Human Health Impacts of

Phthalates Environmental Toxicology

Submitted to: Dr. Abdul Qadir

Submitted by: Sadia Rahat (15)

MS-1ST Semester

Session: 2014-2016

Dated: 15th Feb, 2015

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Table of Contents

Abstract .............................................................................................................................................2

1 Introduction ...............................................................................................................................2

2 Sources of Phthalates ..................................................................................................................2

3 Exposure routs of Phthalates .......................................................................................................4

4 Half-life of Phthalates in humans..................................................................................................5

5 Assessing human exposure of Phthalates......................................................................................5

6 Health Outcomes in infants..........................................................................................................5

7 Health Outcomes in females ........................................................................................................8

8 Health Outcomes in Males...........................................................................................................8

9 Conclusion ................................................................................................................................ 10

10 Suggestions .............................................................................................................................. 10

11 Reference ................................................................................................................................. 11

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Abstract: Phthalates are primarily used as plasticizers in PVC related products. However, a

number of Phthalic Acid Esters (PAEs) have been used in a wide range of products, range from

toys to medical devices and food processing units. PAEs and their metabolites produce

reproductive abnormalities in human males and male-infants. I have reviewed a number of

articles to find out the exposure route of phthalates in human population and their possible health

outcomes. Studies on the human health outcomes of phthalates remained controversial because

of study design limitations. Some of the laboratory findings in human populations are

inconsistent with the animal findings. However, some of them are consistent and helps to

understand toxicity pathways of PAEs. Human population studies, reviewed in this paper are

helpful for showing this association. After reviewing several articles, we have concluded that the

PVC use of phthalates along with its other applications should be readily banned as it causes

severe health impacts in human males and male infants.

1 Introduction

The Diesters of 1, 2-benzenedicarboxylic acid (Phthalic acid), is commonly referred as

phthalates. These are anthropogenic chemicals widely use in industrial sectors. These ubiquitous

chemicals have a wide range of application including consumer products, food processing units,

medical sector etc. (Swan, 2008).

Phthalic acid esters (PAEs) have been used as plasticizers for polyvinyl chloride (PVC)

products (Autian, 1973). These PAEs are reversibly bonded with polymer matrix and under

certain conditions they detach, and release into the environment, that is why these compounds

are ubiquitous and found everywhere in the environment (Marx, 1972; Mayer et al., 1972).

A study conducted in 2003 to chemically analyze 120 homes for indoor air and dust.

Traces of phthalates have been found in both, dust and indoor environment. The most abundant

phthalates found in the air were o-phenylphenol, 4-nonylphenol and 4-tert-butylphenol (Rudel et

al., 2003).

2 Sources of Phthalates

Di (2-ethylhexyl) phthalate (DEHP) is the high molecular weight phthalate. It is

extensively use in polyvinyl (PVC) manufacturing industries. It used as plasticizers in PVCs

which has a wide application in numerous consumer products range from toys, bath books,

flooring, wall coverings, food processing, medical devices and occupational exposure. DEHP

containing products are widely use in medical devices including intravenous tubing and blood &

nutrient bags etc. (Swan, 2008).

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Low molecular weight phthalate, diethyl phthalate (DEP), is renowned as solvent and

plasticizer for cellulose acetate. It is used in manufacturing of in lacquers, varnishes, personal-

care products including perfumes, lotions, and cosmetics and coatings including those used in

making timed-release pharmaceutical products. Díaz found level of DEP in cosmetics, personal

care products, adults and young children, higher than those of DEHP and di-n-butyl phthalate

(DBP) (Díaz et al., 2009).

Indoor-air of food processing units contains high level of PAEs. Dairy products and fatty

food are highly enriched with DEHP, DBP, butylbenzyl phthalate (BzBP) (Kavlock et al., 2002).

Lee and Koo reported in 2004 that DEHP, DBP, DEP used in cosmetics, are the primary source

of phthalate in women (Koo and Lee, 2004). Table 2.1 showed the potential phthalates exposure

sources and their related health outcomes.

Table: Exposure sources of phthalates

Phthalate Exposure source Health outcome

DEP

(Diethyl

phthalate)

Personal care products: fragrances

creams, lotions, shampoos etc.

Pharmaceuticals

Dyes

Pesticides such as insecticides

Reduced growth rate

Decrease food

consumption

Increased organ weights

DBP

(Di-n-butyl

phthalate)

Cellulose acetate plastics

Personal care products: nail polish,

fragrances creams, lotions,

shampoos etc.

Lacquers

Varnishes

Pharmaceuticals

Hepatic and renal effects

Developmental &

reproductive Effects

Reduced fetal weight

Cryptorchidism

Hypospadias

Reduced anogenital

distance in males

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BBzP

(Butylbenzyl

phthalate)

Vinyl flooring

Adhesives and sealants

Car-care products

Toys

Food packaging

Synthetic leather

Industrial solvents

Personal care products: nail polish,

fragrances creams, lotions,

shampoos etc.

Testicular toxicity

Cryptorchidism

Reduced anogenital

Distance

Teratogenic effects

Modulates steroid

hormone levels

DEHP

(Di (2-

ethylhexyl)

phthalate)

PVC plastics used in household

products: toys, floor tiles and

furniture upholstery & wall-

coverings)

Food packaging

Blood storage bags and medical

devices

Hepatocellular carcinoma

Testicular toxicity

Anovulation

Teratogenic effects at high

doses

Affects fetal growth

* Hauser et al., 2005

3 Exposure routs of Phthalates

Humans can expose to the phthalates through inhalation, oral and dermal contact. As far

as oral route is concerned, DEHP possibly enters through dietary products including food, water

and other liquids. In children DEHP enters via mouthing of toys and teethers. DEPs follow the

dermal pathways to enter into individual’s body. It is found in cosmetics and other personal care

products. Phthalates volatilize from PVC products, hair sprays, nail polishes, parenteral (e.g.

phthalates via tubing in neonatal care nurseries) enters into one’s body via inhalation (Swan,

2008).

It should be noted that exposure pathways analyzed in rodents showed different result

than in humans. DEP and MEP (mono-ethyl phthalate) didn’t show any kind of reproductive

abnormalities in lab animals, while phthalates (DEHP, DEP) showed severe reproductive

abnormalities in humans. Exposure of phthalates to the developmental fetus results in permanent

alternations (Swan, 2008).

DEHP has been used for PVC-medical devices such as blood storage bags, neonatal

intensive care units (NICUs), tubing sets, extracorporeal membrane oxygenation, blood

exchange transfusions, and cardiovascular surgery. Those infants who suffered from medical

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procedures, they may receive high concentration of DEHP. This is because absorption capacity

in infants is higher than the adults.

4 Half-life of Phthalates in humans

Phthalates are proven endocrinal disruptors (EDCs) in lab animals and they also showed

testicular dysgenesis in male babies. Phthalates rapidly metabolized in humans and their

calculated half-life is less than 24 hours in human body. In 2005, Koch and his co-worker orally

administer DEHP in humans and found that it is systemically absorbed and excreted through

urine. However, its secondary oxidized metabolites are the probable ultimate developmental

toxicants.

5 Assessing human exposure of Phthalates

There are a number of techniques have been used to analyze human phthalates levels

range from simple traditional methods to highly modernize techniques. This includes

questionnaires, medical records, biomarkers, urine test and analysis of many other many body

fluids and matrices (urine, saliva, serum, breast milk, amniotic fluid, seminal fluid, meconium,

and placenta) (Calafat and McKee, 2006).

In 2008, Teitelbaum and his coworkers reported that a single drop of urine sample is

enough to analyze exposure of phthalates over a six-month period in epidemiological studies in

children (Teitelbaum et al., 2008). Wormuth and his co-workers studies phthalates level in

population samples in Europe and concluded that the DEHP and DBP level in infants was higher

than those of adults (Wormuth et al., 2006). A study conducted on 163 infants showed that about

80% infants exposed to MEP and (mono-Butyl phthalate) MBP directly related to baby care

products including baby creams, lotions, and powders (Sathyanarayana et al., 2008).

Matsumoto and his co-workers reported in 2008 that PAEs and their metabolites produce

reproductive and developmental dys-functionalities in laboratory animals. These abnormalities

include dysfunctional testis, embryolethality, malformations such as fusion of the sternebrae,

cleft-palate and sex differentiation (Matsumoto et al., 2008). These finding raised serious

concerns about possible impacts of phthalate on human reproductive system.

6 Health Outcomes in infants

Before 2000, very few data existed related to human health impacts of phthalates.

However, after 2000 studies conducted on a large scale range from rodents to human, population

samples to find out humans health related toxicity of phthalates (Howdeshell et al., 2008). In

2007 Lee and Koo demonstrated that DEHP, (Mono(2-ethylhexyl)phthalate) MEHP, DBP,

BzBP, di-isononyl phthalate (DINP), di-'isodecyl' phthalate (DIDP) and Di-n-hexyl phthalate

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DnHP causes anti-androgenic effects which ultimately result into shortened anogenital distance

(AGD) in infants (Lee and Koo, 2007).

Foster in 2006 and Welsh in 2008 reported that DEHP, DBP, and BzBP showed a

noticeable reduction in testosterone which in severe cases leads to an individual’s death.

Exposure to these phthalates also causes reduction of insulin-3 (growth factor) which results into

male reproductive syndrome including cryptorchidism, malformations of the epididymis,

hypospadias, seminal vesicles, vas deferens, and prostate. These abnormalities collectively called

as ‘‘phthalate syndromes’’ (Welsh et al., 2008; Foster, 2006). Anti-androgenic substances such

as linuron (L), flutamide (F), p,p-DDE and procymidone (P), were tested. F-like profiles resulted

from P, L, and p,p0-DDE; inducing shortened AGD and it was different from those, produced by

DBP and DEHP (Gray, 2000). Hence it was concluded that shortened AGD can be detected by

single parental phthalate exposure.

Swan with his co-workers conducted a study in 2000, on “Phthalates in Pregnant Women

and Children (PPWC)” in order to analyze relation of mother’s phthalates exposure and its

infants related phthalates syndromes. He concluded that male-infants are more susceptible to

phthalate syndrome than female infants (Swan et al., 2005). In 2006, Main and his co-workers

reported that females who are exposed to phthalates found high level phthalates concentration in

breast milk, collected one to three months after birth. Level of DEHP and MEHP was analyzed

in cord blood of 84 infants. 65 infants registered as MEHP-positive (Main et al., 2006).

In 2000, Blount reported that level of MBP, MBzP, and MEHP were higher in children

age 6-11years and then subsequently decreased with age. High concentration of PAEs in such

age group may be due to the varied dietary habits and use of PVC-toys. Table 6.1 showed the

possible health outcomes in infants, associated with phthalates exposure while table 6.2 showed

the possible health impacts of phthalates under certain time period in infants.

Table-6.1: Health outcomes in infants, associated with phthalates exposure

System

Sex

Health outcome

Phthalates detection

in urine samples

Reproductive Males Increased sperm DNA damage MEP, MEHP

Decreased sperm concentration MBP, MBzP

Decreased sperm motility MEP

Respiratory and Immune system

(Allergy and Asthma)

Males Decreased pulmonary function MEP, MBP

Metabolic Males Increased waist circumference MBzP MEHHP

MEOHP

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MEP

Increased insulin resistance MBP

MBzP MEP

Thyroid Males Thyroid (decreased T3 and T4) MEHP

*Swan, 2008

Table-6.2: Health outcomes in infants associated with phthalates exposure

System Exposure

Timing

Sex Health

Outcome

Phthalates detection

in urine samples

Reproductive Parental

(Almost a year)

Male/Female Shorter

gestational age at birth

MEHP (in cord blood)

Male Shorter anogenital distance

(AGD)

MEHP, Mono(2-ethyl-5-hydroxyhexyl) MEOHP, Mono(2-

ethyl-5-hydroxyhexyl) MEHHP,

MEP, MBP

Lactation (3 months)

Male Increased SHBG (Sex hormone-

binding globulin)

MEP, MBP

Respiratory, Allergy

and Asthma

Early

Childhood

Female Premature

thelarche

DEHP

(in serum)

Childhood Male/Female Rhinitis, Eczema and

Asthma

BzBP (in house dust)

DEHP (in house dust)

*Swan, 2008

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7 Health Outcomes in females

Mortensen with his co-workers conducted a study on 36 women breast milk samples for

mono-Butyl phthalate (MBP) and found free form phthalate metabolites in milk samples which

are highly toxic for infants (Mortensen et al., 2005).

Females usually found high concentration of these phthalates as compared to males.

Women with age 20 to 40 years particularly have shown high concentration of MBP then to the

other age and gender groups (Blount et al., 2000). This increase in women may be due to high

and persistent use of cosmetics and other personal care products (Koo and Lee, 2004). DEHP

also associated with induction of intrauterine inflammatory process (Matsumoto et al., 2008).

Colon and his co-workers conducted a study on 41 Puerto Rican thelarche girls and 35 of

them found with high level concentration of DEP, DBP, DEHP, and MEHP and DMP. So, colon

concluded that PAEs is the possible accelerators of premature breast development in human

females Colon et al. (2000). However, McKee did not agreed with this conclusion as he stated

that laboratory study did not support these result (McKee et al., 2004). Zacharewski also reported

that there is no relationship has been shown for estrogenic response in human females with PAEs

exposure (Zacharewski et al., 1998).

8 Health Outcomes in Males

Fredricsson reported that sperm mortality rate in human is severely affected by DEHP

and DBP exposure (Fredricsson et al., 1993). Increased rate of miscarriage and low pregnancy

rate in human females is the result of DBP exposure (Aldyreva et al., 1975).

Duty in 2003 reported that an increase level of MEP metabolites in urine is the indication

of damage in DNA of sperm (Duty et al., 2003). It was recently confirmed by Hauser in 2007;

who conducted a study on 379 men and found the stated relation of MEP metabolites and

associated sperm DNA damage (Hauser et al., 2007).

Jonsson and his co-workers stated that MEP metabolites in urine also associated with

fewer motile sperm and lower serum luteinizing hormone (LH) values along with high

concentration of immotile sperm (Jonsson et al., 2005). Subhan in 1995 reported the relationship

of MBzP exposure and its resulted decrease in serum follicle- stimulating hormone (FSH) level

(Subhan et al., 1995). DEHP and MEHP cases damage to DNA along with destruction of

lymphocytes in human (Anderson et al., 1999).

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Table-6.3: Showing health outcomes of phthalates exposure in Human males.

Phthalates Health outcomes

PAEs Decrease sperm normal morphology

Increase large testis

Increase sperm motility

DEHP Decrease semen volume

Increase rate of sperm malformation

MEHP Decrease curvilinear velocity of sperm

Decrease Plasma free testosterone

Increase sperm DNA damage

MEP Increase sperm DNA damage

Increase large testis

Decrease sperm motility

Decrease luteinizing hormone

Increase DNA damage in sperm

Decrease sperm linearity

Increase curvilinear velocity of sperm

DBP Decrease semen volume

MBP Decrease sperm concentration

Decrease sperm motility

Decrease curvilinear velocity of sperm

Decrease plasma free testosterone

Increase Inhibin B level

MBzP Decrease sperm concentration

Decrease curvilinear velocity of sperm

Decrease follicle-stimulating hormone

MMP Increase poor sperm morphology

*Matsumoto et al., 2008

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9 Conclusion

Although phthalates have been used on commercial scale for over 50 years but studies

have generally been conducted on human population level within last ten years. We reviewed

data about human exposure pathways to the phthalates and their associated health outcomes.

Evidence from several studies suggests that exposure to PAEs and associated products should be

avoided in order to ensure human safety and environmental health. A number of scientist

concluded that phthalates causes reproductive abnormalities in human males and male-infants.

However they are not agreed on the point that phthalates may cause reproductive phthalate

syndromes in human females. Some of them suggested that, studies should be conducted on

laboratory scale to human-population level in order to access associated risk. Further

epidemiological studies should be conducted to enhance our understanding and risk

management.

10 Suggestions

-As we are concerned with Human safety and environmental health, we should

immediately stop using PAEs in PVC-products, food processing units and personal care

products.

-Studies should be conducted to explore the relationship of adulthood phthalates exposure

and their associated health outcomes.

-Studies should be conducted to explore the best possible alternatives of phthalates to

reduce its use in industrial sector.

-Studies should be conducted to enhance understanding of phthalate exposure and its

effects on human fertility rate.

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