Phthalates are a family of industrial chemicals that have been used for a variety of purposes. As the potential consequences of human exposure to phthalates have raised concerns in the general population, they have been studied in susceptible subjects such as pregnant women, infants and children. This article aims at evaluating the impact of exposure to phthalates on reproductive outcomes and children health by reviewing most recent published literature. Epidemiological studies focusing on exposure to phthalates and pregnancy outcome, genital development, semen quality, precocious puberty, thyroid function, respiratory symptoms and neurodevelopment in children for the last ten years were identified by a search of the PubMed, Medline, Ebsco, Agricola and Toxnet literature bases. The results from the presented studies suggest that there are strong and rather consistent indications that phthalates increase the risk of allergy and asthma and have an adverse impact on children’s neurodevelopment reflected by quality of alertness among girls, decreased (less masculine) composite score in boys and attention deficit hyperactivity disorder. Results of few studies demonstrate negative associations between phthalate levels commonly experienced by the public and impaired sperm quality (concentration, morphology, motility). Phthalates negatively impact also on gestational age and head circumference; however, the results of the studies were not consistent. In all the reviewed studies, exposure to phthalates adversely affected the level of reproductive hormones (luteinizing hormone, free testosterone, sex hormone-binding globulin), anogenital distance and thyroid function. The urinary le vels of phthalates were significantly higher in the pubertal gynecomastia group, in serum in girls with premature thelarche and in girls with precocious puberty. Epidemiological studies, in spite of their limitations, suggest that phthalates may affect reproductive outcome and children health. Considering the suggested health effects, more epidemiologic data is urgently needed and, in the meantime, precautionary policies must be implemented.
This is a preview of subscription content, log in to check access.
Kavlock RJ, Daston GP, DeRosa C, Fenner-Crisp P, Gray LE, et al. Research needs for the risk assessment of health and environmental effects of endocrine disruptors: A report of the US EPA-sponsored workshop. Environ Health Perspect 1996;104:715–740.
Api AM. Toxicological profile of diethyl phthalate: a vehicle for fragrance and cosmetic ingredients. Food Chem Toxicol 2001;39:97–108.
Arcadi FA, Costa C, Imperatore C, Marchese A, Rapisarda A, Salemi M, et al. Oral toxicity of bis(2-ethylhexyl) phthalate during pregnancy and suckling in the Long-Evans rat. Food Chem Toxicol 1998;36:963–970.
Foster PM, Mylchreest E, Gaido KW, Sar M. Effects of phthalate esters on the developing reproductive tract of male rats. Hum Reprod Update 2001;231–235.
Gray LE Jr, Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L. Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol Sci 2000;58:350–365.
Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE. Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer di(2-ethylhexyl) phthalate. Environ Health Perspect 2001;109:229–237.
Tandon R, Seth PK, Srivastava SP. Effect of in utero exposure to di(2-ethylhexyl)phthalate on rat testes. Indian J Exp Biol 1991;29:1044–1046.
Swan SH, Main KM, Liu F, Stewart SL, Kruse SL, Calafat AM, et al. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 2005;113:1056–1061.
Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, et al. Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J Clin Invest 2008;118:1479–1490.
Foster PM. Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. Int J Androl 2006;29:140–147.
Shape RM, Fisher JS, Millar MM, Jobling S, Sumpter JP. Gestational and lactation exposure of rats to xenoestrogens results in reduced testicular size and sperm production. Environ Health Perspect 1995;103:1136–1143.
Tanaka T. Reproductive and neurobehavioral effects of bis(2-ethylhexyl) phthalate (DEHP) in a cross-mating toxicity study of mice. Food Chem Toxicol 2005;43:581–589.
Shea KM. Pediatric exposure and potential toxicity of phthalate plasticizers. Pediatrics 2003;111:1467–1474.
Duty SM, Calafat AM, Silva MJ, Ryan L, Hauser R. Phthalate exposure and reproductive hormones in adult men. Hum Reprod 2005;20(3):604–610.
Hauser R, Meeker JD, Duty S, Silva MJ, Calafat AM. Altered Semen Quality in Relation to Urinary Concentrations of Phthalate Monoester and Oxidative Metabolites. Epidemiol 2006;17:682–691.
Kamrin MA. Phthalate risks, phthalate regulation, and public health: a review. J Toxicol Environ Health B Crit Rev 2009;12:157–174.
Sathyanarayana S, Karr CJ, Lozano P, Brown E, Calafat AM, Liu F, et al. Baby Care Products: Possible Sources of Infant Phthalate Exposure. Pediatrics 2008;121(2):e260–268. DOI: 10.1542/peds.2006-3766.
Wolff MS, Engel SM, Berkowitz GS, Ye X, Silva MJ, Zhu C, et al. Prenatal phenol and phthalate exposures and birth outcomes. Environ Health Perspect 2008;116:1092–1097.
Lottrup AM, Eersson H, Leffers GK, Mortensen J, Toppari NE, Skakkebaek NE, et al. Possible impact of phthalates on infant reproductive health. Int J Androl 2006;29:172–180.
Chalubinski M, Kowalski ML. Endocrine disrupters — potential modulators of the immune system and allergic response. Allergy 2006;61:1326–1335.
Jaakkola JJ, Oie L, Nafstad P, Botten G, Samuelsen SO, Magnus P. Interior surface materials in the home and the development of bronchial obstruction in young children in Oslo, Norway. Am J Pub Health 1999;89:188–192.
Øie L, Hersoug L-G, Madsen JØ. Residential exposure to plasticizers and its possible role in the pathogenesis of asthma. Environ Health Perspect 1997;105:972–978.
Bornehag CG, Sundell J, Weschler CJ, Sigsgaard T, Lundgren B, Hasselgren M, et al. The association between asthma and allergic symptoms in children and phthalates in house dust: A nested case-control study. Environ Health Perspect 2004;112:1393–1397.
Kolarik B, Naydenov K, Larsson M, Bornehag CG, Sundell J. The association between phthalates in dust and allergic diseases among Bulgarian children. Environ Health Perspect 2008;116:98–103.
Latini G, Felice CD, Presta G, Del Vecchio A, Paris I, Ruggieri F, et al. In utero exposure to di-(2-ethylhexyl) phthalate and duration of human pregnancy. Environ Health Perspect 2003;111:1783–1785.
National Research Council. Committee on the Health Risks of Phthalates. Phthalates and Cumulative Risk Assessment: The Task Ahead. Washington: National Academies Press; 2008.
Bornehag CG, Sundell J, Hagerhed-Engman L, Sigsgaard T, Janson S, Aberg N, et al. “Dampness” at home and its association with airway, nose and skin symptoms among 10 851 preschool children in Sweden: A cross sectional study. Indoor Air 2005;15:48–55
Rudel RA, Camann DE, Spengler JD, Korn RL, Brody JG. Phthalates, alkylphenols, pesticides, polybrominated diphenyl ethers, and other endocrine-disrupting compounds in indoor air and dust. Environ Sci Technol 2003;37:4543–453.
Wormuth M, Scheringer M, Vollenweider M, Hungerbühler K. What are the sources of exposure to eight frequently used phthalic acid esters in Europeans? Risk Anal 2006;26:803–824.
Howdeshell KL, Wilson VS, Furr J, Lambright RC, Rider CV, Blystone RC, Hotchkiss AK et al. A Mixture of Five Phthalate Esters Inhibits Fetal Testicular Testosterone Production in the Sprague-Dawley Rat in a Cumulative, Dose-Additive Manner. Toxicol Sci 2008;105(1):153–165.
Sharpe RM. Hormones and testis development and the possible adverse effects of environmental chemicals. Toxicol Lett 2001;120:221–232.
Ablake M, Itoh M, Terayama H, Hayashi S, Shoji S, Naito M, et al. Di-(2-ethylhexyl) phthalate induces severe aspermatogenesis in mice, however, subsequent antioxidant vitamins supplementation accelerates regeneration of the seminiferous epithelium. Int J Androl 2004;27:274–281.
Latini G, Felice CD, Verrotti A. Plasticizers, infant nutrition and reproductive health. Reprod Toxicol 2004;19:27–33.
Calafat AM, Brock JW, Silva MJ, Gray LE, Reidy JA, Barr DB, et al. Urinary and amniotic fluid levels of phthalate monoesters in rats after the oral administration of di-(2-ethylhexyl) phthalate and di-n-butyl phthalate. Toxicology 2006;217:22–30.
Kavlock R, Boekelheide K, Chapin R, Cunningham M, Faustman E, Foster P, et al. Phthalates expert panel report on the reproductive and developmental toxicity of di-n-octyl phthalate. Reprod Toxicol 2002;16:721–734.
Tabacova S, Balabaeva L, Little RE. Maternal exposure to exogenous nitrogen compounds and complications of pregnancy. Arch Environ Health 1997;52:341–347.
Gladen BC, Tabacova S, Baird DD, Little RE, Balabaeva L. Variability of lipid hydroperoxides in pregnant and nonpregnant women. Reprod Toxicol 1999;13:41–44.
Mein KM, Mortensen GK, Kaleva MM, Boisen KA, Damgaard IN, Chellakooty M, et al. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ Health Perspect 2006;114:270–276.
Palanza P, Parmigiani S, vom Saal FS. Urinemarking and maternal aggression of wild female mice in relation to anogenital distance at birth. Physiol Behav 1995;58:827–835.
Hughes CL. Anogenital distance at birth as a predictor of volume of the sexually dimorphic nucleus of the preoptic area of the hypothalamus and pituitary responsiveness in castrated adult rats. Biol Reprod 1992;46:101–104.
Gallavan RH, Holson JF, Stump DG, Knapp JF, Reynolds VL. Interpreting the toxicologic significance of alterations in anogenital distance: potential for confounding effects of progeny body weights. Reprod Toxicol 1999;13:383–390.
Andrade AJ, Grande SW, Talsness CE, Grote K, Chahoud I. A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl)-phthalate (DEHP): non-monotonic dose-response and low dose effects on rat brain aromatase activity. Toxicology 2006;27:185–192.
Swan SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res 2008;108(2):174–184. DOI: 10.1016/j.envres.2008._08.007.
Bustamente-Montes LP, Hernandez-Valero MA, Garcia-Fabila M, Halley-Castillo E, Karam-Calderon MA, Borja-Aburto VH. Prenatal phthalate exposure and decrease in anogenital distance in Mexican male newborns. Epidemiol 2008;19(60):270–275.
Huang P-C, Kuo P-L, Chou Y-Y, Lin S-J, Lee C-C. Association between prenatal exposure to phthalates and the health of newborns. Environ International 2009;35:14–20.
Ge RS, Chen GR, Tanrikut C, Hardy MP. Phthalate ester toxicity in Leydig cells: developmental timing and dosage considerations. Reprod Toxicol 2007;23(3):366–373.
Borch J, Axelstad M, Vinggaard AM, Dalgaard M. Diisobutyl phthalate has comparable anti-androgenic effects to di-n-butyl phthalate in fetal rat testis. Toxicol Lett 2006;163(3):183–190.
Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, et al. Phthalate Exposure and Human Semen Parameters. Epidemiol 2003;14:269–277.
Jönsson AG, Richthoff J, Rylander L, Giwercman A, Lars H. Urinary phthalate metabolities and biomarkers of reproductive function in young men. Epidemiol 2005;16(4):487–493.
Wirth JJ, Rossano MG, Potter R, Puscheck E, Daly DC, Paneth N, et al. A pilot study associating urinary concentrations of phthalate metabolities and semen quality. Sys Biol Reprod Med 2008;54(3):143–154.
Pant N, Shukla M, Patel KD, Shukla Y, Mathur N, Gupta YK, Saxena DK. Correlation of phthalate exposures with semen quality. Toxicol App Pharmacology 2008;231:112–116.
Zhang Y, Zheng L, Chen B. Phthalate exposure and human semen quality in Shanghai: a cross-sectional study. Biomed Environ Sci 2006;19(3):205–209.
Hauser R, Meeker JD, Singh NP, Silva MJ, Ryan L, Duty S, et al. DNA damage in human sperm is related to urinary levels of phthalate monoester and oxidative metabolites. Hum Reprod 2007;22:688–695.
Duty SM, Singh NP, Silva MJ, Barr DB, Brock JW, Ryan L, et al. The relationship between environmental exposures to phthalates and DNA damage in human sperm using the neutral comet assay. Environ Health Perspect 2003;111:1164–1169.
Brown JS Jr. Effects of bisphenol-A and other endocrine disruptors compared with abnormalities of schizophrenia: an endocrine-disruption theory of schizophrenia. Schizophr Bull 2009;35:256–278.
Masuo Y, Morita M, Oka S, Ishido M. Motor hyperactivity caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: A study inspired by the physiological roles of PACAP in the brain. Regul Pept 2004;15:225–234.
Engel SM, Zhu C, Berkowitz GS, Calafat AM, Silva MJ, Miodovnik A, Wolff MS. Prenatal phthalate exposure and performance on Neonatal Behavioral Assessment Scale in multiethnic birth cohort. NeuroToxicol 2009;30:522–528.
Kim BN, Cho SC, Kim Y, Shin MS, Yoo HJ, Kim JW, et al. Phthalates exposure and attention-deficit/hyperactivity disorder in school-age children. Biol Psychiatry 2009;66(10):958–963.
Cho SC, Bhang SY, Hong YC, Shin MS, Kim BN, Kim JW. Relationship between environmental phthalate exposure and the intelligence of school-age children. Environ Health Perspect 2010;118(7):1027–1032.
Engel SM, Miodovnik A, Canfield RL, Zhu C, Silva MJ, Calafat AM, et al. Prenatal phthalate exposure is associated with childhood behavior and executive functioning. Environ Health Perspect 2010;118(4):565–571.
Swan SH, Liu F, Kruse RL, Wang C, Redmon JB, Sparks A, et al. Prenatal phthalate exposure and reduced masculine play in boys. Int J Androl 2009;32:1–9.
Huang PC, Kuo PL, Guo YL, Liao PC, Lee CC. Associations between urinary phthalate monoesters and thyroid hormones in pregnant women. Hum Reprod 2007;22(10):2715–2722.
Meeker JD, Calafat AM, Hauser R. Di(2-ethylhexyl) phthalate metabolites may alter thyroid hormone levels in men. Environ Health Perspect 2007;115(7):1029–1034.
Boas M, Feldt-Rasmussen U, Skakkebaek NE, Main KM. Environmental chemicals and thyroid function. Eur J Endocrinol 2006;154:599–611.
Liwnicz BH, Liwnicz RG. On endocrine function. In: Kaplan LA, editor. Clinical Chemistry: Theory, Analysis and Correlation. 2nd ed. St. Lewis, MO: CV Mosby Company; 1989. p. 607–619.
Partsch CJ, Sippell WG. Pathogenesis and epidemiology of precocious puberty. Effects of exogenous oestrogens. Hum Reprod Update 2001;7:292–302.
Key TJ, Verkasalo PK, Banks E. Epidemiology of breast cancer. Lancet Oncol 2001;2:133–140.
Lopez-Carillo L, Hernandez-Ramirez RU, Calafat AM, Tores-Sanches L, Galvan-Portillo M, Needham LL, et al. Exposure to phthalates and breast cancer risk in Northen Mexico. Environ Health Perspect 2010;118(4):539–544.
Nydick M, Butos J, Dale JH, Rawson RW. Gynecomastia in adolescent boys. JAMA 1961;178:449–454.
Durmaz E, Özmert NE, Erkekoglu P, Giray B, Derman O, Hincal F, et al. Plasma Phthalate Levels in Pubertal Gynecomastia. Pediatrics 2010;125:122–129.
Colón I, Caro D, Bourdony CJ, Rosario O. Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environ Health Perspect 2000;108:895–900.
Qiao L, Zheng L, Cai D. Study of the di-n-butyl phthalate and di-2-ethylhexyl-phthalate level of girls serum related with precocious puberty in Shanghai. Wei Shen Yan Jiu 2007;36(1):93–95 [in Chinese].
Lomenick JP, Calafat AM, Melguizo Castro MS, Mier R, Stenger P, Foster MB, et al. Phthalate exposure and precocious puberty in females. J Pediatr 2010;156(2):221–225.
Brasche S, Bischof W. Daily time spent indoors in German homes — baseline data for the assessment of indoor exposure of German occupants. Int J Hyg Environ Health 2005;208(4):247–253.
Selgrade MK, Lemanske RF Jr, Gilmour MI, Neas LM, Ward MD, Henneberger PK, et al. Induction of asthma and the environment: what we know and need to know. Environ Health Perspect 2006;114:615–619.
Jaakkola JJ, Verkasalo PK, Jaakkola N. Plastic wall ma terials in the home and respiratory health in young children. Am J Pub Health 2000;90:797–799.
Jaakkola JJ, Parise H, Kislitsin V, Lebedeva NI, Spengler JD. Asthma, wheezing, and allergies in Russian schoolchildren in relation to new surface materials in the home. Am J Pub Health 2004;94:560–562.
Larsson M, Hagerhed-Engman L, Kolarik B, James P, Lundin F, Sundell J, et al. PVC flooring and its association with incident asthma in Swedish children. Indoor Air 2010;20:494–501.
Dirven HA, van den Broek PH, Arends AM, Nordkamp HH, de Lepper AJ, Henderson PT, et al. Metabolites of the plasticizer di(2-ethylhexyl) phthalate in urine samples of workers in polyvinyl chloride processing industries. Int Arch Occup Environ Health 1993;64:549–554.
Koch HM, Bolt HM. Angerer J. Di(2-ethylhexyl)phthalate (DEHP) metabolites in human urine and serum after a single oral dose of deuterium-labeled DEHP. Arch Toxicol 2004;78:123–130.
Hauser R, Meeker JD, Park S, Silva MJ, Calafat AM. Temporal variability of urinary phthalate metabolite levels in men of reproductive age. Environ Health Perspect 2004;112:1734–1740.
Silva MJ, Reidy JA, Herbert AR, Preau Jr JL, Needham LL, Calafat AM. Detection of phthalate metabolites in human amniotic fluid. Bull Environ Contam Toxicol 2004;72:1226–1231.
Teitelbaum SL, Britton JA, Calafat AM, Ye X, Silva MJ, Reidy JA, et al. Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States. Environ Res 2008;106(2):257–269.
Moore KL, Persaued TV. The developing human: clinically oriented embryology. Philadelphia: W.B. Saunders; 1998. p. 157–165.
James DK, Steer PJ, Weiner CP, Gonik B. High risk pregnancy: management options. Third Edition. Philadelphia, PA: Elsevier-Saunders; 2005.
Lewis ML, Worobey JW, Ramsay DS, McCormack MK. Prenatal exposure to heavy metals: effect on childhood cognitive skills and health status. Pediatrics 1992;89:1010–1015.
Longnecker MP, Gladen BC, Cupul-Uicab LA, Romano-Riquer SP, Weber JP, Chapin RE, et al. In utero exposure to the antiandrogen 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) in relation to anogenital distance in male newborns from Chiapas, Mexico. Am J Epidemiol 2007;165:1015–1022.
Dallaire F, Dewailly E, Muckle G, Ayotte P. Time trends of persistent organic pollutants and heavy metals in umbilical cord blood of Inuit infants born in Nunavik (Québec, Canada) between 1994 and 2001. Environ Health Perspect 2003;111:1660–1664.
Wang SL, Su PH, Jong SB, Guo YL, Chou WL, Päpke O. In utero exposure to dioxins and polychlorinated biphenyls and its relations to thyroid function and growth hormone in newborns. Environ Health Perspect 2005;113:1645–1650.
Engman LH, Bornehag, CG, Sundell J. How valid are parents questionnaire responses regarding building characteristics, mouldy odour, and signs of moisture problems in Swedish homes? Scand J Publ Health 2007;35:125–132.
This study was performed under the project “Prenatal and postnatal exposure to tobacco smoke, PAHs and heavy metals and the risk of respiratory diseases, allergy and poor mental and physical development” supported by the grant PNRF-218-AI-1/07 from Norway through the Norwegian Financial Mechanism within the Polish-Norwegian Research Fund.
About this article
Cite this article
Jurewicz, J., Hanke, W. Exposure to phthalates: Reproductive outcome and children health. A review of epidemiological studies. IJOMEH 24, 115–141 (2011). https://doi.org/10.2478/s13382-011-0022-2
- Exposure to phthalates
- Children health
- Reproductive outcome