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Effects of phthalic acid esters on fetal health/Uticaj estara ftalne kiseline na fetalno zdravlje.


Interest in chemical matters that disrupt the endocrine system work--endocrine disrupting chemicals (EDCs) has been increased over the last several years. EDCs may affect the synthesis, secretion, mechanism of action, metabolism and elimination of hormones in humans and animals, with harmful health consequences. Phthalates, esters of 1,2-dicarboxylic acid phthalic acid, are synthetic industrial chemical compounds which were introduced in 1920. Ever since 1933 and the synthesis of di (2-ethylhexyl) phthalates (DEHP), the phthalates have been the most common chemical compounds with the possibility to disrupt the endocrine system [1]. The effect of phthalates depends on dosage, duration of action and stage of the development of the individual, thus making the fetus, newborn, and children at puberty the most vulnerable groups [2]. According to the study of Latini et al. from 2003, the exposure to the effects of phthalates begins at the intrauterine stage since the phthalates pass through the placental barrier; another important issue in relation to the phthalates, i.e. EDCs, is that intrauterine exposure may not be manifested until adolescence or even later [1]. It is also known that exposure to phthalates may be manifested only as disorders of the next generations (through modification of factors that regulate gene expression) [1]. Because of the known harmful effects, the European Union countries as well as our country have limited the use of DEHP, butyl benzyl phthalate (BzBP) and di-n-butyl phthalate (DBP) in the production of children's toys and items intended for the child care, while the restrictions on the use of di-isononyl phthalate (DINP), di-isodecyl phthalate (DIDP) and di-n-octyl phthalate (DNOP) apply only to the manufacturers of toys and items intended for child care that children can put in the mouth [3]. Application of DEHP and DBP and BzBP is not permitted in cosmetic production in the European Union because of reproductive toxicity [4].

Metabolism of Phthalates

After they enter the body, phthalates are subjected to hydrolysis and conjugation [4]. Monoestar phthalates are created by hydrolysis. In vivo and in vitro studies proved monoester phthalates to be biologically more active than their diesters [5,6]. Short chain phthalates are excreted in the urine as monoester phthalates, and the long chain phthalates are subjected to further metabolism in terms of hydroxylation and oxidation after which they are excreted in urine and feces [7, 8]. Their biological half-life is short, more than 60% is excreted in 24 hours [1, 9].

Exposure to Phthalates

Low molecular weight phthalates, for example di-methyl phthalate (DMP), DBP, are present in cosmetic products (nail polish, perfumes, facial creams, shampoos, body lotions ...), while high molecular weight phthalates, for example DEHP, BBzP, DNOP, DINP, DIDP, are present in plastic containers, adhesives, clothes of raincoat type and plastic products with polyvinyl chloride which is added in order to improve flexibility [4]. Phthalates are also found in medical instruments such as central venous and urinary catheters, as well as in packaging for total parenteral nutrition and intravenous infusion. They are also present in some medications [11]. Foodstuffs, such as cereals, bread, biscuits, cakes, nuts, oils and fats, can be found in packaging made of plastics containing DEHP, DBP and DEHP and di-isobutil phthalate (DIBP), and thus they are in contact with phthalates [12].

Toys are another important source of exposure to phthalate (soothers, teethers, bath toys), and they can enter the body either orally, or by inhalation, through skin and parenterally [1,10].

Determination of Phthalate Levels in Humans

Phthalates do not tend to bioaccumulate and their half-life is less than 24 hours [1,10]. There have been attempts at determining phthalate levels in saliva, serum, seminal fluid, meconium and placenta but, the validation of these procedures have shown that phthalates are excreted in a very small percentage in this way [13, 14]. Urine, maternal milk, serum and amniotic fluid are most frequently used nowadays as material to assess the presence of phthalates in the body [15]. Urine was proven to be the best sample in epidemiological studies in regards to the rapid metabolism of phthalates and high concentrations of the metabolites in the urine. Further advantages of urine as material for determining levels of phthalates is that it can be collected in a noninvasive way and may reflect exposure to phthalates in the last few days, even weeks [16, 17]. In all the above mentioned samples, the level of monoesters, i.e. phthalates metabolites, are determined because the level of monoesters is higher than the level of diesters of phthalic acid, and the contamination of the sample by ubiquitous diesters during the collection, storage and analysis itself is avoided [18].

Fetal Testicular Dysgenesis Syndrome

In the last fifteen years, a number of studies on experimental animals (rats) have proven that phthalates, especially DEHP, DBP, BBzP, when acting in a critical period of the development of genital tract, lead to disturbances in androgen-signaling pathway [18,19]. In almost all previous studies, the anti-androgen effect of phthalates in newborn males was examined, but it was also shown that the negative effects of phthalates on female health are reflected in anovulation, premature puberty, changes in the duration of pregnancy and other disorders [2, 10].

Fetal testicular dysgenesis syndrome ("phthalate syndrome" in rodents) involves disorders of male genital tract in terms of shortened anogenital distance, hypospadia, cryptorchidism, malformations of the seminal vesicles, prostate, and epididymis [18, 20]. According to contemporary literature, the stated syndrome is a consequence of reduced level of fetal testosterone, insulin-like growth factor-3 (IGF-3) and follicule stimulating hormone (FSH) [18, 21]. A negative correlation between levels in breast milk and free testosterone of babies was observed, while there was a positive correlation between mono-ethyl phthalate (MEP) and mono-butyl (MBP) with sex hormone bingind globuline (SHBG) and mono-metyl phthalate (MMP) and MEP and MBP with the ratio of lutenzing hormone (LH) and free testosterone [22].

Other effects of phthalates on health

Exposure to phthalates is significantly associated with the duration of pregnancy [2]. According to some studies, the chemical structure of DEHP and prostaglandin/thromboxane, interleukin-1 connects the phthalates with induction of intrauterine inflammatory processes as well as shortening of pregnancy [2, 23]. Some results suggested an association between levels of mono-(2-ethylhexyl) phthalate in preconceptional period and early pregnancy loss, while many authors pointed out the impact of phthalates on the low birth weight [9, 16, 18].

Recent research suggests a possible effect on neurocognitive development, as well as on the development of allergies, asthma, testicular carcinoma, hepatic and renal damages, insulin resistance and obesity, thyroid dysfunction [18].

An interesting fact is that exposure to a certain type of phthalates varies among different socioeconomic groups, which is probably the consequence of certain products whose use is significantly different among these groups [24].


Considering the widespread use of phthalates and exposure of large human population to phthalates in the environment, food or items for personal use their harmful impact on health need to be tested. Numerous experimental, epidemiological and observational studies of human population have suggested their most common side effects, but there are still many uncertainties. It is characteristic that detrimental effect is not only dose dependent. The duration of exposure is rather important: exposure to low doses of phthalates over a long period of time can lead to endocrine and metabolic disorders. Especially sensitive categories are the fetus and newborn, as well as pubertal children. Endocrine disrupting chemicals have the epigenetic influence and these disorders can be manifested in the next generations. Further research aimed at timely recognition of adverse effects and adjusting the concentrations of the chemical compounds in products is needed in order to avoid their adverse effects on human health.

EDCs   -endocrine disrupting chemicals
DEHP   -di (2-ethylhexyl) phthalates
MEHP   -mono(ethyl-hexyl) phthalate
BBzP   -butyl benzyl phthalate
DBP    -di-n-butyl phthalate
DINP   -di-isononyl phthalate
DIDP   -di-isodecyl phthalate
DMP    -di-methyl phthalate
DnOP   -di-n-octyl phthalate
MEP    -mono-ethyl phthalate
MBP    -mono-butyl phthalate
MMP    -mono-methyl phthalate

DOI: 10.2298/MPNS1406172B

Rad je primljen 11. III 2014.

Recenziran 20. III 2014.

Prihvacen za stampu 25. III 2014.



[1.] Frederiksen H, Skakkebek NE, Andersson AM. Metabolism of phthalates in humans. Mol Nutr Food Res 2007; 51:899911.

[2.] Latini G, De Felice C, 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; 111:1783-5.

[3.] CDC's Fourth national report on human exposure to environmental chemicals, updated tables, february 2012; Available from:

[4.] Commission directive 2004/93/EC of 21 September 2004 amending council directive 76/768/EEC for the purpose of adapting its Annexes II and III to technical progress. Brussels: European Parliament; 2004.

[5.] Heindel JJ, Powell CJ. phthalate ester effects on rat Sertoli cell function in vitro: effects of phthalate side chain and age og animal. Toxicol Appl Pharmacol. 1992; 115:116-23.

[6.] Blount BC, Silva MJ, Caudill SP, Needham LL, et al. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 2000; 108:979-82.

[7.] Koch HM, Bolt HM, Preuss R, Angerer J. New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium labeled DEHP. Arch Toxicol 2005; 79:367-76.

[8.] Silva MJ, Barr DB, Reidy JA, Kato K, Malek NA, Hodge CC, et al. Glucuronidation patterns of common urinary and serum monoester phthalates metabolites. Arch Toxicol 2003; 77:561-7.

[9.] Braun JM, Sathyanarayana S, Hauser R. Phthalate exposure and children's health. Curr Opin Pediatr 2013; 25:247-54.

[10.] Rudel RA, Gray JM, Engel CL, Rawsthorne TW, Dodson RE, Ackerman JM, et al. Food packaging and bisphenol A and bis(2-ethylhexyl)phthalate exposure: findings from a dietary intervention. Environ Health Perspect 2011; 119:914-20.

[11.] Hernandez-Diaz S, Mitchell AA, Kelly KE, Calafat AM, Hauser R. Medications as a potential source of exposure to phthalates in U.S. population. Environ Health Perspect 2009; 117:185-9.

[12.] Wormuth M, Scheringer M, Vollenweider M, Hungerbuchler K. What are the sources of exposure to eight frequently used phtalic acid esters in Europeans? Risk Anal 2006; 26:803-24.

[13.] Kato K, Silva M, Needham L, Calafat A. Quantifying phthalate metabolites in human meconium and semen using automated off-line solid-phase extraction coupled with on-line SPE and isotope-dilution high performance liquid chromatography-tandem mass spectrometry. Anal Chem 2006; 78:6651-5.

[14.] Silva M, Reidy J, Samandar E, Herbert A, Needham L, Calafat A. Detection of phthalate metabolites in human saliva. Arch Toxicol 2005; 79:647-52.

[15.] Calafat AM, McKee RH. Integrating biomonitoring exposure data into the risk assasment process: phthalates (diethyl phthalate and di(2-ethylhexyl)phthalate) as a case study. Environ Health Perspect 2006; 114:1783-9.

[16.] Braun JM. Smith KW, Williams PL. Variability of urine phthalate metabolite an bisphenol a concentrations before and during pregnancy. Environ Health Perspect 2012; 120:739-45.

[17.] Hauser R, Meeker JD, Park S, Silva JM, Calafat AM. Temporal variability of urinary phthalate metabolit levels in men of reproductive age. Environ Health Perspect 2004; 112:1734-40.

[18.] Swan SH. Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res 2008; 108:177-84.

[19.] Foster PM, Mylchreest E, Gaido KW, Sar M. Effects of phthalate esters on the developing reproductive tract of male rats. Hum Reprod Update 2001; 7:231-5.

[20.] Welsh M, Saunders PT, Fisken M, Scott HM, Hutchinson HM, Smith LB, et al. Identification in rats of a programming window for reproductive tract masculinisation, disruption of which leads to hypospadias and cryptorchism. J Clin Invest 2008; 118:1478-90.

[21.] Sharpe RM, Irvine DS. How strong is the evidence of a link between environmental chemicals and adverse effects on human reproductive health? Br Med J 2004; 328:447-51.

[22.] Main KM, Mortensen GK, Kaleva MM, Boisen KA, Da-magaard IN, et al. Human breast milk contamination with phthalates alternations of endogenous reproductive hormones in infants three months of age. Environ Health Perspect 2006; 114:270-6.

[23.] Maroziene L, Grazuleviciene R. Maternal exposure to low-level air pollution and pregnancy outcomes: a population based study. Environ Health Perspect 2002; 9:6.

[24.] Kobrosly RW, Parlett LE, Stahlhut RW, Barret ES, Swan SH. Socioeconomic factors and phthalate metabolite concentratins among United States women of reproductive age. Environ Res 2012; 115:11-7.

Ivana BAJKIN (1), Artur BJELICA (2,3), Tijana ICIN (1), Vesna DOBRIC (4), Branka KOVACEV ZAVISIC (1,3) and Milica MEDIC STOJANOSKA (1,3)

Clinical Centre of Vojvodina, Novi Sad

Department of Endocrinology, Diabetes and Metabolic Diseases (1)

Department of Gynecology and Obstetrics (2)

University of Novi Sad, Faculty of Medicine (3)

Health Centre, Novi Sad (4)

Corresponding Author: Dr Ivana Bajkin, Klinika za endokrinologiju, dijabetes i bolesti metabolizma, 21000 Novi Sad, Hajduk Veljkova 1-7, E-mail:
Table 1. Phthalate diesters and their metabolites (taken from
Frederiksen H, Skakkebek NE, Andersson AM. Metabolism of phthalates in
humans, Mol Nutr Food Res 2007;51:899-911.)

Tabela 1. Diestri ftalata i njihovi metaboliti (preuzeto iz
Frederiksen H, Skakkebek NE, Andersson AM. Meta- bolism of phthalates
in humans. Mol Nutr Food Res 2007;51:899-911.)


di-methyl-phthalate/di-metil-falat                              DMP

di-ethyl-phthalate/di-etil-ftalat                               DEP

di-n-butyl phthalate/'di-n-butil-ftalat                         DBP

di-n-butil-phthalate/di-n-butil-ftalat                          DBP

di-iso-butyl phthalate/di-izo-butil-ftalat                      DiBP

butyl benzyl phthalate/butil-benzil-ftalat                      BBzP

di-2-ethyl-hexyl phthalate di-2-etil-heksilftalat               DEHP

di-iso-nonyl phthalate/di-izo-nonil-ftalat


mono-methyl-phthalate/mono-metil-ftalat                         MMP

mono-ethyl-phthalate/mono-etil-ftalat                           MEP

mono-butyl phthalate/mono-butil-ftalat                          MBP

mono-butil-ftalat/mono-izo-butil-ftalat                         MBP

mono-iso-butyl phthalate/mono-butil-benzil ftalat               MiBP

mono-butyl benzyl phthalate/mono2-etil-heksil-ftalat            MBzP

mono2-ethyl -hexyl phthalate mono-2-etil-5 hidroksiheksil       MEHP

mono-2-ethyl-5 hydroxyhexyl phthalate mono-2-etil-5           5OHMEHP
oksoheksil ftalat

mono-2-ethyl-5 oxohexyl phthalate mono-2-etil-5               5oxoMEHP
karboksipentil ftalat

mono--2-ethyl-5 carboxy pentyl phthalate mono-2-etil-5        5chMEHP
karboksipentil ftalat

mono-2-carboxy-hexyl-phthalate                                2chMMHP


mono-iso-nonyl phthalate/mono-izo-nonil-ftalat                  MiNP

mono-hydroxy-iso-nonyl phthalatet mono-hidroksi-izo-nonil-    OH-MiNP

mono-oxo-iso-nonyl phthalate                                  oxo-MiNP


mono-carboxy-iso-octyl phthalate mono-karboksi-izo-oktil-     cx-MiNP
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Title Annotation:Professional article/Strucni clanak
Author:Bajkin, Ivana; Bjelica, Artur; Icin, Tijana; Dobric, Vesna; Zavisic, Branka Kovacev; Stojanoska, Mil
Publication:Medicinski Pregled
Article Type:Report
Date:May 1, 2014
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