408 S. S. Bleehen experiences of the author are given in using various skin bleaching creams in the treat- ment of various disorders of pigmentation in man. HISTORICAL BACKGROUND--THE SEARCH FOR AN EFFECTIVE DEPIGMENTING PREPARATION In 1936 Octtel (1) noted that when hydroquinone was fed to black haired cats, their coats turned grey after about 6-8 weeks. Subsequently, in 1940, Oliver, Schwartz and Warren (2) reported a number of cases of depigmentation of the skin occurring among Negro workers in a tannery. This occupational leucoderma was due to an antioxidant, the monobenzyl ether of hydroquinone, which was present in the rubber gloves which these workers wore. The compound was later used in varying concentrations in creams for the treatment of melanin hyperpigmentation (3). It soon was apparent that it was variable in its depigmenting effect and frequently irritated the skin (4). Even more alarming were the frequent reports of confetti-like areas of &pigmentation occurring in the treated areas of skin as well as vitiligo-like areas occurring at distant sites which often spread, even after therapy was discontinued. These therapeutic cosmetic disa.sters are still common and in recent years, there has been an epidemic of monobenzone leuco- melanoderma in South Africa affecting perhaps over a thousand cases (5, 6). In addition to the known depigmenting agents--hydroquinone and the monobenzyl ether of hydro- quinone, the monomethyl ether of hydroquinone (7) and the monoethyl ether of hydro- quinone (8) were found by Brun to be effective depigmenting agents when applied to the pigmented nipples of guinea-pigs. Studies by Chavin and Schlesinger (9, 10) showed a number of groups of chemical compounds, when injected into black goldfish, had a selective destructive effect on the pigment cells. These workers found several mercaptoamines were potent depigmenting compounds. Two of these, 2-mercaptoethylamine hydrochloride (MEA) and N(2- mercaptoethyl)-dimethylamine hydrochloride (MEDA) were potent depigmenting agents when applied to the skin of black guinea-pigs (11). Both MEA and MEDA, however, are very malodorous and therefore could not be used clinically in man. Other compounds discovered by Chavin and Schlesinger to produce &pigmentation in black goldfish were later tested on black guinea-pigs and of these, 4-isopropylcatechol (4-IPC) was found to be the most potent (12). This compound was more effective than known depigmenting compounds, e.g. hydroquinone and the monobenzyl and monomethyl ethers of hydro- quinone. Outbreaks of occupational leucoderma have been reported in Russia by Chumakov, Babanov and Stairnov (13), in Japan by Okumuru and Shirai (14), in Holland by Malten et al. (15), in the United States by Kahn (16) and in the UK by Calnan and Cooke (17) among workers in contact with p-tertiary butyl phenol and with p-tertiary butyl catechol (18). However, these substituted phenols cannot be used in the treatment of hyper- melanosis in man since, like the monobenzyl ether of hydroquinone, they frequently produce a permanent leucoderma which extends from sites of application to distant areas and also because they often irritate the skin and produce sensitisation. 4-isopropyl- catechol has been used in the treatment of hypermelanosis in man (19) but though it is a potent depigmenting agent, it is irritant to the skin and should be used with caution. Recently, Kligman and Willis (20) have described a new formula for depigmenting human skin using 0'1•o tretinoin, 5•o hydroquinone and 0'1•o dexamethasone as a lotion or cream. These workers found it to be effective in the depigmenting of normal

Skin bleaching preparations 409 negro skin as well as in the treatment of various disorders of pigmentation. This formu- lation of hydroquinone was more potent than standard preparations. SCREENING COMPOUNDS FOR THEIR DEPIGMENTING EFFECT Of animal models, the guinea-pig has been found to be most useful for screening topically applied chemical compounds for their depigmenting effect (11, 12, 21). Creams contain- ing concentrations of 1 to 10K of various test chemicals have been applied to the epilated skin of pure black guinea-pigs for five days each week for periods of one month and their depigmenting potency assessed and compared with control areas treated with the cream base only (12). The assessment has been made visually, but also can be measured using a reflectance spectrophotometer. Of compounds tested using this bioassay method, Bleehen et al. (12) found that 4- isopropylcatechol was the most potent. However, when used in concentrations of 3• or more it was irritant to the skin and, like other substituted phenols, it was a sensitizer. So far, no depigmenting compound has been discovered which is reliable, effective and completely safe. All the compounds potent in producing cutaneous depigmentation have certain drawbacks, particularly their irritant effect on the skin. Other animals with black skins such as pigs have been used to screen compounds but the ultimate test for these compounds is their effect on man. The variation in the response to different species of animals to a drug is often considerable and what may be a potent depigmenting compound for guinea-pigs may not be for man. MODES OF ACTION OF DEPIGMENTING COMPOUNDS Exogenous compounds can interfere with the biological processes involved in the pro- duction and transfer of pigment granules. The possible modes of action are :- The compounds may selectively destroy the melanocytes. They may inhibit the formation of melanosomes and alter their structure. Inhibit the biosynthesis of tyrosinase. Inhibit the formation of melanin. They could interfere with the transfer of melanosomes. They could have a chemical effect on melanin or enhance the degradation of melano- somes in keratinocytes. Recent experimental studies have shown that a number of substituted phenols both in vivo (12, 21, 22) and in vitro (23, 24) have a specific melanocytotoxic effect. Hydro- quinone produces similar toxic effects on functional melanocytes affecting not only the formation, melanization and degradation of melanosomes, but also producing disrup- tion of membraneous cytoplasmic organelles (25). Studies on the melanocytotoxic action of the monomethyl ether of hydroquinone and on 4-isopropylcatechol have shown that both compounds have dose dependent lethal effects on cultures of normal guinea-pig melanocytes as shown by Riley (23) and malignant melanocytes by Bleehen (24). It seems likely that these compounds are con- verted by tyrosinase to form highly toxic oxidation products and electron spin resonance studies indicate that these metabolites are probably fi'ee radicals (23). These free radicals initiate a chain reaction of lipid peroxidation resulting in the irreversible damage of the lipoprotein membranes of the melanocyte and producing the death of this cell.