Toxicity and Endocrine Disrupting Effect of Parabens

파라벤류의 독성과 내분비계장애 효과

  • Ahn, Hae-Sun (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Nah, Won-Heum (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Lee, Jae-Eun (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Oh, Yeong-Seok (Department of Life Science, College of Natural Sciences, Hanyang University) ;
  • Gye, Myung-Chan (Department of Life Science, College of Natural Sciences, Hanyang University)
  • 안혜선 (한양대학교 자연과학대학 생명과학과) ;
  • 나원흠 (한양대학교 자연과학대학 생명과학과) ;
  • 이재은 (한양대학교 자연과학대학 생명과학과) ;
  • 오영석 (한양대학교 자연과학대학 생명과학과) ;
  • 계명찬 (한양대학교 자연과학대학 생명과학과)
  • Received : 2009.11.15
  • Accepted : 2009.11.26
  • Published : 2009.11.30

Abstract

Parabens are alkyl esters of p-hydroxybenzoic acid, which are widely used in foods, cosmetics, and pharmaceutic products as preservatives. Absorbed parabens are metabolized fastly and excreted. Actually human body is exposed to complex mixture of parabens. Safety assessment at various toxicological end points revealed parabens have a little acute, subacute and chronic toxicities. Some reports have argued that as parabens have estrogenic activity, they are associated with the incidence of breast cancer through dermal absorption by cosmetics. There is an inference that antiandrogenic activity of parabens may give rise to a lesion of male reproductive system, but also there is an contrary. At cellular level, parabens may inhibit mitochondrial function of sperms and androgen production in testis, but also there is an contrary. Parabens seem to have little or no toxicity in embryonic development. Parabens can cause hemolysis, membrane permeability change in mitochondria and apoptosis, suggesting cellular toxicity of parabens. Parabens evoked endocrine disruption in several fish species and have toxic effect on small invertebrates and microbes. Therefore, the toxicity of parabens should be considered as a potentially toxic chemical in the freshwater environment. In conclusion, though parabens may be considered as a low toxic chemical, more definite data are required concerning the endocrine disrupting effect of parabens on human body and aquatic animals according to route and term of exposure as well as the residual concentration of parabens.

파라벤은 p-하이드록시 벤조산(p-hydroxybenzoic acid)의 알킬에스테르로, 비교적 빠르게 흡수, 대사 및 배설되는 살균성 보존제로 식품, 화장품, 약품 등에 널리 사용되고 있다. 실제 인체는 파라벤 복합물에 노출된다. 파라벤의 안전성에 관한 연구결과들에 대한 고찰 결과 파라벤 종류에 따라 다양한 독성종말점을 대상으로 파라벤의 급성, 아급성 및 만성독성 영향은 비교적 적은 것으로 나타났다. 파라벤은 에스트로젠 유사활성을 가지며 화장품을 통한 경피흡수를 통해 유방암과의 상관성이 보고되었으나, 이와 상반된 견해도 있다. 파라벤의 항안드로젠성은 남성생식기계의 장애를 유발할 수 있으나 이와 상반된 견해도 있다. 파라벤은 정자의 미토콘드리아 기능 및 남성호르몬 생성을 저해할 수 있으나 이와 상반된 견해도 있다. 배아발달에는 독성이 없는 것으로 나타났다. 세포독성으로는 세포용혈, 미토콘드리아 막투과성 변화, 세포사멸 등을 유발할 수 있다. 수환경에서 파라벤은 환경에스트로젠으로 작동하여 어류에서 내분비장애 효과를 발휘한다. 결론적으로 파라벤은 저독성물질로 분류할 수 있으나, 인체 및 수생동물들에서 파라벤의 노출경로 및 농도, 사용기간 등에 따른 독성과 내분비계장애 효과에 대하여는 다양한 종말점을 대상으로 좀 더 구체적인 독성자료들이 요구된다.

Keywords

References

  1. Alslev B, B Korsgaard and P Bjerregaard. 2005. Estrogenicity of butylparaben in rainbow trout Oncorhynchus mykiss exposed via food and water. Aquat. Toxicol. 72:295-304 https://doi.org/10.1016/j.aquatox.2005.01.005
  2. Andersen HR, AM Andersson, SF Arnold, H Autrup, M Barfoed, NA Beresford, P Bjerregaard, LB Christiansen, B Gissel, R Hummel, EB J${\o}$rgensen, B Korsgaard, R Le Guevel, H Leffers, J McLachlan, A M${\o}$ller, JB Nielsen, N Olea, A Oles-Karasko, F Pakdel, KL Pedersen, P Perez, NE Skakkeboek, C Sonnenschein and AM Soto, JP Sumpter, SM Thorpe and P Grardjean. 1999. Comparison of short-term estrogenicity tests for identification of hormone-sisrupting chemicals. Environ. Health Perspect. 107(Suppl. 1):89-108
  3. Applied Research Laboratories. 1939. Special Research Report
  4. Bairati GG, A Lombardo and G Tettamanti. 1994. The esters of p-hydroxy-benzoate (parabens) inhibit the release of lysosomal enzymes by mitogen-stimulated peripheral human lymphocytes in culture. Chlinica. Chimica. Acta. 224:147-157 https://doi.org/10.1016/0009-8981(94)90181-3
  5. Batts AH, C Marriott, GP Martin, CF Wood and SW Bond. 1990. The effect of some preservations used in nasal preparations on the mucus and ciliary components of mucociliary clearance. J. Pharm. Pharmacol. 42:145-151 https://doi.org/10.1111/j.2042-7158.1990.tb05374.x
  6. Beral V. 2003. Breast cancer and hormone replacement in the million women study. Lancet. 362:419-27 https://doi.org/10.1016/S0140-6736(03)14065-2
  7. Bjerregaard P, DN Anderson, KL Pedersen, KL Pedersen and B Korsgaard. 2003. Estrogenic effect of propylparaben (propylhydroxybenzoate) in rainbow trout Oncorhynchus mykiss after exposure via food and water. Comp. Biochem. Physiol. C 136:309-317 https://doi.org/10.1016/j.cca.2003.10.004
  8. Blair RM, H Fang, WS Branham, BS Hass, SL Dial, CL Moland, W Tong, L Shi, R Perkins and DM Sheehan. 2000. The estrogen receptor binding affinities of 188 natural and xenochemicals: structural diversity of ligands. Toxicol. Sci. 534:138-153
  9. CTFA. 1980c. Acute oral, dermal and mucus membrane toxicity testing of product containing butyl paraben and propyl paraben. CTFA Code No. 2-7-52
  10. Darbre PD, A Aljarrah, WR Miller, NG Coldham, MJ Sauer and GS Pope. 2004. Concentrations of parabens in human breast tumours. J. Appl. Toxicol. 24:5-13 https://doi.org/10.1002/jat.958
  11. Darbre PD, JR Byford, LE Shaw, RA Horton, GS Pope and MJ Sauer. 2002. Oestrogenic activity of isobutylparaben in vitro and in vivo. J. Appl. Toxicol. 22:219-226 https://doi.org/10.1002/jat.860
  12. Darbre PD, JR Byford, LE Shaw, S Hall, NG Coldham, GS Pope and MJ Sauer. 2003. Oestrogenic activity of benzylparaben. J. Appl. Toxicol. 23:43-51 https://doi.org/10.1002/jat.886
  13. Darbre PD and PW Harvey. 2008. Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks. J. Appl. Toxicol. 28:561-567 https://doi.org/10.1002/jat.1358
  14. Daston GP. 2004. Developmental toxicity evalultion of butylparaben in Sprague-Dawley rats. Birth Defects Res., Part B, Dev. Reprod. Toxicol. 71:296-302 https://doi.org/10.1002/bdrb.20016
  15. Dhooge W, N van Larebeke, G Koppen, V Nelen, G Schoeters and R Vlietinck. 2006. Serum dioxin-like activity is associated with reproductive parameters in young men from the general Flemish population. Environ. Health Perspect. 114:1670-1676
  16. Elder RL. 1984. The cosmetic ingredient review-a safety evaluation program. J. Am. Acad. Dermatol. 11:1168-1174 https://doi.org/10.1016/S0190-9622(84)80205-4
  17. FDRL. 1972. Teratologic evaluation of FDA 71-38 (methyl paraben) U.S. NTIS report (PB-221 785), pp42
  18. Fisher JS, KJ Turner, D Brown and RM Sharpe. 1999. Effect of neonatal exposure to estrogenic compounds on deelopment of the excurrent ducts of the rat testis through puberty to adulthood. Environ. Health Persp. 107:397-405 https://doi.org/10.1289/ehp.99107397
  19. Fitak B and S Krauz. 1969. Effect of preservative agents on the content of nucleic acids and proteins in animal cells in tissue culture. II. Effect of preservative agents on animal cells. Rocz. Panstw. Zakl. Hig. 20:698-710
  20. Frederiksen H, C Taxvig, U Hass, AM Vinggaard and C Nellemann. 2008. Higher levels of ethyl paraben and butyl paraben in rat amniotic fluid than in maternal plasma after subcutaneous administration. Toxicol. Sci. 106:376-383 https://doi.org/10.1093/toxsci/kfn171
  21. Glander HG, M Rytter and C Schonborn. 1984. Studies on the mycotic and bacterial risk of contamination and the use of nipagin in the artificial insemination of cryosperm. Zentralbl. Gynakol. 106:573-584
  22. Golden R, J Gandy and G Vollmer. 2005. A review of the endocrine; activity of parabens and implications for potential risks to human health. Crit. Rev. Toxicol. 35:435-458 https://doi.org/10.1080/10408440490920104
  23. Hagedorn-Leweke U and BC Lippold. 1995. Absorption of sunscreens and other comjpounds through human skin in vivo: derivation of a method to predict maximum fluxes. Pharm. Res. 12:1354-1360 https://doi.org/10.1023/A:1016286026462
  24. Hamilton JT, Y Zhou and AW Gelb. 1990. Paraben preservatives but not succinylcholine are cerebral vasodilators in vitro. Anesthesiology 73:1252-1257 https://doi.org/10.1097/00000542-199012000-00025
  25. Handa O, S Kokura, S Adachi, T Takigi, Y Naito, T Tanigawa, N Yoshida and T Yoshikaw. 2006. Methylparaben potentiates UV-induced damage of skin keratinocytes. Toxicol. 227:62-72 https://doi.org/10.1016/j.tox.2006.07.018
  26. Harvey PW. 2003. Parabens, oestrogenicity, underarm cosmetics and breast cancer: a perspective on a hypothesis. J. Appl. Toxicol. 23:285-288 https://doi.org/10.1002/jat.946
  27. Harvey PW. 2005. Comment on developmental toxicity evaluation of butylparaben in Sprague-Dawley rats. Birth Defects Res. B Dev. Reprod. Toxicol. 74:114-115 https://doi.org/10.1002/bdrb.20033
  28. Harvey PW and P Darbre. 2004. Endocrine Disrupters and Human Health: Could oestrogenic chemicals in body care cosmetics adversely affect breast cancer incidence in women? J. Appl. Toxicol. 24:167-176 https://doi.org/10.1002/jat.978
  29. Harvey PW and DJ Everett. 2006. Significance of the detection of esters of p-hydroxybenzoic acid (parabens) in human breast tumours. J. Appl. Toxicol. 24:1-4
  30. Hoberman AL, DK Schreur, T Leazer, GP Daston and P Carthew. 2008. Lack of effect of butylparaben and methyoparaben on the reproductive system in male rats. Birth Def. Res. (Part B) 83:123-133 https://doi.org/10.1002/bdrb.20153
  31. Hossaini A, JJ Larsen and JC Larsen. 2000. Lack of oestrogenic effects of food preservaives (parabens) in uterrotrophic assays. Food Chem. Toxicol. 38:319-323 https://doi.org/10.1016/S0278-6915(99)00160-X
  32. Inui M, T Adachi, S Takenaka, H Inui, M Nakazawa, M Ueda, H Watanabe, C Mori, T Iguchi and K Miyatake. 2003. Effect of UV screens and preservatives on vitellogenin and choriogenin production in male medaka (Oryzias latipes). Toxicology 194:43-50 https://doi.org/10.1016/S0300-483X(03)00340-8
  33. Inai Y, H Aoki, R Akamizu, ET Nishida and S Tokuoka. 1985. Tumorigenicity study of butyl and isobutyl p-hydroxybenzoates administered orally to mice. Food Chem. Toxicol. 23:575-578 https://doi.org/10.1016/0278-6915(85)90181-4
  34. Ishidate MJ and K Yoshikawa. 1980. Chromosome aberration tests with Chinese hamster cells in vitro with and without metabolic activation-A comparative study on mutagens and carcinogens. Arch. Toxicol. 4:41-44
  35. Jackson EM. 1992. Moisturizers of today. J. Toxicol. Cutaneous Ocul. Toxicol. 11:173-184 https://doi.org/10.3109/15569529209042706
  36. Janjua NR, GK Mortensen, AM Andersson, B Kongshoj, NE Skakkebaek and HC Wulf. 2007. Systemic uptake of diethyl phthalate, dibutyl phthalate, and butyl paraben following whole-body topical application and reproductive and thyroid hormone levels in humans. Environ. Sci. Technol. 41:5564-5570 https://doi.org/10.1021/es0628755
  37. Jian L and WP Li. 1993a. Ciliotoxicity of methyl- and propylp- hydroxy-benzoates a dose-response and surface-response study. J. Pharmacy and Pharmacol. 45:925-927 https://doi.org/10.1111/j.2042-7158.1993.tb05624.x
  38. Jian L and WP Li. 1993b. Kinetics evaluation of the ciliotoxicity of methyl- and propyl-p-hydroxybenzoates using factorial experiments. J. Pharmacy and Pharmacol. 45:98-101 https://doi.org/10.1111/j.2042-7158.1993.tb03691.x
  39. Kang KS, JH Che, DY Ryu, TW Kim, GX Li and YS Lee. 2002. Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl $\rho$-hydroxybenzoic acid (butyl paraben). J. Vet. Med. Sci. 64:227-235 https://doi.org/10.1292/jvms.64.227
  40. Kawaquchi M, K Morohoshik, J Masuda, G Watanabe, M Morita, H Imai, K Taya and T Himi. 2009. Maternal isobutylparaben exposure decreases the plasma corticosterone level in dams and sensitivity to estrogen in female offspring rats. J Vet. Med. Sci. 71:1027-1033 https://doi.org/10.1292/jvms.71.1027
  41. Koda T, T Unezu, R Kamata, K Morohoshi, T Ohta and M Morita. 2005. Uterotrophic effects of benzophenone derivatives and p-hydroxybenzoate used in ultraviolet screens. Environ. Res. 98:40-45 https://doi.org/10.1016/j.envres.2004.05.015
  42. Lakeram M, AJ Paine, DJ Lockley, DJ Sanders, R Pendlington and B Forbes. 2006. Transesterification of p-hydroxybenzoic acid esters (parabens) by human intestinal (Caco-s) cells. Xenobiotica 36:739-749 https://doi.org/10.1080/00498250600738637
  43. Leite AM. 2006. Estudo de desreguladores endocrinos numa Estacao de Tratamento de Aguas Residuais (Master thesis). Vila Real: University of Tras-os-Montes and Alto Douro
  44. Lemini C, R Jaimez, ME Avila, Y Franco, F Larrea and AE Lemus. 2003. In vivo and in vitro estrogen bioactivities of alkyl parabens. Toxicol. Ind. Health. 19:69-79 https://doi.org/10.1191/0748233703th177oa
  45. Lemini C, G Silva, C Timossi, D Luque, A Valverde, M Gonzalez-Marti, A Hernandez, C Rubio-Poo, B Chavez Lara and F Valezuela. 1997. Estrogenic effects of p-hydroxybenzoic acid in CD1 mice. Environ. Res. 75:130-134 https://doi.org/10.1006/enrs.1997.3782
  46. Maddox GL. 1982. Three perspectives on the 1981 White House Conference on Aging. Research Geronotologist 22:126-127 https://doi.org/10.1093/geront/22.2.126
  47. Manawadu BR, SR Mostow and FM Laforce. 1979. Impairment of tracheal ring ciliary activity by halothane. Anesth. Analg. 58:500-504
  48. Martins F, A Margarida, MM Oliveira, PJ Oliveira, P Francisco and FP Peixoto. 2008. Toxicity of parabens in testis mitochondria: a possible role on male infertility. Biochim. Biophys. Acta-Bioenergetics 1777:s60-61
  49. Matthews C, J Davidson, E Bauer, JL Morrison and AP Richardson. 1956. p-Hydroxybenzoic acid esters as preservatives. II. Acute and chronic toxicity in dogs, rats, and mice. J. Am. Pharm. Assoc. (Baltim) 45:260-267 https://doi.org/10.1002/jps.3030450420
  50. McGrath KG. 2003. An earlier age of breast cancer diagnosis related to more frequent use of antiperspirants/deodorants and underarm shaving. Eur. J. Cancer Prev. 12:479-485 https://doi.org/10.1097/00008469-200312000-00006
  51. Mikula P, R Dobsikova, Z Svobodova and J Jarkovsky. 2006. Evaluation of xenoestrogenic potential of propylparaben in zebrafish (Danio rerio). Neuro Endocrinol. Lett. 27:104-107
  52. Mirick DK, S David and DB Thomas. 2002. Antiperspirant use and the risk of breast cancer. J. Natl. Cancer. Inst. 94:1578-1580 https://doi.org/10.1093/jnci/94.20.1578
  53. Mizuno H, H Hirai, S Kawai and T Nishida. 2009. Removal of estrogenic activity of iso-butylparaben and n-butylparaben by laccase in the presence of 1-hydroxybenzotriazole. Biodegradation 20:533-539 https://doi.org/10.1007/s10532-008-9242-y
  54. Nakagawa Y and P Moldeus. 1998. Mechanism of p-hydroxybenzoate ester-induced mitochondrial dysfunction and cytotoxicity in isolated rat hepatocytes. Biochem. Pharmacol. 55:1907-1914 https://doi.org/10.1016/S0006-2952(98)00097-5
  55. Nakagawa Y and G Moore. 1999. Role of mitochondrial membrane permeability transition in p-hydroxybenzoate esterinduced cytotoxicity in rat hepatocytes. Biochem. Pharmacol. 58:811-816 https://doi.org/10.1016/S0006-2952(99)00147-1
  56. Nes IF and T Eklund. 1983. The effects of paraben on DNA, RNA and protein-synthesis in Escherichia coli and Bacillus subtilis. J. Appl. Bacteriol. 54:237-242 https://doi.org/10.1111/j.1365-2672.1983.tb02612.x
  57. Oishi S. 2001. Effects of butylparaben on the male reproductive system in rat. Toxicol. Ind. Health 17:31-39 https://doi.org/10.1191/0748233701th093oa
  58. Oishi S. 2002a. Effects of propylparaben on the male reproductive system. Food Chem. Toxicol. 40:1807-1813 https://doi.org/10.1016/S0278-6915(02)00204-1
  59. Oishi S. 2002b. Effects of butylparaben on the male reproductive system in mice. Arch. Toxicol. 76:423-429 https://doi.org/10.1007/s00204-002-0360-8
  60. Oishi S. 2004. Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. Food. Chem. Toxicol. 42:1845-1849 https://doi.org/10.1016/j.fct.2004.06.015
  61. Okamoto Y, T Hayashi, S Matsunami, K Ueda and N Kojima. 2008. Combined activation of methyl paraben by light irradiation and esterase metabolism toward oxidative DNA damage. Chem. Res. Toxicol 21:1594-1599 https://doi.org/10.1021/tx800066u
  62. Okubo T, Y Yokoyama and I Kano. 2001. ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ER$\alpha$ and PR. Food Chem. Toxicol. 39:1225-1232 https://doi.org/10.1016/S0278-6915(01)00073-4
  63. Orth DS. 1980. Use of parabens as cosmetic preservatives. Int. J. Dermatol. 19:504-505 https://doi.org/10.1111/j.1365-4362.1980.tb00369.x
  64. Paxeus N. 1996. Organic pollutants in the effluents of large wastewater treatment plants in Sweden. Water Res. 30:1115-1122 https://doi.org/10.1016/0043-1354(95)00278-2
  65. Pedersen KL, SN Pedersen, LB Christiansen, B Korsgaard and P Bjerregaard. 2000. The preservatives ethyl-, propyl- and butylparaben are oestrogenic in an in vivo fish assay. Pharmacol. Toxicol. 86:110-113 https://doi.org/10.1034/j.1600-0773.2000.d01-20.x
  66. Prusakiewicz JJ, HM Harville, Y Zhang, C Ackermann and RL Voorman. 2007. Parabens inhibit human skin estrogen sulfotransferase activity: possible link to paraben estrogenic effects. Toxicology 232:248-256 https://doi.org/10.1016/j.tox.2007.01.010
  67. Pugazhendhi D, AJ Sadler and PD Darbre. 2007. Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J. Appl. Toxicol. 2:67-77
  68. Rastogi SC, A Schouten, N de Kruijf and JW Weijland. 1995. Contents of methyl-, ethyl-, propyl-, butyl- and benzylparaben in cosmetic products. Contact Derm. 32:28-30 https://doi.org/10.1111/j.1600-0536.1995.tb00836.x
  69. Routledge EJ, J Parker, J Odum, J Ashby and JP Sumpter. 1998. Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. Toxicol. Appl. Phrmacol. 153:12-19 https://doi.org/10.1006/taap.1998.8544
  70. Sabalitschka T and R Neufeld-Crzelliter. 1954. Behavior of phydroxybenzoic acid in human body. Arzneimittel-Forsch. 4:575-579
  71. Sado I. 1973. Synergistic toxicity of official permissible preservative food additives, Jap. J. Hygiene 28:463-476 https://doi.org/10.1265/jjh.28.463
  72. Sharpe RM and NE Skakkebaek. 1993. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 341:1392-1395 https://doi.org/10.1016/0140-6736(93)90953-E
  73. Shaw J and D de Catanzaro. 2009. Estrogenicity of parabens revisited: impact of parabens on early pregnancy and an uterotrophic assay in mice. Reprod. Toxicol. 28:26-31 https://doi.org/10.1016/j.reprotox.2009.03.003
  74. Sheu CW, D Salomon, JL Simmons, T Sreevalsan and E Freese. 1975. Inhibitory effects of lipophilic acids and related compounds on bacteria and mammalian cells. Anrimicrob. Agents Chemotherapy 7:349-363 https://doi.org/10.1128/AAC.7.3.349
  75. Sokol H. 1952. Recent developments in the preservations of pharmaceuticals. Drug Standards 20:89-106
  76. Song BL, HY Li and DR Peng. 1989. In vitro spermicidal activity of parabens against human-spermatozoa. Contraception 39:331-335 https://doi.org/10.1016/0010-7824(89)90065-6
  77. Song BL, DR Peng, HY Li, GH Zhang, J Zhang, KL Li and TQ Zhao. 1991. Evaluation of the effect of butyl p-hydroxybenzoate on the proteolytic activity and membrane function of human spermatozoa. J. Reprod. Fertil. 91:435-440 https://doi.org/10.1530/jrf.0.0910435
  78. Soni MG, GA Burdock, SL Taylor and NA Greenberg. 2001. Safety assessment of propyl paraben: a review of the published literature. Food Chem. Toxicol. 39:513-532 https://doi.org/10.1016/S0278-6915(00)00162-9
  79. Soni MG, SL Taylor, NA Greenberg and GA Burdock. 2002. Evaluation of the health aspects of methyl paraben: a review of the published literature. Food Chem. Toxicol. 40:1335-1373 https://doi.org/10.1016/S0278-6915(02)00107-2
  80. Soni MG, IG Carabin and GA Brdock. 2005. Safety assessment of esters of p-hydroxybenzoic acid (parabens). Food Chem. Toxicol. 43:985-1015 https://doi.org/10.1016/j.fct.2005.01.020
  81. Soto AM, C Sonnenschein, KL Chung, MF Fernandez, N Olea and FO Serrano. 1995. The E-screen assay as a tool to identify estrogens:an update on estrogenic environmental pollutants. Environ. Health Perspect. 103:113-122
  82. Tavares RS, FC Martins, PJ Oliveira, J Ramalho-Santos and FP Peixoto. 2009. Parabens in male infertility-Is there a mitochondrial connection? Reprod. Toxicol. 27:1-7 https://doi.org/10.1016/j.reprotox.2008.10.002
  83. Taxvig C, AM Vinggaard, U Hass, M Axelstad, J Boberg, PR Hansen, H Frederiksen and C Nellemann. 2008. Do paragens have the ability to interfere with steroidogenesis? Toxicol. Sci. 106:206-213 https://doi.org/10.1093/toxsci/kfn148
  84. Terasaki M, M Makino and N Tatarazako. 2009. Acute toxicity of parabens and their chlorinated by-products with Daphnia magna and Vibrio fischeri bioassays. J. Appl. Toxicol. 29:242-247 https://doi.org/10.1002/jat.1402
  85. Tsukamoto H and S Terada. 1964. Metabolism of drugs. XLVII. Metabolic fate of p-hydroxybenzoic acid and its derivatives in rabbits. Chemical and Pharmaceutical Bull. 12:765-769 https://doi.org/10.1248/cpb.12.765
  86. Verma RJ and V Asnani. 2007. Ginger extract amiliorates paraben induced biochemical changes in liver and kidney of mice. Acta. Pol. Pharm. 64:217-220
  87. Vo TT and EB Jeung. 2009. An evaluation of estrogenic activity of parabens using uterine calbindin-D9K gene in an immatuve rat model. Toxicol. Sci. 112:68-77 https://doi.org/10.1093/toxsci/kfp176