Personal care products and endocrine disruption: A critical review of the literature

This article reviews laboratory and epidemiological research into the endocrine disruptive effects of components of personal care products, namely, phthalate esters, parabens, ultraviolet (UV) filters, polycyclic musks, and antimicrobials. High doses of phthalates in utero can produce “phthalate syndrome,” demasculinizing effects in male rat offspring due to impaired testosterone production by fetal testes. However, evidence linking phthalate exposure to similar effects in humans appears inconclusive. Furthermore, phthalate exposure derived from personal care products is within safe limits and its principal bioavailable phthalate, diethyl phthalate (DEP), does not produce “phthalate syndrome.” Parabens exhibit very weak estrogen activity in vitro and in vivo, but evidence of paraben-induced developmental and reproductive toxicity in vivo lacks consistency and physiological coherence. Evidence attempting to link paraben exposure with human breast cancer is nonexistent. Select UV filters at high doses produce estrogenic, antithyroid, and other effects in rats in vivo. Again, no evidence links UV filter exposure to endocrine disruptive effects in humans. Some polycyclic musks weakly bind to estrogen, androgen, or progestin receptors and exhibit primarily antagonistic activity in vitro, which for the most part, has yet to be confirmed in vivo in mammals. The antimicrobials triclocarban and triclosan evoke weak responses mediated by aryl hydrocarbon, estrogen, and androgen receptors in vitro, which require confirmation in vivo. Preliminary observations suggest a novel interaction between triclocarban and testosterone. In conclusion, although select constituents exhibit interactions with the endocrine system in the laboratory, the evidence linking personal care products to endocrine disruptive effects in humans is for the most part lacking.

[1]  N. Manabe,et al.  Conflict of estrogenic activity by various phthalates between in vitro and in vivo models related to the expression of Calbindin-D9k. , 2005, The Journal of reproduction and development.

[2]  M. Henseler,et al.  Endocrine Active UV Filters : Developmental Toxicity and Exposure Through Breast Milk , 2008 .

[3]  B. van der Burg,et al.  Endocrine effects of polycyclic musks: do we smell a rat? , 2008, International journal of andrology.

[4]  Richard A. Anderson,et al.  Edinburgh Research Explorer Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat , 2007 .

[5]  H. Jarry,et al.  Effects of estradiol, benzophenone-2 and benzophenone-3 on the expression pattern of the estrogen receptors (ER) alpha and beta, the estrogen receptor-related receptor 1 (ERR1) and the aryl hydrocarbon receptor (AhR) in adult ovariectomized rats. , 2004, Toxicology.

[6]  P. Foster,et al.  Study of the testicular effects and changes in zinc excretion produced by some n-alkyl phthalates in the rat. , 1980, Toxicology and applied pharmacology.

[7]  Russ Hauser,et al.  Phthalate exposure and reproductive hormones in adult men. , 2005, Human reproduction.

[8]  Shio‐Jean Lin,et al.  Association between prenatal exposure to phthalates and the health of newborns. , 2009, Environment international.

[9]  M. Soni,et al.  Safety assessment of esters of p-hydroxybenzoic acid (parabens). , 2005, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[10]  S. Oishi Effects of propyl paraben on the male reproductive system. , 2002, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[11]  J. Resko,et al.  Negative feedback regulation of gonadotropin secretion by androgens in fetal rhesus macaques. , 1985, Biology of reproduction.

[12]  R. Maronpot,et al.  Triclosan: A critical review of the experimental data and development of margins of safety for consumer products , 2010, Critical reviews in toxicology.

[13]  C. Lemini,et al.  Estrogenic effects of p-hydroxybenzoic acid in CD1 mice. , 1997, Environmental research.

[14]  Jorma Toppari,et al.  Human Breast Milk Contamination with Phthalates and Alterations of Endogenous Reproductive Hormones in Infants Three Months of Age , 2005, Environmental health perspectives.

[15]  Robert F. Herrick,et al.  Phthalate Exposure and Human Semen Parameters , 2003, Epidemiology.

[16]  N. Skakkebaek,et al.  Systemic uptake of diethyl phthalate, dibutyl phthalate, and butyl paraben following whole-body topical application and reproductive and thyroid hormone levels in humans. , 2007, Environmental science & technology.

[17]  Michael A. Kamrin,et al.  Phthalate Risks, Phthalate Regulation, and Public Health: A Review , 2009, Journal of toxicology and environmental health. Part B, Critical reviews.

[18]  H. Harville,et al.  Parabens inhibit human skin estrogen sulfotransferase activity: possible link to paraben estrogenic effects. , 2007, Toxicology.

[19]  V. Katch,et al.  Effects of exercise intensity on food consumption in the male rat. , 1979, The American journal of clinical nutrition.

[20]  A. Piersma,et al.  Aromatase inhibiting and combined estrogenic effects of parabens and estrogenic effects of other additives in cosmetics. , 2008, Toxicology and applied pharmacology.

[21]  L Earl Gray,et al.  Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[22]  J Ashby,et al.  Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic. , 1998, Toxicology and applied pharmacology.

[23]  R. Frydman,et al.  Phthalates Impair Germ Cell Development in the Human Fetal Testis in Vitro without Change in Testosterone Production , 2008, Environmental health perspectives.

[24]  J. Furr,et al.  A mixture of five phthalate esters inhibits fetal testicular testosterone production in the sprague-dawley rat in a cumulative, dose-additive manner. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[25]  G. S. Pope,et al.  Concentrations of parabens in human breast tumours , 2004, Journal of applied toxicology : JAT.

[26]  G. Daston Developmental toxicity evaluation of butylparaben in Sprague-Dawley rats. , 2004, Birth defects research. Part B, Developmental and reproductive toxicology.

[27]  A. Burdorf,et al.  The hypothalamus-pituitary-testis axis in boys during the first six months of life: a comparison of cryptorchidism and hypospadias cases with controls. , 2009, International journal of andrology.

[28]  M. Denison,et al.  In Vitro Biologic Activities of the Antimicrobials Triclocarban, Its Analogs, and Triclosan in Bioassay Screens: Receptor-Based Bioassay Screens , 2008, Environmental health perspectives.

[29]  Bart van der Burg,et al.  Interaction of polycyclic musks and UV filters with the estrogen receptor (ER), androgen receptor (AR), and progesterone receptor (PR) in reporter gene bioassays. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[30]  J. G. Vandenbergh,et al.  A Mixture of the “Antiandrogens” Linuron and Butyl Benzyl Phthalate Alters Sexual Differentiation of the Male Rat in a Cumulative Fashion1 , 2004, Biology of reproduction.

[31]  B. Bernard Studies of the Toxicological Potential of Tripeptides (L-Valyl-L-prolyl-L-proline and L-lsoleucyl-L-prolyl-L-proline): I. Executive Summary , 2005 .

[32]  L. Gray,et al.  Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p′-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproduc , 1999, Toxicology and industrial health.

[33]  R. Witorsch Low-dose in utero effects of xenoestrogens in mice and their relevance to humans: an analytical review of the literature. , 2002, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[34]  R. Kiyama,et al.  Evaluation of estrogenic activity of phthalate esters by gene expression profiling using a focused microarray (EstrArray). , 2008, Environmental Toxicology and Chemistry.

[35]  Jean C Hubinger,et al.  Analysis of consumer cosmetic products for phthalate esters. , 2006, Journal of cosmetic science.

[36]  T. R. Harrison,et al.  Harrison's Endocrinology , 2006 .

[37]  R. Kruse,et al.  Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure , 2005, Environmental health perspectives.

[38]  A. Charles,et al.  Oestrogenic and androgenic activity of triclosan in breast cancer cells , 2008, Journal of applied toxicology : JAT.

[39]  Julie Boberg,et al.  Do Parabens Have The Ability To Interfere With Steroidogenesis , 2008 .

[40]  J. Fisher,et al.  Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. , 2004, Reproduction.

[41]  B. Hammock,et al.  Triclocarban enhances testosterone action: a new type of endocrine disruptor? , 2008, Endocrinology.

[42]  N. Skakkebaek,et al.  Systemic absorption of the sunscreens benzophenone-3, octyl-methoxycinnamate, and 3-(4-methyl-benzylidene) camphor after whole-body topical application and reproductive hormone levels in humans. , 2004, The Journal of investigative dermatology.

[43]  J. Nicolas,et al.  Estrogenic Activity of Cosmetic Components in Reporter Cell Lines: Parabens, UV Screens, and Musks , 2005, Journal of toxicology and environmental health. Part A.

[44]  A. B. Hill The Environment and Disease: Association or Causation? , 1965, Proceedings of the Royal Society of Medicine.

[45]  G. S. Pope,et al.  Oestrogenic activity of parabens in MCF7 human breast cancer cells , 2002, The Journal of Steroid Biochemistry and Molecular Biology.

[46]  R. Sharpe,et al.  Testicular dysgenesis syndrome: mechanistic insights and potential new downstream effects. , 2008, Fertility and sterility.

[47]  R. Pieters,et al.  AHTN and HHCB show weak estrogenic--but no uterotrophic activity. , 1999, Toxicology Letters.

[48]  Paul M D Foster,et al.  Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. , 2006, International journal of andrology.

[49]  H Fang,et al.  The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[50]  J. Larsen,et al.  Lack of oestrogenic effects of food preservatives (parabens) in uterotrophic assays. , 2000, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[51]  O. Rosario,et al.  Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. , 2000, Environmental health perspectives.

[52]  H. Koo,et al.  ESTIMATED EXPOSURE TO PHTHALATES IN COSMETICS AND RISK ASSESSMENT , 2004, Journal of toxicology and environmental health. Part A.

[53]  M. P. Donovan,et al.  Failure of monoethylhexyl phthalate to cause teratogenic effects in offspring of rabbits. , 1979, Toxicology and applied pharmacology.

[54]  W. Seinen,et al.  Transcriptional Activation of Estrogen Receptor ERα and ERβ by Polycyclic Musks Is Cell Type Dependent , 2002 .

[55]  M. Forest,et al.  HYPOTHALAMIC‐PITUITARY‐GONADAL RELATIONSHIPS IN MAN FROM BIRTH TO PUBERTY , 1976, Clinical endocrinology.

[56]  Raphael J Witorsch,et al.  Endocrine disruptors: can biological effects and environmental risks be predicted? , 2002, Regulatory toxicology and pharmacology : RTP.

[57]  David C Christiani,et al.  The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. , 2002, Environmental health perspectives.

[58]  S. Oishi Effects of butylparaben on the male reproductive system in rats , 2001, Toxicology and industrial health.

[59]  Kyung-Sun Kang,et al.  Decreased sperm number and motile activity on the F1 offspring maternally exposed to butyl p-hydroxybenzoic acid (butyl paraben). , 2002, The Journal of veterinary medical science.

[60]  J. Sumpter,et al.  A variety of environmentally persistent chemicals, including some phthalate plasticizers, are weakly estrogenic. , 1995, Environmental health perspectives.

[61]  R. Golden,et al.  A Review of the Endocrine Activity of Parabens and Implications for Potential Risks to Human Health , 2005, Critical reviews in toxicology.

[62]  K. Crofton,et al.  Short-term in vivo exposure to the water contaminant triclosan: Evidence for disruption of thyroxine. , 2007, Environmental toxicology and pharmacology.

[63]  N. Skakkebæk Testicular dysgenesis syndrome. , 2003 .

[64]  R. Sharpe "Additional" effects of phthalate mixtures on fetal testosterone production. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[65]  M. Vallotton,et al.  3 Disorders of the adrenal cortex , 1992 .

[66]  M. Longnecker,et al.  Anogenital distance in human male and female newborns: a descriptive, cross-sectional study , 2004, Environmental health : a global access science source.

[67]  N. Skakkebaek Testicular Dysgenesis Syndrome , 2003, Hormone Research in Paediatrics.

[68]  Peter Schmid,et al.  Endocrine activity and developmental toxicity of cosmetic UV filters--an update. , 2004, Toxicology.

[69]  F. A. Andersen Annual Review of Cosmetic Ingredient Safety Assessments: 2007-2010 , 2011, International journal of toxicology.

[70]  Kim Boekelheide,et al.  Fetal mouse phthalate exposure shows that Gonocyte multinucleation is not associated with decreased testicular testosterone. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[71]  H. Jarry,et al.  Multi-organic endocrine disrupting activity of the UV screen benzophenone 2 (BP2) in ovariectomized adult rats after 5 days treatment. , 2004, Toxicology.

[72]  H. Jarry,et al.  Pharmacokinetics and metabolism of benzophenone 2 in the rat. , 2008, Toxicology.

[73]  M. Vrijheid,et al.  Risk of hypospadias in relation to maternal occupational exposure to potential endocrine disrupting chemicals , 2003, Occupational and environmental medicine.

[74]  P. Foster,et al.  Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[75]  A. Grüters,et al.  Endocrine active compounds affect thyrotropin and thyroid hormone levels in serum as well as endpoints of thyroid hormone action in liver, heart and kidney. , 2004, Toxicology.

[76]  J. Meredith,et al.  Thyroid hormone, glucocorticoids, and prolactin at the nexus of physiology, reproduction, and toxicology. , 2004, Toxicology and applied pharmacology.

[77]  J. A. Thomas,et al.  Toxicity and metabolism of monoethylhexyl phthalate and diethylhexyl phthalate: a survey of recent literature. , 1982, Journal of toxicology and environmental health.

[78]  A. Hoberman,et al.  Lack of effect of butylparaben and methylparaben on the reproductive system in male rats. , 2008, Birth defects research. Part B, Developmental and reproductive toxicology.

[79]  M. Nieuwenhuijsen,et al.  Endocrine Disruptors in the Workplace, Hair Spray, Folate Supplementation, and Risk of Hypospadias: Case–Control Study , 2008, Environmental health perspectives.

[80]  Shanna H Swan,et al.  Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. , 2008, Environmental research.

[81]  L. Giudice,et al.  Endocrine-disrupting chemicals: an Endocrine Society scientific statement. , 2009, Endocrine reviews.

[82]  F. Larrea,et al.  In vivo and in vitro estrogen bioactivities of alkyl parabens , 2003, Toxicology and industrial health.

[83]  P. Foster,et al.  Male reproductive tract malformations in rats following gestational and lactational exposure to Di(n-butyl) phthalate: an antiandrogenic mechanism? , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[84]  P. Leffler,et al.  Mono-(2-ethylhexyl) phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes. , 2008, Reproduction.

[85]  Lee B. Smith,et al.  Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. , 2008, The Journal of clinical investigation.

[86]  E Mylchreest,et al.  Effects of phthalate esters on the developing reproductive tract of male rats , 2001, Human reproduction update.

[87]  M. Schlumpf,et al.  Region-Specific Growth Effects in the Developing Rat Prostate Following Fetal Exposure to Estrogenic Ultraviolet Filters , 2008, Environmental health perspectives.

[88]  M. Schlumpf,et al.  Estrogen Sensitivity of Target Genes and Expression of Nuclear Receptor Co-Regulators in Rat Prostate after Pre- and Postnatal Exposure to the Ultraviolet Filter 4-Methylbenzylidene Camphor , 2007, Environmental health perspectives.

[89]  S. Oishi Effects of butyl paraben on the male reproductive system in mice , 2002, Archives of Toxicology.

[90]  M. Palmert,et al.  Regulation and disorders of pubertal timing. , 2005, Endocrinology and metabolism clinics of North America.

[91]  Emily K Gibson,et al.  The effects of triclosan on puberty and thyroid hormones in male Wistar rats. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[92]  S. Oishi Lack of spermatotoxic effects of methyl and ethyl esters of p-hydroxybenzoic acid in rats. , 2004, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[93]  S. Kaplan Disorders of the adrenal cortex. I. , 1979, Pediatric clinics of North America.

[94]  P. Foster,et al.  Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to Di(n-butyl) phthalate during late gestation. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[95]  J. Furr,et al.  Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[96]  Bruce Blumberg,et al.  Endocrine disrupting chemicals , 2011, The Journal of Steroid Biochemistry and Molecular Biology.

[97]  P. Darbre,et al.  Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks , 2008, Journal of applied toxicology : JAT.

[98]  H. Jarry,et al.  Pure estrogenic effect of benzophenone-2 (BP2) but not of bisphenol A (BPA) and dibutylphtalate (DBP) in uterus, vagina and bone. , 2004, Toxicology.

[99]  I. Kano,et al.  ER-dependent estrogenic activity of parabens assessed by proliferation of human breast cancer MCF-7 cells and expression of ERalpha and PR. , 2001, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[100]  J. Köhrle,et al.  Effects of a 5-day treatment with the UV-filter octyl-methoxycinnamate (OMC) on the function of the hypothalamo-pituitary-thyroid function in rats. , 2007, Toxicology.

[101]  Shuk-Mei Ho,et al.  Chapel Hill bisphenol A expert panel consensus statement: integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. , 2007, Reproductive toxicology.

[102]  H. Jarry,et al.  Multi-organic risk assessment of estrogenic properties of octyl-methoxycinnamate in vivo A 5-day sub-acute pharmacodynamic study with ovariectomized rats. , 2005, Toxicology.

[103]  G. S. Pope,et al.  Oestrogenic activity of isobutylparaben in vitro and in vivo , 2002, Journal of applied toxicology : JAT.

[104]  T. Koda,et al.  Estrogenic activity of 37 components of commercial sunscreen lotions evaluated by in vitro assays. , 2005, Toxicology in vitro : an international journal published in association with BIBRA.

[105]  A. John Bailer,et al.  Statistics for Environmental Biology and Toxicology , 2020 .

[106]  A. Grüters,et al.  Endocrine Disruptors and the Thyroid Gland—A Combined in Vitro and in Vivo Analysis of Potential New Biomarkers , 2007, Environmental health perspectives.

[107]  M. Schlumpf,et al.  In vitro and in vivo estrogenicity of UV screens. , 2001, Environmental health perspectives.

[108]  Validity of Anogenital Distance as a Marker of in Utero Phthalate Exposure , 2006, Environmental health perspectives.

[109]  K. Inai,et al.  Tumorigenicity study of butyl and isobutyl p-hydroxybenzoates administered orally to mice. , 1985, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[110]  B. van der Burg,et al.  In vitro and in vivo antiestrogenic effects of polycyclic musks in zebrafish. , 2004, Environmental science & technology.

[111]  L Earl Gray,et al.  A mixture of seven antiandrogens induces reproductive malformations in rats. , 2008, International journal of andrology.

[112]  E. Bauer,et al.  P-Hydroxybenzoic acid esters as preservatives. II. Acute and chronic toxicity in dogs, rats, and mice. , 1956, Journal of the American Pharmaceutical Association. American Pharmaceutical Association.

[113]  A. Wennberg,et al.  Percutaneous absorption of the sunscreen benzophenone‐3 after repeated whole‐body applications, with and without ultraviolet irradiation , 2006, The British journal of dermatology.

[114]  A. Grüters,et al.  The ultraviolet filter benzophenone 2 interferes with the thyroid hormone axis in rats and is a potent in vitro inhibitor of human recombinant thyroid peroxidase. , 2007, Endocrinology.

[115]  G. S. Pope,et al.  Oestrogenic activity of benzylparaben , 2003, Journal of applied toxicology : JAT.

[116]  Suzanne M. McCahan,et al.  The orl rat with inherited cryptorchidism has increased susceptibility to the testicular effects of in utero dibutyl phthalate exposure. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[117]  F. A. Andersen Annual Review of Cosmetic Ingredient Safety Assessments—2004/20051 , 2006, International journal of toxicology.

[118]  TheCosmetic IngredientReview Annual Review of Cosmetic Ingredient Safety Assessments—2002/20031 , 2005, International journal of toxicology.