment of acne vulgaris. Pharmacol Toxicol. 1988;63:307-309. 21. Bonfil RD, Momki S, Conti CJ, et al. Benzoyi peroxide enhances the invasive ability of a mouse epidermal carcinoma cell line. Int J Cancer. 1989;44:165-169. 22. Cartwright H, Cunliffe WJ. Malignant melanoma, benzoyi peroxide and acne: A pilot epidemiological case-control investigation. Br J Dermatol. 1988;118:239-242. 23. Wright WE, Peters JM, Mack TM. Organic chemicals and malignant melanoma. Am J Ind Med. 1983;4:577-581. 24. IARC. Monographs on the Evaluation ofthe Carcinogenie Risk of Chemicals to Humans-Allyl Compounds, Aldehydes, Epoxides and Peroxides. Lyon: World Health Organization, International Agency for Research on Cancer, 1985: 267-283. 25. Hogan DJ, To T, Lane PR, et al. Risk factors for basal cell carcinoma. Int J Dermatol. 1989;28:591-594. 26. Jones GRN. Skin cancer: Risk to individuals using the tumour promoter benzoyi peroxide for acne treatment. Human Toxicol. 1985;4:75-78. 27. Eaglstein WH. Allergic contact dermatitis to benzoyi peroxide. Arch Dermatol. 1968;97:527. 28. Leyden JJ, Kligman AM. Contact sensitization to benzoyi peroxide. Contact Dermatitis. 1977;3:273-275. 29. Poole RL, Griffith JF, MacMillan FSK. Experimental contact sensitization with benzoyi peroxide. Arch Dermatol. 1970; 102:635-639. 30. Haustein UF, Tegetmeyer L, Zielger V. Allergic and irritant potential of benzoyi peroxide. Contact Dermatitis. 1985;13:252257. 31. Balato N, Lembo G, Nappa P, et al. Benzoyi peroxide reactions in acne patients. Contact Dermatitis. 1984;10:255. 32. Jensen O, Petersen SH, Vesterager L. Contact sensitization to benzoyi peroxide following topical treatment of chronic leg ulcers. Contact Dermatitis. 1980;6:179-182. 33. Mann RJ, Peachey RDG. Allergen transfer between individuals as a cause of contact dermatitis. Contact Dermatitis. 1987; 17:164-165. 34. Morelli R, Lanzarini M, Vincenzi C, et al. Contact dermatitis due to benzoyi peroxide. Contact Dermatitis. 1989;2O:238. 35. Morillas IM, Martinez AA, Lozano JLS, et al. Is Benzoyi peroxide an irritant or sensitizer? Contact Dermatitis. 1987; 16:232. 36. Rietschel RL, Duncan SH. Benzoyi peroxide reactions in an acne study group. Contact Dermatitis. 1982;8:323-326. 37. Hogan DJ. Widespread dermatitis as a complication ofthe treatment of leg ulcers and stasis dermatitis. Can Med Assoc J. 1988;138:336-338.
Benzoyi Peroxide Carcinogenicity and Aiiergenicity Daniel J. Hogan, M.D.
Benzoyi peroxide does not occur naturally. It has been a standard and effective topical treatment of acne for the past 25 years (Eig. 1).'"^ Benzoyi peroxide is available in varying concentrations in a number of different vehicles for topical use. Preparations containing high concentrations of benzoyi peroxide are no more effective in the treatment of acne than those containing 2.55% benzoyi peroxide.^ By an occlusive method of application, benzoyi peroxide is also used to treat cutaneous ulcers.'*' In 1930, benzoyi peroxide powder was advocated as an ideal treatment of poison ivy dermatitis because it was suggested that benzoyi peroxide would oxidize the Rhus antigen; however, this indication fefl out of favor when an explosion due to ignition of a benzoyi peroxide powder dressing by the lighting of a cigarette caused damage to the skin and muscles of a patient's hands.*-' Eortunately, patients do not have to worry about explosions when applying modern topical formulations of benzoyi peroxide! Pure benzoyi peroxide has caused industrial injuries and fatalities due to its flammability and explosiveness.* Benzoyi peroxide is used in a number of industrial processes because it is a good source of free radicals. It is used in the mining industry, in the manufacture of plastics, automobile putty, and roof-bolting systems, as a curing agent for silicon rubber, as a source of free radicals in resin cements used in dentistry, and as a initiator in the synthesis of poly vinyl chloride. It is used to bleach flour, and its use for bleaehing cheeses has also been approved.* In this article, the two adverse effects of benzoyi peroxide that are of greatest concern—its potential carcinogenicity and its allergenieity—are reviewed.
From the Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, Florida. Address correspondence to: Daniel J. Hogan, M.D., Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, P. O. Box 016250, Miami, FL 33101. Juty 1991, Vol. 30, No. 7
Benzoyi Peroxide as a Tumor Promotor Studies of experimental carcinogenesis classify chemicals according to operational terms as tumor initiators, promoters, and progressors.^ Initiators, the primary inducers of tumors, are believed to induce irreversible damage to DNA. Promoters increase the number of initiated cells, but their damage is reversible. Progressors can induce malignancy in benign tumor cells and their damage is irreversible. Extensive experimental studies demonstrate that benzoyi peroxide has signiflcant tumor promoter aetivity in the mouse skin initiator-promoter tumor model, in the cheek pouch epithelium of the hamster, and in Syrian golden hamster skin after oral administration of a carcinogenic dose of 7,12-dimethylbenz(a) anthracene (DMBA).'°-"*''*-^° In contrast to the classic tumor promoter croton oil, which contains 12-O-tetradencanoylphorbol-13-acetate) (TPA), benzoyi peroxide does not act as a tumor promoter after tumor initiation with ultraviolet light.'"" No co-carcinogenic effect of benzoyi peroxide and ultraviolet light has been observed in these animal studies. Only one of the many studies of the earcinogenic effects of benzoyi peroxide after long-term topical administration to the skin of various strains of mice and Syrian golden hamsters has demonstrated a possible complete carcinogenic effect. This study used a relatively small number of mice that appeared to have an unusually high incidence of spontaneous tumors and a high death rate.'" Tumor promotion by croton oil and some other substances has been demonstrated in mice and occasionally in hamsters and rats. Tumor promotion studies have not been reproduced in higher animals.-" Tumor promoters induce mitoses. It appears that it is easier to destabilize the cellular DNA of rodents through mitogenie stimuli than it is to destabilize the cellular DNA of higher animals and especially humans. The possibility of oncogene activation appears to be considerably higher in rodents than in humans. The epider467
468
International Journal of Dermatology • July 1991
Benzoyi Fferoxide Figure 1. Chemical structure of benzoyi peroxide.
mis is three times and the stratum corneum, which protects the skin from cutaneous irritants and chemical agents, is two times thicker in humans than in mice. The target cells for carcinogenesis are closer to the surface and less well protected in mice than in humans. These factors probably account in large part for the high susceptibility of mouse skin to topically applied carcinogens and the readily seen tumor promotion effect. It has been postulated that benzoyi peroxide stimulates malignant progression because its application as a third-stage agent after the classical two-step chemical carcinogenesis protocol in the mouse skin model gives rise to an increased conversion of papillomas to carcinomas.'* Pretreatment of a mouse squamous cell carcinoma cell line tissue culture with benzoyi peroxide increased the capacity of those cells to migrate through a porous filter coated with matigel.^' Epidemioiogic Studies Only one published study has specifically evaluated benzoyi peroxide therapy as a risk factor for skin cancer .^^ This preliminary study of patients with malignant melanoma and eontrols found no evidence that prior use of benzoyi peroxide was a risk factor for cutaneous malignant melanoma. An hypothesis-generating study based on the Los Angeles County Cancer Surveillance Program noted that chemists with malignant melanoma had worked with more organic chemicals and had greater exposure to multiple chemicals, including benzoyi peroxide, than a group of older, less well-educated chemists.^-' The International Agency for Research on Cancer (IARC) ofthe World Health Association has reviewed benzoyi peroxide. Their expert committee found insufficient evidence to elassify the carcinogenicity of benzoyi peroxide.^'* Zbinden feels it would be ludicrous for the use of benzoyi peroxide to be restricted because ofthe observation of tumor promoter activity in rodent skin while the misuse of ultraviolet light in commercial tanning
Vol. 30
salons and during recreational activity is not curtailed.^° There may be, however, a link between acne, its treatments, and skin cancer—particularly basal cell carcinoma.^' Some toxicologists have recommended that the use of benzoyi peroxide for acne be eurtailed.^* We require more definitive epidemiologic studies regarding benzoyi peroxide treatment of acne as a risk factor for skin cancer before disregarding the numerous animal studies of benzoyi peroxide and skin cancer. Ailergic Contact Dermatitis to Benzoyi Peroxide Allergic contact dermatitis to benzoyi peroxide was reported shortly after this medication became widely available for the treatment of acne.^' Researchers from the Procter and Gamble Company and Leyden and Kligman found that benzoyi peroxide was a potent skin sensitizer in repeat insult pateh tests in humans and guinea pigs.^*'^' The most recent study of the allergic and irritant potential of benzoyi peroxide by Haustein et al. found benzoyi peroxide to be a weak allergen and a strong irritant.^" Only 11 ofthe 155 acne patients in their series had clinical signs of intolerance to benzoyi peroxide; 10 of these 11 patients were able to continue using benzoyi peroxide. Positive Patch Test Reactions to Benzoyi Peroxide Various authors have published their results of patch testing patients with various dermatoses and controls to benzoyi peroxide (Table 1). The reported incidence of positive patch test reactions varies from 0% to 75% t,4,5,t5,27,29-36 jj^g highest reported ineidence was in a group of 41 patients with leg ulcers treated with 20% benzoyi peroxide under occlusion.'* A high incidence of positive patch test reactions to benzoyi peroxide would be expected in this group due to the following: (1) benzoyi peroxide is a sensitizer; (2) occlusion increases the risk of sensitization; (3) a high concentration of benzoyi peroxide was apphed; (4) patients with stasis dermatitis appear to be easily sensitized to topical medications; and (5) the multiple sensitivities present in these patients may increase the risk of nonspecific patch test reactions due to the excited skin syndrome.^^ The incidence of positive patch test reactions to benzoyi peroxide does not appear to increase with the duration of benzoyi peroxide use.^" Most patients with positive patch test reactions to benzoyi peroxide were able to continue using this medication."'^"'^* Contact dermatitis has been reported to rarely interfere with benzoyi peroxide treatment of decubitus and other cutaneous ulcers.' Agathos and Bandmann, who noted a 76% in-
No. 7
Benzoyi Peroxide • Hogan
469
Table 1. Frequency of Positive Patch Test Reactions to Benzoyi Peroxide Among Patients Using Benzoyi Peroxide and Controls Positive Reactions (M/F) Author (year) Eaglstein(1968) Jensen (1980)
Diagnosis of Patients
Miscellaneous Leg ulcer treated with 10%BPgel Lindemayr(1981) Miscellaneous Contact dermatitis Acne treated with BP Rietschel(1982) Acne controls BP X 12 wk for acne Haustein (1985) Acne before BP Acne after 8 wk BP Acne on long-term BP Controls Balato (1984) Acne Agathos (1984) Acne Dermatitis Leg ulcer treated with 20% BP lotioti
Vehicle for Patients Patch Tests
No. of 41 16 94 69 59 32 28 100 93 72 100 50 13 739 41
5% BP
Petrolatum Petrolatum
2.4%
Gel
3.1%(3%/4%) 5.8%(ll%/2%) 5%
BP gel in petrolatum
——
Petrolatum
Petrolatum Petrolatum
19%(12%/29%) 34% (28%/43%) 29% (27%/33%) 29% (29%/29%) 0% —
2% BP
1% BP
_ 50%
_ —
— — 19% — 25% — 2% (0%/5%) — 0% — 0% — 0% 0% — 0% 0% — 4.1% — 76%
0..1% BP _
4% 0% 0% 0% 0% —
BP: benzoyi peroxide.
eidence rate of positive patch test reactions to benzoyi peroxide among leg ulcer patients using 20% benzoyi peroxide under occlusion, observed that only 9% of patients had to discontinue benzoyi peroxide because of severe loeal dermatitis.'* The incidence of positive patch test reactions to benzoyi peroxide used in the treatment of acne is of greater interest because the vast majority of patients treated with benzoyi peroxide use it for this reason. The prevalence of positive patch test reactions to benzoyi peroxide is similar or higher in patients with dermatitis than in patients with acne."*'" Cunliffe found that acne patients rarely have allergic contact dermatitis to benzoyi peroxide.' It has been suggested that patients with acne may be resistant to allergic contact dermat i t i s 30,34,36
Dermatitis at one site lowers the threshold of all the skin to reaet to cutaneous irritants.^^ Lindemayr and Drobil noted that patients with initial positive patch test reactions to benzoyi peroxide, which appeared irritant in nature, had negative patch test reaetions when previously inflamed acne lesions had improved." Irritant contact dermatitis, which occurs frequently in acne patients initiating treatment with topical benzoyi peroxide, probably lowers the threshold of reactivity of the skin to patch tests with materials tested near an irritant concentration, such as 5% benzoyi peroxide gel. Most acne patients appear to have "hardening" or accommodation to the irritant effect of topical benzoyi peroxide.'
Case Reports A number of case reports document patients with allergic contact dermatitis to benzoyi peroxide. Cunliffe obtained a positive patch test reaction in one of six benzoyi peroxide-treated acne patients who were patch tested to 0.1 % benzoyi peroxide.' Eour patients had positive patch test reactions to 1 % benzoyi peroxide. Some patients become sensitized to benzoyi peroxide from its use for rosacea and chronic paronychia.^'* Benzoyi peroxide has also been reported to cause allergic contact dermatitis in individuals exposed to benzoyi peroxide transferred to their skin from the skin of others or from inanimate objects.-'^ Patch Test Concentrations The concentrations of benzoyi peroxide used in patch tests range from 0.1 % to 5% benzoyi peroxide in petrolatum. The incidence rate of positive patch test reactions varies from 0% to 34% in acne patients.''^"'^''^* Haustein et al. found that 29% of acne patients and unexposed controls had a positive patch test reaction to 5% benzoyi peroxide in yeflow, soft paraffin.^" Haustein et al. noted that from 19% to 34% ofthe patients with various dermatologic disorders patch tested to 5% benzoyi peroxide had positive patch test reactions. Almost all had negative reactions to 1% benzoyi peroxide. Agathos and Bandmann noted positive patch test reactions in 76% of their leg ulcer patients patch tested to 1% benzoyi peroxide.'* Haustein et al. recommended
470
International Journal of Dermatology • July 1991
that benzoyi peroxide be patch tested at concentrations of 0.15-1% in petrolatum. The majority of previous studies had patch tested patients to 5% benzoyi peroxide in petrolatum or in a gel base. Some patients in previous studies may have had irritant patch test reactions to 5% benzoyi peroxide rather than true positive (allergic) reactions. The most appropriate concentration for patch testing appears to be 1% benzoyi peroxide. This eoneentration minimizes irritant patch test reactions to benzoyi peroxide, particularly in patients with disorders other than leg ulcers. Conclusion An early study indicated that benzoyi peroxide was a potent cutaneous sensitizer. Eurther studies and clinical experience have demonstrated that benzoyi peroxide used to treat acne is a rare sensitizer. Benzoyi peroxide is clearly a tumor promoter in mice. It may stimulate malignant progression of benign tumors and enhance the invasive ability of skin cancers in mice. Additional epidemiologic studies are needed to support the clinical impression that the regular use of benzoyi peroxide is not a risk factor for skin cancer.
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