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Susceptibility and resistance of skin to carcinogenesis
TOXICOLOGY AND APPLIED PHARMACOLOOY,SUPPLEMENT NO. 3) 68-71 (1969)
Susceptibility and Resistance of Skin to Carcinogenesis EUGENE J, VAN SCOTT
Department of Derntatology, Temple University Health Services Center, Philadelphia, Pennsylvania 19140
In an open discussion of the subject of safety of cosmetics, a discussion designed to assess current states and possibly to influence formulation of regulatory guidelines for the future, it seems proper and relevant to give some attention to the question of the fundamental biologic importance of cosmetics. To lend balance to this perspective, it should be recalled that biologic systems, both plants and animals, are oriented primarily toward survival. Such orientation is not only rudimentary but also elementary, involving requirements for food and for reproduction of the individual. While costactics may bear some relationship to the latter in the courting practices of man and some animals, it seems fair to assume that integumental adornment is not a primary requirement for survival, nor absolutely essential for reproduction. This does not say that beautification is biologically unimportant, for this would imply that too many of man's preoccupations are biologically trivial. A concern for personal beauty is not a characteristic singular to man, and evidence of such COllcern is found in many subhuman species. In most species beautification of the integument is under genetic control without conscious emotional embellishment on the part of the individual organism --or at least without outwardly discernible signs of this. In other species, including fish, birds, and mammals, emotional release is accompanied by changes of skin color or display of plumage or other cutaneous appendageal appurtenances. This too is genetic, unchanging, and reflexive. In man, colorful display of the integument and its various components reaches the highest level, is mostly under conscious control even though seeming to be instinctive. Profound attention to cosmetic achievement has not been only recently acquired by man, for it is distinctly prevalent in primitive cultures, where integumental decoration may reach extremes. The early Greeks helped to formalize cosmetics into a discipline of sorts, contributing the word "kosmetikos" with the meaning "skilled in decorating." The Egyptians perhaps did most to establish cosmetics into modern civilization; the most renowned of them in this regard was Cleopatra, whose skilful application of the art of personal adornment has sustained her as an eternal model to feminine beautification. And, as has been pointed out by Harry (1957), biblical references to the early use of cosmetics may be cited, e.g., "When Jehu was come to Jezreel, Jezebel heard of it; and she painted her face and tired her head, and looked out at a window" (II Kings ix: 30). It seems fair to conclude that cosmetics are biologically important to man. Although not necessary for survival, and not essential for reproduction, cosmetics somehow seem eminently important to man's scheme of living. National sales of cosmetic products and services, currently estimated at several billion dollars yearly, attest to this involvement. 68
SKIN AND CARCINOGENESIS
69
Since cosmetics constitute a significant part of man's environmental exposures, it is important to ensure that actual use hazards from cosmetics be kept at a minimum. Historically, not all cosmetic ingredients have been innocuous or harmless. A list of some questionable materials used in cosmetic lotions, powders, and balms during the past century include bichloride of mercury, arsenious acid, potassium cyanide, lead salts, and an array of products from wood and coal and their tar derivatives, as well as general irritants, such as croton oil (Cooley, 1873). Several of the latter constitute a formidable group of materials now classified as initiating and promoting agents in carcinogenesis (Weisburger and Weisburger, 1967). The remarkable barrier protective properties of the human cutaneous integument have probably played an important role in thwarting serious toxicity. While the skirt has been the most consistently exposed to cosmetic preparations, it is important to keep in mind that sites other than skin are also distinctly exposed, e.g., the respiratory and gastrointestinal tracts. Therefore, in the absence of reliable medical records on individual patients, and in the absence of population data from the past, it should not be assumed that there has been total absence of toxicity from an agent applied to the skin. Without underrating the importance of the epidermal barrier in protecting the body against many of its environmental encounters, it should be kept in mind that not all skin areas are equivalent in resisting transepidermal penetration of chemicals. The fact that in contact allergic dermati.tis of the hands, the palms are frequently spared while the dorsa exhibit marked reactions is evidence of such a difference. A further example is found in a comparison of general body skin to the skin of the scrotum, the latter being exceedingly permeable even though little morphologic difference from epidermis of other body regions is detectable (Smith et al., 1961). Difference in penetrability of the epidermis is correlated with regional differences in susceptibility to environmental carcinogens. And indeed, the first recorded instance of environmental carcinogenesis, i.e., scrotal cancer in chimney sweeps, is the classic example in this regard. While the whole integument was exposed to the carcinogens contained in soot, the site developing cancer was the area of skin now known to be the most permeable. Parenthetically, it has been noted that the use of a cosmetic, i.e., soap, played a singular preventive role in this type of cancer (Shimkin, 1968). At this point in time we are, however, confronted with some imponderables. In man, a general resistance of most skin areas to environmental chemical carcinogens must be invoked to explain the fact that no known skin cancers to date have followed the widespread use of tar preparations in dermatologic therapy. Today, with several generations of countless patients with chronic dermatoses having received prolonged therapy with coal and wood tars--and frequently with_ concurrent intensive ultraviolet light exposure--it is astounding that there has not yet been recorded a case of skin cancer induced by such exposure. This has not been due to low carcinogenic properties of this therapy, for therapeutic tar ointments have been shown to be highly carcinogenic when applied to the skin of mice (Urbach, 1959). The resistance of human skin to carcinogenesis by therapeutic tar preparations cannot be ignored nor unrealistically diminished, for it is clear that many substances applied to the skin are absorbed through the epidermis. Absorption studies are not needed to support such a conclusion, for it is implicit in the frequency with which contact allergic dermatitis occurs, where the elicitation of such allergic responses
70
VAN SCOTT
requires that the contactant reach not only the viable epidermal cells, but circulating lymphocytes as well. The relative impermeability o f the epidermis as a protection against potentially toxic materials applied topically is inconsequential in those instances where such materials have recourse to other avenues of entry into the body, such as the mucosal interfaces between the body and its environment, i.e., the ocular surface mucosa, the mucosal linings of the respiratory and alimentary tracts, and the genitourinary mucosa as well. Such sites are exposed to various cosmetic preparations--powders, perfumes, eyeshadow preparations, lipstick, toothpaste and mouth fresheners, hair sprays, and others. Cosmetic ingredients therefore may gain systemic entry through diverse routes and carcinogenic hazards that may exist from their use are not necessarily confined to the skin as long as these other sites are at risk. The practical question of how safe a cosmetic should be is not readily answerable. Care should be taken if a single answer is sought, for hazards are relative and vary f r o m one category of cosmetic to another. Certainly the number of people exposed to cosmetics is large, and with some preparations the exposed group may include vast populations. The time of exposure is variable depending on whether a preparation has long-term popularity or not. With some preparations, exposure, whether intermittent or continuous, may extend over years. With few exceptions, a particular ingredient of a cosmetic preparation usually is not absolutely essential and can be replaced by a satisfactory substitute ingredient. It seems important therefore to assure a high order of safety for cosmetics. In regard to carcinogenesis, a highly sensitive screening system would seem desirabIe. Such a screen should give predictive information as to whether a material would be carcinogenic at the site of direct exposure during use, as well as whether it might be carcinogenic at distant sites following its absorption and possible metabolic alteration. Carcinogenicity under conditions of concurrent exposure to other carcinogenic stimuli (e.g., ultraviolet light) perhaps also should be determined because of the commonness o f such dual exposure in actual usage. And equally important are better epidemiological systems to elicit information on actual carcinogenic effects detectable in man, for it should be remembered that the best laboratory systems to date have failed to detect arsenic as a carcinogen, although it is a carcinogen as determined by clinical observations in man. Finally, the design of screens to identify carcinogenic materials is important only insofar as the information gained from the system is put to use by actual exclusion o f these materials from man's environment. Carcinogenic hazards are relative, and first concerns should be given to those materials and factors found to be most hazardous. It seems reasonable to recommend for exclusion from man's environment materials to which he is already exposed and which are already known to be carcinogenic for man, as well as being concerned with those that will be found to be carcinogenic for man. REFERENCES COOLEY, A. J. (1873). Hand-Book of Perfumes and Cosmetics. Lippincott, Philadelphia, Pennsylvania. HARRY, R. G. (1957). Cosmetics: Their Principles and Practices, p. xxiii. Chemical Publ. Co., New York.
SKIN AND CARCINOGENESIS
7i
SmMKIN, M. B. (1968). Environmental carcinogens. Arch. Environ. Health 16, 513-521. SMITH, J. G., JR., FISCHER,R. W., and BLANK, H. (1961). The epidermal barrier. J. Invest. DermatoL 36, 337-343. URBACH, F. (1959). Modification of ultraviolet carcinogensis by photoactive agents. Jr. Invest. Dermatol. 32,, 373-378. WEISBURO~R, J. H,, and WEISBUROER, E. K. (1967). Tests for chemical carcinogens. In: Methods in Cancer Research (H. Busch, ed.), Vol. I, pp. 307-398. Academic Press, New York.
Susceptibility and Resistance of Skin to Carcinogenesis EUGENE J, VAN SCOTT
Department of Derntatology, Temple University Health Services Center, Philadelphia, Pennsylvania 19140
In an open discussion of the subject of safety of cosmetics, a discussion designed to assess current states and possibly to influence formulation of regulatory guidelines for the future, it seems proper and relevant to give some attention to the question of the fundamental biologic importance of cosmetics. To lend balance to this perspective, it should be recalled that biologic systems, both plants and animals, are oriented primarily toward survival. Such orientation is not only rudimentary but also elementary, involving requirements for food and for reproduction of the individual. While costactics may bear some relationship to the latter in the courting practices of man and some animals, it seems fair to assume that integumental adornment is not a primary requirement for survival, nor absolutely essential for reproduction. This does not say that beautification is biologically unimportant, for this would imply that too many of man's preoccupations are biologically trivial. A concern for personal beauty is not a characteristic singular to man, and evidence of such COllcern is found in many subhuman species. In most species beautification of the integument is under genetic control without conscious emotional embellishment on the part of the individual organism --or at least without outwardly discernible signs of this. In other species, including fish, birds, and mammals, emotional release is accompanied by changes of skin color or display of plumage or other cutaneous appendageal appurtenances. This too is genetic, unchanging, and reflexive. In man, colorful display of the integument and its various components reaches the highest level, is mostly under conscious control even though seeming to be instinctive. Profound attention to cosmetic achievement has not been only recently acquired by man, for it is distinctly prevalent in primitive cultures, where integumental decoration may reach extremes. The early Greeks helped to formalize cosmetics into a discipline of sorts, contributing the word "kosmetikos" with the meaning "skilled in decorating." The Egyptians perhaps did most to establish cosmetics into modern civilization; the most renowned of them in this regard was Cleopatra, whose skilful application of the art of personal adornment has sustained her as an eternal model to feminine beautification. And, as has been pointed out by Harry (1957), biblical references to the early use of cosmetics may be cited, e.g., "When Jehu was come to Jezreel, Jezebel heard of it; and she painted her face and tired her head, and looked out at a window" (II Kings ix: 30). It seems fair to conclude that cosmetics are biologically important to man. Although not necessary for survival, and not essential for reproduction, cosmetics somehow seem eminently important to man's scheme of living. National sales of cosmetic products and services, currently estimated at several billion dollars yearly, attest to this involvement. 68
SKIN AND CARCINOGENESIS
69
Since cosmetics constitute a significant part of man's environmental exposures, it is important to ensure that actual use hazards from cosmetics be kept at a minimum. Historically, not all cosmetic ingredients have been innocuous or harmless. A list of some questionable materials used in cosmetic lotions, powders, and balms during the past century include bichloride of mercury, arsenious acid, potassium cyanide, lead salts, and an array of products from wood and coal and their tar derivatives, as well as general irritants, such as croton oil (Cooley, 1873). Several of the latter constitute a formidable group of materials now classified as initiating and promoting agents in carcinogenesis (Weisburger and Weisburger, 1967). The remarkable barrier protective properties of the human cutaneous integument have probably played an important role in thwarting serious toxicity. While the skirt has been the most consistently exposed to cosmetic preparations, it is important to keep in mind that sites other than skin are also distinctly exposed, e.g., the respiratory and gastrointestinal tracts. Therefore, in the absence of reliable medical records on individual patients, and in the absence of population data from the past, it should not be assumed that there has been total absence of toxicity from an agent applied to the skin. Without underrating the importance of the epidermal barrier in protecting the body against many of its environmental encounters, it should be kept in mind that not all skin areas are equivalent in resisting transepidermal penetration of chemicals. The fact that in contact allergic dermati.tis of the hands, the palms are frequently spared while the dorsa exhibit marked reactions is evidence of such a difference. A further example is found in a comparison of general body skin to the skin of the scrotum, the latter being exceedingly permeable even though little morphologic difference from epidermis of other body regions is detectable (Smith et al., 1961). Difference in penetrability of the epidermis is correlated with regional differences in susceptibility to environmental carcinogens. And indeed, the first recorded instance of environmental carcinogenesis, i.e., scrotal cancer in chimney sweeps, is the classic example in this regard. While the whole integument was exposed to the carcinogens contained in soot, the site developing cancer was the area of skin now known to be the most permeable. Parenthetically, it has been noted that the use of a cosmetic, i.e., soap, played a singular preventive role in this type of cancer (Shimkin, 1968). At this point in time we are, however, confronted with some imponderables. In man, a general resistance of most skin areas to environmental chemical carcinogens must be invoked to explain the fact that no known skin cancers to date have followed the widespread use of tar preparations in dermatologic therapy. Today, with several generations of countless patients with chronic dermatoses having received prolonged therapy with coal and wood tars--and frequently with_ concurrent intensive ultraviolet light exposure--it is astounding that there has not yet been recorded a case of skin cancer induced by such exposure. This has not been due to low carcinogenic properties of this therapy, for therapeutic tar ointments have been shown to be highly carcinogenic when applied to the skin of mice (Urbach, 1959). The resistance of human skin to carcinogenesis by therapeutic tar preparations cannot be ignored nor unrealistically diminished, for it is clear that many substances applied to the skin are absorbed through the epidermis. Absorption studies are not needed to support such a conclusion, for it is implicit in the frequency with which contact allergic dermatitis occurs, where the elicitation of such allergic responses
70
VAN SCOTT
requires that the contactant reach not only the viable epidermal cells, but circulating lymphocytes as well. The relative impermeability o f the epidermis as a protection against potentially toxic materials applied topically is inconsequential in those instances where such materials have recourse to other avenues of entry into the body, such as the mucosal interfaces between the body and its environment, i.e., the ocular surface mucosa, the mucosal linings of the respiratory and alimentary tracts, and the genitourinary mucosa as well. Such sites are exposed to various cosmetic preparations--powders, perfumes, eyeshadow preparations, lipstick, toothpaste and mouth fresheners, hair sprays, and others. Cosmetic ingredients therefore may gain systemic entry through diverse routes and carcinogenic hazards that may exist from their use are not necessarily confined to the skin as long as these other sites are at risk. The practical question of how safe a cosmetic should be is not readily answerable. Care should be taken if a single answer is sought, for hazards are relative and vary f r o m one category of cosmetic to another. Certainly the number of people exposed to cosmetics is large, and with some preparations the exposed group may include vast populations. The time of exposure is variable depending on whether a preparation has long-term popularity or not. With some preparations, exposure, whether intermittent or continuous, may extend over years. With few exceptions, a particular ingredient of a cosmetic preparation usually is not absolutely essential and can be replaced by a satisfactory substitute ingredient. It seems important therefore to assure a high order of safety for cosmetics. In regard to carcinogenesis, a highly sensitive screening system would seem desirabIe. Such a screen should give predictive information as to whether a material would be carcinogenic at the site of direct exposure during use, as well as whether it might be carcinogenic at distant sites following its absorption and possible metabolic alteration. Carcinogenicity under conditions of concurrent exposure to other carcinogenic stimuli (e.g., ultraviolet light) perhaps also should be determined because of the commonness o f such dual exposure in actual usage. And equally important are better epidemiological systems to elicit information on actual carcinogenic effects detectable in man, for it should be remembered that the best laboratory systems to date have failed to detect arsenic as a carcinogen, although it is a carcinogen as determined by clinical observations in man. Finally, the design of screens to identify carcinogenic materials is important only insofar as the information gained from the system is put to use by actual exclusion o f these materials from man's environment. Carcinogenic hazards are relative, and first concerns should be given to those materials and factors found to be most hazardous. It seems reasonable to recommend for exclusion from man's environment materials to which he is already exposed and which are already known to be carcinogenic for man, as well as being concerned with those that will be found to be carcinogenic for man. REFERENCES COOLEY, A. J. (1873). Hand-Book of Perfumes and Cosmetics. Lippincott, Philadelphia, Pennsylvania. HARRY, R. G. (1957). Cosmetics: Their Principles and Practices, p. xxiii. Chemical Publ. Co., New York.
SKIN AND CARCINOGENESIS
7i
SmMKIN, M. B. (1968). Environmental carcinogens. Arch. Environ. Health 16, 513-521. SMITH, J. G., JR., FISCHER,R. W., and BLANK, H. (1961). The epidermal barrier. J. Invest. DermatoL 36, 337-343. URBACH, F. (1959). Modification of ultraviolet carcinogensis by photoactive agents. Jr. Invest. Dermatol. 32,, 373-378. WEISBURO~R, J. H,, and WEISBUROER, E. K. (1967). Tests for chemical carcinogens. In: Methods in Cancer Research (H. Busch, ed.), Vol. I, pp. 307-398. Academic Press, New York.