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Paraben

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General chemical structure of a paraben
(a para-hydroxybenzoate)
where R = an alkyl group

Parabens are a class of widely used preservatives in cosmetic and pharmaceutical products. Chemically, they are a series of parahydroxybenzoates or esters of parahydroxybenzoic acid (also known as 4-hydroxybenzoic acid). Parabens are effective preservatives in many types of formulas. These compounds, and their salts, are used primarily for their bactericidal and fungicidal properties. They can be found in shampoos, commercial moisturizers, shaving gels, personal lubricants, topical/parenteral pharmaceuticals, spray tanning solution, makeup,[1] and toothpaste. They are also used as food additives.

Their efficacy as preservatives, in combination with their low cost, the long history of their use, and the inefficacy of some natural alternatives like grapefruit seed extract (GSE),[2] probably explains why parabens are so commonplace. No effective direct links between parabens and cancer have been established.[3] However, there is concern that the estrogen-mimicking aspect of parabens may be a factor in the increasing prevalence of early puberty in girls.[4]

Chemistry

Parabens are esters of para-hydroxybenzoic acid, from which the name is derived. Common parabens include methylparaben (E number E218), ethylparaben (E214), propylparaben (E216), butylparaben and heptylparaben (E209). Less common parabens include isobutylparaben, isopropylparaben, benzylparaben and their sodium salts. The general chemical structure of a paraben is shown at the top right of this page, where R symbolizes an alkyl group such as methyl, ethyl, propyl or butyl.

Synthesis

All commercially used parabens are synthetically produced, although some are identical to those found in nature. They are produced by the esterification of para-hydroxybenzoic acid with the appropriate alcohol, such as methanol, ethanol, or n-propanol. para-Hydroxybenzoic acid is in turn produced industrially from a modification of the Kolbe-Schmitt reaction, using potassium phenoxide and carbon dioxide.

Toxicology

Studies on the acute, subchronic, and chronic effects in rodents indicate that parabens are practically non-toxic.[5][6] Parabens are rapidly absorbed, metabolized, and excreted.[5] The major metabolites of parabens are p-hydroxybenzoic acid (pHBA), p-hydroxyhippuric acid (M1), p-hydroxybenzoyl glucuronide (M3), and p-carboxyphenylsulfate (M4).[7]

Allergic reactions

In individuals with normal skin, parabens are, for the most part, non-irritating and non-sensitizing. Parabens can, however, cause skin irritation and contact dermatitis and rosacea in individuals with paraben allergies, a small percentage of the general population.[8]

Breast cancer

Average levels of 20 nanograms/gram of parabens have been detected in a small sample of 20 breast tumors.[9] No link can be determined from current studies, and more research is called for.[10][11][12]

The lead researcher of the UK study, molecular biologist Philippa Darbre, reported that the ester-bearing form of the parabens found in the tumors indicate that they came from something applied to the skin, such as an underarm deodorant, cream or body spray, and stated that the results helped to explain why up to 60% of all breast tumors are found in just one-fifth of the breast - the upper-outer quadrant, nearest the underarm[10] (though this is controversial[13]). "From this research it is not possible to say whether parabens actually caused these tumors, but they may certainly be associated with the overall rise in breast cancer cases. Given that breast cancer is a large killer of women and a very high percentage of young women use underarm deodorants, I think we should be carrying out properly funded, further investigations into parabens and where they are found in the body," says Philip Harvey, an editor of the Journal of Applied Toxicology, which published the research.[10] A 2004 study at Northwestern University found that an earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving.[14] "I personally feel there is a very strong correlation between the underarm hygiene habits and breast cancer," said immunologist Dr. Kris McGrath, the author of the study.[11]

This research has fueled a popular belief that the parabens in underarm deodorants and other cosmetics can migrate into breast tissue and contribute to the development of tumors.

However, no direct evidence of a causal link between parabens and cancer has been shown. A 2005 review of the data available at that time concluded "it is biologically implausible that parabens could increase the risk of any estrogen-mediated endpoint, including effects on the male reproductive tract or breast cancer" and that "worst-case daily exposure to parabens would present substantially less risk relative to exposure to naturally occurring endocrine active chemicals in the diet such as the phytoestrogen daidzein."[3] The American Cancer Society also concluded that there was insufficient scientific evidence to support a claim that use of cosmetics such as antiperspirants increase an individual's risk of developing breast cancer.[15]

Most of the available paraben toxicity data are from single-exposure studies. Further assessment of the additive and cumulative risk of multiple paraben exposure from daily use of multiple cosmetic and/or personal care products is needed. [16]

Estrogenic activity

Animal experiments have shown that parabens have weak estrogenic activity, acting as xenoestrogens.[17] In an in vivo study, the effect of butylparaben was determined to be approximately 100,000 times weaker than that of estradiol, and was only observed at a dose level approximately 25,000 times higher than the level typically used to preserve products.[18] The study also found that the in vivo estrogenic activity of parabens is reduced by about three orders of magnitude compared to in vitro activity.

The estrogenic activity of parabens increases with the length of the alkyl group. It is believed that propylparaben is estrogenic to a certain degree as well,[19] though this is expected to be less than butylparaben by virtue of its less lipophilic nature. Since it can be concluded that the estrogenic activity of butylparaben is negligible under normal use, the same should be concluded for shorter analogs.

Some estrogens are known to drive the growth of tumors; however the estrogenic activity and mutagenic activity of estrogens are not the same, with the latter dependent on free radical chemistry and not estrogen receptor activity.[20] Nonetheless, this study has elicited some concern about the use of butylparaben, and to a lesser extent other parabens as well, in cosmetics and antiperspirants. A 2005 safety assessment of parabens concluded that cosmetics containing parabens do not, on the basis of currently available evidence, pose a health risk; because of the low doses involved and the low probability that parabens will penetrate into the tissue, remain intact, and accumulate there.[5]

Sun exposure

Studies indicate that methylparaben applied on the skin may react with UVB leading to increased skin aging and DNA damage.[21][22]

Regulation

The European Scientific Committee on Consumer Products (SCCP) stated in 2006 that the available data on parabens do not enable a decisive response to the question of whether propyl, butyl and isobutyl paraben can be safely used in cosmetic products at individual concentrations up to 0.4%, which is the allowed limit in the EU.[23]

Controversy

The above-mentioned studies have sparked scientific debate that in turn led to popular controversy, largely propagated by mass e-mail.[24][25] Darbre's paper led to further discussion over possible carcinogenicity and estrogenic effects being expressed over the continued use of parabens as preservatives.[26][27]

The mainstream cosmetic industry believes that parabens, like most cosmetic ingredients, are safe based on their long term use and safety record and recent scientific studies.[28][29] Public interest organizations which raise awareness about cosmetic ingredients believe that further research is necessary to determine the safety of parabens, under the precautionary principle.[27] The concerns about endocrine disruptors have led consumers and companies to search for paraben-free alternatives.[30] Grapefruit seed extract that is promoted as a natural preservative was identified as containing artificial preservatives such as methylparaben.[2]

See also

References

  1. ^ (www.fda.gov)
  2. ^ a b von Woedtke T, Schluter B, Pflegel P, Lindequist U, Julich WD (June 1999). "Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation to preservative substances contained". Pharmazie. 54 (6). Greifswald, Germany: Institute of Pharmacy, Ernst Moritz Arndt University,: 452–6. PMID 10399191.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  3. ^ a b Golden R, Gandy J, Vollmer G (2005). "A review of the endocrine activity of parabens and implications for potential risks to human health". Critical Reviews in Toxicology. 35 (5): 435–58. doi:10.1080/10408440490920104. PMID 16097138.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Weil, Elizabeth (March 30, 2012). "Puberty Before Age 10: A New 'Normal'?". The New York Times.
  5. ^ a b c Soni MG, Carabin IG, Burdock GA (2005). "Safety assessment of esters of p-hydroxybenzoic acid (parabens)". Food and Chemical Toxicology. 43 (7): 985–1015. doi:10.1016/j.fct.2005.01.020. PMID 15833376.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Soni MG, Taylor SL, Greenberg NA, Burdock GA (2002). "Evaluation of the health aspects of methyl paraben: a review of the published literature". Food and Chemical Toxicology. 40 (10): 1335–73. doi:10.1016/S0278-6915(02)00107-2. PMID 12387298.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Anon, "Final Amended Report on the Safety Assessment of Methylparaben, Ethylparaben, Propylparaben, Isopropylparaben, Butylparaben, Isobutylparaben, and Benzylparaben as used in Cosmetic Products", Int. J. Toxicol. 2008, vol. 27, 1. doi:10.1080/10915810802548359
  8. ^ Nagel JE, Fuscaldo JT, Fireman P. Paraben allergy (April 11, 1977). "Paraben allergy". J Am Med Assoc. 237 (15): 1594–5. doi:10.1001/jama.237.15.1594. PMID 576658.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS (Jan–Feb 2004). "Concentrations of parabens in human breast tumours". J Appl Toxicol. 24 (1): 5–13. doi:10.1002/jat.958. PMID 14745841.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b c Vince G (12 January 2004). "Cosmetic chemicals found in breast tumours". New Scientist.
  11. ^ a b Lagorio, Christine (Dec 5, 2005). "The Cancer-Antiperspirant "Myth": Could Shaving And Antiperspirant Be Related To Breast Cancer?". CBS News. Retrieved 2 Jan 2009.
  12. ^ Harvey PW, Darbre P (2004). "Endocrine disruptors and human health: Could estrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women? A review of evidence and call for further research". Journal of Applied Toxicology. 24 (3): 167–76. doi:10.1002/jat.978. PMID 15211609.
  13. ^ Ed Friedlander MD (2 March 2010). "Anti-Perspirants -- Not a Breast Cancer Risk".
  14. ^ McGrath, Kris (December 2003). "An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving" (PDF). European Journal of Cancer Prevention. 12 (6): 479–85. doi:10.1097/00008469-200312000-00006. PMID 14639125.
  15. ^ The American Cancer Society Antiperspirants and Breast Cancer Risk
  16. ^ Parabens: potential impact of low-affinity estrogen receptor binding chemicals on human health. J Toxicol Environ Health B Crit Rev. 2013;16(5):321-35. http://www.ncbi.nlm.nih.gov/pubmed/23909435 doi: 10.1080/10937404.2013.809252.
  17. ^ Byford JR, Shaw LE, Drew MG, Pope GS, Sauer MJ, Darbre PD (January 2002). "Oestrogenic activity of parabens in MCF7 human breast cancer cells". J Steroid Biochem Mol Biol. 80 (1): 49–60. doi:10.1016/S0960-0760(01)00174-1. PMID 11867263.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ Edwin J. Routledge; et al. (1998). "Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic". Toxicology and Applied Pharmacology. 153 (1): 12–19. doi:10.1006/taap.1998.8544. PMID 9875295.
  19. ^ Cashman AL, Warshaw EM (June 2005). "Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties". Dermatitis. 16 (2): 57–66. doi:10.1097/01206501-200506000-00001. PMID 16036114.
  20. ^ Fernandez SV, Russo IH, Russo J (2006-04-15). "Estradiol and its metabolites 4-hydroxyestradiol and 2-hydroxyestradiol induce mutations in human breast epithelial cells". Int J Cancer. 118 (8): 1862–8. doi:10.1002/ijc.21590. PMID 16287077.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Osamu Handa, Satoko Adachi, Tomohisa Takagi; et al. (3 October 2006). "Methylparaben potentiates UV-induced damage of skin keratinocytes". Toxicology. 227 (1–2): 62–72. doi:10.1016/j.tox.2006.07.018. PMID 16938376.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Yoshinori Okamoto, Tomohiro Hayashi, Shinpei Matsunami, Koji Ueda, Nakao Kojima (July 26, 2008). "Combined activation of methyl paraben by light irradiation and esterase metabolism toward oxidative DNA damage". Chemical Research in Toxicology. 21 (8): 1594–9. doi:10.1021/tx800066u. PMID 18656963.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ SCCP: Opinion on Parabens. Colipa No P82 10 Oct 2006.
  24. ^ Jones J (September 20, 2000). "Can rumors cause cancer?". Journal of the National Cancer Institute. 92 (18): 1469–71. doi:10.1093/jnci/92.18.1469. PMID 10995800.
  25. ^ "Antiperspirants do NOT cause breast cancer". Breastcancer.org. August 15, 2008. Retrieved April 15, 2010.; "Link between antiperspirants and breast cancer?". Breastcancer.org. October 2, 2008. Retrieved May 3, 2012.; "Common Fears With No Evidence: Antiperspirants and Bras". Breastcancer.org. March 20, 2012. Retrieved May 3, 2012.
  26. ^ Harvey, PW; Everett, DJ (2004). "Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumours". Journal of applied toxicology : JAT. 24 (1): 1–4. doi:10.1002/jat.957. PMID 14745840.
  27. ^ a b Rita Arditti (June 9, 2004). "Cosmetics, parabens, and breast cancer". Organic Consumers Association.
  28. ^ "The truth about antiperspirants and breast cancer". Unilever.
  29. ^ "Underarm Hygiene Does Not Cause Breast Cancer". ChemistryViews.
  30. ^ Lebovits SC (May 26, 2008). "Cosmetics firms heed calls for organics". The Boston Globe.
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