human health impacts of phthalates
TRANSCRIPT
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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