Parabens detection in different zones of the human breast: consideration of source and implications of findings

Published online in Wiley Online Library: 7 March 2012 (wileyonlinelibrary.com) DOI 10.1002/jat.2743 Parabens detection in different zones of thehuman breast: consideration of source andimplications of findings ABSTRACT: This article is a discussion of the recent study by Barr, Metaxas, Harbach, Savoy and Darbre (2012; J. Appl. Toxicol. 32;doi: 10.1002/jat.1786) reporting residues of five paraben esters in the human breast, at concentrations up to the microgram pergram tissue range and with highest concentrations in the axilla area (closest to the underarm). The conclusion is that the detectionof intact esters that have escaped the action of esterases is consistent with a local (dermal) exposure source since the metaboliccapacity of the gut and liver would produce p-hydroxybenzoic acid as the common metabolite. Whereas the zone concentrationdifferences (propylparaben was found at highest concentrations in the axilla) support an underarm exposure model, sevensubjects reportedly never used underarm cosmetics, and other exposure sources, including other cosmetic product types, arediscussed. The findings are placed into context with the limited regulatory toxicology database on parabens, oestrogenic actionof the parabens, and status of the parabens, cosmetics and human health debate. Copyright 2012 John Wiley & Sons, Ltd.
Keywords: axilla; breast; cosmetics; deodorant; estrogenic; human health; parabens; paraben esters; propylparaben; underarm;xenoestrogen and medial giving a total of 160 samples) to provide informationon potential concentration gradients from areas nearest the A recent study reports that paraben esters are detected in the underarm across to the sternum. Results showed that one or human breast (Barr et al., 2012) with highest concentrations of more paraben esters were detected in 158/160 breast tissue some esters in the axillary zone adjacent to the underam.
samples and that all five of the paraben esters that were investi- This is a contribution to the general debate on the safety of gated were detected in 96/160 breast tissue samples. The overall parabens, their use as anti-microbial preservatives in a variety median values in nanograms per gram (ng gÀ1) tissue for of consumer applications, including food, pharmaceuticals and the 160 tissue samples were highest for n-propylparaben cosmetics, and potential health risks, particularly relating to their [16.8 (range 0–2052.7)] and methylparaben [16.6 (range 0–5102.9)] oestrogenic activity. The health risks of parabens have focussed and overall median value for total paraben was 85.5 ng gÀ1 tissue on breast cancer because of the role of oestrogen in this disease (range 0–5134.5). In addition, there were reported differences (for background see Miller, 1996; Beral, 2003; Easton et al., 1993; in paraben concentrations across the four regions of the Lipworth, 1995) and the detection of these synthetic oestrogenic breast: n-propylparaben was found at significantly higher chemicals in the breast, and this latest study raises some levels in the axilla than mid or medial regions. Given the interesting questions that are worthy of comment and perspec- previous hypothesis that a potential source of parabens in the tive. It is important to point out at the outset that the tissues breast is from the dermal application of underarm body/personal studied were from mastectomy patients. Such patients had care products, the finding of highest levels in the axilla region is breast removal for medical reasons following diagnosis. It is not consistent with this route of exposure. However, the authors also possible to obtain healthy breast tissue from ‘controls’ requiring report that ‘the source of the paraben cannot be identified, but donation of a healthy whole breast for obvious and ethical paraben was measured in the 7/40 patients who reported never reasons. The Barr et al. (2012) study is a contribution to the liter- having used underarm cosmetics in their lifetime’. This finding ature on human exposure and body burdens of parabens, and indicates sources of paraben esters other than underarm can be viewed as a sample of the population as a whole, and cosmetics, but as discussed below, the fact that intact esters were does not correlate tissue concentrations of parabens with cause detected is consistent with a dermal exposure route rather than an of breast disease in the patient donors studied (discussed later).
oral route. The data from this latest study, the most extensiveexamination of parabens in human breast so far published, The paper by Barr et al. (2012), extending earlier work (Darbre *Correspondence to: P. W. Harvey, Toxicology Department, Covance Laboratories et al., 2004), reports that a range of paraben esters (methyl, ethyl, UK Ltd, Otley Road, Harrogate, North Yorkshire HG3 1PY, UK.
E-mail: philip.harvey@covance.com n-propyl, isobutyl and n-butyl) were detected in breast tissuesamples derived from mastectomies from 40 women. Tissue Toxicology Department, Covance Laboratories UK Ltd, Otley Road, Harrogate, was analysed from four zones of the breast (axilla, lateral, mid Copyright 2012 John Wiley & Sons, Ltd.
confirms previous work and raises a number of questions on the technical regulatory instrument of GRAS (Generally Regarded entire parabens, personal care product and human health de- as Safe) not specifically requiring further work.
bate, particularly relating to the source and toxicologicalsignificance of the paraben esters.
Oestrogenic Potency of Parabens Compared with TissueConcentrations Consideration of Potential Sources of Paraben Esters in the Another central argument on the safety of parabens revolves around their weak oestrogenic activity and this is relevant to Concerning the source of the paraben esters, the fact that 7/40 reproductive and developmental toxicity and carcinogenicity.
women report never having used underarm cosmetics, yet had All the parabens have been shown to have oestrogenic activity measurable parabens levels, indicates that there are other in human breast cancer cells and other models (e.g. Routledge sources of environmental exposure and indeed the paraben et al., 1997; Darbre et al., 2002, 2003; Gomez et al., 2005; Vo esters are ubiquitous, and used as preservatives in a variety of et al., 2010; and see Darbre and Harvey, 2008 for summary of products from food to pharmaceuticals. It is important to note approximately 20 studies). The safety database is lacking in regu- that they are used extensively in a variety of cosmetic types that latory standard toxicology, and it is even further weakened by may be applied to the skin, such as moisturizers and sun lotion the lack of data on toxicity by the dermal route, which is most (discussed later), and which are not specifically underarm cos- relevant to risk assessment for cosmetics; this has been metics or deodorants. Additionally, the dermal route of exposure previously discussed (Harvey, 2003; Harvey and Darbre, 2004; is considered more plausible when intact esters are detected, Darbre and Harvey, 2008). The main defence raised for the and other authors reporting human exposures and body fluid absence of toxicological risk concerns the potency of the concentrations of paraben esters consider cosmetics of some paraben esters in comparison to oestradiol [generally quantified form or another as the likely sources (Calafat et al., 2010). This in the region of 10 000–100 000 times less, e.g. Routledge et al.
is because the metabolic esterase activity of the gut and liver (1998); and WHO (2007) record potency of propylparaben and (relevant to oral exposure) is considered to greatly exceed that butylparaben as 30 000 and 10 000 times less than oestradiol, of the skin, and oral exposures would result in rapid liver respectively, for their evaluation purposes]. However, oestradiol metabolism of the esters to produce the common metabolite occurs in breast tissue in the picogram per gram of tissue range p-hydroxybenzoic acid (e.g. Abbas et al., 2010; Lakeram et al., (Clarke et al., 2001 reports endogenous oestradiol concentrations 2006; Jewell et al., 2007). Paraben esters typically used in cos- in normal human breast adipose of 0.203 nM or 55.3 pg gÀ1 of metics pass through human skin in vitro/ex vivo (El Hussein tissue) but the results reported by Barr et al. (2012) show tissue et al., 2007) and Ishiwatari et al. (2007) has shown persistence concentrations of parabens, in the worst cases, in the microgram of unmetabolized methylparaben in the skin. Controlled human per gram of breast tissue range, which is 1 million-fold higher dermal dosing studies have shown absorption of intact paraben than that of oestradiol. Clearly, the magnitude of exposure would esters through the skin (Janjua et al., 2007, 2008). The Barr et al.
seem to more than compensate for the reduction in potency.
(2012) study was designed to analyse tissue residues, not to The question then arises of whether this concentration of monitor sources or control exposures, thus the relative contribu- chemical could result in oestrogenic stimulus within breast tion from different types of body care cosmetics, even in the tissue. Harvey and Everett (2006) present a calculation of women who did use underarm cosmetics, is unknown in the potential oestrogenic potency of paraben esters detected in context of their study. That the highest concentrations of propyl- the breast using data from the original Darbre et al. (2004) paraben were detected in the axilla is also consistent with a der- study: the values used were generally lower than those mal/local site of application rather than systemic biodistribution, reported in the latest study (Barr et al., 2012), but the conclu- even assuming that paraben esters survived metabolism intact.
sion was that the detected paraben ester concentrations couldprovide an oestrogenic stimulus based on corrected oestro- Toxicological Significance of the Concentrations of Paraben genic potency equivalents. As is pointed out in Barr et al.
(2012), the influence of multiple esters, and the interactions An important consideration concerns whether the concentra- with other xenoestrogens and chemicals to which humans tions of parabens found in the breast are toxicologically are exposed (and also reported to be detected in human significant. The answer to this question is confounded by breast, e.g. Guttes et al., 1998, or human breast milk, e.g.
the lack of modern toxicology studies on the paraben esters Solomon and Weiss, 2002) remains unknown in a human and particularly that there has been no adequate evaluation health context, but all are factors which add to oestrogenic of carcinogenicity (see Soni et al., 2001, 2002, 2005). None burden. However, it is important to record that data exist on of the studies referred to in Soni et al.’s reviews follow an the paraben esters that, when combined, they provide an acceptable regulatory standard carcinogenicity study proto- additive oestrogenic stimulus at concentrations where each col in terms of dose groups, number of animals, duration ester alone was ineffective (Darbre, 2009; Darbre and Charles, of treatment, breadth or depth of evaluation, and one study 2010), and this has an important bearing on the biological on rats (Mathews as cited in Soni et al., 2005) dates to 1956 activity of multiple chemical residues and additive ‘mixture’ yet is used as a pivotal evaluation upon which human safety effects. As oestrogens, both natural and synthetic, are a is judged. This may be acceptable for certain chemicals primary risk factor for breast cancer (see Miller, 1996; Beral, for which there is limited human exposure but not for chemi- 2003; Easton et al., 1993; Lipworth, 1995), then the additional cals such as parabens for which such a large population is stimulus of xenoestrogenic residues in breast tissue can be exposed, and which show significant tissue concentrations.
considered potentially adverse. Research is lacking concerning Almost all the toxicology is by the oral route. Thus risk the quantification of any increased risk. It should be noted assessment is largely based on assumption, opinion and the that the toxicological concern with paraben esters in the Copyright 2012 John Wiley & Sons, Ltd.
breast is not confined to oestrogenic activity: Goodson et al.
cancer in underarm cosmetic users. Both studies have design (2011) report that methylparaben promotes cell cycling and limitations that confound interpretation. The tenet that there apoptosis evasion in human breast epithelial cells, which could ‘is no evidence that personal care products (antiperspirants or provide the molecular basis for malignant transformation, deodorants) are related to breast cancer’ is technically correct, Pugazhendhi et al. (2007) report on the gene expression but only because studies have not been conducted to investi- profiles of methyl and butyl esters in MCF7 cells and Tayama gate any relationship. Such arguments provide false reassurance et al. (2008) report that propylparaben and butylparaben by masking the inadequacies of empirical evidence and knowl- cause DNA damage detectable in comet assays and induction edge. The entire debate on whether xenoestrogens, including of chromosome aberrations and sister-chromatid exchanges.
chemicals in cosmetic products, affect human health hascertainly reached no conclusion in the last decade, yet theoestrogenic chemicals in body care cosmetics scenario provides The Parabens, Personal Care Product and Health Debate one of the few examples for controlled study of environmental The hypothesis that personal care products containing oestrogenic exposures and health effects (compounds can be identified, chemicals, such as the paraben esters, may be detrimental to exposures quantified and controlled, biological monitoring in health and potentially contribute to increased breast cancer risk urine and dose–response evaluation, large population of users, (Darbre, 2001, 2003, 2009; Harvey, 2003; Harvey and Darbre, 2004; amenable to prospective design and follow-up, etc). Parabens Darbre and Harvey, 2008; Darbre and Charles, 2010) has a root basis are not the only compounds used in underarm cosmetics with in two observations. The first concerns the marked increase in oestrogenic activity or other toxicological concerns: aluminium breast cancer cases over recent decades (see references in Darbre, is the primary ingredient in antiperspirants and has been 2001, 2003, 2005b), which is strongly suggestive of environmental detected in the human breast (Exley et al., 2007; Mannello or lifestyle aetiological factors. This rise in incidence correlates with et al., 2009, 2011), is oestrogenic (Darbre, 2005a, 2006), and many factors of lifestyle that show change over the past few has recently been shown to promote anchorage-independent decades, including diet, obesity, acceleration of menarche and growth and other changes in human breast cells relevant to can- other endogenous oestrogen-related factors, and alcohol, but they cer development (Sappino et al., 2012). Sappino et al. (2012) also correlate with use of personal care and underarm products report that aluminium chloride (AlCl3) has actions similar to an (Darbre, 2001, 2003, 2005b). Only a small proportion of breast activated oncogene, inducing proliferation stress, DNA double- cancer can be related to ‘nonenvironmental’ biological, genetic or strand breaks and senescence in normal human mammary inherited factors (Easton et al., 1993; Lipworth, 1995). The second epithelial cells. Additionally, long-term exposure to AlCl3 is the location of tumours, with a disproportionate predominance generated and selected for cells able to bypass p53/p21Waf1- very specifically in the upper outer quadrant and the left breast mediated cellular senescence, thus providing the molecular which has been suggested to be related to locality of applied basis for transformation to cancerous cells. Interestingly, products (this quadrant borders the underarm) and handedness methylparaben shows dose-dependent apoptosis evasion and of application (Darbre, 2005b; and see Darbre, 2001, 2003).
induction of cell cycling in human breast epithelial cells, inter- The argument is that there should be a random distribution, or at preted as consistent with the functional changes that are least equal distribution across breast quadrants of cancers in the attributed to malignant onset in breast tissue (Goodson et al., breast, if an endogenous biological–genetic factor is operative.
2011). It should be stressed that this is not evidence that Breast tissue is derived from common progenitor cells and cells parabens, aluminium salts or personal care products in general comprising a tissue are essentially clones that should share a cause breast cancer; however, there are signals of concern common genotype and propensity to develop cancer. The fact that that such compounds are not as safe as previously generally tissue in different regions of the breast does not share the same considered and further research is warranted.
incidence of cancer suggests that an external or environmentalinfluence is operative. Ellsworth et al. (2004a) report higher genomic instability in the outer quadrants of the breast andsuggest that environmental chemicals/carcinogenic agents could Concerning the source of the parabens esters in Barr et al.
contribute to fields of genomic instability localized to specific areas (2012), the data contain interesting patterns. The fact that intact of the breast (Ellsworth et al., 2004b). Behavioural and hygiene esters were detected more strongly suggests a dermal route factors are not unusual in human cancers related to dermal of exposure rather than oral. The gradient of concentrations with exposures, as evidenced by the cases of scrotal cancers in various highest levels found in the outer axillary (underarm) area occupational groups related to soot, mineral oil and other for some esters is consistent with local exposures (or application) hydrocarbon exposures (reviewed in Azike, 2009). As such, a differ- to this area. This region of the breast also has highest cancer ential environmental factor, such as a chemical input variably incidence (e.g. Darbre, 2003, 2005b). That 7/40 women with applied across and between breasts from the application of parabens residues were reported as never having used personal care products, is certainly plausible.
underarm cosmetics suggests other sources of exposure in these Whether breast cancer is related to underarm cosmetic or subjects. Parabens are used in a variety of other personal care personal care product use is a separate question to the probable products (Rastogi et al., 1995; Rastogi, 2000), not just underarm source of the parabens esters reported in Barr et al. (2012). It is antiperspirants or deodorants, and such lotions, sun creams also a question that will remain unanswered unless properly and moisturizers are commonly applied to the breast, chest constructed and controlled large-scale investigations are con- and upper arms. It is considered less likely that oral exposures ducted since the current data set of two studies (Mirick et al., contribute to the reported parabens residues because of 2002; McGrath, 2003) report conflicting results. Mirick et al.
the metabolic arguments previously outlined [additional (2002) report no difference in breast cancer incidence in antiper- evidence supporting a nonoral source is that n-propylparaben spirant users and McGrath (2003) reported earlier onset of breast and n-butylparaben have effectively been withdrawn from food Copyright 2012 John Wiley & Sons, Ltd.
use (WHO, 2007 see below) and yet n-propylparaben is detected and butylparaben from the specification of Acceptable Daily in the breast at highest concentrations in the axilla], but Intake for parabens collectively (essentially excluding them oral exposures are relevant in total body burden scenarios. By as approved food use additives), based on toxicological logical extension, the source of parabens in the women who concerns, and it is surprising that there is a lack of consistency did report using underarm products cannot be considered to applied to the evaluation of data by agencies regulating be exclusively from underarm products either and may include other consumer products, since the latest SCCS (2011) still allows other sources. There is no information in the data concerning their use at 0.19%, in addition to other paraben esters, in body bioaccumulation or half-life of the paraben esters. However, calculations based on percentage use of parabens in cosmetics,estimated application rates and measured residues (e.g. Harvey and Everett, 2006) would seem to indicate that the concentra-tions reported in Barr et al. (2012) would be from unrealistically Abbas S, Greige-Gerges H, Karam N, Piet M-H, Netter P, Magdalou J. 2010.
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