A Global Assessment of Phthalates Burden and Related Links To Health Effects

EI-03456; No of Pages 25
Environment International xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Environment International
journal homepage: www.elsevier.com/locate/envint
Review article
A global assessment of phthalates burden and related links to health effects

Ioanna Katsikantami a, Stavros Sifakis b,1, Manolis N. Tzatzarakis c,1, Elena Vakonaki c, Olga-Ioanna Kalantzi d,
Aristidis M. Tsatsakis c,⁎, Apostolos K. Rizos a
a
Department of Chemistry, University of Crete, and Foundation for Research and Technology-Hellas, FORTH-IESL, GR-71003 Heraklion, Crete, Greece
b
Department of Obstetrics and Gynecology, University Hospital of Heraklion, GR-71003 Heraklion, Crete, Greece
c
Center of Toxicology Science and Research, Medical School, University of Crete, GR-71003, Heraklion, Crete, Greece
d
Department of Environment, University of the Aegean, GR-81100 Mytilene, Greece
a r t i c l e i n f o a b s t r a c t
Article history: Phthalates are ubiquitous environmental contaminants which are used in industry as plasticizers and additives in
Received 28 June 2016 cosmetics. They are classified as Endocrine Disrupting Chemicals (EDCs) which impair the human endocrine sys-
Received in revised form 13 September 2016 tem inducing fertility problems, respiratory diseases, childhood obesity and neuropsychological disorders. The
Accepted 14 September 2016
aim of this review is to summarize the current state of knowledge on the toxicity that phthalates pose in humans
Available online xxxx
based on human biomonitoring studies conducted over the last decade. Except for conventional biological matri-
Keywords:
ces (such as urine and serum), amniotic fluid, human milk, semen, saliva, sweat, meconium and human hair are
Phthalates also employed for the estimation of exposure and distribution of pollutants in the human body, although data are
Biomonitoring not enough yet. Children are highly exposed to phthalates relative to adults and in most studies children's daily
Toxicity intake surpasses the maximum reference dose (RfD) set from US Environmental Protection Agency (US EPA).
Long-term exposure However, the global trend is that human exposure to phthalates is decreasing annually as a result of the strict reg-
Health effects ulations applied to phthalates.
© 2016 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.1. Phthalates in industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1.2. Phthalates in human body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Abbreviations: 2OH-MiBP, mono 2-hydroxy-isobutyl phthalate; AC, abdominal circumference; AGD, anogenital distance; ASD, autism spectrum disorder; ATSDR, Agency for Toxic
Substances and Disease Registry; BBzP, benzyl butyl phthalate; BMI, body mass index; BPD, biparietal diameter; BW, body weight; DBEP, di 2-n-butoxyethyl phthalate; DBP, di butyl
phthalate; DCHP, di cyclohexyl phthalate; DEHP, di 2-ethylhexyl phthalate; DEEP, di 2-ethoxyethyl phthalate; DEP, di ethyl phthalate; DI, daily intake; DiBP, di isobutyl phthalate;
DiDP, di isodecyl phthalate; DiNP, di isononyl phthalate; DiUP, di isoundecyl phthalate; DMEP, di-2-methoxyethyl phthalate; DMP, di methyl phthalate; DMPP, di 4-methyl-2-pentyl
phthalate; DnHP, di n-hexyl phthalate; DnOP, di n-octyl phthalate; DnPeP, di n-pentyl phthalate; DPHP, di 2-propylheptyl phthalate; DPP, dipentyl phthalate; DTDP, di isotridecyl
phthalate; EC JRC, European Commission Joint Research Center; ECPI, European Council for Plasticizers and Intermediates; EC SCENIHR, European Commission Scientific Committee on
Emerging and Newly-Identified Health Risks; EDCs, endocrine disrupting chemicals; EU CSTEE, European Union Scientific Committee on Toxicity, Ecotoxicity and the Environment;
FDA, Food and Drug Administration; FL, femur length; FT4, free T4; FUE, urinary excretion factor; HC, head circumference; HDS, High DNA Stainability; HMW, high molecular weight;
IQ, intelligence quotient; LBW, Low birth weight; LH, luteinizing hormone; LIN, linearity; LMW, low molecular weight; LOD, Limit of detection; LOQ, Limit of quantification; MBzP,
mono benzyl phthalate; MCHP, mono cyclohexyl phthalate; MCiHxP, mono carboxy isohexyl phthalate; MCiOP or cx-MiNP or 7cx-MMeHP, mono carboxy-isooctyl phthalate; MCiPeP,
mono carboxy isopentyl phthalate; MCMHP or 2cx-MMHP, mono 2-carboxymethylhexyl phthalate; MCNP or cx-MiDP, mono-carboxy-isononyl phthalate; MCPP, mono 3-
carboxypropyl phthalate; MECPP or 5cx-MEPP, mono 2-ethyl-5-carboxypentyl phthalate; MEHHP or 5OH-MEHP, mono 2-ethyl-5-hydroxyhexyl phthalate; MEHP, mono ethylhexyl
phthalate; MEOHP or 5oxo-MEHP, mono 2-ethyl-5-oxohexyl-phthalate; MEP, mono ethyl phthalate; MHBP or 3OH-MnBP, mono 3-hydroxybutyl phthalate; MHiDP or OH-MiDP,
monohydroxy-isodecyl phthalate; MHiNP or OH-MiNP or 7OH-MMeOP, mono hydroxy-isononyl phthalate; MiBP, mono iso-butyl phthalate; MiDP, mono isodecyl phthalate; MMP,
mono methyl phthalate; MnBP, mono n-butyl phthalate; MnOP, mono n-octyl phthalate; MiNP, mono isononyl phthalate; MnPeP, mono n-pentyl phthalate; MOiDP or oxo-MiDP,
monooxoisodecyl phthalate; MOiNP or oxo-MiNP or 7oxo-MMeOP, mono oxoisononyl phthalate; MRL, minimum risk level; NICU, Neonatal Intensive Care Unit; PCOS, polycystic ovary
syndrome; PE, phthalate ester; PM, phthalate metabolite; PVC, polyvinyl chloride; RfD, reference dose; SD, standard deviation; SHBG, sex hormone–binding globulin; T4, thyroxine;
TDI, tolerable daily intake; TDS, testicular dysgenesis syndrome; US EPA, United States Environmental Protection Agency; VCL, curvilinear velocity; VSL, straight line velocity; WC,
waist circumference; WHO, World Health Organization.
⁎ Corresponding author at: Medical School, University of Crete, 71003 Heraklion, Crete, Greece.
E-mail address: tsatsaka@uoc.gr (A.M. Tsatsakis).
1
Authors with equal contribution.
http://dx.doi.org/10.1016/j.envint.2016.09.013
0160-4120/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article as: Katsikantami, I., et al., A global assessment of phthalates burden and related links to health effects, Environ Int (2016),
2 I. Katsikantami et al. / Environment International xxx (2016) xxx–xxx
2.1. Review questions and objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

2.2. Criteria for study inclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
2.3. Data registry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3. Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1. Toxicity in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1.1. Toxicity in newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1.2. Toxicity in children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.1.3. Toxicity in adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2. Phthalates in biological matrices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.1. Phthalate metabolites in human urine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.2. Association between maternal urine and amniotic fluid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.3. Phthalates and their metabolites in human milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.4. Phthalates and their metabolites in blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.5. Phthalate metabolites in human hair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
3.2.6. Phthalates in other biological matrices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
4. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
1. Introduction polymers such as polyvinyl chloride (PVC). The plasticized products in-
clude wire and cables, flooring, truck tarpaulins, wall coverings, self-ad-
1.1. Phthalates in industry hesive films or labels, synthetic leather, coated fabrics, roofing
membranes and automotive applications (AgPU, 2006; Cao, 2010;
Phthalates are the esters of 1,2-benzenedicarboxylic acid (o-phthalic ECPI, 2014; Wilkes et al., 2005).
acid) and their chemical structure consists of one benzene ring and two LMW phthalates include dibutyl phthalate (DBP), diisobutyl phthal-
ester functional groups linked with two consecutive carbons on the ring ate (DiBP), butyl benzyl phthalate (BBzP) and di 2-ethylhexyl phthalate
(Fig. 1). Phthalates are produced by the reaction between an alcohol and (DEHP), and are used in PVC products, as well as in medical devices, ad-
the phthalic anhydrite. Alcohols that are used range from methanol and hesives, paints, inks and enteric-coated tablets. Dimethyl phthalate
ethanol up to tridecanol (ECPI, 2014; Park et al., 2014). The hydrocarbon (DMP) and diethyl phthalate (DEP), with one and two carbon atoms
chains of the ester groups are obtained from the alcohol, they are either on their hydrocarbon chain respectively, are not classified in any
straight or branching and they are responsible for the name and the dif- group because they are not used as plasticizers, so they are not related
ferent properties among phthalates (Fernandez et al., 2012). to PVC. They are used as solvents and fixatives in fragrances, additives
Phthalate esters (PEs) are classified into two distinct groups accord- in cosmetics, medical devices, household and personal care products
ing to the length of their carbon chain. High molecular weight (HMW) (AgPU, 2006; Carlstedt et al., 2013; Chou and Wright, 2006; ECPI,
phthalates include those with 7–13 carbon atoms in their carbon 2014; FDA, 2010; Frederiksen et al., 2013; Green et al., 2005; Koo and
chain and low molecular weight (LMW) those with 3–6 carbon atoms Lee, 2004; Philippat et al., 2012; Schettler et al., 2006; Schlumpf et al.,
in their backbone. The most common HMW phthalates are diisodecyl 2010).
phthalate (DiDP), diisononyl phthalate (DiNP), di2-propylheptyl The interaction of the plasticizer with the polymer resin macromol-
phthalate (DPHP), diisoundecyl phthalate (DiUP) and diisotridecyl ecules is not permanent (Wilkes et al., 2005). So, under temperature
phthalate (DTDP) and they are widely used in industry as plasticizers variations and pH influence (Bošnir et al., 2007; Keresztes et al., 2013),
to increase softness, flexibility, elongation and durability of rigid phthalates are able to migrate from the plastic product to the
Fig. 1. A) The reaction between the phthalic anhydride and an alcohol (ROH) to produce a phthalate ester (Lorz et al., 2012). B) The structure of three Low Molecular Weight phthalates.
I. Katsikantami et al. / Environment International xxx (2016) xxx–xxx 3
Table 1
Phthalates, their metabolites and their respective urinary excretion factors (FUE) calculated 24 h after oral dose administration.
PEs Primary metabolite Secondary metabolite FUE (monoester) Total FUE (diester) Reference
DMP MMP 0.690 0.690 Itoh et al. (2007)

DEP MEP 0.690 0.690 Itoh et al. (2007)
DBP MnBP 0.840 0.922 Koch et al. (2012)
3OH-MnBP or MHBP 0.069 Koch et al. (2012)
MCPP 0.048 Koch et al. (2012)
DiBP MiBP 0.703 0.902 Koch et al. (2012)
2OH-MiBP 0.193 Koch et al. (2012)
BBzP MBzP 0.730 0.730 Itoh et al. (2007)
DEHP MEHP 0.059 0.670 Koch et al. (2005)
MEHHP or 5OH-MEHP 0.150 Koch et al. (2005)
MEOHP or 5oxo-MEHP 0.233 Koch et al. (2005)
MECPP or 5cx-MEPP 0.185 Koch et al. (2005)
MCMHP or 2cx-MMHP 0.042 Koch et al. (2005)
DiNP MiNP 0.021 0.395 Koch and Angerer (2007)
MHiNP or OH-MiNP or 7OH-MMeOP 0.184 Koch and Angerer (2007)
MOiNP or oxo-MiNP or 7oxo-MMeOP 0.099 Koch and Angerer (2007)
MCiOP or cx-MiNP or7cx-MMeHP 0.090 Koch and Angerer (2007)
MCiHxP Unavailable value Koch and Angerer (2007)
DiDP MiDP MHiDP or OH-MiDP Unavailable value Unavailable value Kato et al. (2007)
MOiDP or oxo-MiDP Unavailable value Kato et al. (2007)
MCNP or cx-MiDP Unavailable value Kato et al. (2007)
MCiPeP Unavailable value Kato et al. (2007)
environment. Food or water that has been in contact with containers Parent compounds or their metabolites are distributed in the circu-
and products containing phthalates is contaminated with these latory system (Ashley-Martin et al., 2014; Hines et al., 2009; Högberg
chemicals (Dirtu et al., 2013; Koch et al., 2013; Sui et al., 2014). Indoor et al., 2008; Koch and Calafat, 2009; Lin et al., 2011), breast milk
air is also polluted if there are plastic products such as PVC flooring (Calafat et al., 2004; Hines et al., 2009; Högberg et al., 2008; Kim et al.,
(Adibi et al., 2008; Bergh et al., 2010; Carlstedt et al., 2013; Koch et al., 2015; Lin et al., 2011; Main et al., 2006; Schlumpf et al., 2010), amniotic
2013). Except for cosmetics, clothing has also a possible role on dermal fluid (Huang et al., 2009; Jensen et al., 2015; Silva et al., 2004; Wittassek
exposure to phthalates either protective or accelerating (Gong et al., et al., 2009), semen (Frederiksen et al., 2010; Wang et al., 2016, 2015a)
2016). Phthalates have been detected in trousers and on skin covered and saliva (Hines et al., 2009; Niino et al., 2001; Silva et al., 2005). Their
by clothing. Phthalate levels on covered skin by clothing were lower deposition at storage sites such as adipose tissue (human hair) in adults
compared to bare skin, indicating that clothing may have a protective (Chang et al., 2013) and meconium for infants (Kato et al., 2006; Li et al.,
role. However, both phthalate levels in clothing and on the underlying 2013; Zhang et al., 2009) is still a subject of research.
skin were increased with increasing wearing time. LMW phthalates Phthalates interfere with the body's endocrine system inducing de-
are sufficiently removed from clothing with laundering. In summary, velopmental and reproductive toxicity (EC JRC, 2008; EFSA, 2005; EU,
the routes of exposure are through ingestion, inhalation, skin absorption 2005; WHO, 2013). As endocrine disrupting chemicals (EDCs), they
and intravenous injection (CDC, 2015; Gong et al., 2016; Hoppin et al., mimic naturally occurring hormones like estrogens and androgens, pro-
2013). ducing overstimulation, they bind to a receptor and block the endoge-
nous hormone from binding and finally, they interfere or block the
1.2. Phthalates in human body hormone or receptor metabolism in the liver (National Institute of
Health, 2010). The compounds that induce the toxicity are supposed
When phthalates enter human body they are metabolized to their to be the free monoesters while the parent compounds and the
respective hydrolytic and oxidative monoesters and they are excreted glucuronidated metabolites are considered to be non-toxic (Stein et
via the biological fluids, urine (Axelsson et al., 2015) and sweat (Hines al., 2013). However, in most studies there is no discrimination between
et al., 2009; Silva et al., 2005). The fractional excretion in urine is calcu- the free and glucuronidated metabolites.
lated for each metabolite 24 h after oral dose administration. There is no The aim of this review study is to present the current state of knowl-
urinary excretion factor (FUE) available for DiDP metabolites and three edge on human phthalate exposure based on human biomonitoring
metabolites of DiNP. The typical metabolic reactions involve hydrolysis data. The levels of phthalate metabolites (PMs) in human biological
of the diesters to their respective monoesters, oxidation and conjuga- specimens are presented as well as the toxicity that these compounds
tion with glucuronic acid (Kato et al., 2007; Koch and Angerer, 2007; pose in humans. Based on literature research, a worldwide comparison
Koch et al., 2006; Silva et al., 2006a, 2006b). The hydrolytic metabolites between exposure of adults and children is made and the global annual
of DMP, DEP and BBzP, MMP, MEP and MBzP respectively, are sufficient- progress of human exposure is also presented.
ly hydrophilic and they are excreted without oxidation steps (Table 1).
DBP and DiBP are excreted mainly as the hydrolytic monoester (84% and 2. Methods
70% of the administered dose, respectively) and their total percentage
fraction in human urine is about 90% after 24 h of the oral dose. HMW 2.1. Review questions and objective
phthalates (DEHP and DiNP) are excreted as the hydrolytic monoester
and oxidative metabolites but the primary metabolite represents only The aim of this review is to collect the most recent data about the
a small fraction relatively to the total amount excreted. As the toxicity of phthalates in different population groups, including pregnant
phthalates' molecular weight is increasing 24-hour-excretion rate is de- mothers and their newborns, children and adults and to answer ques-
creased. After oral exposure to DEHP the 67% of the administered dose is tions posed for human exposure to phthalates. The first issue is if expo-
excreted (Koch et al., 2005) while for DiNP the value is 40% (Koch and sure to phthalates is associated with disorders and diseases detected in
Angerer, 2007). Unmetabolized phthalates are likely to be present in humans the last decades and if these health impacts in adults are asso-
urine (Genuis et al., 2012; Jornet-Martínez et al., 2015). ciated with prenatal and childhood exposure to phthalates. The second
issue is what we know about the storage of phthalates in the human 3.1.1. Toxicity in newborns
body. Are there enough studies dealing with the presence of phthalates Fetuses and newborns are more vulnerable to toxic chemicals
in storage sites of the human body? Strict regulation is applied for the because they have an immature metabolism and they cannot easily ex-
use of phthalates in industry. Is there a positive outcome of the strict crete the pollutants. Exposure to hormone mimickers during develop-
regulations applied for phthalates with regards to human exposure? ment has permanent adverse health impacts that are noticeable after
Generally, children are highly exposed relative to adults due to their birth, during childhood or even later in life. Hormones have a significant
lower body mass. What is the level of this high exposure and is this role in cell differentiation and organ formation during prenatal develop-
below or above the US Environmental Protection Agency (US EPA) ref- ment. The immune system and lungs continue developing after birth
erence dose (RfD) value? Finally, this study aims to investigate how until the child becomes 10 years old and the central nervous system to-
human exposure to phthalates fluctuates in worldwide scale. gether with the reproductive system are fully developed during adult-
hood indicating that except for prenatal exposure to EDCs, exposure
2.2. Criteria for study inclusion during childhood and adulthood is also important (WHO, 2013).
Although the association of prenatal exposure with birth outcomes
The types of studies included in this review are cohort, case control, is a controversial issue (Suzuki et al., 2010), most studies associate pre-
cross-sectional and animal studies published online until March 2016. natal exposure with Low Birth Weight (LBW) of infants (Huang et al.,
We searched the PubMed (http://www.ncbi.nlm.nih.gov/pubmed) da- 2014; Zhang et al., 2009) and low rate of weight gain (Valvi et al.,
tabases combining the keywords phthalates; human exposure/toxicity; 2015), shorter AGD in males and females (Huang et al., 2009; Swan et
prenatal; neonates; children; asthma; obesity; autism; diabetes; endome- al., 2005), shorter pregnancy duration and preterm birth (Huang et al.,
triosis; hypospadias; cryptorchidism; cancer; neurodevelopment; thyroid; 2014; Latini et al., 2003), adverse effects on birth length, head circum-
blood pressure; reproductive toxicity; pregnant rats; meconium; serum; ference (HC), biparietal diameter (BPD), abdominal circumference
urine; hair; amniotic; breast milk; semen; saliva; sweat; placenta. We ex- (AC) and femur length (FL) in both male and female infants (Huang et
cluded articles that were not written in English and studies that were al., 2014). These abnormalities reflect in uterus-delayed development
conducted before 2000 because we want to present data of the last fif- (Table 2). Male and female newborns appear to be affected by different
teen years. Articles that examined human exposure to phthalates to- phthalates and in a different way indicating that phthalates have sex-
gether with other compounds were included. We included studies, specific effects (Engel et al., 2009; Huang et al., 2014, 2009; Wolff et
which detected phthalates or their metabolites in all biological fluids al., 2008). For example, DiNP, di cyclohexyl phthalate (DCHP), DBP,
(urine, amniotic fluid, breast milk, semen, saliva, sweat and blood) DEHP, di 2-ethoxyethyl phthalate (DEEP), di n-hexyl phthalate
and other biological matrices (meconium, placenta tissue, hair). Studies (DnHP), DEP and BBzP seem to have adverse effects on female growth
which linked phthalate exposure with adverse health outcomes in parameters while di 2-n-butoxyethyl phthalate (DBEP) and di pentyl
adults, children and newborns were also included. Animal studies for phthalate (DPP) affect male infants (Huang et al., 2014). Exposure to
pregnant rats were selected to assess the agreement between the re- HMW phthalates is inversely associated with orientation and quality
sults from animal experiments and human data. We focused on studies of alertness in infant girls and LMW phthalates are positively associated
published during the last decade except for some older studies, which with motor performance in boys (Engel et al., 2009).
were also included due to the small amount of the available data with Mono 2-ethyl-5-carboxypentyl phthalate (MECPP) in amniotic fluid
regards to some of the issues on phthalate human exposure. We also is associated with altered testosterone and insulin like factor 3 levels in
searched the US EPA (https://www3.epa.gov/), FDA (http://www.fda. fetuses while mono carboxy-isooctyl phthalate (MCiOP) is correlated
gov/), Health Canada (http://www.hc-sc.gc.ca/index-eng.php), WHO with cryptorchidism and hypospadias cases (Jensen et al., 2015). Expo-
(http://www.who.int/en/), EC JRC (https://ec.europa.eu/jrc/en) and sure to DBP still has unclear effects on thyroid activity in pregnant
NIEHS (http://www.niehs.nih.gov/) databases using the keywords women. Thyroid hormones, including thyroxine (T4) and free T4
phthalate and DEHP. In total 106 human studies and 4 animal studies (FT4), are negatively associated with urinary levels of DBP (Huang et
are presented in this review. al., 2007). Thyroid hormones are critical for development of the fetal
brain. During the second trimester, fetal thyroid gland begins to produce
2.3. Data registry its own thyroid hormone but it is still dependent of maternal thyroid
(American Thyroid Association, 2014). Altered maternal thyroid hor-
Age, gender, the number of the studied population, the year and the mone levels during gestation induce mental retardation and have ad-
country where the research was conducted are important data that verse effects on fetal neurodevelopment which may be visible later in
were collected and recorded from all selected studies. Median and childhood (Cohen, 2014; Morreale de Escobar et al., 2004; Morreale de
mean values, ranges and detectability of phthalates were recorded to Escobar, 2001; Oerbeck et al., 2003).
estimate the presence of the compounds in the biological matrices. Maternal exposure to phthalates results in exposure of infants
Health impacts and raised statistical associations were also recorded through breastfeeding. The calculated DEHP daily intake (DI) of breast
and presented in this study. feeding infants in Korea (Kim et al., 2015) exceeded the RfD of anti-
androgenicity for up to 8% of infants and about 6% of infants exceeded
3. Results and discussion the Tolerable Daily Intake (TDI) for DBP. Breast milk levels of the phthal-
ate metabolites were positively associated with maternal diet and water
3.1. Toxicity in humans consumption. Quite a few studies on the presence of PEs or PMs in
breast milk have been conducted (Calafat et al., 2004; Hines et al.,
Testicular cancer, male infertility, genital malformations and repro- 2009; Högberg et al., 2008; Kim et al., 2015; Lin et al., 2011; Main et
ductive abnormalities including hypospadias and cryptorchidism are al., 2006; Schlumpf et al., 2010). However, further studies of health ef-
known as the Testicular Dysgenesis Syndrome (TDS), which is affected fects related to phthalates are necessary. Mono ethyl phthalate (MEP)
by a combination of genetic predisposition, lifestyle factors and environ- in human milk is positively associated with increased levels of sex hor-
mental exposure to chemicals (Skakkebaek et al., 2003). Phthalates as mone-binding globulin (SHBG) and increased ratio between luteinizing
hormone mimickers seem to play an important role in the manifesta- hormone (LH) and free testosterone, mono n-butyl phthalate (MnBP) is
tion of the syndrome in humans (Jensen et al., 2015; Jurewicz et al., inversely correlated with free serum testosterone and mono isononyl
2013; Pant et al., 2011). The age and development stage of the organism phthalate (MiNP) is associated with increased levels of luteinizing hor-
seem to be a very important factor that determines the system that will mone (LH) (Main et al., 2006). These altered reproductive hormone
be injured and the extent of the adverse outcomes (WHO, 2013). levels indicate adverse effects on Leydig cell function and reduced
Table 2
Health and birth outcomes in mother-infant pairs.
Reference Study Biological Mean/Median range of compounds Outcome (for creatinine or gestational Health effects
population matrix (μg/L) age corrected concentrations)
Shapiro et al. (2015) 1152 pregnant Urine (1st MEP, MnBP, MBzP, MCPP, MEHP, No significant associations with impaired No health effect
women, Canada trimester) MEHHP, MEHHP, MEOHP, MCHP, glucose tolerance or gestational diabetes mellitus
MnOP, MiNP, MMP; mean range:
bLOD-38.8
Valvi et al. (2015) 391 pregnant Urine (1st, MEHP, MEHHP, MEOHP, MECPP, Associations with lower rate of weight gain Developmental toxicity
women-infant 2nd, 3rd MBzP, MEP, MiBP, MnBP; median (MEHP, MEHHP, MEOHP, MECPP, MBzP)
pairs, Spain trimester) range: 11.0–405 μg/g creatinine
Huang et al. (2014) 207 mother-infant Cord Blood DMP, DEP, DMEP, DBP, DEEP, DiBP, All phthalates except DCHP were associated with Duration of human
pairs, China DPP, DMPP, DBEP, DCHP, DnHP, preterm birth. After adjusting for gestational age, pregnancy
BBzP, DEHP, DnOP, DINP; mean they were associated with decreased birth weight Developmental toxicity
range: 6.69–187.16 and length (DMEP, DPP, DBEP), decreased HC
(DnHP), decreased FL (DBP, DCHP, DEHP, DEP),
decreased AC (DnHP, BBzP, DiNP, DEP). No
associations came up for BPD.
Philippat et al. (2012) 287 pregnant Urine (1st MEP, MnBP, MiBP, MBzP, MCPP, Possible association between MCNP and birth Developmental toxicity
women, France and 2nd MEHP, MEOHP, MECPP, MCiOP, length
trimester) MCNP; median range: 3.1–105.53
Suzuki et al. (2010) 149 pregnant Urine (1st, MMP, MEP, MnBP, MiBP, MBzP, No associations with birth weight, birth length, No health effect
women, Japan 2nd, 3rd MEHP, MEHHP, MEOHP, MiNP, HC and gestational age
trimester) MnOP; mean range: 0.019–46.2
Engel et al. (2009) 295 mother-infant Maternal urine MMP, MEP, MnBP, MiBP, MBzP, Strong inverse associations with orientation and Neurological toxicity
pairs, USA MEHP, MEHHP, MEOHP, MECPP, quality of alertness in girls (MBzP, MECPP, MEHHP, Sex-specific effects
MCPP; median range: 1.7–385.8 MEOHP, MEHP,
MCPP) and a slight positive association with motor
performance in boys (MMP, MEP, MnBP, MiBP)
Huang et al. (2009) 65 pregnant Amniotic fluid MnBP, MEHP, MEP, MBzP, MMP; Significant positive correlation between MnBP Anti-androgen effects
women, Taiwan and maternal median range: bLOD-85.2 (amniotic in the two matrices, a significantly negative
urine (1st fluid); bLOD-78.4 (urine) correlation between MnBP in amniotic fluid and
trimester) short AGD
Zhang et al. (2009) 201 mother-infant Cord blood, DEP, DBP, DEHP, MEHP, MnBP; Dose-response associations with short birth length Developmental toxicity
pairs, China maternal median range: 500–2700 (cord (DEHP) and low birth weight (DBP, MnBP, DEHP,
blood, blood); 600–2900 (maternal blood); MEHP)
Meconium 1.7–5.5 (meconium)
Wolff et al. (2008) 382 pregnant Urine (3rd MECPP, MEHHP, MEOHP, MEHP, Significant correlations with maternal BMI Duration of human
women, USA trimester) MBzP, MCPP, MiBP, MnBP, MEP, (MBzP, positive; MMP, negative) and positive pregnancy and
MMP; median range: 1.6–380 associations with duration of pregnancy and development of
infant HC (MMP, MEP, MnBP, MiBP, MBzP) adiposity
Huang et al. (2007) 76 pregnant Urine (2nd MnBP, MBzP, MEP, MEHP, MMP; Strong inverse correlations with thyroid Maternal
women, Taiwan trimester) median range: 0.9–81.8 hormones T4 and FT4 (MnBP) hypothyroidism
Risk for mental
retardation and fetal
neurodevelopment
Main et al. (2006) 130 Male Breast milk MMP, MEP, MnBP, MBzP, MEHP, Strong inverse associations with free serum Adverse effect on
newborns, MiNP; median range: 0.09–101 testosterone levels (MnBP) and positive Leydig cell function
Denmark, Finland associations with serum LH levels (MiNP), SHBG Anti-androgen effects
levels and the ratio LH:free testosterone (MEP)
Swan et al. (2005) 134 pregnant Maternal MBP, MBzP, MCPP, MEP, MiBP, MMP; Inverse associations with anogenital index Anti-androgen effects
women-male urine (3rd median range: 0.7–128.4 (AGD/weight) (MEOHP, MEHHP, MEP, MBzP,
newborns, USA trimester) MiBP, MnBP)
Latini et al. (2003) 84 newborns, Italy Cord blood DEHP, MEHP; mean range: 0.52–1.19 Strong inverse association with gestational age Duration of human
(MEHP) pregnancy
No significant correlations with gender,
complications during delivery and birth
weight (MEHP, DEHP)
androgen activity. According to the EU Risk Assessment for DEHP (EC kg/day to 0.352 mg/kg/day (Weuve et al., 2006). This value is about 2
JRC, 2008), exposure to DEHP from breast milk is calculated to be orders of magnitude over the RfD set from US EPA for DEHP, which is
6 μg/kg bw/day and exposure from infant formulas is almost twice 0.022 mg/kg/day (US EPA, 1987c). It should be mentioned that in
higher, 13 μg/kg bw/day. 2012 France became the first country in the EU to ban the use of DEHP
Hospital equipment and supplies in Neonatal Intensive Care Units in pediatric, neonatology and maternity wards in hospitals and the
(NICU) are also significant sources of DEHP for newborns (EC law came into effect in July 2015 (US Health systems, 2012).
SCENIHR, 2008; FDA, 2002; Green et al., 2005; Su et al., 2012; Weuve
et al., 2006). Infants in NICU are multiply exposed to DEHP through 3.1.2. Toxicity in children
feeding tubes, infusion tubing systems, umbilical catheters, PVC blood It is still not clear which way neonatal exposure to phthalates affects
bags, transfusion tubing systems and others (CERHR, 2005; FDA, 2002; their health later on in life. Adolescents who had been exposed to
Health Canada, 2002). Each NICU uses different medical devices phthalates in NICU had normal growth, no adverse effects on physical
resulting in different exposure levels among newborns (Green et al., parameters including height, weight, HC and pubertal maturity (Rais-
2005). Depending on the device, the DEHP exposure for some infants Bahrami et al., 2004). Thyroid, liver, and renal functions were unaffected
may be 5 to 20-fold greater than the TDI. An upper bound at 3 mg/kg/ by EDCs, males had no genital malformations, and sex hormone levels
day is set for DEHP-multiply exposed newborns in NICU (FDA, 2002). were within normal range for both genders. However, more recent
The estimated DI of DEHP for infants in NICU ranges from 0.233 mg/ studies note that prenatal exposure is associated with neurobehavioral
Table 3
Health outcomes in children.
Reference Study Matrix Mean/Median range of compounds (μg/L) Outcome Health effects
population
(years of age)
Arbuckle et al. 1044 children Urine MBzP, MnBP, MCHP, MEP, MEHP, MEHHP, Significant positive associations with emotional Learning and
(2016) (6–11), Canada MEOHP, MnOP, MMP, MCPP, MiNP; mean range: symptoms in girls (MBzP) and behavioral
bLOD-33.11 hyperactivity/inattention (MCPP) problems
Inverse associations with risk of attention deficit Poor attentional
disorder and attention deficit hyperactivity performance
disorder (MEHP)
Huen et al. (2016) 334 pregnant Urine (1st MEP, MnBP, MiBP, MEHP, MEOHP, MEHHP, Strong inverse association with Alu methylation DNA damage
women-children and 2nd MECPP, MBzP, MCPP, MCiOP, MCNP; median (MEHHP, MEOHP) and positive association with Genomic
pairs (9), USA trimester) range: 1.7–167.2 μg/g creatinine LINE-1 mehtylation (MCiOP, MCNP) in 9-year old instability
blood
Lien et al. (2015) 122 pregnant Maternal MMP, MEP, MnBP, MiBP, MBzP, MEOHP, MEHHP, Positive associations with externalizing problems Behavioral
women-children urine (3rd MEHP; mean range: 20.20–124.5 and aggressive behavior (MEP, MnBP, MiBP, syndromes
pairs (8), trimester) MEOHP, MEHHP, MEHP), significant positive
Taiwan associations with social problems (MEOHP) and
positive but non-significant association with
internalizing behavior (MnBP, MiBP)
Trasande and 1619 children Urine MEP, MnBP, MiBP, MMP, MBzP, MCPP, MEHP, Significant positive association with systolic Risk for
Attina (2015) (6–19), USA MEOHP, MECPP, MEHHP, MCiOP, MCNP, MiNP blood pressure (MCiOP, MCNP, MiNP) hypertension
No associations with triglyceride or high density
lipoprotein
Valvi et al. (2015) 391 pregnant Urine (1st, MEHP, MEHHP, MEOHP, MECPP, MBzP, MEP, Significant negative associations with BMI in boys Sex-specific
women-children 2nd, 3rd MiBP, MnBP; median range: 11.0–405 μg/g and positive in girls (MEHP, MEHHP, MEOHP, toxicity
(1–7), Spain trimester) creatinine MECPP, MBzP), significant negative associations Growth and blood
with systolic blood pressure in girls (MEP, MnBP, pressure
MiBP, MEHP, MEHHP, MEOHP, MECPP, MBzP)
No associations with waist to height ratio or
diastolic blood pressure
Xie et al. (2015) 167 boys (11), Urine MnBP, MMP, MEP, MEHP, MEHHP, MEOHP: Significant inverse associations with serum Anti-androgen
China median range: 2.33–37.43 testosterone level (MEP, MnBP, total phthalate effects
concentrations) and significant positive Delay of growth
associations with children with constitutional and puberty
delay of growth and puberty (MnBP, MEP, MEHP,
total phthalate concentrations)
Zhang et al. (2015) 430 children Urine MnBP, MMP, MEP, MEHP, MEHHP, MEOHP: Inverse associations with pubic hair development Speed up and
(6–14), China mean range: 0.96–22.32 in boys (MnBP) and positive associations with delayed pubertal
breast onset (MnBP, MMP, MEP, MEHP), speed up onset in girls and
breast development progression and earlier boys respectively
menarche onset in girls (MEHP) Sex-specific
toxicity
Factor-Litvak et al. 328 pregnant Maternal MnBP, MBzP, MEHHP, MEHP, MEP, MiBP; mean Significant inverse associations with IQ scores Mental
(2014) women-children urine (3rd range: 4.95–160.5 (MnBP, MiBP), perpetual reasoning (MnBP, MiBP, development
pairs (7), USA trimester) MBzP), processing speed (MnBP, MiBP), verbal effects
comprehension (MiBP) and working memory Learning
(MnBP, MiBP) problems
The associations between MnBP and IQ score, Sex-specific
perpetual reasoning and working memory were toxicity
stronger in girls than in boys. The associations
between MnBP and processing speed, MBzP and
perpetual reasoning and MiBP and verbal
comprehension were stronger in boys than in
girls.
Kobrosly et al. 153 pregnant Maternal MEHP, MEHHP, MEOHP, MiBP, MnBP, MBzP, Positive associations with somatic complaints Neurobehavioral
(2014) women-children urine (1st, MEP; mean range: 2.34–81.01 and inverse associations with anxiety problems in disorders and
pairs, USA 2nd, 3rd girls (MEHHP, MEHP, MEOHP, MBzP) somatic
trimester) In boys there were significant positive complaints
associations with attention problems, Behavioral
oppositional/defiant problems, conduct problems
problems, rule breaking and externalizing Sex-specific
behavior (MiBP, MnBP, MBzP). toxicity
Park et al. (2014) 179 children Urine MEHP, MEOHP, MnBP; mean range: 43.82–68.03 Significant positive correlations with poor Poor attentional
(8–9), Korea μg/g attentional performance and increasing risk of performance
attention deficit hyperactivity disorder (MEHP,
MEOHP, MnBP)
Bertelsen et al. 623 children Urine MEP, MnBP, MiBP, MBzP, MCPP, MEHP, MEOHP, Significant positive associations with current Asthma
(2013) (10), Norway MEHHP, MECPP, MCiOP, MCNP; median range: asthma (MCNP, MCiOP)
2.1–138.0 No associations with allergic sensitization
Stein et al. (2013) 50 children Urine MEHP, MEHHP, MEOHP, MECPP; median range: Associations between DEHP metabolism and Toxicity for
(10.26 ± 3.83), 3.33–238.58 autism spectrum disorder (ASD) individuals with
USA ASD due to
inadequate
detoxification
Trasande et al. 2838 children Urine MEP, MnBP, MiBP, MBzP, MCPP, MEHP, MEOHP, Positive associations with systolic blood pressure Risk for
(2013) (6–19), USA MECPP, MEHHP (MEHP, MEHHP, MEOHP, MECPP) hypertension
Table 3 (continued)
Reference Study Matrix Mean/Median range of compounds (μg/L) Outcome Health effects
population
(years of age)
Wang et al. (2013) 259 children Urine MEHP, MECPP, MEHHP, MEOHP, MCMHP, MCHP, Positive associations with BMI and WC (MEP and Childhood obesity
(8–15), China MBzP, MnBP, MHBP, MiBP, MMP, MEP; median MEHP significantly associated, MEOHP, MCMHP,
range: 0.05–47.2 MCHP, MiBP, MMP, MnBP, MHBP)
Kasper-Sonnenberg 104 Urine MMP, MEP, MBzP, MnBP, MHBP, MCPP, MiBP, Inverse associations with BMI (MiBP, 2OH-MiBP, No health effect
et al. (2012) mother-child 2OH-MiBP, MCHP, MnPeP, MEHP, MEOHP, MnBP, MHBP, MBzP)
pairs (7), MEHHP, MECPP, OH-MiNP, oxo-MiNP, cx-MiNP, Significant associations between DiBP exposure
Germany OH-MiDP, oxo-MiDP, cx-MiDP, MnOP; mean and environmental tobacco smoke exposure
range: bLOQ-66.2
Cho et al. (2010) 621 children (9), Urine MEHP, MEOHP, MnBP: median range: 20.5–50.4 Inverse associations with children's IQ, Mental
Korea vocabulary and block design scores (MEOHP, development
MEHP, MnBP) effects
Bornehag et al. 400 children House BBzP, DEHP, DEP, DiBP, DnBP, DiNP: mean range: Associations between phthalates and PVC Asthma and
(2004) (3–8), Sweden dust 0.073–0.789 mg/g flooring (BBzP, DEHP), positive associations with allergic symptoms
rhinitis (BBzP), eczema (BBzP) and asthma
(DEHP)
disorders and syndromes and low Intelligence Quotient (IQ) scores at asthma in children between 2 and 8 years old are attributed to both pre-
the age between 6 and 10 years old (Table 3). The US Consumer natal and postnatal exposure to MEP, MBzP and DEHP metabolites (Ku
Product Safety Commission (2014) reviewed the reproductive and et al., 2015). Urinary MEHP and MEP in children between 8 and
neurodevelopmental toxicity of phthalates and reports that human ex- 15 years old are positively associated with Body Mass Index (BMI) and
posure to certain phthalates should be reduced. Waist Circumference (WC) which are used as indicators for obesity.
Maternal exposure to DEP and DEHP during pregnancy is associated Two oxidative metabolites of DEHP, mono 2-ethyl-5-hydroxyhexyl
with differences in DNA methylation which alters gene expression and phthalate (MEHHP) and mono 2-ethyl-5-oxohexyl phthalate
it can adversely affect health later in life (Huen et al., 2016). Urinary (MEOHP) show age and sex related associations with obesity (Wang
MEP from pregnant women is strongly associated with low methylation et al., 2013). However, in younger children between 1 and 7 years old,
of Alu repeats in cord blood and exposure to DEHP during the third tri- BMI is negatively associated with prenatal exposure to MBzP and
mester of pregnancy is inversely associated with DNA methylation in DEHP metabolites (Valvi et al., 2015). There are some indications that
blood from 9-year old children. These data indicate that prenatal expo- phthalate metabolism is associated with Autism Spectrum Disorder
sure to phthalates can adversely affect human health through genomic (ASD) (Stein et al., 2013). Phthalate metabolites are detoxified through
instability. the glucuronidation pathway, but this is somehow compromised in in-
Prenatal exposure to DBP and DEHP is related to poor attentional dividuals with ASD. The metabolites of the HMW phthalates DiDP,
performance, delinquent and aggressive behavior such as rule breaking DiNP and DEHP are significantly associated with high systolic blood
behavior, and oppositional or defiant problems (Kobrosly et al., 2014; pressure in children and adolescents between 6 and 19 years old
Lien et al., 2015; Park et al., 2014). Maternal exposure to DEHP is posi- (Trasande and Attina, 2015; Trasande et al., 2013).
tively associated with somatic complaints such as headache and lower Inhalation is proved to be a significant route of exposure to
symptoms of anxiety in girls (Kobrosly et al., 2014). Elevated urinary phthalates. Indoor air is polluted with EDCs due to their presence in
levels of PMs in children between 6 and 11 years old are linked to learn- plastic products that exist in the room. This has been ascertained by
ing and behavioral problems and especially mono benzyl phthalate the collection of indoor air and settled dust samples (Bornehag et al.,
(MBzP) is associated with emotional symptoms in girls (Arbuckle et 2004; Sukiene et al., 2016). In the most recent study (Sukiene et al.,
al., 2016). Phthalates also have an effect on the intelligence of school- 2016) consumer products with deuterium-labeled phthalates and
aged children. Although IQ is dependent on familial and social factors, adipates were placed in homes to investigate the emission processes
there is evidence that prenatal exposure to DEHP, DBP and DiBP is in- and the labeled compounds were detectable in the air and dust samples.
versely associated with child verbal comprehension, processing speed, It has been proved that children who are sleeping in bedrooms with PVC
perceptual reasoning and working memory (Cho et al., 2010; flooring suffer from asthma, rhinitis and eczema (Larsson et al., 2010;
Factor-Litvak et al., 2014). As already mentioned, neurodevelopmental Shu et al., 2014). BBzP and DEHP are detected in samples of dust from
deficits, neuropsychological disorders and mental retardation in chil- molding and shelves in bedrooms with PVC flooring and they are asso-
dren are resulting from impaired thyroid activity during gestation, ciated with rhinitis, eczema (BBzP) and asthma (DEHP) in children
which may be partially induced by the action of EDCs such as phthalates. (Bornehag et al., 2004). These results are also confirmed by the analysis
According to recent human biomonitoring studies, phthalates have of biological samples from children: urinary MBzP from infants is corre-
been shown to speed up pubertal onset in girls, delay pubertal develop- lated with the presence of PVC flooring in the bedroom (Carlstedt et al.,
ment in boys and play a role for the manifestation of childhood obesity 2013) and urinary MCNP and MCOP from 10-year-old children are asso-
(Ku et al., 2015; Shi et al., 2015; Wang et al., 2013; Xie et al., 2015; Zhang ciated with asthma (Bertelsen et al., 2013). For the first time, Kasper-
et al., 2015). More specifically, earlier menarche onset and accelerated Sonnenberg et al. (2012) reported a significant positive association be-
breast development are associated with urinary MnBP, MMP, MEP and tween internal exposure to tobacco smoke and DiBP exposure among
mono ethylhexyl phthalate (MEHP) in girls between 6 and 14 years mothers and their children. The authors, considering data from related
old, while delayed pubic hair and testis development are associated references, suppose that DiBP may be used in cigarette manufacture.
with urinary MnBP in boys (Shi et al., 2015; Zhang et al., 2015). Elevated Phthalate exposure between family members is positively associat-
concentrations of PMs in children with delayed growth and puberty are ed, especially between mothers and children, implying common
associated with lower testosterone levels in serum (Xie et al., 2015). Al- sources of exposure through the environment or lifestyle habits (Ait
though it is not clear whether effects on pubertal timing are derived Bamai et al., 2015). The use of personal care products is usually recom-
from in utero exposure, it seems that exposure during childhood is of mended from mothers and is positively associated with urinary concen-
the same importance as prenatal exposure. Allergic symptoms and trations of phthalates in adults and children (Philippat et al., 2015).
3.1.3. Toxicity in adults 3.2. Phthalates in biological matrices

Although phthalates are associated with childhood obesity, it could
not be confirmed for adults (Dirtu et al., 2013). Urinary levels of nine 3.2.1. Phthalate metabolites in human urine
PMs did not pose significant differences between obese and control Human urine is the most common used matrix for human bio-
groups and no associations with BMI or WC came up (Table 4). On the monitoring studies (Table 5), since metabolites are in high concen-
other hand, similarly to children, phthalates are correlated with respira- tration and there is no risk for external contamination because
tory problems in adults (Hoppin et al., 2013). Exposure to BBzP (urinary there is no lipase or esterase activity to metabolize parent com-
MBzP) induces allergic symptoms, including wheeze, asthma, hay fever pounds (Calafat et al., 2004; Kim et al., 2015; Main et al., 2006).
and rhinitis and urinary levels of mono 3-carboxypropyl phthalate The comparison of urinary metabolite levels between schoolchildren
(MCPP), MEHP, MEOHP and MEHHP are associated with allergic sensi- and their parents showed that urinary concentrations are much
tization. As previously mentioned, phthalates affect mainly the sex hor- higher in children and are strongly correlated with their mothers
mones (estrogens and androgens) causing infertility and gynecological (Ait Bamai et al., 2015). MECPP is mostly detected in urine from chil-
disorders. dren (92.7%) than in adults (56.7%–57.6%), because in children oxi-
dative metabolism is enhanced and they excrete larger amounts of
metabolites (Becker et al., 2009; Koch et al., 2004a; Lin et al., 2011;
3.1.3.1. Males. All human biomonitoring studies support the notion that Song et al., 2013). Phthalate excretion is associated with gender
exposure to phthalates impairs semen quality and decreases sex hor- and age. Among children, DBP and DEHP metabolites are highly ex-
mone levels causing fertility problems in reproductive-age men creted in boys than in girls and MEP is positively related to the age
(Bloom et al., 2015; Liu et al., 2012; Wang et al., 2016, 2015a, 2015b). for both genders. Adolescents excrete higher amounts of MEP com-
High DNA Stainability (HDS) is an indicator of sperm immaturity, to- pared to children suggesting higher exposure through cosmetics
gether with increased DNA fragmentation, decreased sperm motility (Frederiksen et al., 2011).
and semen volume, sperm aneuploidy, straight line velocity (VSL), cur- Urinary levels are suitable for the comparison of human exposure
vilinear velocity (VCL) and linearity (LIN) all indicators of male among countries (Fig. 2). Median value of urinary levels detected in
infertility. the European population (209.06 μg/L) is very close to the corre-
Urinary levels of some PMs (MEP and MnBP) are positively asso- sponding value for America (199.70 μg/L) but high relatively to
ciated with sperm DNA damage (Hauser et al., 2006; Jurewicz et al., Asia (125.25 μg/L). European population is exposed almost 40.1%
2013), while oxidative metabolites of DEHP are inversely associated more than Asians, despite the phthalate incidence in Taiwan in
indicating that they may have a ‘protective’ role (Hauser et al., 2006). 2011. DEHP and DiNP were added illegally in foods and health sup-
All DEHP metabolites (MEHP, MEOHP, MEHHP and MECPP) and plements as clouding agents and it was noticed accidentally by the
MBzP are positively associated with HDS (Axelsson et al., 2015), Taiwan Food and Drug Administration. After the episode urine spec-
and together with MiNP they are associated with abnormal sperm imens from children and adults were collected and analyzed for PMs
heads and tails (larger sizes) and sperm morphological alterations (Chen et al., 2016). In total, there were 347 individuals exposed of
(Bloom et al., 2015; Wang et al., 2016, 2015b). DEHP and DBP, as whom 237 were children and 13 adolescents. Children were highly
well as DMP, have adverse effects on sperm motility (Axelsson et exposed compared to adults. Among the adults, 86% had low expo-
al., 2015; Bloom et al., 2015; Jurewicz et al., 2013; Pant et al., 2011). sure, while 63% of the children had DIs over the RfD set from US
MEHP and mono oxoisononyl phthalate (MOiNP) are negatively as- EPA (20 μg/kg bw/day) and 11% had DI over 100 μg/kg bw/day. The
sociated with testosterone levels and follicle-stimulating hormone maximum detected DI for children was 414.1 μg/kg bw/day while
respectively, while all DEHP metabolites, DiNP metabolites (MiNP, for adults 126.4 μg/kg bw/day.
MCiOP, MOiNP), MnBP and MBzP are associated with decreases in On a worldwide scale, the levels of urinary metabolites are higher
semen volume, total sperm counts and concentrations (Axelsson et in adults than in children, but due to the low body weight (BW) of
al., 2015; Bloom et al., 2015; Jurewicz et al., 2013; Wang et al., children and the low urine volume excreted daily, their DI of
2016, 2015b). MnBP, MBzP and MEHP are associated with low VCL phthalates is much higher than for adults (Fig. 3). The general annu-
and VSL parameters (Bloom et al., 2015; Jurewicz et al., 2013) and to- al trend for both children and adults is that exposure to phthalates is
gether with MEP they increase sperm aneuploidy (Jurewicz et al., declining. This has been observed since 1996 when industrial pro-
2013). duction of phthalates started to decline (Helm, 2007) as a result of
strict regulations. In this review study, we observed this trend
from 2000 until today. It should be noted that although the declining
3.1.3.2. Females. Health impacts in women who have been exposed to pattern is obvious in the urinary levels detected in humans, these
phthalates include endometriosis, leiomyomata (Upson et al., 2013; values should be corrected and normalized and thus DI should
Weuve et al., 2010), breast cancer (López-Carrillo et al., 2009) and be employed for the annual distribution. The decrease in total
type-2 diabetes (Sun et al., 2014). MEHP, MEOHP and MEHHP are in- phthalate DI for children and adults is about 66.4% and 40.3%,
versely associated with endometriosis risk and leiomyomata, while respectively.
MnBP is positively associated with the disorders. MEP is significantly Total phthalate DI is higher for children but legislation is strict only
correlated with breast cancer while MBzP and MCPP are inversely for DEHP (Table 6). The RfD set by the US EPA is 20 μg/kg bw/day and
associated with the disease. MnBP, MiBP and MECPP are positively as- it is the lowest value set for DEHP. In almost all studies included in
sociated with type-2 diabetes especially in middle-aged women. this review, DI calculated for children was over the RfD, indicating that
Antiandrogenic activity of phthalates in men, especially DBP, BBzP children belong to the highly exposed groups and, as mentioned in
and DEHP seems to influence women as well since they have been as- Sections 2.1 and 2.2, the toxicity induced from EDCs is permanent and
sociated with lower testosterone levels in pregnant women has severe health outcomes (Fig. 4). On the other hand, adults are less
(Sathyanarayana et al., 2014). Females exposed to these phthalates exposed to DEHP and the majority is below the RfD. More specifically,
are more likely to get pregnant (Vélez et al., 2015) and have a de- about 85% of the studies in children are 45 to 535% above the RfD but
creased likelihood of polycystic ovary syndrome (PCOS), a condition in adults, 10% of the studies are about 3 to 23.5% higher than the RfD.
characterized as hyperandrogenemia (Vagi et al., 2014). Finally, it The annual progress of human exposure to DEHP (both children and
seems that there is an increased risk of pregnancy-induced hyperten- adults) follows the same declining trend as for the total phthalates.
sive diseases for pregnant women exposed to BBzP (Werner et al., The decrease in DEHP DI for children and adults is about 68.1% and
2015). 48.9%, respectively.
Table 4
Health and reproductive outcomes in adults.
Reference Study population Matrix Mean/Median range of compounds (μg/L) Outcome Health effects
(years of age)
Wang et al. 687 men (32 ± Semen MMP, MEP, MnBP, MBzP, MEHP, MEHHP, Significant positive associations with decreased sperm Impaired semen
(2016) 5.4), China MEHHP, MEOHP, MnOP; median range: volume (MnBP, MEHP, MEHHP, MEOHP), abnormal heads quality
bLOD-0.85 and tails (MBzP), VCL and VSL (MBzP, MEHP, %MEHP) and Altered
negative associations with abnormal midsections (MBzP) reproductive
Non-significant positive associations with estradiol (MMP) hormone levels
and LH (MEP) and inverse associations with total
testosterone (MEOHP)
Axelsson et al. 314 men Urine and MEP, MnBP, MBzP, MEHP, MECPP, Positive associations with semen volume (%MEHP, MCiOP, Impaired semen
(2015) (17–20), serum MEOHP, MEHHP, MCiOP, MOiNP, MHiNP; MOiNP, MHiNP), inverse associations with testosterone and quality and
Sweden median range: 0.028–1.1 (serum); 2.8–47 free testosterone (%MEHP), inverse associations with sperm maturation
(urine) motility (MEHP, MEOHP, MEHHP, MECPP) and positive Altered
associations with HDS (MEHP) reproductive
hormone levels
Bloom et al. 501 men Urine MEHP, MCMHP, MEOHP, MECPP, MMP, Associations with lower motility, altered sperm head and Impaired semen
(2015) (19–51), USA MEP, MCPP, MnOP, MiNP, MiBP, MnBP, morphology (MCMHP, MEHHP, MEOHP, MECPP, MMP, quality
MCHP, MBzP; median range: bLOQ-86.4 MiNP), low total sperm counts (MCMHP, MiNP, MEHHP,
MBzP) and low sperm concentration (MBzP, MMP, MCMHP,
MEHHP, MEOHP, MiNP)
Vélez et al. 1597 pregnant Urine (1st MnBP, MEP, MBzP, MMP, MCHP, MiNP, Associations with short time to pregnancy (total Potential
(2015) women (32.85 trimester) MnOP, MCPP, MEHP, MEOHP, MEHHP; phthalates) anti-androgen
± 4.96), Canada median range: 0.1–28 effects
Wang et al. 1040 men (32 Urine MMP, MEP, MnBP, MBzP, MEHP, MEHHP, Significant associations with low sperm concentration and Impaired semen
(2015b) ± 5.36), China MEOHP, MnOP; median range:0.03–69.89 total sperm counts (MnBP), significant positive associations quality.
with abnormal sperm heads (MEHP, %MEHP)
No significant correlations with sperm motility
Werner et al. 369 pregnant Urine MEP, MBzP, MCPP, MnBP, MiBP, MEHP, Significant association with diastolic blood pressure (MBzP) Risk of
(2015) women (29.5 ± (2nd MEHHP, MEOHP, MECPP; median range pregnancy-induced
5.8), USA trimester) (MBzP): 3.9–23 μg/g creatinine hypertension
Sathyanarayana 180 pregnant Urine (1st, MnBP, MBzP, MEP, MiBP, MEHP, MEHHP, Associations with testosterone levels (MEHP, MEHHP, Altered
et al. (2014) women 2nd, 3rd MEOHP; median range: 2.70–126.40 MEOHP, MnBP have a positive correlation but MEP has an reproductive
(20–42), USA trimester) inverse association) hormone levels
Vagi et al. 102 women Urine MBzP, MnBP, MEP, MCNP, MCiOP, MCPP, Inverse associations with PCOS likelihood (MBzP, MnBP) Decreased
(2014) (18–45), USA MECPP, MEHHP, MEHP, MEOHP, MiBP; likelihood of PCOS
mean range: 2.4–138.3
Sun et al. 1941 women Urine MEHP, MEHHP, MEOHP, MECPP, MnBP, Significant positive associations with Type 2 Diabetes Risk of type 2
(2014) (32–52), USA MiBP, MEP, MBzP; median range: (MnBP, MiBP) diabetes
1055.1–1495.6 nmol/L (total phthalate
metabolites)
Dirtu et al. 152 adults, Urine MMP, MEP, MECPP, MEOHP, MEHHP, No associations with obesity No health effects
(2013) Belgium MEHP, MiBP, MnBP, MBzP; median range: Significant positive associations with serum TSH levels in
3–147 control-females (MECPP, MOHP, MnBP, MBzP)
Hoppin et al. 1546 adults Urine MiBP, MnBP, MEP, MMP, MBzP, MCiOP, Significant positive associations with current asthma, Allergic symptoms
(2013) (45.6 ± 0.9), MCNP, MCPP; median range: current wheeze, current hay fever and current rhinitis but and allergic
USA bLOD-101.83 non-significant with allergic sensitization (MBzP) sensitization
MEP was inversely associated with hay fever and allergic
sensitization but positively associated with allergic
sensitization among Mexican Americans.
Jurewicz et al. 269 men Urine MEHHP, MEHP, MBzP, MnBP, MEP, MiNP; Significant associations with decrease in sperm motility Impaired semen
(2013) (22–57), Poland median range: 1.1–83.4 (MEHP, MEHHP, MiNP), VSL, VCL (MnBP) and testosterone quality
level (MEHP)
The lack of chromosome 21 was significantly associated
with MnBP. MBzP, MnBP, MEHP and MEP increased the
sperm aneuploidy.
Upson et al. 287 women Urine MEHP, MEHHP, MEOHP, MECPP, MBzP, Significant inverse association with endometriosis risk Risk of
(2013) (25–34), USA MEP, MiBP, MnBP; median range: (MEHP, MEHHP, MEOHP) endometriosis
1.3–61.9 Non-significant association between MBzP and MEP and
increased endometriosis risk
Liu et al. (2012) 97 men (31.5 ± Urine MMP, MEP, MnBP, MBzP, MEHP, MEOHP; Significant positive associations with VSL of sperm motion Impaired semen
4.80), China median range: bLOD-15.4 (MEP) quality
Non-significant positive correlation with sperm
concentration (MMP, MEP)
Pant et al. 180 men Semen DEHP, DnBP; median range: 50–170 Significant inverse association with sperm motility and Impaired semen
(2011) (21–40), India viability (DEHP, DBP) in infertile men quality
Weuve et al. 1227 women Urine MnBP, MEP, MEHP, MBzP, MEHHP, Positive (MnBP) and inverse (MEHP) associations with Risk of
(2010) (20–54), USA MEOHP; mean range: 3.3–216.2 ng/mg endometriosis and leiomyomata endometriosis and
creatinine MEHHP and MEOHP were positive associated with leiomyomata.
endometriosis.
López-Carrillo 454 women, Urine MEP, MnBP, MiBP, MCPP, MEHP, MEHHP, Significant positive (MEP) and inverse associations (MBzP, Risk of breast
et al. (2009) Mexico MEOHP, MECPP; mean range: MCPP) with incident breast cancer cancer
2.68–169.58 μg/g creatinine
Hauser et al. 379 men Urine MEP, MBzP, MnBP, MMP, MEHP, MEOHP, Positive association with increased DNA damage (MEP, Impaired semen
(2006) (20–54), USA MEHHP; median range: 4.0–154 MEHP) inverse association with sperm concentration quality
(MnBP) and a suggestive evidence of an association DNA damage
between low sperm concentration and MBzP
Table 5
Concentration of phthalates and their metabolites (μg/L) in human urine.
Reference N (country, year) Population (years of age) Compounds Mean (±SD) Median Range % Detection
frequency
Ait Bamai et al. (2015) 125 (Japan, 2009–2010) Mothers (27–51) MnBP − bLOD bLOD-37 33.9
MiBP − 47.3 bLOD-6946 95.3
MBzP − 11.6 bLOD-445 74.0
MEHP − 28.6 bLOD-416 85.8
MEOHP − 47.3 bLOD-199 98.4
MECPP − 7.5 bLOD-182 56.7
90 Fathers (31–56) MnBP − bLOD bLOD-57 39.1
MiBP − 52.6 bLOD-2084 92.4
MBzP − 13.4 bLOD-269 73.9
MEHP − 24.6 bLOD-597 73.9
MEOHP − 44.6 bLOD-205 98.9
MECPP − 7.5 bLOD-419 57.6
178 Children (7–12) MnBP − bLOD bLOD-36 29.2
MiBP − 47.0 bLOD-6995 96.6
MBzP − 16.3 bLOD-1616 80.3
MEHP − 19.7 bLOD-522 81.5
MEOHP − 51.5 bLOD-3000 99.4
MECPP − 34.9 bLOD-5357 92.7
Axelsson et al. (2015) 314 (Sweden, 2008–2010) Men (17–20) MEP 190 (670) 41 2.0–6900 100
MnBP 64 (64) 47 1.0–690 100
MBzP 22 (30) 13 0.5–260 100
MEHP 4.1 (6.3) 2.8 bLOD-97 97
MECPP 22 (38) 15 1.6–600 100
MEOHP 16 (62) 9.6 0.5–1100 100
MEHHP 35 (110) 21 1.1–1900 100
MCiOP 30 (61) 16 1.4–810 100
MOiNP 12 (34) 5.0 0.2–500 100
MHiNP 19 (62) 8.4 0.5–980 100
Bloom et al. (2015) 473 (USA, 2005–2009) Men (19–51) MEHP − 1.18 –10.6-733 51.4
MCMHP − 18.5 –0.47–803 99.8
MEHHP − 15.2 0.01–3116 99.0
MEOHP − 6.95 0.01–914 98.8
MECPP − 20.4 –0.05–3308 99.3
MMP − 0.54 –0.48–72 38.3
MEP − 86.4 0.08–6733 99.8
MCPP − 5.56 –0.29–1089 97.1
MnOP − –0.05 –0.32–7.45 3.6
MiNP − 0.00 –0.62–43.8 4.5
MiBP − 4.36 –0.58–77.4 97.6
MnBP − 7.28 –0.02–2708 99.3
MCHP − 0.00 –0.17–6.82 4.1
MBzP − 3.57 –0.10–420 96.2
Chen et al. (2015) 30 (Taiwan, 2010) Girls (4–13) MMP − 7.91 2.01–29.1 100
MEP − 40.6 6.0–710 100
MnBP − 99.3 19.0–927 100
MBzP − 6.45 0.39–85.6 100
MEHP − 8.65 2.61–84.6 100
MEOHP − 32.2 15.1–563 100
MEHHP − 67.9 29.9–1082 100
MECPP − 65.7 24.2–871 100
Jornet-Martínez et al. (2015) 18 (Spain) General population (22–85) DEP 3 − bLOD-4.5 17
DBP 0.5 − bLOD-1.2 50
DEHP 2.2 − bLOD-6.8 28
MEHP 3 − bLOD-3 6
Myridakis et al. (2015) 239 (Greece, 2009–2011) Mothers MEP 141.9 133.9 2.6–4103.7 100
MnBP 32.1 36.1 bLOD-94,670.7 95.9
MiBP 36.7 39.2 bLOD-616.1 98
MBzP 6.9 6.0 bLOD-199.4 91.6
MEHP 7.0 7.6 bLOD-3401.3 72.7
MEHHP 22.1 25.7 bLOD-6267.3 96.4
MEOHP 15.5 17.6 bLOD-3610.6 93.6
239 Children (2.3 ± 0.72) MEP 35.3 34.4 bLOD-2460.1 99.6
MnBP 23.3 23.9 bLOD-1250.5 96.2
MiBP 36.0 34.4 bLOD-886.0 98.7
MBzP 6.8 6.5 bLOD-241.9 86.2
MEHP 3.8 2.8 bLOD-95.01 57.3
MEHHP 24.9 30.5 bLOD-626.3 97.1
MEOHP 16.9 20.0 bLOD-391.1 95.4
Wang et al. (2015b) 1040 (China, 2013) Men (32 ± 5.36) MMP − 20.78 − 92.69
MEP − 18.48 − 96.82
MnBP − 69.89 − 100.00
MBzP − 2.92 − 98.94
MEHP − 5.79 − 97.21
MEHHP − 13.86 − 100.00
Table 5 (continued)
frequency
MEOHP − 7.92 − 100.00

MnOP − 0.03 − 14.33
Xie et al. (2015) 57 (China, 2013–2014) Boys (8–15)-cases MMP − 24.16 − 100
120 MEP − 8.43 − 86
MnBP − 37.43 − 100
MEHP − 2.33 − 92
MEHHP − 13.37 − 100
MEOHP − 5.17 − 100
Boys–control group MMP − 13.47 − 100
MEP − 3.77 − 61
MnBP − 15.6 − 100
MEHP − 1.44 − 83
MEHHP − 7.68 − 100
MEOHP − 3.14 − 100
Arbuckle et al. (2014) 1788 (Canada, 2008–2011) Pregnant women MMP bLOD bLOD bLOD-1000 14.7
MEP 32.02 28.00 bLOD-13,000 99.8
MnBP 11.59 12.00 bLOD-3100 99.7
MBzP 5.20 5.20 bLOD-420 99.3
MEHP 2.24 2.20 bLOD-340 97.7
MEOHP 6.39 6.50 bLOD-980 99.6
MEHHP 9.16 9.40 bLOD-1200 99.1
MnOP bLOD bLOD bLOD-7.90 2.2
MCPP 0.86 bLOD bLOD-370 82.2
MCHP bLOD bLOD bLOD-77 7.8
MiNP bLOD bLOD bLOD-9.20 1.5
Cantonwine et al. (2014) 139 (Puerto Rico, Pregnant women (18–40) MEP 102.2 99.2 12,700 100
2010–2012) MnBP 19.2 20.9 413 98.7
MiBP 10.9 11.0 964 100
MBzP 3.9 4.0 305 98.4
MEHP 3.3 3.7 141 92.9
MEOHP 8.9 9.3 281 100
MEHHP 10.7 11.5 361 100
MECPP 19.6 19.9 749 100
MCPP 2.3 2.2 109 98.9
MCNP 2.3 2.2 59.8 99.7
MCiOP 16.4 14.2 1230 100
Fisher et al. (2014) 80 (Canada, 2009–2010) Pregnant women (25–40) MnBP 16.02 17.09 − 99.2
MBzP 9.85 9.30 − 100
MCPP 1.42 2.40 − 97.8
MEHHP 13.22 14.28 − 90.4
MEHP 2.24 2.80 − 100
MEOHP 7.89 8.56 − 93.9
MEP 30.82 24.70 − 100
2OH-MiBP 4.26 4.00 − 100
MCMHP 2.90 3.08 − 100
MECPP 10.49 10.25 − 100
MHBP 1.30 1.27 − 98.4
MHiNP 1.97 1.77 − 99.6
MOiDP 0.13 0.17 − 92.6
MiBP 7.04 6.98 − 100
Kobrosly et al. (2014) 153 (California, 2010) Children (6–10) MEP 81.01 − − 99.3
MBzP 6.59 − − 96.1
MnBP 13.61 − − 97.4
MiBP 2.34 − − 82.4
MEOHP 11.50 − − 96.7
MEHHP 13.04 − − 97.4
MEHP 3.65 − − 79.1
Larsson et al. (2014) 95 (Sweden, 2011) Mothers (b45) MEP 43.4 42.40 − 100
MnBP 63.01 59.19 − 100
MBzP 12.81 12.56 − 100
MEHP 2.32 2.64 − 97.9
MEOHP 8.68 8.04 − 100
MEHHP 14.94 13.40 − 100
MECPP 11.53 10.69 − 100
MCiOP 19.74 15.55 − 100
MHiNP 8.33 6.54 − 100
MOiNP 4.85 3.87 − 100
97 (Sweden, 2011) Children (6–11) MEP 28.83 24.68 − 100
MnBP 76.87 79.25 − 100
MBzP 19.91 22.17 − 100
MEHP 2.74 2.87 − 100
MEOHP 15.68 16.34 − 100
MEHHP 24.56 24.50 − 100
MECPP 21.54 22.77 − 100
(continued on next page)
Table 5 (continued)
frequency
MCiOP 21.66 19.89 − 100

MHiNP 9.72 8.95 − 100
MOiNP 5.63 5.19 − 100
Bertelsen et al. (2013) 623 (Norway) Children (8.8–12.5) MEP 60.9 56.7 8.5–6006 100
MnBP 138.8 138.0 10.4–1480 100
MiBP 53.6 49.2 3.1–1480 100
MBzP 30.7 29.3 2.1–6710 100
MCPP 7.8 7.5 bLOD-384.0 96.3
MEHP 7.8 7.8 bLOD-203.0 96.6
MEOHP 49.8 49.7 2.4–1220 100
MEHHP 78.6 76.6 4.0–1770 100
MECPP 101.2 98.2 11.3–3520 100
MCOP 6.1 6.0 0.8–474.0 100
MCNP 2.2 2.1 bLOD-168.0 96.3
Hoppin et al. (2013) 2325 (U.S.A, 2005–2006) General population (N6) MMP 1.51 (0.07) bLOD − 38.0
MEP 109.24 101.83 − 99.6
(6.33)
MnBP 19.55 (0.81) 20.06 − 99.5
MiBP 5.19 (0.30) 5.70 − 97.1
MBzP 8.22 (0.52) 8.73 − 98.4
MEHP 3.01 (0.13) 2.40 − 66.6
MEOHP 16.14 (0.81) 14.99 − 98.9
MEHHP 25.35 (1.23) 23.33 − 99.8
MECPP 38.28 (1.90) 34.40 − 100
MCPP 2.04 (0.10) 2.02 − 96.1
MCNP 2.71 (0.11) 2.61 − 89.9
MCiOP 5.35 (0.36) 4.98 − 95.1
MCHP 0.44 (0.00) bLOD − 2.2
MiNP 1.05 (0.02) bLOD − 13.0
MnOP 1.32 (0.00) bLOD − 1.1
Frederiksen et al. (2013) 145 (Denmark, 2011) Mothers (31–52) MEP 74 29 3.1–582 100
MnBP 26 20 1.9–180 100
MiBP 48 36 3.7–321 100
MBzP 6.1 4 bLOD-38 92
MEHP 4.7 1.7 bLOD-308 91
MEHHP 21 12 1.3–350 100
MEOHP 10 6.1 bLOD-237 99
MECPP 15 8.2 1.3–356 100
MnOP 0.01 bLOD bLOD-0.3 5
MCPP 5.4 4.1 bLOD-71 99
MiNP 0.30 bLOD bLOD-5.8 15
MHiNP 5.3 2.7 bLOD-42 97
MOiNP 2.9 1.4 bLOD-23 90
MCiOP 9.8 6.2 0.37–85 100
MiDP bLOD bLOD bLOD 0.0
143 (Denmark, 2011) Children (6–11) MEP 28 20 4.2–211 100
MnBP 39 32 5.3–598 100
MiBP 74 54 8.7–144 100
MBzP 11 7.0 bLOD-104 97
MEHP 4.5 2.0 bLOD-222 92
MEHHP 32 23 2.1–347 100
MEOHP 16 12 0.86–258 100
MECPP 23 15 2.1–550 100
MCPP 16 7.4 0.80–343 100
MiNP 0.88 bLOD bLOD-55 17
MHiNP 13 5.0 0.46–567 100
MOiNP 7.2 2.6 bLOD-345 99
MCiOP 22 7.8 1.3–1282 100
MiDP bLOD bLOD bLOD 0
Song et al. (2013) 392 (Korea, 2011) Children (b6) MEHP 12.7 14.9 bLOD-173.8 98.7
MEHHP 74.3 80.3 3.9–514.5 100
MEOHP 75.7 83.3 4.5–620.1 100
265 Mothers (20–39) MEHP 8.9 10.2 bLOD-279.0 97.4
MEHHP 28.4 28.5 bLOD-1003 95.1
MEOHP 20.8 25.5 bLOD-473.4 98.9
140 Male adults (20–39) MEHP 8.2 8.6 bLOD-144.2 98.6
MEHHP 22.7 26.0 bLOD-242.0 85.0
MEOHP 9.9 18.2 bLOD-219.7 97.1
157 Female adults (20–39) MEHP 8.3 9.6 bLOD-82.6 97.5
MEHHP 24.9 28.2 bLOD-498.3 81.5
MEOHP 9.5 19.5 bLOD-354.8 98.1
Tranfo et al. (2013) 83 (Central Italy) Female adults (36.5 ± 7.2) MEP 54.81 61 − 98
MnBP 24.47 32.5 − 99
MBzP 5.39 4.85 − 94
Table 5 (continued)
frequency
MEHP 2.49 2.1 − 74

MEHHP 9.02 8.37 − 100
74 Male adults (40.4 ± 7.3) MEP 64.73 73.2 − 98
MnBP 45.24 41.2 − 99
MBzP 6.93 1.44 − 94
MEHP 3.62 1.08 − 74
MEHHP 12.89 3.22 − 100
Téllez-Rojo et al. (2013) 135 (Mexico) Pregnant women (27.2 ± 5.4) MEP 138 − − 100
MnBP 85.61 − − 100
MiBP 2.30 − − 97.8
MBzP 3.54 − − 98.5
MCPP 1.75 − − 99.3
MEHP 6.56 − − 95.6
MEHHP 22.08 − − 100
MEOHP 14.23 − − 100
MECPP 39.65 − − 100
Carlstedt et al. (2013) 83 (Sweden) Infants MEP 19.8 19.6 2.7–270.4 100
MnBP 40.2 39.1 4.7–315.5 100
MBzP 9.7 10.5 0.4–194.9 100
MEOHP 7.5 8.8 0.6–76.7 100
MEHHP 5.1 5.0 0.1–82.4 100
Genuis et al. (2012) 20 (Canada) Adults (21–68) MEP 535 (1560) 107 6.76–6978 100
MiBP 122 (96.6) 74.4 20.7–342 100
MEHP 12.4 (23.7) 35.1 1.11–108 100
Kasper-Sonnenberg et al. 103 (Germany, 2007–2009) Mothers (39.2 ± 4.6) MMP 1.3 1.2 bLOD-1095 66
(2012) MEP 50.5 53.8 5.1–756 100
MnBP 32.8 30.9 4.4–267 100
MHBP 2.0 3.3 bLOQ-29.6 75
MCPP 0.6 0.4 bLOQ-12.6 55
MiBP 44.5 43.0 bLOQ-958 100
2OH-MiBP 20.7 20.1 2.3–449 100
MBzP 6.6 6.3 0.7–149 100
MCHP bLOQ bLOQ bLOQ 0
MnPeP bLOQ bLOQ bLOQ-1.3 2
MEHP 4.4 4.6 bLOQ-808 100
MEHHP 16.8 17.3 1.6–416 100
MEOHP 12.0 12.9 1.1–279 100
MECPP 21.2 20.5 3.4–379 100
MHiNP 11.3 11.4 1.2–61.3 100
MOiNP 3.6 3.6 bLOQ-26.4 100
MCiOP 5.6 5.5 0.7–48.7 100
MHiDP 1.7 2.0 bLOQ-34.0 98
MOiDP 0.4 0.4 bLOQ-15.4 89
MCNP 0.6 0.7 bLOQ-16.3 95
MnOP bLOQ bLOQ bLOQ 0
104 Children (6.8 ± 0.6) MMP 4.9 3.8 bLOQ-402 98
MEP 39.1 33.6 2.7–1787 100
MnBP 12.5 11.7 2.0–274 100
MHBP 6.9 8.7 bLOQ-51.5 96
MCPP 2.6 2.6 bLOQ-25.9 97
MiBP 66.2 68.7 1.8–1284 100
2OH-MiBP 35.0 36.4 bLOQ-355 99
MBzP 12.5 11.7 0.5–368 100
MCHP bLOQ bLOQ bLOQ 0
MnPeP bLOQ bLOQ bLOQ 2
MEHP 3.9 4.0 bLOQ-27.7 100
MEHHP 29.3 31.0 1.6–163 100
MEOHP 26.2 26.4 1.9–135 100
MECPP 41.8 42.1 7.3–259 100
MHiNP 15.7 15.0 4.1–95.9 100
MOiNP 5.9 5.3 0.2–54.4 100
MCiOP 10.2 9.5 1.5–60.3 100
MHiDP 2.1 2.3 bLOQ-63.8 97
MOiDP 0.6 0.5 bLOQ-19.2 95
MCNP 1.3 1.2 bLOQ-45.3 100
MnOP bLOQ bLOQ bLOQ 0
Liu et al. (2012) 150 (China, 2009–2010) Adults (31.5 ± 4.8) MMP 26.9 (56.5) − − 99.3
MEP 175 (892) − − 100
MnBP 25.7 (42.1) − − 97.3
MBzP 0.42 (2.89) − − 44.7
MEHP 1.63 (2.36) − − 98.7
MEOHP 2.70 (2.55) − − 100
Casas et al. (2011) 118 (Spain, 2004–2008) Pregnant women MEP − 324 − 100
MnBP − 27.5 − 100
Table 5 (continued)
frequency
MiBP − 29.9 − 100

MBzP − 10.5 − 99.2
MCPP − 1.5 − 97.5
MEHP − 4.4 − 84.9
MEHHP − 17.3 − 100
MEOHP − 15.7 − 100
MECPP − 32.2 − 100
MCOP − 4.0 − 97.5
MCNP − 2.8 − 96.6
19 Children (4) MEP − 755.0 − 100
MnBP − 30.2 − 100
MiBP − 41.9 − 100
MBzP − 33.0 − 100
MCPP − 6.1 − 100
MEHP − 6.2 − 100
MEHHP − 57.4 − 100
MEOHP − 44.6 − 100
MECPP − 115.0 − 100
MCOP − 7.5 − 100
MCNP − 4.0 − 100
Frederiksen et al. (2011) 129 (Denmark, 2006–2008) Children and adolescents MEP − 29 4.9–585 100
(6–21) MnBP + − 111 19–595 100
MiBP
MBzP − 17 bLOD-315 96.1
ΣDEHP − 107 17–733 100
ΣDiNP − 31 3.0–281 100
Lin et al. (2011) 100 (Taiwan, 2001–2002) Pregnant women (21–39) MnBP 72.29 52.39 1.41–928 100
MiBP 12.49 10.32 1.02–269 100
MBzP 0.96 1.23 bLOD-55 64
MEHP 10.82 10.46 0.14–218 100
MEHHP 22.73 21.74 1.29–617 100
MEOHP 23.1 20.8 0.91–645 100
MECPP 32.6 27.91 1.19–859 100
MCMHP 7.52 7.04 0.09–183 100
MHiNP 0.57 bLOD bLOD-364 31
MOiNP 0.41 bLOD bLOD-288 40
MCiOP 0.59 bLOD bLOD-281 39
59 Children (5) MnBP 75.09 70.22 12.35–16,455 100
MiBP 25.24 28.54 4.16–165 100
MBzP 3.61 3.66 bLOD-42.85 93.3
MEHP 10.07 8.4 1.78–73.86 100
MEHHP 36.41 30.98 4.13–943.87 100
MEOHP 28.30 23.41 3.79–623 100
MECPP 61.07 53.24 8.87–1390 100
MCMHP 13.00 11.68 1.04–428 100
MHiNP 9.67 7.94 0.6–1188 96.6
MOiNP 5.86 4.3 bLOD-352.62 100
MCiOP 12.23 9.42 1.22–915.6 100
Cho et al. (2010) 621 (Korea, 2008) Children (9 ± 0.7) MnBP 48.9 (2.2) 50.470 2.076–1645.49 100
MEHP 21.3 (2.3) 24.721 0.506–445.37 100
MEOHP 18.0 (2.4) 20.556 0.065–291.11 100
Frederiksen et al. (2010) 60 (Denmark, 2006) Healthy men (18.2–26.2) MEP 325.58 54.44 6.19–4115.13 100
MnBP 42.49 36.83 2.26–159.16 100
MiBP 65.55 47.32 3.51–342.76 100
MBzP 50.72 36.44 3.62–509.31 100
MEHP 9.18 4.85 0.19–59.12 100
MEHHP 46.56 26.13 bLOD-423.87 98.3
MEOHP 34.40 20.04 0.72–264.89 100
MECPP 24.70 17.04 1.52–126.43 100
MnOP bLOD bLOD bLOD-0.16 1.7
MHiNP 6.31 3.31 bLOD-141.64 95
MOiNP 3.68 1.62 bLOD-89.08 81.7
MCiOP 8.85 4.26 bLOD-171.83 91.7
Suzuki et al. (2010) 149 (Japan, 2005–2008) Pregnant women (31.9 ± 4.5) MMP 6.95 6.49 0.42–464 100
MEP 7.42 6.01 0.252–1067 100
MnBP 46.2 48.1 2.92–504 100
MBzP 4.27 3.46 bLOD-992 99
MEHP 4.14 4.44 bLOD-70.3 99
MEHHP 8.08 8.61 0.425–89.7 100
MEOHP 8.6 9.2 0.686–132 100
Becker et al. (2009) 599 (Germany, 2003–2006) Children (3–14) DBP 95.6 93.4 1090 100
MiBP 94.3 88.1 2050 100
Table 5 (continued)
frequency
MBzP 17.5 18.1 468 100

MEHP 6.4 6.7 319 99.8
MEHHP 47.9 46.0 3640 100
MEOHP 37.0 36.3 2490 100
MECPP 62.5 61.4 4490 100
MCMHP 20.8 20.4 1080 100
MHiNP 11.0 11.0 198 100
MOiNP 5.4 5.4 86.7 99.8
MCiOP 12.7 12.7 195 99.8
Engel et al. (2009) 295 (USA, 1998–2002) Pregnant women (〈20−30) MMP − 1.7 − 61.7
MEP − 385.8 − 99.7
MnBP − 36.2 − 100
MiBP − 6.2 − 97.6
MBzP − 23.8 − 99.7
MEHP − 6.1 − 91.2
MEHHP − 19.6 − 99.3
MEOHP − 17.9 − 98.9
MECPP − 35.8 − 99.7
MCPP − 3.4 − 98.3
Hines et al. (2009) 33 (USA, 2004–2005) Lactating women (18–38) MMP − bLOD − 13
MEP − 73.1 − 100
MnBP − 14 − 89
MiBP − 3.8 − 82
MBzP − 9.6 − 100
MCPP − 3.2 − 97
MEHP − 3.0 − 71
MEHHP − 18.6 − 97
MEOHP − 12.0 − 97
MECPP − 27.3 − 100
Wittassek et al. (2009) 11 (Germany) Pregnant women (24–37) MnBP 35.2 23.7 97.0 100
MiBP 50.6 33.6 161 100
MBzP 6.3 5.0 12.1 100
MEHP 74.0 55.6 242 100
MEHHP 18.8 10.5 38.1 100
MEOHP 18.3 12.0 35.3 100
MECPP 33.0 27.0 84.5 100
MCMHP 6.4 4.2 13.0 100
MHiNP 5.9 2.5 23.3 100
MOiNP 2.3 1.3 11.0 81.8
MCiOP 5.8 5.6 17.3 100
Högberg et al. (2008) 38 (Sweden, 2001) Pregnant women (23–39) MMP 2.3 (3.0) 1.2 0.50–15 52.6
MEP 84 (141) 35 0.50–761 97.4
MnBP 53 (45) 46 5.1–198 100
MiBP 21 (24) 16 0.52–130 89.5
MBzP 16 (10) 13 2.2–38 100
MCPP 1.9 (1.7) 1.5 0.5–9.1 65.8
MEHP 13 (10) 9 2.9–57 100
MEHHP 25 (27) 15 1.4–126 100
MEOHP 19 (19) 11 0.54–83 97.4
Wolff et al. (2008) 382 (USA, 1998–2002) Pregnant women (24 ± 6.2) MMP − 1.6 bLOD-10,834 60.7
MEP − 380 bLOD-44,740 99.5
MnBP − 36 bLOD-11,133 99.7
MiBP − 6.2 bLOD-131 97.4
MCPP − 3.2 bLOD-129 98.2
MBzP − 22 bLOD-668 99.4
MEHP − 6.0 bLOD-526 90.6
MEOHP − 17 bLOD-1335 99.0
MEHHP − 20 bLOD-2051 99.2
MECPP − 35 bLOD-2054 99.5
Huang et al. (2007) 76 (Taiwan, 2005–2006) Pregnant women (33.6 ± 3.3) MnBP − 81.8 13.2–580.0 96
MBzP − 0.9 0.9–35.3 17
MEP − 27.7 0.7–5466.0 100
MEHP − 20.6 5.85–381.0 100
MMP − 4.3 0.7–237.2 63
The DIs presented in this study are calculated using the following In the above equation UCpm represents urinary concentration of
equation (Koch et al., 2007; Koch and Calafat, 2009; Wittassek et al., each phthalate metabolite and it is expressed as μg/L, UV is the total
2007): urinary volume excreted within 24 h and it is approximately 0.7 L
for children (Montenegro-Bethancourt et al., 2015) and 1.5 L for
adults (Dirtu et al., 2013), F UE is the urinary excretion factor of
UCpm UV MWp each phthalate metabolite as shown in Table 1 and MWp and
DIðμg=kg bw=dayÞ ð1Þ MWpm are the molecular weight of phthalate and its metabolite
F UE bw MWpm
respectively. Although in some studies DIs are presented, we
600 EUROPE AMERICA ASIA

Total PMs (µg/L)
500
400
300
200
100
0
Fig. 2. Global comparison of total phthalate metabolite levels detected in urine from adults in studies published between 2000 and 2015.
chose to calculate them again so that the values of the parameters (22.1–85.5 μg/L in amniotic fluid compared to 24.6–78.0 μg/L in
used in the Eq. (1) are the same in order to allow a global urine). The detected metabolites in amniotic fluid are MnBP, MEHP,
comparison. MiBP and MEP (Huang et al., 2009; Silva et al., 2004; Wittassek et al.,
2009) at very high detection rate (90–100%) and are strongly correlated
with their presence in urine (Huang et al., 2009; Wittassek et al., 2009).
3.2.2. Association between maternal urine and amniotic fluid Metabolites of HMW phthalates (MEHHP, MEOHP, mono cyclohexyl
At about 10 to 20 weeks of gestation amniotic fluid composition is phthalate or MCHP, MiNP and mono n-octyl phthalate or MnOP) have
similar to fetal plasma and after the second half of pregnancy, fetal uri- not been detected at levels above the Limit of Detection (LOD) in any
nation contributes to the content and volume of amniotic fluid sample of amniotic fluid (Silva et al., 2004).
(Underwood et al., 2005). Table 7 summarizes the phthalate metabolite The results from animal experiments help for the better understand-
levels found in amniotic fluid from studies published between 2004 and ing of the processes that occur in a living organism. Amniotic fluid and
2009. Note that there are no recent studies for phthalates in amniotic maternal levels of MEHP and MnBP were examined in pregnant rats
fluid. after oral administration of the parent compounds (Calafat et al.,
In utero exposure is estimated via the determination of phthalate 2006). Monoesters in urine were mainly in their glucuronidated form,
monoesters in maternal urine and amniotic fluid (Huang et al., 2009; while in the amniotic fluid they were present as free metabolites. Statis-
Wittassek et al., 2009). Reported median concentrations in amniotic tically significant correlations were obtained between oral dose of DEHP
fluid are either lower than urinary levels (bLOD – 7.8 μg/L in amniotic and amniotic fluid and urine levels. The general trend for both human
fluid compared to 1.3–55.6 μg/L in urine), or close to urinary levels
Total Phthalate DI (µg/kg bw/day)
1200
Total PMs (µg/L)
1000 250
Children - A Children - B
800 200
600 150
400 100
200 50
0 0
Levels - Annual Distribution Total PhthalateDI-Annual Distribution

Total Phthalate DI (µg/kg bw/day)
35.0
30.0
Total PMs (µg/L)
600 Adults - C Adults - D

500 25.0
400 20.0
300 15.0
200 10.0
100 5.0
0 0.0
Levels - Annual Distribution Total Phthalate DI-Annual Distribution
Fig. 3. Global comparison between exposure of children (top) and adults (bottom). Global annual progress of human exposure (children and adults) is indicated with the linear declining
curve in all diagrams. Urinary levels (left) and daily intakes (right) for both children and adults have the same pattern.
Table 6 seem to be eliminated more slowly than in plasma. After exposure of

Maximum exposure levels (expressed as Minimum Risk Level, Tolerable Daily Intake and pregnant rats to DiNP, the testosterone levels in testes of male fetuses
Reference Dose) set from international Committees and Organizations. Acute exposure oc-
curs for up to 14 days, intermediate exposure for more than 14 days and less than a year
were decreased indicating the anti-androgenicity of this phthalate and
and chronic exposure for more than one year. the impacts of maternal exposure during pregnancy in fetus.
PEs Committee MRL/TDI/RfD mg/kg Reference

3.2.3. Phthalates and their metabolites in human milk
bw/day
Phthalates are present in breast milk due to maternal exposure via
DEP ATSDR MRL (acute exposure) 7 ATSDR (1995) food consumption or cosmetics (Kim et al., 2015). The levels of PMs de-
MRL (chronic exposure) 5
tected in human milk are summarized in Table 8. Primary metabolites
USEPA RfD 0,8 US EPA (1987a)
DBP ATSDR MRL 0,5 ATSDR (2001) are more frequently detected than oxidative metabolites (Hines et al.,
US EPA RfD 0,1 US EPA (1987b) 2009) and they are mainly free than glucuronidated (Calafat et al.,
EU CSTEE TDI 0,1 EU CSTEE (1998) 2004). Mean and median values are much lower than urinary values
Health TDI 0,06 Health Canada
and similar to those in amniotic fluid. MiNP was the metabolite with
Canada (1994a)
BBzP US EPA RfD 0,2 US EPA (1988)
the highest median concentration in samples collected from mothers
EU CSTEE TDI 0,2 EU CSTEE (1998) in Denmark (101 μg/L) and Finland (89 μg/L), indicating that HMW
DEHP US EPA RfD 0,020 US EPA (1987c) phthalates are hydrophobic and they are more prevalent in human
ATSDR MRL (chronic exposure) 0,06 ATSDR (2002) milk than in other matrices (Main et al., 2006). Unmetabolized com-
MRL (intermediate 0,1
pounds are likely to be present in human milk (Högberg et al., 2008).
exposure)
EU CSTEE TDI 0,05 EU CSTEE (1998) Metabolites were detected at lower levels than their parent compounds
Health TDI 0,044 Health Canada but no significant correlation was observed. DEP, DBP, BBzP, DEHP and
Canada (1994b) di n-octyl phthalate (DnOP) were detected at concentrations between
WHO TDI 0,025 WHO (2003)
0.06 (BBzP) and 305 μg/L (DEHP) while BBzP and DEHP were the
most frequently detected compounds.
biomonitoring and animal studies is that higher concentrations are ob- 3.2.4. Phthalates and their metabolites in blood
served in urine compared to amniotic fluid. A male volunteer was intentionally exposed to DEHP after oral ad-
The metabolism of DBP and the distribution of its metabolites in ma- ministration of deuterium-labeled DEHP to monitor the distribution of
ternal and fetal plasma, placenta, and amniotic fluid from pregnant rats three DEHP metabolites (MEHP, MEHHP and MEOHP) in human
were studied after repeated exposure to the parent compound (Clewell serum and urine (Koch et al., 2004b). The major metabolite in serum
et al., 2009). Metabolites appeared rapidly in maternal blood and pla- was d4-MEHP while in urine d4-MEOHP followed by d4-MEHHP and
centa while their appearance in fetal plasma and amniotic fluid was de- d4-MEHP. Similarly, studies based on environmental exposure note
layed. There was no indication of accumulation in maternal or fetal that DEHP oxidative metabolites are not detectable in serum samples
plasma. Interestingly, amniotic fluid showed different dose-response and the primary metabolite MEHP is the most abundant one (Hines et
trends than expected indicating that more complex processes take al., 2009; Lin et al., 2011). However, the oxidative metabolites MECPP
place than simple passive exchange with either maternal or fetal and MCiOP are intended to be better serum markers than primary
plasma. MEHP and MiNP (Frederiksen et al., 2010). Due to significant correla-
The disposition of DiNP after administration in pregnant rats has also tions between serum and urinary levels of MEP, MiBP (Frederiksen et
been investigated (Clewell et al., 2013). All DiNP metabolites (MiNP, al., 2010), MECPP and mono 2-carboxymethylhexyl phthalate
mono hydroxylisononyl phthalate or MHiNP, MOiNP, MCiOP) were de- (MCMHP) (Lin et al., 2011), metabolites in serum could be used as bio-
tected in maternal urine, maternal and fetal plasma and tissues. Levels markers in human biomonitoring studies. In all published studies in-
in fetal plasma were higher than in amniotic fluid and placenta, similar cluded in this review (Table 9) the total PM levels are higher in urine
to fetal testes while they were exceeded by the levels in maternal plas- compared with serum.
ma. Elevated concentrations in maternal liver compared to maternal In addition to human milk, unmetabolized compounds may also be
plasma were observed and the oxidative metabolites of DiNP in liver present in blood (Guo et al., 2010; Högberg et al., 2008; Huang et al.,
140
DEHP DI (µg/kg bw/day)
Children
DEHP DI (µg/kg bw/day)
120 30.0
100 25.0 Adults
80 20.0
60 15.0
40 10.0
20 5.0
0 0.0
Puerto-Rico (2010-2012)
Japan (2005-2008)
Japan (2009-2010)
Canada (2009-2010)
Canada (2008-2011)
Spain (2004-2008)
China (2009-2010)
USA (1998-2002)
USA (2004-2005)
USA (2005-2006)
USA (2005-2009)
Greece (2009-2011)
Germany (2007-2009)
Sweden (2008-2010)
China (2013)
Sweden (2001)
Sweden (2011)
Korea (2011)
Taiwan (2001-2002)
Denmark (2006)
Denmark (2011)
DEHP DI - Annual Distribution DEHP DI - AnnualDistribution
Fig. 4. Global comparison of DEHP daily intake between children (left) and adults (right).The solid line represents the annual drop of human exposure to DEHP and the dot line the RfD set
from US EPA.
Table 7
Concentrations of phthalate metabolites (μg/L) in human amniotic fluid.
Reference N (country, year) PMs Mean Median Range % Detection frequency
Huang et al. (2009) 64 female; male newborns (Taiwan, 2005–2006) MMP – bLOD bLOD-2.92;bLOD –
MEP – bLOD bLOD-6.5;bLOD-7.7 –
MnBP – 85.5;81.3 39.3–192.0;28.4–145.0 100
MBzP – bLOD bLOD-233.0;bLOD-104.0 –
MEHP – 24.0;22.1 bLOD-148.0;bLOD-110.0 N90
Wittassek et al. (2009) 11 (Germany) MnBP 9.1 7.8 18.7 100
MiBP 10.0 4.2 35.7 100
MBzP 2.1 1.9 2.8 100
MEHP 2.4 1.6 8.4 100
MEHHP bLOQ bLOQ 0.31 72.7
MEOHP bLOD bLOD bLOQ 18.2
MECPP 0.90 0.53 2.7 100
MCMHP 0.60 0.64 0.92 100
MHiNP bLOD bLOD bLOQ 9.1
MOiNP bLOD bLOD bLOD 0
MCiOP 0.51 bLOD 4.9 9.1
Silva et al. (2004) 54 (USA) MEP – bLOD bLOD-9.0 92.6
MnBP – 5.8 bLOD-263.9 39
MEHP – bLOD bLOD-2.8 24
Table 8
Concentrations of phthalates and their metabolites (μg/L) in human milk.
Reference N (country, year) Compounds Mean (±SD) Median Range % Detection frequency
Kim et al. (2015) 62 (Korea, 2012) MEP – 0.37 – 100

MnBP – 1.70 – 82
MiBP – 1.10 – 79
MEHP – 2.08 – 89
Lin et al. (2011) 30 (Taiwan, 2001–2002) MnBP 2.88 4.05 bLOD-32.03 70
MiBP 1.10 0.50 bLOD-39.7 33.3
MBzP 1.10 bLOD bLOD-0.70 10
MEHP 2.49 3.60 bLOD-46.53 73.3
MEHHP bLOD bLOD bLOD 0
MEOHP 0.26 bLOD bLOD-0.55 6.7
MECPP 0.28 bLOD bLOD-3.72 6.7
2cx-MEPP bLOD bLOD bLOD 0
MHiNP bLOD bLOD bLOD 0
MCiOP bLOD bLOD bLOD 0
Schlumpf et al. (2010) 20 (Switzerland, 2006) MnBP 34.05 (26.00) 26.20 9.60–122.00 100
MiBP 7.88 (6.21) 5.95 1.20–29.80 100
MEHP 26.61 (18.03 24.25 2.60–66.20 100
7OH-MMeOP 1.12 (0.30) 1.20 0.60–1.50 30
Hines et al. (2009) 33 (USA, 2004–2005) MEHHP 0.3 – 0.2–0.3 7.7
MEOHP 0.3 – – 2.6
MECPP 0.2 – 0.1–0.4 12.8
MCPP 0.2 – – 2.6
Högberg et al. (2008) 42 (Sweden, 2001) MEP bLOD bLOD 0.50–2.5 2.4
MnBP 1.2 (1.3) 0.54 0.54–5.7 26.2
MiBP bLOD bLOD 0.52–2.1 4.7
MBzP 0.64 (0.63) 0.50 0.50–4.4 7.1
MEHP 1.3 (1.3) 0.49 0.49–6.5 38.1
DEP 0.30 (0.24) 0.22 0.22–1.45 19.0
DBP 2.8 (3.4) 1.5 1.5–20 28.6
BBzP 0.75 (0.80) 0.49 0.06–4.4 97.6
DEHP 17 (47) 9.0 0.45–305 92.9
DnOP 1.1 (2.3) 0.24 0.24–11 23.8
Main et al. (2006) 65 (Denmark, 1997–2001) MMP – 0.10 bLOD-5.53 95
MEP – 0.93 0.07–33.6 100
MnBP – 4.3 0.6–10,900 100
MBzP – 0.9 0.2–14 100
MEHP – 9.5 1.5–191 100
MiNP – 101 27–469 100
65 (Finland, 1997–2001) MMP – 0.09 bLOD-0.37 95
MEP – 0.97 0.25–41.4 100
MnBP – 12 2.4–123 100
MBzP – 1.3 0.4–26 100
MEHP – 13 4.0–1410 100
MiNP – 89 28–230 100
Calafat et al. (2004) 3 (USA) MnBP 1.3 (1.5) – – –
MEHP 7.8 (6.8) – – –
MiNP 15.9 (7.7) – – –
Table 9
Concentrations of phthalates and their metabolites (μg/L) in blood and serum.
Reference N (country, year) Matrix Population (years of age) Compounds Mean (±SD) Median Range % Detection frequency
Axelsson et al. (2015) 314 (Sweden, Serum Men (17.5–20.5) MECPP 0.56 (0.44) 0.45 0.13–5.0 100
2008–2010) MEOHP 0.20 (0.14) 0.16 0.03–1.2 100
MEHHP 0.36 (0.47) 0.21 0.07–3.9 100
MCiOP 2.2 (5.5) 1.1 0.17–77 100
MOiNP 0.059 (0.19) 0.028 bLOD-2.9 98
MHiNP 0.38 (1.5) 0.17 0.01–25 100
Huang et al. (2014) 207 (China, 2011–2012) Cord blood Pregnant women DMP 6.69 – bLOD 24.64
(28.06 ± 3.28) DEP 8.99 – bLOD 32.85
DMEP 8.11 – 3.72 60.87
DBP 68.14 – 36.21 100.00
DEEP 32.96 – 3.84 57.49
DiBP 31.34 – 16.69 100.00
DPP 26.64 – bLOD 18.36
DMPP 11.81 – bLOD 19.81
DBEP 53.51 – 1.36 72.46
DCHP 125.02 – 13.67 88.89
DnHP 8.08 – bLOD 28.50
BBzP 22.55 – bLOD 45.89
DEHP 187.16 – 19.70 100.00
DnOP 27.66 – bLOD 29.47
DiNP 13.42 – 0.68 83.57
Genuis et al. (2012) 20 (Canada) Serum Adults (21–68) MEP 5.69 (8.61) 3.88 0.84–39.2 100
MiBP 26.1 (23.9) 17.8 4.0–77 100
MEHP 28.2 (9.65) 27.6 17–52.6 100
DBP 35.1 (28.3) 37.6 bLOD-79.0 84
DEHP bLOD bLOD bLOD-35.0 10
Lin et al. (2011) 30 (Taiwan, 2001–2002) Serum Pregnant women (21–39) MnBP 2.88 23.90 13.10–39.70 100
MiBP 1.10 3.44 1.29–6.68 100
MEHP 2.49 3.02 1.52–32.20 100
MEHHP bLOD bLOD bLOD-0.47 10
MEOHP bLOD bLOD – 0
MECPP 0.28 1.28 bLOD-10.70 96.67
2cx-MEPP bLOD 1.56 bLOD-11.24 96.67
MHiNP bLOD bLOD bLOD-1.79 3.33
MCiOP bLOD bLOD bLOD-4.05 13.33
Guo et al. (2010) 10 (China) Serum General population DMP 9.8 (4.8) – bLOD-14.3 –
(22–28) DEP 13.5 (7.2) – bLOD-28.7 –
DBP 135.4 (87.4) – 26.1–214.8 –
BBzP 37.6 (20.4) – 15.7–54.8 –
DEHP 218.0 – 80.1–342.1 –
(129.0)
DnOP 57.0 (41.1) – 16.9–70.9 –
Frederiksen et al. 60 (Denmark, 2006) Serum Healthy men (18.2–26.2) MEP 4.15 bLOD bLOD-64.89 43.3
(2010) MnBP 0.43 bLOD bLOD-1.51 13.3
MiBP 0.72 bLOD bLOD-4.36 33.3
MEHP 6.74 7.88 bLOD-15.93 83.3
MEHHP 0.09 bLOD bLOD-0.80 3.3
MEOHP 0.06 bLOD bLOD-0.84 5.1
MECPP 0.66 0.52 bLOD-4.07 70
MHiNP bLOD bLOD bLOD-3.17 1.7
MOiNP bLOD bLOD bLOD-0.75 1.7
MCiOP 0.67 bLOD bLOD-25.23 43.3
Zhang et al. (2009) 113 (China, 2005–2006) Cord blood Healthy newborns DEP – 2000 – 76.1
DBP – 1800 – 74.8
DEHP – 500 – 67.3
MEHP – 1100 – 71.4
Maternal DEP – 2200 – 79.4
blood DBP – 2200 – 82.9
DEHP – 600 – 72.3
MEHP – 1400 – 80.1
88 (China, 2005–2006) Cord blood LBW newborns DEP – 1600 – 96.6
DBP – 2700 – 97.7
DEHP – 600 – 77.1
MEHP – 2500 – 85.2
Maternal DEP – 2000 – 94.3
blood DBP – 2900 – 92.9
DEHP – 700 – 84.3
MEHP – 2900 – 88.6
Högberg et al. (2008) 36 (Sweden, 2001) Serum Pregnant women (23–39) MEP 1.2 (2.3) 0.50 0.50–14 19.4
MnBP 1.8 (3.3) 0.54 0.54–20 47.2
Table 9 (continued)
MiBP 0.87 (1.8) 0.50 0.50–11 8.3

MEHP 0.77 (0.80) 0.49 0.49–4.5 16.7
Blood DEP 0.31 (0.26) 0.24 0.0066–1.1 80.5
DBP 1.2 (1.6) 0.78 0.21–9.1 69.4
BBzP 0.29 (0.27) 0.25 0.050–1.4 80.5
DEHP 5.9 (21) 0.50 0.50–129 47.2
DnOP 1.5 (2.1) 0.70 0.70–10.0 19.4
2014). In general, DBP, DiBP and DEHP are the most commonly detected Danish men during 2006 (Frederiksen et al., 2010) did not exceed 50.0%
phthalates and DEHP is the phthalate detected at higher concentrations; and ranged from 16.9% (MiBP) to 40.7% (MnBP). MEHP was the most
5.9 μg/L (Högberg et al., 2008), 218 μg/L (Guo et al., 2010) and commonly detected metabolite of DEHP (25.4%) compared to its oxida-
187.16 μg/L (Huang et al., 2014). Seven uncommon phthalates were de- tive metabolites (1.7%–5.1%). The metabolites of DiNP, MiNP and MCiOP
tected in cord blood from Chinese pregnant women, at high levels and were also detected at 12.1% and 1.7%. MEP in seminal was significantly
at significant detection frequencies (Huang et al., 2014). More specifi- correlated with MEP in serum and urine, but no other correlations
cally, di-2-methoxyethyl phthalate (DMEP), DEEP, DBEP and DCHP were observed. The mean concentrations ranged from 0.07 μg/L
were detected in greater than 57.0% of the samples tested and DPP, (MEOHP) to 1.00 μg/L (MEP), which are low, compared to 0.055 μg/L
di4-methyl-2-pentyl phthalate (DMPP) and DnHP were detected in (MEOHP) – 5.8 μg/L (MEP)that have been detected in Chinese men dur-
18.4%, 19.8% and 28.5% of the samples respectively. ing 2013 (Wang et al., 2016). MnBP, MEHP and MEHHP were detected
in almost all individuals while MMP, MEP, MBzP and MEOHP were de-
3.2.5. Phthalate metabolites in human hair tected at 35%, 67%, 29% and 79% respectively. MnOP was the metabolite
Although urine is generally preferred for biomonitoring studies, hair with the lowest concentration (0.031 μg/L) and detection rate (13%).
specimen has a great potential to assess long term exposures. In the past Although analyzing semen or parent compounds is avoided due to
years it had been reported that phthalates are excreted from the human contamination problems, in a study conducted in China during 2008–
body and they are not accumulated in adipose tissue (Schmid and 2009 (Wang et al., 2015a) the researchers noted differences between
Schlatter, 1985). Thus, until today, most studies were focused on biolog- the exposure of healthy and infertile men (Table 9). Mean values in fer-
ical fluids. Researchers from Taiwan (Chang et al., 2013) first developed tile men ranged from 4.13 μg/L (DBP) to 13.68 μg/L (DEHP), while in in-
a method for the determination of five DEHP metabolites (MEHP, fertile men from 10.61 μg/L (DEP) to 27.66 μg/L (DEHP). Maximum
MEHHP, MEOHP, MECPP, MCMHP) in human hair and it was successful- concentrations were detected for DBP and DEHP (293 μg/L and
ly applied to ten real samples (Table 10). MEHP was the metabolite with 504 μg/L, respectively) and together with BBzP they had the higher de-
the higher mean concentration in hair (44.9 pg/mg). MEOHP and tection frequency in samples (60.7%–81.3%).
MEHHP were detected at 9.2 and 5.7 pg/mg respectively, while Another uncommon matrix for the biomonitoring of phthalates is
MECPP and MCMHP were not at detectable levels suggesting that meconium (Table 10). Meconium starts to be accumulated in fetus at
MEOHP and MEHHP are the more suitable biomarkers in hair analysis. week 16 of gestation and it is not excreted until after delivery. The
The presence of DiNP metabolites in hair from rats is examined after chemicals to which the fetus is being exposed in uterus are accumulated
administration of the parent compound (Hsu et al., 2015). Hair and rat in meconium (Ostrea et al., 2008) and the levels of the metabolites de-
urine specimens were analyzed simultaneously and the levels of the tected in meconium are significantly higher (p b 0.0001) than in cord
three main DiNP metabolites (MiNP, MOiNP and MHiNP) in hair were blood (Li et al., 2013). MnBP and MEHP have been detected in meconi-
strongly correlated with urine. One human hair sample was also ana- um from LBW and healthy infants (control group) from China during
lyzed, in which MiNP was the main metabolite at 40.44 μg/g and other 2005–2006 (Zhang et al., 2009). Cord blood and maternal blood were
seven DiNP metabolites were detected at levels between 0.19 and also analyzed for both groups to estimate the exposure to the parent
4.07 μg/g. However, in rat hair MiNP was the compound with the lowest compounds DEP, DBP, DEHP and the metabolite MEHP. Maternal
concentration and MHiNP was the main metabolite. There are not blood, cord blood (Table 9) and meconium from LBW infants (Table
enough data to explain the different ratio of DiNP metabolites in 10) were most contaminated relatively to healthy newborns indicating
human and rat hair and thus the authors suggest that it should be fur- a greater exposure to phthalates. Meconium levels were higher in both
ther investigated. healthy and LBW infants (1.7 mg/g–5.5 mg/g) compared to maternal
(0.6 mg/L–2.2 mg/L) and cord blood (0.5 mg/L–2.7 mg/L) enhancing
3.2.6. Phthalates in other biological matrices the fact that chemicals are accumulated.
A group of volunteers chewed PVC toys under controlled conditions Parent compounds and metabolites have also been detected in
and the migration of phthalates from plastic products in saliva was sweat (Genuis et al., 2012). Metabolites MEP, MiBP and MEHP were de-
assessed (Niino et al., 2001). The research confirmed that diesters in sa- tected in all samples collected from 18 individuals while DBP and
liva are metabolized to their respective hydrolytic monoesters. Unex- DEHPwere detected in 22% and 61% of the samples respectively (Table
pectedly, the HMW phthalate DiNP was the main phthalate in saliva 10). The comparison between urinary and sweat levels showed that
relatively to DBP and DEHP. Similarly, in another research, the more hy- MEHP is more efficiently excreted in sweat, while MEP is mainly excret-
drophobic phthalates had higher detectability relatively to MMP and ed in urine. Compounds excreted in sweat originate from storage sites,
MEP (Silva et al., 2005). This could happen due to the different pharma- for example adipose tissue or from the circulatory system. Thus,
cokinetic factors between urine and saliva, the different solubility of bioaccumulated phthalates are excreted from human body through
MEP in the biological fluids or the combination of all. Oxidative metab- perspiration.
olites may also be present in human saliva (Hines et al., 2009), although
in low levels and detection frequencies (Table 9). 4. Conclusions
In seminal plasma DMP, DEP, DBP, BBzP and DEHP and their metab-
olites are the mostly detected compounds. The DiNP metabolites have This review study has tried to figure out the association of prenatal
also been detected at very low levels (Table 10). The detection frequen- exposure to phthalates with birth outcomes and adverse health effects
cy of MEP, MnBP, MiBP and MBzP in samples collected from 60 healthy appeared in childhood or adulthood. Most studies agree that there are
Table 10
Concentrations of phthalates and their metabolites in uncommon biological matrices. Levels in liquid matrices are expressed as μg/L and levels in meconium are expressed as mg/g.
Hsu et al. (2015) 1 (China) Hair (μg/g) – MiNP – 40.44 – 100

MOiNP – 0.47 – 100
MHiNP – 0.56 – 100
MCiOP – 0.89 – 100
MCiPeP – 1.64 – 100
MCiHxP – 0.19 – 100
Chang et al. (2013) 10 (China) Hair (pg/mg) – MEHP 44.9 – 15.3–96.2 100
MEOHP 9.2 – 3.3–23.4 100
MEHHP 5.7 – 2.3–13.5 100
MECPP bLOQ – bLOQ 0
MCMHP bLOD – bLOD 0
Hines et al. (2009) 62 (USA, 2004–2005) Saliva Lactating women(18–38) MEHHP bLOD – – 0
MEOHP bLOD – – 0
MECPP 2.3 – – 1.6
MCPP 2.2 – – 1.6
Silva et al. (2005) 39 (USA) Saliva Adults MMP – bLOD bLOD-3.1 8
MEP – bLOD bLOD-91.4 38
MnBP – 5.0 bLOD-65.8 85
MiBP – 2.4 bLOD-17.9 79
MBzP – bLOD bLOD-353.6 44
MEHP – bLOD bLOD-6.8 46
Wang et al. (2016) 687 (China, 2013) Semen Men (32 ± 5.4) MMP 5.8 bLOD – 35
MEP 2.3 0.50 – 67
MnBP 1.2 0.85 – 99
MBzP 0.091 bLOD – 29
MEHP 2.2 0.79 – 100
MEHHP 0.25 0.17 – 100
MEOHP 0.055 0.022 – 79
MnOP 0.031 bLOD – 13
Wang et al. (2015a) 107 (China, 2008–2009) Semen Infertile Men (23–45) DEP 10.61 (14.06) – – 43.9
BBzP 23.85 (30.86) – – 70.1
DBP 21.66 (33.9) – – 60.7
DEHP 27.66 (37.73) – – 81.3
DnOP 10.90 (16.56) – – 37.4
94 Healthy men (23–45) DEP 5.66 (7.64) – – –
BBzP 8.16 (10.94) – – –
DBP 4.13 (5.35) – – –
DEHP 13.68 (20.22) – – –
DnOP 5.69 (4.47) – – –
Frederiksen et al. (2010) 60 (Denmark, 2006) Semen Healthy men (18.2–26.2) MEP 1.00 bLOD bLOD −11.16 30.5
MnBP 0.77 bLOD bLOD −9.64 40.7
MiBP 0.64 bLOD bLOD −4.97 16.9
MBzP 0.35 bLOD bLOD −7.97 18.6
MEHP 0.45 bLOD bLOD −12.32 25.4
MEHHP 0.12 bLOD bLOD −2.80 5.1
MEOHP 0.07 bLOD bLOD −1.20 5.1
MECPP bLOD bLOD bLOD −0.47 1.7
MiNP 0.19 bLOD bLOD −1.74 12.1
MHiNP bLOD bLOD bLOD 0
MCiOP bLOD bLOD bLOD-0.28 1.7
Genuis et al. (2012) 20 (Canada) Sweat Adults (21–68) MEP 91.1 (172) 29.9 3.94–750 100
MiBP 111 (75.3) 100 46.0–378 100
MEHP 27.3 (21.4) 12.4 2.68–68.6 100
DBP bLOD bLOD bLOD-58.6 22
DEHP 49.9 (133) 15.5 bLOD-576 61
Zhang et al. (2009) 113 (China, 2005–2006) Meconium Healthy infants MnBP – 1.7 – 74.3
MEHP – 2.9 – 76.1
88 LBW infants MnBP – 2.2 – 95.5
MEHP – 5.5 – 87.5
correlations between in utero exposure to certain phthalates and abnor- The question is whether health impacts in children linked to
malities appeared in newborns such as preterm birth, birth length and phthalates are due to in utero exposure or exposure during childhood.
weight, head circumference and altered reproductive hormone levels Although some follow up studies have been conducted, data are still
that reflect in uterus delayed development and anti-androgen effects. not enough. Prenatal exposure has been associated with neurobehav-
Male and female newborns appear to be affected by different phthalates ioral disorders and behavioral syndromes in children such as aggressive
and in different way indicating that phthalates are sex-specific. Mater- behavior, learning problems, mental development effects and genomic
nal hypothyroidism during pregnancy is strongly associated with uri- instability. Asthma and allergic symptoms, obesity, anti-androgen ef-
nary phthalate metabolites posing an increased risk for mental fects, delay of growth and puberty, and changes in systolic blood pres-
retardation and fetal neurodevelopment. Plus to maternal exposure, sure, have been associated with exposure to phthalates during
medical devices in NICUs turn to be a significant source of DEHP in childhood.
newborns.
In adults, exposure to phthalates has been linked to respiratory urine of German children. Int. J. Hyg. Environ. Health 212 (6), 685–692. http://dx.
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associated with TDS syndrome, reduced testosterone levels and sperm phate and phthalate esters using gas chromatography with positive ion chemical ion-
quality indicating that they may have a possible role in male infertility. ization tandem mass spectrometry and its application to indoor air and dust. Rapid
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Bornehag, C.G., Sundell, J., Weschler, C.J., Sigsgaard, T., Lundgren, B., Hasselgren, M.,
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Hägerhed-Engman, L., 2004. The association between asthma and allergic symptoms
small number of metabolites and applied in a small number of human in children and phthalates in house dust: a nested case-control study. Environ. Health
samples. So there is still a lot of work to be done in this direction. Perspect. 112 (14), 1393–1397. http://dx.doi.org/10.1289/ehp.7187.
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Conflict of interest nary concentrations of phthalates and phenols in a population of Spanish pregnant
women and children. Environ. Int. 37 (5), 858–866. http://dx.doi.org/10.1016/j.
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The authors declare that there are no conflicts of interest or any CDC, 2015. Centers for Disease Control and Prevention. National Biomonitoring Program.
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A Global Assessment of Phthalates Burden and Related Links To Health Effects

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EI-03456; No of Pages 25

Environment International xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

journal homepage: www.elsevier.com/locate/envint

A global assessment of phthalates burden and related links to health effects

2.1. Review questions and objective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

DMP MMP 0.690 0.690 Itoh et al. (2007)

3.1.3. Toxicity in adults 3.2. Phthalates in biological matrices

MEOHP − 7.92 − 100.00

(continued on next page)

MCiOP 21.66 19.89 − 100

MEHP 2.49 2.1 − 74

(continued on next page)

MiBP − 29.9 − 100

MBzP 17.5 18.1 468 100

600 EUROPE AMERICA ASIA

Levels - Annual Distribution Total PhthalateDI-Annual Distribution

600 Adults - C Adults - D

Levels - Annual Distribution Total Phthalate DI-Annual Distribution

Table 6 seem to be eliminated more slowly than in plasma. After exposure of

PEs Committee MRL/TDI/RfD mg/kg Reference

DEHP DI - Annual Distribution DEHP DI - AnnualDistribution

Reference N (country, year) PMs Mean Median Range % Detection frequency

Kim et al. (2015) 62 (Korea, 2012) MEP – 0.37 – 100

(continued on next page)

MiBP 0.87 (1.8) 0.50 0.50–11 8.3

Hsu et al. (2015) 1 (China) Hair (μg/g) – MiNP – 40.44 – 100

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