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Additional Responses to the Controversy
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Soni et al have stated in multiple articles that parabens are virtually nontoxic, and quickly absorbed, metabolized, and excreted in urine8,13,21 They have also not found carcinogenic potential to be associated with parabens in reviews of the literature In reference to the controversy pertaining to the study by Byford et al, they argue that the evidence is ambiguous at best regarding the estrogenic risks of parabens, noting that the available studies do not consider the dose-, route-, and species-dependent metabolism and elimination rates of parabens They do, however, conclude that a study of reproductive toxicity may be useful8 Darbre responded to the furor over the suggestions of an etiologic connection between underarm cosmetics and breast cancer by noting that the strongest supportive evidence of this contention was the unaccounted for clinical observations revealing a disproportionately high incidence of breast cancer in the upper outer quadrant of the breast, proximate to where these products are applied He suggested that such data should prompt multidisciplinary research to ascertain the effects of the long-term use of the constituent chemicals of underarm cosmetics22 In a commentary on Darbre s article, Harvey acknowledged that while parabens are generally regarded as safe, recent reports have indicated estrogenic effects associated with these preservatives He echoed Darbre s call for additional research on underarm cosmetics, particularly on components facilitating estrogenic activity, noting the paucity of data on the long-term effects of weakly estrogenic chemicals on human health23 In a subsequent article by Harvey and Darbre, the authors suggest that should further data on the influence of topically applied paraben-containing products
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indicate adverse effects on human health via endocrine disruption, this mode of interruption, given the clarity of exposure, should be more amenable to assessment, measurement, and intervention Further, they suggest that the potential public health impact and the size of the exposed population should provide incentive for study24 It is important to realize that the presence of parabens in the breast cancer tumors identified in the Byford study is not evidence of a causal link between parabens and breast cancer, cosmetics in general and breast cancer, or even underarm products and breast cancer If parabens ultimately turn out to be implicated in the etiologic pathway of certain breast cancers or other tumors, it is worth remembering that parabens are used in food products as well,13 leaving the source of potential causal factors difficult to identify As yet, no one has any idea (or has evaluated) whether it is the consumption of parabens or their application to the skin that is responsible for their presence in human tissue In addition, no one knows what the presence of parabens in human tissue means Nevertheless, such studies raise important questions
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COSMETIC DERMATOLOGY: PRINCIPLES AND PRACTICE
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The Estrogenicity of Parabens
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Using the uterotrophic assay in immature and adult ovariectomized CD1 mice and in immature Wistar rats, Lemini et al subcutaneously injected animals for three consecutive days with various doses of parabens or vehicle They found that uterine weight was increased and all parabens but MP competed with estradiol for estrogen binding sites The investigators concluded that their in vivo and in vitro data confirm the estrogenicity of parabens25 Lemini et al followed up on these results by presenting a morphometric analysis of the uteri from mice treated with parabens compared with estradiol that confirmed the induction of estrogenic histologic alterations in the uteri of ovariectomized mice26 Acknowledging the various estrogenic effects of parabens seen recently in vivo, Prusakiewicz et al hypothesized that parabens increase estrogen levels by inhibiting estrogen sulfotransferases (SULTs) in skin They tested this theory in human skin cytosolic fractions and normal human epidermal keratinocytes (NHEKs) The investigators found that SULT inhibition potency increased with increasing length of the paraben ester chain, with butyl paraben displaying the
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greatest inhibitory capacity, suppressing cutaneous cytosol sulfation of estradiol, and estrone thus potentially increasing local estrogen levels They concluded that the estrogenicity of parabens included in topical skin care products and medications may promote or contribute to cutaneous antiaging benefits27 The level of estrogenicity bears scrutiny in future studies given the seemingly fine line between the potential salutary, antiaging effects of estrogen, as well as the detrimental, carcinogenic activity While acknowledging the weakly estrogenic activity of parabens identified in recent in vitro tests and reported in vivo effects such as increased uterine weight associated with butyl, isobutyl, and benzyl paraben and male reproductive effects linked to butyl and propyl paraben, Golden et al argued that the parabens with demonstrated activity are several orders of magnitude less active than estrogen and that it is biologically implausible that parabens could raise the risk of any estrogen-mediated health effects Further, they concluded that a worst-case scenario in terms of daily parabens exposure would pose significantly less risk as compared to the risk of exposure to naturally-occurring dietary endocrine-active chemicals (EACs) such as the phytoestrogen daidzein (an isoflavone found in soy)11
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