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Journal of Toxicology and Environmental Health, Part B: Critical Reviews Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uteb20
Parabens: Potential impact of Low-Affinity Estrogen receptor Binding chemicals on Human health a
a
Ebru Karpuzoglu , Steven D. Holladay & Robert M. Gogal Jr.
a
a
Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine , University of Georgia , Athens , Georgia , USA Published online: 02 Aug 2013.
To cite this article: Ebru Karpuzoglu , Steven D. Holladay & Robert M. Gogal Jr. (2013) Parabens: Potential impact of LowAffinity Estrogen receptor Binding chemicals on Human health, Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 16:5, 321-335, DOI: 10.1080/10937404.2013.809252 To link to this article: http://dx.doi.org/10.1080/10937404.2013.809252
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Journal of Toxicology and Environmental Health, Part B, 16:321–335, 2013 Copyright © Taylor & Francis Group, LLC ISSN: 1093-7404 print / 1521-6950 online DOI: 10.1080/10937404.2013.809252
PARABENS: POTENTIAL IMPACT OF LOW-AFFINITY ESTROGEN RECEPTOR BINDING CHEMICALS ON HUMAN HEALTH Ebru Karpuzoglu, Steven D. Holladay, Robert M. Gogal, Jr.
Downloaded by [Moskow State Univ Bibliote] at 10:40 04 December 2013
Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA Parabens, alkyl esters of p-hydroxybenzoic acid, are widely used in cosmetics, pharmaceuticals, personal care products and as food additives to inhibit microbial growth and extend product shelf life. Consumers of these compounds are frequently exposed via the skin, lips, eyes, oral mucosa, nails, and hair. Parabens are estrogenic molecules but exert weaker activity than natural estrogens, which would imply a low risk. Consistent with this idea, a number of recent commission reports from different countries suggested that parabens pose a negligible endocrine-disrupting risk at the recommended doses. However, individuals are not routinely exposed to a single paraben, and most of the available paraben toxicity data, reviewed in these reports, are from single-exposure studies. Further, assessing the additive and cumulative risk of multiple paraben exposure from daily use of multiple cosmetic and/or personal care products is presently not possible based on current studies. In this review, current and recent studies of paraben exposure and public health policies as well as critical gaps in the knowledge are discussed and new research directions regarding multiple exposures and novel target cohorts are recommended.
Parabens are alkyl esters of p-hydroxybenzoic acid widely used in cosmetics, including foundations, powders, eye shadows, mascara, lip glosses, lipsticks, and nail polishes, and in pharmaceuticals and personal care products (PCP) such as lotions, sunscreens, cleansers, shampoos, deodorants, hair care products, and toothpaste, which are in frequent contact with skin, lips, eyes, oral mucosa, nails, and hair. Tables 1 and 2 depict the frequency of use and percent of use of parabens in a select number of PCP and cosmetic products, respectively (CTFA 2008). Parabens are also common ingredients in food products used to inhibit microbial growth and extend product shelf life (Liao et al. 2013). The synthetic parabens include methyl-, ethyl-, propyl-, isobutyl-, butyl-, isopropyl-, and benzyl-, show increasing antimicrobial activity
with increasing alkyl chain length (Figure 1) (Darbre et al. 2002; 2003; Golden et al. 2005). The estrogen receptor binding affinities of parabens are 10,000- to 100,000-fold lower than for estrogen (17β-estradiol; shown in Figure 1 for comparison), and decrease in order as: isobutylparaben > butylparaben > isopropylparaben = propylparaben > ethylparaben (Vo et al. 2010). Such parabens have been in use for more than 80 years due to (1) antibacterial and fungicidal properties, (2) high stability at different pH and temperatures, (3) inertness, and (4) low cost, which has resulted in widespread, chronic human exposures (Daughton and Ternes 1999). This review focuses on current knowledge regarding potential effects of parabens on endocrineresponsive systems, including the reproductive, immune, and nervous systems.
Address correspondence to Robert M. Gogal, Jr., Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7382, USA. E-mail: [email protected] 321
322
0.16–0.4% 0.07–0.4% 0.2–0.44% 0.15–0.4% 0.1–0.5% 0.0008–0.3% 0.15–0.4% 0.1–0.4% 0.1–0.4%
533 787 317 631 167 35 63 381 331
227 183
135 29 61
591 215 478
403
0.04–0.4% 0.03–0.2%
0.001–0.3% 0.002–0.2% 0.1–0.3%
0.05–0.35% 0.03–0.35% 0.1–0.4%
0.03–0.3%
0.16–0.7% 0.1–0.3% 0.1–0.5% 0.17–0.6% 0.15–1%
296 189 282 338 286
4 33
Baby products (number of products) Shampoos (38) Creams, lotions, oils, or powders (67) — 0.2–0.4%
0.15–0.5% 0.25–0.54% 0.13–0.6% 0.1–0.35% 0.07–0.4%
613 213 485 77 67
4 31
520
325 193 250 308
541 190 477 83 45
0.1% 0.2%
0.1–0.62%
0.05–0.4% 0.02–0.5% 0.1–0.5% 0.1–0.6%
0.1–0.5% 0.1–0.32% 0.05–0.4% 0.13–0.2% 0.05–0.15%
Percent in product
Frequency of use
Percent in product
Frequency of use
Eyes (number of products) Eye shadow (1061) Mascara (308) Eyeliner (liquid or pencil) (639) Eyebrow pencil (124) Eye makeup remover (114) Face (number of products) Foundations (530) Makeup Base (i.e., primers) (273) Powders (447) Blushes (cream or powder) (459) Lips Lipstick (1681)
Cosmetic products
Propylparaben
Methylparaben
TABLE 2. Frequency of use and percent concentration of parabens in cosmetic products
Cleansing creams, lotions, or gels (1009) Moisturizers (1200) Face and neck skin care (546) Body skin care (creams, lotions etc.) (992) Night skin care (229) Deodorants (281) Sunscreen skin care (Creams, gels, sprays, lotions) (138) Shampoos (1022) Hair conditioners (715)
PCP (number of products)
Percent in product
Propylparaben Frequency of use
Frequency of use
Percent in product
Methylparaben
0.03–0.2% 0.001–0.3%
0.0001–0.25% 0.002–0.1% 0.04–0.2%
0.001–0.3% 0.03–0.3% 0.001–0.4%
0.0006–0.54%
Percent in product
1 12
72
150 35 119 84
295 127 23 5 17
Frequency of use
— —
0.0002–0.2%
0.001–0.5% 0.00006–0.35% 0.04–0.5% 0.04–0.3%
0.06–0.49% 0.00002–0.4% 0.03–0.4% 0.4% 0.03–0.3%
Percent in product
Ethylparaben
108 33
64 10 22
268 169 153
181
Frequency of use
Ethylparaben
TABLE 1. Frequency of use and percent concentration of parabens in Personal Care Products (PCP)
0.01–0.25% 0.02–0.25%
0.04–0.15% 0.002% 0.03–0.4%
0.06–0.2% 0.09–0.4% 0.09–0.4%
0.0006–0.54%
Percent in product
2 21
218
96 51 67 35
199 80 398 60 27
Frequency of use
— 0.05%
0.0008–0.1%
0.06–0.2% 0.00006–0.1% 0.07–0.14% 0.07–0.2%
0.05–0.3% 0.00002–0.21% 0.05–0.2% 0.05–0.1% 0.07–0.15%
Percent in product
Butylparaben
108 49
65 10 28
278 157 157
195
Frequency of use
Butylparaben
Downloaded by [Moskow State Univ Bibliote] at 10:40 04 December 2013
0.02–0.1% 0.01–0.02%
— 0.002% 0.02%
0.0002–0.02% 0.02–0.09% 0.02–0.4%
0.003–0.1%
1 5
11
15 1 6 2
3 17 9 4 6
Frequency of use
— —
0.0001–0.4%
0.00001–0.06% 0.00003–0.02% 0.00001–0.04% 0.00001–0.04%
0.05–0.4% 0.000007–0.1% 0.02–0.1% 0.06% 0.02%
Percent in product
Isobutylparaben
38 12
14 3 9
67 75 52
67
Percent in product
Isobutylparaben Frequency of use
POTENTIAL HEALTH IMPACT OF PARABENS
CH3
323
CH3
HO CH 3 methylparaben
ethylparaben
CH CH33 propylparaben
CH3 butylparaben
Downloaded by [Moskow State Univ Bibliote] at 10:40 04 December 2013
CH3 CH3 isopropylparaben
recent study, blood samples from 268 pregnant women all showed traces of at least several of the 163 different chemicals evaluated, including parabens used in PCP (Woodruff et al. 2011). In addition to adult exposure, children up to 9 yr of age are exposed to approximately 61 PCP ingredients daily, suggesting potential endocrine-modulating effects (EWG 2007). Collectively, these reports suggest that parabens exposure frequency and concentration vary significantly by individual, and exposure is widespread in adults and children of both genders, with women on average receiving the highest exposure.
17β-estradiol
FIGURE 1. The structure of parabens and estrogen (17βestradiol).
PARABEN PRODUCTION AND SOURCES In a 1984 study, greater than 13,000 cosmetic products were found to contain parabens (Elder 1984), and by 1987 approximately 7000 kg of parabens was used annually in cosmetics and PCP (Soni et al. 2005). Given that the number and type of PCP and cosmetics have increased since the 1980s, it is reasonable to predict that the percentage of products containing parabens and thus frequency of human exposure to these chemicals have also risen in societies where cosmetics and PCP are in constant use. One question that remains unresolved is whether frequent exposure to varying concentrations of these weakly estrogenic compounds poses a threat to humans, in particular, estrogen-sensitive human cohorts. In a 2004 survey, the Environmental Working Group (EWG) reported that women on average used 12 PCP containing a total of 168 ingredients per day, whereas men used approximately 10 products with a total of 85 ingredients daily (EWG 2004). The skin, with one of the largest body surface areas, absorbs approximately 50 to 70% of a topically applied PCP (Bronaugh et al. 1994). However, there are no available data for potential harmful effects of topical parabens exposure on immune-mediated skin irritations such as eczema or allergies (Savage et al. 2012). In a
THE SKIN: PRIMARY GATEWAY OF PARABEN ENTRY INTO THE BODY A number of in vitro and in vivo studies demonstrated that skin might absorb parabens, which are then readily detected in tissue, blood, and urine samples. In a comparative animal study, human skin was observed to retain parabens longer than skin of rats, suggesting a potential for prolonged estrogenic influence on human skin (Harville et al. 2007). In a related study, butylparaben was applied via a topical cream and was shortly thereafter detected in the blood of the human subjects (Janjua et al. 2007). Further, the absorption of methyl-, ethyl-, and propylparaben via the skin was found to be 60, 40, and 20%, respectively, 8 h after application, independent of different formulations of the creams (Pedersen et al. 2007). Analysis of plasma samples from 332 women showed median levels of 9.4 ng/ml methylparaben,
Journal of Toxicology and Environmental Health, Part B: Critical Reviews Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/uteb20
Parabens: Potential impact of Low-Affinity Estrogen receptor Binding chemicals on Human health a
a
Ebru Karpuzoglu , Steven D. Holladay & Robert M. Gogal Jr.
a
a
Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine , University of Georgia , Athens , Georgia , USA Published online: 02 Aug 2013.
To cite this article: Ebru Karpuzoglu , Steven D. Holladay & Robert M. Gogal Jr. (2013) Parabens: Potential impact of LowAffinity Estrogen receptor Binding chemicals on Human health, Journal of Toxicology and Environmental Health, Part B: Critical Reviews, 16:5, 321-335, DOI: 10.1080/10937404.2013.809252 To link to this article: http://dx.doi.org/10.1080/10937404.2013.809252
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
Journal of Toxicology and Environmental Health, Part B, 16:321–335, 2013 Copyright © Taylor & Francis Group, LLC ISSN: 1093-7404 print / 1521-6950 online DOI: 10.1080/10937404.2013.809252
PARABENS: POTENTIAL IMPACT OF LOW-AFFINITY ESTROGEN RECEPTOR BINDING CHEMICALS ON HUMAN HEALTH Ebru Karpuzoglu, Steven D. Holladay, Robert M. Gogal, Jr.
Downloaded by [Moskow State Univ Bibliote] at 10:40 04 December 2013
Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA Parabens, alkyl esters of p-hydroxybenzoic acid, are widely used in cosmetics, pharmaceuticals, personal care products and as food additives to inhibit microbial growth and extend product shelf life. Consumers of these compounds are frequently exposed via the skin, lips, eyes, oral mucosa, nails, and hair. Parabens are estrogenic molecules but exert weaker activity than natural estrogens, which would imply a low risk. Consistent with this idea, a number of recent commission reports from different countries suggested that parabens pose a negligible endocrine-disrupting risk at the recommended doses. However, individuals are not routinely exposed to a single paraben, and most of the available paraben toxicity data, reviewed in these reports, are from single-exposure studies. Further, assessing the additive and cumulative risk of multiple paraben exposure from daily use of multiple cosmetic and/or personal care products is presently not possible based on current studies. In this review, current and recent studies of paraben exposure and public health policies as well as critical gaps in the knowledge are discussed and new research directions regarding multiple exposures and novel target cohorts are recommended.
Parabens are alkyl esters of p-hydroxybenzoic acid widely used in cosmetics, including foundations, powders, eye shadows, mascara, lip glosses, lipsticks, and nail polishes, and in pharmaceuticals and personal care products (PCP) such as lotions, sunscreens, cleansers, shampoos, deodorants, hair care products, and toothpaste, which are in frequent contact with skin, lips, eyes, oral mucosa, nails, and hair. Tables 1 and 2 depict the frequency of use and percent of use of parabens in a select number of PCP and cosmetic products, respectively (CTFA 2008). Parabens are also common ingredients in food products used to inhibit microbial growth and extend product shelf life (Liao et al. 2013). The synthetic parabens include methyl-, ethyl-, propyl-, isobutyl-, butyl-, isopropyl-, and benzyl-, show increasing antimicrobial activity
with increasing alkyl chain length (Figure 1) (Darbre et al. 2002; 2003; Golden et al. 2005). The estrogen receptor binding affinities of parabens are 10,000- to 100,000-fold lower than for estrogen (17β-estradiol; shown in Figure 1 for comparison), and decrease in order as: isobutylparaben > butylparaben > isopropylparaben = propylparaben > ethylparaben (Vo et al. 2010). Such parabens have been in use for more than 80 years due to (1) antibacterial and fungicidal properties, (2) high stability at different pH and temperatures, (3) inertness, and (4) low cost, which has resulted in widespread, chronic human exposures (Daughton and Ternes 1999). This review focuses on current knowledge regarding potential effects of parabens on endocrineresponsive systems, including the reproductive, immune, and nervous systems.
Address correspondence to Robert M. Gogal, Jr., Department of Veterinary Biosciences and Diagnostic Imaging, College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7382, USA. E-mail: [email protected] 321
322
0.16–0.4% 0.07–0.4% 0.2–0.44% 0.15–0.4% 0.1–0.5% 0.0008–0.3% 0.15–0.4% 0.1–0.4% 0.1–0.4%
533 787 317 631 167 35 63 381 331
227 183
135 29 61
591 215 478
403
0.04–0.4% 0.03–0.2%
0.001–0.3% 0.002–0.2% 0.1–0.3%
0.05–0.35% 0.03–0.35% 0.1–0.4%
0.03–0.3%
0.16–0.7% 0.1–0.3% 0.1–0.5% 0.17–0.6% 0.15–1%
296 189 282 338 286
4 33
Baby products (number of products) Shampoos (38) Creams, lotions, oils, or powders (67) — 0.2–0.4%
0.15–0.5% 0.25–0.54% 0.13–0.6% 0.1–0.35% 0.07–0.4%
613 213 485 77 67
4 31
520
325 193 250 308
541 190 477 83 45
0.1% 0.2%
0.1–0.62%
0.05–0.4% 0.02–0.5% 0.1–0.5% 0.1–0.6%
0.1–0.5% 0.1–0.32% 0.05–0.4% 0.13–0.2% 0.05–0.15%
Percent in product
Frequency of use
Percent in product
Frequency of use
Eyes (number of products) Eye shadow (1061) Mascara (308) Eyeliner (liquid or pencil) (639) Eyebrow pencil (124) Eye makeup remover (114) Face (number of products) Foundations (530) Makeup Base (i.e., primers) (273) Powders (447) Blushes (cream or powder) (459) Lips Lipstick (1681)
Cosmetic products
Propylparaben
Methylparaben
TABLE 2. Frequency of use and percent concentration of parabens in cosmetic products
Cleansing creams, lotions, or gels (1009) Moisturizers (1200) Face and neck skin care (546) Body skin care (creams, lotions etc.) (992) Night skin care (229) Deodorants (281) Sunscreen skin care (Creams, gels, sprays, lotions) (138) Shampoos (1022) Hair conditioners (715)
PCP (number of products)
Percent in product
Propylparaben Frequency of use
Frequency of use
Percent in product
Methylparaben
0.03–0.2% 0.001–0.3%
0.0001–0.25% 0.002–0.1% 0.04–0.2%
0.001–0.3% 0.03–0.3% 0.001–0.4%
0.0006–0.54%
Percent in product
1 12
72
150 35 119 84
295 127 23 5 17
Frequency of use
— —
0.0002–0.2%
0.001–0.5% 0.00006–0.35% 0.04–0.5% 0.04–0.3%
0.06–0.49% 0.00002–0.4% 0.03–0.4% 0.4% 0.03–0.3%
Percent in product
Ethylparaben
108 33
64 10 22
268 169 153
181
Frequency of use
Ethylparaben
TABLE 1. Frequency of use and percent concentration of parabens in Personal Care Products (PCP)
0.01–0.25% 0.02–0.25%
0.04–0.15% 0.002% 0.03–0.4%
0.06–0.2% 0.09–0.4% 0.09–0.4%
0.0006–0.54%
Percent in product
2 21
218
96 51 67 35
199 80 398 60 27
Frequency of use
— 0.05%
0.0008–0.1%
0.06–0.2% 0.00006–0.1% 0.07–0.14% 0.07–0.2%
0.05–0.3% 0.00002–0.21% 0.05–0.2% 0.05–0.1% 0.07–0.15%
Percent in product
Butylparaben
108 49
65 10 28
278 157 157
195
Frequency of use
Butylparaben
Downloaded by [Moskow State Univ Bibliote] at 10:40 04 December 2013
0.02–0.1% 0.01–0.02%
— 0.002% 0.02%
0.0002–0.02% 0.02–0.09% 0.02–0.4%
0.003–0.1%
1 5
11
15 1 6 2
3 17 9 4 6
Frequency of use
— —
0.0001–0.4%
0.00001–0.06% 0.00003–0.02% 0.00001–0.04% 0.00001–0.04%
0.05–0.4% 0.000007–0.1% 0.02–0.1% 0.06% 0.02%
Percent in product
Isobutylparaben
38 12
14 3 9
67 75 52
67
Percent in product
Isobutylparaben Frequency of use
POTENTIAL HEALTH IMPACT OF PARABENS
CH3
323
CH3
HO CH 3 methylparaben
ethylparaben
CH CH33 propylparaben
CH3 butylparaben
Downloaded by [Moskow State Univ Bibliote] at 10:40 04 December 2013
CH3 CH3 isopropylparaben
recent study, blood samples from 268 pregnant women all showed traces of at least several of the 163 different chemicals evaluated, including parabens used in PCP (Woodruff et al. 2011). In addition to adult exposure, children up to 9 yr of age are exposed to approximately 61 PCP ingredients daily, suggesting potential endocrine-modulating effects (EWG 2007). Collectively, these reports suggest that parabens exposure frequency and concentration vary significantly by individual, and exposure is widespread in adults and children of both genders, with women on average receiving the highest exposure.
17β-estradiol
FIGURE 1. The structure of parabens and estrogen (17βestradiol).
PARABEN PRODUCTION AND SOURCES In a 1984 study, greater than 13,000 cosmetic products were found to contain parabens (Elder 1984), and by 1987 approximately 7000 kg of parabens was used annually in cosmetics and PCP (Soni et al. 2005). Given that the number and type of PCP and cosmetics have increased since the 1980s, it is reasonable to predict that the percentage of products containing parabens and thus frequency of human exposure to these chemicals have also risen in societies where cosmetics and PCP are in constant use. One question that remains unresolved is whether frequent exposure to varying concentrations of these weakly estrogenic compounds poses a threat to humans, in particular, estrogen-sensitive human cohorts. In a 2004 survey, the Environmental Working Group (EWG) reported that women on average used 12 PCP containing a total of 168 ingredients per day, whereas men used approximately 10 products with a total of 85 ingredients daily (EWG 2004). The skin, with one of the largest body surface areas, absorbs approximately 50 to 70% of a topically applied PCP (Bronaugh et al. 1994). However, there are no available data for potential harmful effects of topical parabens exposure on immune-mediated skin irritations such as eczema or allergies (Savage et al. 2012). In a
THE SKIN: PRIMARY GATEWAY OF PARABEN ENTRY INTO THE BODY A number of in vitro and in vivo studies demonstrated that skin might absorb parabens, which are then readily detected in tissue, blood, and urine samples. In a comparative animal study, human skin was observed to retain parabens longer than skin of rats, suggesting a potential for prolonged estrogenic influence on human skin (Harville et al. 2007). In a related study, butylparaben was applied via a topical cream and was shortly thereafter detected in the blood of the human subjects (Janjua et al. 2007). Further, the absorption of methyl-, ethyl-, and propylparaben via the skin was found to be 60, 40, and 20%, respectively, 8 h after application, independent of different formulations of the creams (Pedersen et al. 2007). Analysis of plasma samples from 332 women showed median levels of 9.4 ng/ml methylparaben,
