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Phthalates and Their Impacts on Human Health

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Phthalates are a series of widely used chemicals that demonstrate to be endocrine disruptors and are detrimental to human health. Phthalates can be found in most products that have contact with plastics during producing, packaging, or delivering. Despite the short half-lives in tissues, chronic exposure to phthalates will adversely influence the endocrine system and functioning of multiple organs, which has negative long-term impacts on the success of pregnancy, child growth and development, and reproductive systems in both young children and adolescents. Several countries have established restrictions and regulations on some types of phthalates; however, we think that more countries should establish constraints or substitute measures for phthalates to reduce health risks. This article aims to summarize the adverse impacts of phthalates on human health, analyze the toxicity mechanism, assess the risks, and finally provide feasible strategies to reduce exposure of the public to phthalates.
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healthcare
Review
Phthalates and Their Impacts on Human Health
Yufei Wang 1,2 and Haifeng Qian 1, *


Citation: Wang, Y.; Qian, H.
Phthalates and Their Impacts on
Human Health. Healthcare 2021,9,
603. https://doi.org/10.3390/
healthcare9050603
Academic Editor: Andrea Tittarelli
Received: 27 March 2021
Accepted: 12 May 2021
Published: 18 May 2021
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Copyright: © 2021 by the authors.
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Attribution (CC BY) license (https://
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4.0/).
1College of Environment, Zhejiang University of Technology, Hangzhou 310032, China; jdwang@zjut.edu.cn
2School of Public Health and Preventive Medicine, Monash University, Melbourne 3000, Australia
*Correspondence: hfqian@zjut.edu.cn; Tel.: +86-13588450337; Fax: +86-571-88320599
Abstract:
Phthalates are a series of widely used chemicals that demonstrate to be endocrine disruptors
and are detrimental to human health. Phthalates can be found in most products that have contact
with plastics during producing, packaging, or delivering. Despite the short half-lives in tissues,
chronic exposure to phthalates will adversely influence the endocrine system and functioning of
multiple organs, which has negative long-term impacts on the success of pregnancy, child growth and
development, and reproductive systems in both young children and adolescents. Several countries
have established restrictions and regulations on some types of phthalates; however, we think that
more countries should establish constraints or substitute measures for phthalates to reduce health
risks. This article aims to summarize the adverse impacts of phthalates on human health, analyze the
toxicity mechanism, assess the risks, and finally provide feasible strategies to reduce exposure of the
public to phthalates.
Keywords: risk assessment; endocrine disruptors; plastics; health impact; child growth
1. Introduction
Plastic has brought great benefits to society since it was invented in 1907, however,
it also has many negative impacts on the environment and human health, which has
become a global problem. People are constantly exposed to plastics via contaminated
food, packaging leachate (e.g., water bottle and medical devices), atmospheric fallout
and urban dust containing microplastics, personal care products (PCPs) (e.g., cosmetic
packaging), and synthetic clothing [
1
,
2
]. Long-term plastic exposure would inevitably
lead to the leaching of many harmful substances. The most concerns include phthalates,
bisphenol A (BPA), and polychlorinated biphenyls (PCB). These substances have been
identified as endocrine-disrupting chemicals (EDCs) which interfere with normal hormonal
actions [
3
,
4
]. Phthalates are a series of chemical substances, which are mainly used as
plasticizers added to polyvinyl chloride (PVC) plastics for softening effects. Phthalates can
potentially disrupt the endocrine system [
5
]. Health concerns regarding the detrimental
impacts of phthalates on the development and reproductive system have been raised in the
recent decades [
6
]. Compared to adults, children are much more vulnerable and sensitive
to phthalates exposure, especially during early growth [
7
]. This review aims to summarize
the impacts of phthalates on human health, especially on children, the mechanism and risk
assessment of phthalates, and provide feasible strategies to reduce exposure of the public
to phthalates.
2. Phthalates Applications and Exposure Routes
Phthalates, such as diethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), diethyl
phthalate (DEP), di-isononyl phthalate (DiNP), and di-iso-decyl phthalate (DiDP), are
mainly used in the plastic industries as plasticizers to produce polyvinyl chloride (PVC).
The short-branched low molecular weight phthalates, such as dimethyl phthalate (DMP)
and DEP, are also widely produced and used in many industries, such as PCPs (e.g., hair
products), pharmaceuticals, and medical devices (e.g., medical tubing) (Table 1). The global
Healthcare 2021,9, 603. https://doi.org/10.3390/healthcare9050603 https://www.mdpi.com/journal/healthcare
Healthcare 2021,9, 603 2 of 9
consumption of DEHP was estimated at 3.07 million tons (Global demand for plasticizers
continues to rise, 2017). The estimated global market of phthalates in 2020 is expected to
reach 10 billion USD and would still be widely used in plasticizers [8].
Table 1. Common phthalate compounds.
Compounds Abbreviation Where It Can Be Found Also Named As
Diethylhexyl phthalate DEHP Plasticizer Di-2-ethylhexyl phthalate;
Bis-2-ethylhexyl phthalate.
Dibutyl phthalate DBP
Nail polishers; plasticizer; an additive
to adhesives or printing inks; Di-n-butyl phthalate, DnBP, DNBP
Diethyl phthalate DEP
Toothbrushes; automobile parts; tools;
toys; food packaging; cosmetics;
insecticides; aspirin Ethyl phthalate; Di-n-ethyl phthalate
Di-isononyl phthalate DiNP Plasticizer Bis(7-methyloctyl) phthalate; DINP
Di-iso-decyl phthalate DiDP Plasticizer Di(i-decyl) phthalate; diisodecyl
phthalate; DIDP
Butyl benzyl phthalate BBP Plasticizer Benzyl n-butyl phthalate; n-Butyl
benzyl phthalate
Mono-(2- ethylhexyl) phthalate MEHP Vinyl tiles; food conveyor belts;
carpet tile; artificial leather tert-Butyldimethylsilyl
2-ethylhexyl phthalate
Di-isobutyl phthalate DiBP Plasticizer; adhesive Di(i-butyl)phthalate;
Isobutyl phthalate;
di-l-butyl phthalate; DIBP
Dioctyl phthalate DnOP Household items and building
products; food applications Di-n-octyl phthalate; DNOP
Plastic waste has received scrutiny by governmental and regulatory bodies. Global
plastic use consumes more than 3 million tons of phthalates per year [
9
]. Due to their
ubiquity in the environment, human exposure to phthalates leached from waste plastics is
virtually unavoidable. For instance, in China, plastic usage tripled over eight years from
2003 and 2011, and reached over 50 million tons of raw plastics produced and estimated
to keep increasing in the following years [
9
]. As a result, the relative higher exposure to
phthalates was found in China due to the high usage of plastics. In the USA, more than
340 million pounds of phthalates are consumed every year and cause potential health and
environmental risks [
10
]. Phthalates can be easily leaching into food, water, and other
products applied directly to the human body. The detrimental health and environmental
effects have been increasingly studied to assess the extent of the impacts on society. An
important phthalate exposure route could be consisted of ingestion, inhalation, and dermal
contact mainly via PCPs [
9
]. Some dairy products, fish, seafood, and oils are found to
have a high level of phthalates. For the residents who live near phthalates manufacturing
industries, phthalates are more likely to enter the body through absorption via the skin
and the polluted air due to fugitive emission [
10
]. Phthalates are semi-volatile organic
compounds (SVOCs). DEHP and DBP are the main compounds in both indoor and outdoor
air phthalates [
11
]. Dermal absorption also occurs from the daily use of PCPs containing
phthalates via plastic package. Infants are exposed to phthalates by drinking breast milk
with their mothers exposed to DEHP and DiNP, and sucking on toys containing DEHP,
DBP, and BBP [
10
]. Phthalates are also found to cross the placenta-blood barrier, which is
the major exposure route of the fetus [12].
3. Bio-Metabolism of Phthalates in Human Body
The bio-metabolism in the human body is very rapid since phthalates have short
biological half-lives, about 12 h [
13
]. Figure 1presents the metabolic patterns. The first
step of metabolism is hydrolyzation after absorption into cells. The second step is conju-
gation to form the hydrophilic glucuronide conjugate, which is catalyzed by the enzyme
uridine 5
0
-diphosphoglucuronyl transferase [
14
]. The type of phthalates determines its
Healthcare 2021,9, 603 3 of 9
toxicological fate in the body. Short-branched phthalates are often hydrolyzed to mo-
noester phthalates and then excreted in the urine, while long-branched phthalates mainly
undergo several bio-transformations, such as hydroxylation and oxidation, and then ex-
creted in urine and feces as phase 2 conjugated compounds [
15
]. For example, the DEHP,
which has complex branched chains, may be hydrolyzed to mono(2-ethylhexyl) phthalate
(MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate, mono(2-ethyl-5-oxohexyl) phthalate,
mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-carboxymethylhexyl) phtha-
late (MCMHP) or other metabolites. The metabolites of DEHP above could also be found
in serum. According to the animal experiments, exposure to MEHP causes reproductive
dysfunction in female zebrafishes, which is possibly due to the alteration in endocrine
activities (elevated cortisol levels) [16]. In addition, according to half-life and distribution
pattern, previous studies indicated that MECPP in urine and MCMHP in serum could
be used as suitable biomarkers [
14
]. Most of the phthalates and their metabolites can be
found in urine and feces, but some phthalates compounds (e.g., DEHP) and their metabo-
lites can also be excreted in sweat [
17
]. Wittassek and Angerer found that the oxidative
metabolism of DEHP is age-related. Younger children at the age of 6–7 years excrete more
oxidative DEHP metabolites compared to mono-(2-ethylhexyl) phthalate (MEHP), one of
the metabolites, than adults aged between 19 and 90 years [18].
Figure 1. The metabolic pathway for phthalates.
4. Phthalates Toxicology and Risk Assessment
In rodent studies, it was found that phthalates have low acute toxicity with a median
lethal dose (LD
50
) of 1–30 g/kg bodyweight, and its toxicity is mainly concentrated in the
liver, kidney, thyroid gland tissue, and testis [
6
]. Evidence for adverse effects on repro-
duction and development in animals and humans is ample. According to the laboratory
experiment on pregnant animals, exposure to DBP at 100 mg/kg bodyweight/day is toxic
to fetal development [
6
]. The no-observed-adverse-effect level for DEHP to humans is
4.8 mg/kg bodyweight/day and the tolerate daily intake (TDI) is 48
µ
g/kg bodyweight [
19
].
Studies found that low molecular phthalates, such as DEP, can acutely irritate the skin,
conjunctiva, and mucous membrane of the oral and nasal cavities [
20
]. Phthalate exposure
is associated with adverse developmental effects in terms of increased prenatal mortal-
ity, reduced growth and birth weight, skeletal, visceral, and external malformations in
rodents [
6
]. Experiments on male rats found that the nervous system is rather sensitive to
low doses of DEHP exposure during puberty [
21
]. The impacts of phthalates on human
beings vary from gene expression to physiological changes. High molecular weight ph-
thalates exposure is found to cause methylation status of imprinted genes, which could
be directly related to androgen response, estrogen response, protein secretion, and sper-
matogenesis [
22
,
23
]. Human epidemiological studies have shown a significant association
between phthalates exposures and adverse reproductive outcomes in both women and
men, for instance, type II diabetes and insulin resistance, overweight/obesity, allergy,
asthma [
24
]. Among all phthalates, DEHP was most frequently tested and had the highest
concentration in food, except in beef where di-n-octyl phthalate (DnOP) has the highest
concentration [
25
]. In household dust, DEHP (median contamination level in indoor air:
400–700 ng/m
3
, (max. 410,000) mg/kg) has been found at high concentrations [
6
]. Evi-
Healthcare 2021,9, 603 4 of 9
dence found that DEHP was significantly related to insulin resistance and higher systolic
blood pressure and the reproduction system problems, including earlier menopause, low
birth weight, pregnancy loss, and preterm birth [
4
]. During 2003–2004, the National Health
and Nutrition Examination Survey (NHANES) found that the US population has been
widely exposed to phthalates [
26
]. Women were found to be exposed at higher levels than
men due to frequent use of PCPs (e.g., soaps and cosmetics) [
26
]. A systematic review
and meta-analysis concluded that phthalates metabolites MBzP and MiBP were negatively
associated with breast cancer among females [
27
]. Risk assessment of chemicals involves
a comparison of the actual level of exposure to the acceptable level of exposure, mostly
TDI values. But phthalates are a group of chemicals with individually different TDIs but
with similar metabolites and impacts on the human body. Hence, the cumulative risk
assessment is more appropriate to measure the risk of phthalates presented by summing
the hazard quotient (HQ) as a hazard index (HI). Søeborg, et al. measuring the HQs and
HIs of five phthalates, including DEHP, DBP, BBP, DINP, and DIDPA, found that DEHP and
DBP contributed the greatest proportion of the HI. According to the NHANES data, the HI
values of 10% of pregnant women exceeded 1, which means 10% of pregnant women were
negatively impacted by phthalates, meanwhile, the Study for Future Families (SFF) found
that the HI values of 4–5% of infants exceeded 1 [28].
5. Impacts of Phthalates on Children
When it comes to the impacts on children, epidemiological studies about phthalates
toxicity focused on pregnancy outcomes, genital development, semen quality, precocious
puberty, thyroid function, respiratory symptoms, and neurodevelopment [
29
]. Table 2
summarizes the health impacts on children. Among the epidemiological studies, it was
revealed that exposure to phthalates adversely affected the level of reproductive hormones
(luteinizing hormone, free testosterone, sex hormone-binding globulin), anogenital distance,
and thyroid function [
29
]. Altered thyroid function is found to be associated with thyroid
cancer [
30
]. A recent Chinese study concluded that phthalates exposure is related to the
disrupted arginine and proline metabolism, resulting in the development of overweight
and obesity among school-age children [
31
]. A 20-year birth cohort study found that
prenatal phthalates exposure is negatively associated with height and weight during
infancy and positively associated with height during childhood [
32
]. Another prospective
study demonstrated that DiDP is associated with respiratory system health among boys
aged under 5 years [
33
]. Phthalates have also been found to be linked to social impairment
of children, the same as BPA [
8
]. Previous studies have found that infants and toddlers
when contacting polymer toys may be exposed to levels of 5 to 44
µ
g/kg bodyweight/day
of DiNP [6]. Later studies reported that around 20% of the children have been exposed to
higher levels of phthalates than the cumulative TDI for DEHP and DBP [
18
]. In 2013–2014,
over half of tests for phthalates for persons aged over 6 years found positive results for
DEHP, and almost all women and children had DBP metabolites, according to the National
Center for Health Statistics (NCHS) [
10
]. In Austria, few exceedances of TDI values of
phthalates were observed among children, whereas the exceedances of TDI-based HIs for
adults were in rare cases [
34
]. A study measuring the phthalates in air and dust in California
(USA), found that 82–89% of children had DBP exposure exceeding the reproductive health
benchmarks, and 8–11% of children aged less than 2 years exposed to DEHP exceeding
cancer benchmarks [
35
]. A study conducted in China found that the cumulative risk
because exposure to phthalates was higher in preschool children aged 3–6 years compared
to the reports in German and Danish [
36
,
37
]. Rice, vegetables, and flour are the main
sources of DEHP in China [
38
]. Xu, et al. reported that phthalates, mainly DEHP, DnBP,
and DiBP, exist in commonly used plastic express packing bags, suggesting these bags may
be the current main source of exposure of the population to phthalates [
39
]. In addition, the
intake of vegetables grown in plastic greenhouses made children experience higher (nearly
3 times) DEHP and DnBP exposure than adults [
40
]. Foods containing fat (e.g., dairy and
meat) tend to be more likely to absorb phthalates from the packaging. From the review of
Healthcare 2021,9, 603 5 of 9
the literature, we believe that the exposure pathway depends on the food, air, or products
containing phthalates.
Table 2. Health impacts on children.
Category Health Concerns
Endocrine systems
Weight (overweight and obesity) and height
Type II diabetes and insulin resistance
Thyroid function and increased risk of thyroid cancer
Higher systolic blood pressure
Anogenital distance
Precocious puberty
Males: genital development, semen quality
Females: pregnancy outcome (pregnancy loss and preterm birth,
low birth weight), reproductive hormones (including lueinizing
hormone, sex hormone-binding globulin, earlier menopause)
Others Respiratory system: allergy and asthma
Nervous system: delayed neurodevelopment, social impairment
6. Restrictions on Phthalates
Since the turn of the century, restrictions on phthalates have been proposed in many
Asian and western countries (Table 3). In 2001, Japan prohibited DiNP and DEHP in toys
and DEHP in food-handling gloves [
41
]. Since 2007, Europe banned DEHP, DBP, and BBP
in all PVC and other plasticized materials in all toys and childcare articles, and DiNP,
DiDP, and di-n-octyl phthalate (DnOP) for those products that can be placed in children’s
mouth [
42
]. Recently, di-isobutyl phthalate (DiBP) was added to the restrictions in 2018
in 28 EU countries [
43
]. In 2008, the US Congress announced the Consumer Protection
Safety Act (CPSA) that permanently banned the products, especially children’s toys and
childcare articles, containing DEHP, DBP, and BBP at levels >0.1% by weight [
44
]. Australia
also banned certain products that contained more than 1% of DEHP and could be chewed
or sucked by children up to and including 36 months of age [
45
]. This ban also applied
to food vessels and utensils, besides toys and childcare articles. Similar restrictions also
have been announced for the exported products from China, the biggest manufacturer
and consumer of phthalates, and Canada. The latest phthalates regulations in China
in 2017 set detection limitations of 16 phthalates in food, food containers, and packing
materials (GB 5009.271-2016, GB/T 21928-2008, GB 9685-2016, GB 15593-1995). Dissolved
DEHP detected in transfusion (infusion) equipment should not be more than 10 mg/mL
(GB 14232.1-2004/ISO 3826-1, GB 24613-2009). It has been reported that over 100 healthcare
institutions around the world are reducing the use of PVC and phthalates [46].
Table 3. Restrictions in Japan, Europe, the US, Australia, and China.
Country Restrictions
Japan [41] DiNP and DEHP are banned in toys; DEHP is banned in food-handling gloves
Europe [42,43]DEHP, DBP, DiBP, and BBP are banned in all PVC and plasticized toys and childcare articles;
DiNP, DiDP, and DnOP are banned for products that can be placed in children’s mouth
The United States [44]
Products containing DEHP, DBP, and BBP at levels >0.1% by weight shall be banned, especially
children’s toys, and childcare articles; children’s products that can be placed in a child’s mouth
or childcare articles containing more than 0.1% of DiNP, DiDP, and DnOP are banned
Australia [45]Children’s plastic products containing, or have a component containing more than 1% by
weight DEHP are banned
China (National Standard of the
People’s Republic of China)
16 phthalates are restricted in food and food containers, including DNP, DnOP, DEHP, DiNP,
DiBP, BBP, etc; dissolved DEHP in transfusion (infusion) equipment is restricted to less than
10 mg/mL; the total amount of DEHP, BBP, DBP in childcare articles should not be more
than 0.1%.
Healthcare 2021,9, 603 6 of 9
7. Strategic Recommendations
Current evidence and research suggest the need for further restrictions and strategies
to reduce the exposure to phthalates. Feasible strategies are as following:
(1)
Reassess and apply the restrictions where appropriate on high-risk products. DEHP,
DBP, BBP, DiNP, DiDP, DnOP, and DiBP are now limited in certain products in many
countries, which could contribute to reducing phthalates exposure. Less exposure will
be observed if similar restrictions are applied in those countries that do not currently
apply phthalates restrictions. Products with high phthalates exposure risk need to
be strictly limited, such as food packaging, PCPs, medical devices, products likely to
be sucked or ingested by infants, children, and adolescents. Pregnant women and
lactating women have also been identified as vulnerable groups, and it is, therefore,
necessary to impose stricter standards on the products that contact such specific
groups of people.
(2)
Phthalate alternatives (PA) with less toxicity and leakage should also be considered,
especially in the health care industry. The leaching of DEHP in the environment is
uncontrollable but can be avoided by using DEHP-free alternatives [
47
]. The con-
centration of phthalates needs to be limited in the products that are most frequently
used but people are not aware of the toxic exposure. In the medical industry, trioctyl
trimellitate (TOTM) and diisononylester (DINCH) are found to be promising DEHP
alternatives (Thomas, et al., 2021). Besides, epoxidised soybean oil (ESBO), di-(2-
ethylhexyl) terephthalate (DEHT), and acetyl tributyl citrate (ATBC) are popular PAs
in the plasticizer market. In Europe, PVC-free medical and DEHP-free devices are
available, by using polyethylene, polypropylene, polyurethane, and other polyolefins,
silicone, ethylene-vinyl acetate, and multi-layerlaminate plastics as alternatives [
47
].
The alternative softeners are citrates, benzoates, trimellitates, and adipates, with much
lower toxic levels than DEHP (Ruzickova, et al., 2004). Where practicable, using glass
containers instead of plastic packaging, avoiding heating food in plastic containers,
avoiding using fragrance that may contain phthalates, and reading the label of PCPs
can easily reduce the exposure to phthalates in daily life [
47
]. Also, testing drinking
water routinely for phthalates can keep residents at safe levels of exposure. When
processing food, it is advisable to use phthalate-free gloves, utensils, and packaging to
reduce exposure in food. The most recent exposure assessment found decreased ph-
thalates and increased PA in humans [
48
]. Few adolescent participants were detected
to have higher estimated daily intakes than health-based guidance values.
(3)
To protect children, soft vinyl toys, old plastic toys, and teething rings should be
avoided. Children should be kept away from waste sites of factories, especially plastic
manufacturers, which can help to avoid dermal and airborne intake. A recent study at
a kindergarten in China found that there were relatively high phthalates exposures in
indoor air and dust, compared to the outdoor environment [
49
]. In the community, it
is also necessary to limit and measure the level of phthalates in kindergarten, schools,
hospitals, and shopping malls. Even though PA use may reduce the phthalates
levels, PA exposure cannot be ignored as well, especially from tap water and air
particles [
50
]. Public awareness needs to be improved to educate vulnerable members
of the community to avoid using plastics voluntarily, especially plastics containing
phthalates.
8. Conclusions
While the benefits of plastics are enjoyed worldwide, the environment and human
health are adversely influenced (Figure 2). Phthalates, as endocrine-disrupting chemicals
and SVOCs, are detrimental to the reproductive, neurological, and developmental systems
of human from multiple exposure pathways. Children are at a higher level of exposure and
more vulnerable to phthalates. Currently, many phthalates are banned and restricted in
multiple countries. Plastic manufacturers and suppliers are required to understand plastic
regulations to meet national and international standards. Till now, information related to
Healthcare 2021,9, 603 7 of 9
occupational exposure to phthalates remains limited. Further research is required to assess
the risk of occupational exposure to phthalates.
Figure 2. Phthalates application and the impacts on human health.
Author Contributions:
Y.W. and H.Q. conceptualized the review and visualized the interrelationship.
Y.W. searched all the related literature, wrote the original draft of the manuscript and performed the
formal analysis. H.Q. validated the conclusion and contributed substantially to the revisions. H.Q.
acquired funding for this research. Both authors have read and agreed to the published version of
the manuscript.
Funding: This research was funded by National Natural Science Foundation of China (21777144).
Conflicts of Interest: The authors declare no conflict of interest.
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... In vitro and in-vivo studies have shown phthalate exposure to induce structural and functional changes at the cellular level under specific doses (Baralić et al., 2021;Sonkar et al., 2016;Zhang and Choudhury, 2021). Due to growing health concerns, although controversial, phthalates have been restricted in several countries (Wang and Qian, 2021). ...
... Breast cancer is one of the critical public health problems contributing to high morbidity and mortality among the female population around the globe (Sung et al., 2021). Phthalate exposure is considered a risk factor for several diseases, including breast cancer (Ahern et al., 2019;Holmes et al., 2014;Morgan et al., 2017;Reeves et al., 2019;Wang and Qian, 2021;Wu et al., 2021a). However, the molecular players altered upon phthalate exposure and their role in breast cancer are yet to be comprehensively understood. ...
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Phthalates have been extensively used as plasticizers while manufacturing plastic-based consumer products. Estradiol mimicking properties and association studies suggest phthalates may contribute to breast cancer (BC). We performed an in-silico analysis and functional studies to understand the association between phthalate exposure and BC progression. Search for phthalate-responsive genes using the comparative toxicogenomics database identified 20 genes as commonly altered in response to multiple phthalates exposure. Of the 20 genes, 12 were significantly differentially expressed between normal and BC samples. In BC samples, 9 out of 20 genes showed a negative correlation between promoter methylation and its expression. AHR, BAX, BCL2, CAT, ESR2, IL6, and PTGS2 expression differed significantly between metastatic and non-metastatic BC samples. Gene set enrichment analysis identified metabolism, ATP-binding cassette transporters, insulin signaling, and type II diabetes as highly enriched pathways. The diagnostic assessment based on 20 genes expression suggested a sensitivity and a specificity >0.91. The aberrantly expressed phthalate interactive gene influenced the overall survival of BC patients. Drug-gene interaction analysis identified 14 genes and 523 candidate drugs, including 19 BC treatment-approved drugs. Di(2-ethylhexyl) phthlate (DEHP) exposure increased the growth, proliferation, and migration of MCF-7 and MDA-MB-231 cells in-vitro. DEHP exposure induced morphological changes, actin cytoskeletal remodeling, increased ROS content, reduced basal level lipid peroxidation, and induced epithelial to mesenchymal transition (EMT). The present approach can help to explore the potentially damaging effects of environmental agents on cancer risk and understand the underlined pathways and molecular mechanisms.
... In vitro and in-vivo studies have shown phthalate exposure to induce structural and functional changes at the cellular level under specific doses (Baralić et al., 2021;Sonkar et al., 2016;Zhang and Choudhury, 2021). Due to growing health concerns, although controversial, phthalates have been restricted in several countries (Wang and Qian, 2021). ...
... Breast cancer is one of the critical public health problems contributing to high morbidity and mortality among the female population around the globe (Sung et al., 2021). Phthalate exposure is considered a risk factor for several diseases, including breast cancer (Ahern et al., 2019;Holmes et al., 2014;Morgan et al., 2017;Reeves et al., 2019;Wang and Qian, 2021;Wu et al., 2021a). However, the molecular players altered upon phthalate exposure and their role in breast cancer are yet to be comprehensively understood. ...
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Phthalates have been extensively used as plasticizers while manufacturing plastic-based consumer products. Estradiol mimicking properties and association studies suggest phthalates may contribute to breast cancer (BC). We performed an in-silico analysis and functional studies to understand the association between phthalate exposure and BC progression. Search for phthalate-responsive genes using the comparative toxicogenomics database identified 20 genes as commonly altered in response to multiple phthalates exposure. Of the 20 genes, 12 were significantly differentially expressed between normal and BC samples. In BC samples, 9 out of 20 genes showed a negative correlation between promoter methylation and its expression. AHR, BAX, BCL2, CAT, ESR2, IL6, and PTGS2 expression differed significantly between metastatic and non-metastatic BC samples. Gene set enrichment analysis identified metabolism, ATP-binding cassette transporters, insulin signaling, and type II diabetes as highly enriched pathways. The diagnostic assessment based on 20 genes expression suggested a sensitivity and a specificity >0.91. The aberrantly expressed phthalate interactive gene influenced the overall survival of BC patients. Drug-gene interaction analysis identified 14 genes and 523 candidate drugs, including 19 BCE treatment-approved drugs. Di(2-ethylhexyl) phthlate (DEHP) exposure increased the growth, proliferation, and migration of MCF7 and MDAMB231 cells in-vitro. DEHP exposure induced morphological changes, actin cytoskeletal remodeling, increased ROS content, reduced basal level lipid peroxidation, and induced epithelial to mesenchymal transition (EMT). The present approach can help explore the potentially damaging effects of environmental agents on cancer risk and understand the underlined pathways and molecular mechanisms.
... Phthalate exposure is widespread, as measurable levels of many urinary phthalate metabolites have been detected in nearly all U.S. National Health and Examination Survey participants (NHANES) [7]. Exposure can occur from ingestion, inhalation, and dermal contact with products that contain phthalates [8]. ...
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Background Exposure to endocrine disruptors, such as phthalates, may impact bone mineral density (BMD) through a variety of mechanisms. Studies of phthalate exposure and BMD in humans are scarce. Objectives To synthesize published data on the association between phthalate metabolites and BMD in humans and to provide methodological suggestions for future research. Methods A single investigator searched PubMed for relevant studies, including observational studies of phthalate exposure and BMD in children and postmenopausal women. Twelve studies were screened with 5 meeting the eligibility criteria and included for review. A quality assessment form was used as a quality measure and key information was extracted from the included studies. Results In one prospective study among postmenopausal women, higher levels of monocarboxyoctyl phthalate (MCOP) and monocarboxynonyl phthalate (MCNP) were significantly associated with lower BMD among nonusers of hormone therapy (HT). In cross-sectional studies of postmenopausal women, monoethyl phthalate (MEP), mono-n-butyl phthalate (MnBP), mono (3-carboxypropyl) phthalate (MCPP), and mono-benzyl phthalate (MBzP) were negatively associated with BMD, and MCNP was positively associated with BMD, but these results were not replicated across studies. In studies of fetal exposure to phthalates and childhood BMD, significant positive associations between MCPP and BMD in children at age 12 years were found in 1 study, while associations were null in the other study. Conclusions Studies among postmenopausal women provide suggestive evidence of an association between urinary phthalate metabolite concentration and decreased BMD. Results from studies of childhood BMD are inconclusive given the limited data and their limitations. More research is needed to address limitations and further investigate the association between phthalate exposure and human BMD.
... There is evidence that DEHP oral bioavailability was 7% at dose of 100 mg/kg in rat, actually 7 mg/kg is absorbed in rat (equivalent 1.13 mg/ kg DEHP in human) [62]. The NOAEL for DEHP is 4.8 mg/kg in human [63] and DEHP daily exposure is 0.21-2.1 mg/kg in an adult [62]. Exposure to DEHP in daily life increased risk of injuries in human [62]. ...
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Phthalates are one of the most widely used plasticizers in polymer products, and they are increasingly being exposed to people all over the world, generating health concerns. Phthalates are often used as excipients in controlled-release capsules and enteric coatings, and patients taking these drugs may be at risk. In both animals and human, phthalates are mainly responsible for testicular dysfunction, ovarian toxicity, reduction in steroidogenesis. In this regard, for a better understanding of the health concerns corresponding to phthalates and their metabolites, still more research is required. Significantly, multifarious forms of phthalates and their biomedical effects are need to be beneficial to investigate in the various tissues or organs. Based on these investigations, researchers can decipher their toxicity concerns and related mechanisms in the body after phthalate's exposure. This review summarizes the chemical interactions, mechanisms, and their biomedical applications of phthalates in animals and human.
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פסולת ימית נפוצה בכל חלקי הסביבה הימית, משפיעה רבות עליה ועל החיים בה, ומהווה מקור לדאגה עולמית. צבי ים, הנפוצים בכל העולם, משתמשים בבתי גידול מרובים במהלך מחזור חייהם, חשופים למגוון רחב של מפגעים וכמות גבוהה של פסולת. אוכלוסיית צבי הים בים התיכון נמצאת תחת איום, בפרט באגן הלבנט שבו אחוזי התמותה הגבוהים ביותר בים בתיכון. המפגש בין צבי הים לסוגי הפלסטיק השונים מתרחש בכל אזורי המחייה שלהם ולכן נבחרו כביו אינדיקטורים עבור ניטור השפעת הפסולת הימית על בע"ח. הפגיעה מפלסטיק מגוונת, ומתחלקת לשני סוגים עיקריים: הסתבכות ועיכול. הפסולת שגורמת להסתבכות מתחלקת לשתי קטגוריות עיקריות: ציוד דיג (אקטיבי ופסיבי) ופסולת ממקור יבשתי. הפגיעה מציוד דיג יכולה לנבוע מדיג אקטיבי ברשתות דיג ומכמורת, קרסים ומערכי חכות בעודן פעילות במרחב המחייה של הצבים. שחרור הצב שהסתבך ללא טיפול מתאים עלול להוביל בהדרגה גם להסתבכות פסיבית שגורמת לזיהומים, נמקים, לתזונה לקויה, לאבדן גפיים ולמוות. דו"ח זה מציג לראשונה מידע על השפעת פסולת הפלסטיק על צבי ים בישראל ממידע שנאסף במשך 22 שנים במרכז להצלת צבי הים וכן בפיילוט של שנה בניטור פסולת בקיבות צבי הים, שנעשה בשיתוף פעולה של המרכז עם החברה לחקר ימים ואגמים לישראל. ניתוח המידע מצביע על לא פחות ממצב חירום סביבתי. המרכז הארצי להצלת צבי ים אוסף נתונים בנוגע לפגיעות צבים החל משנת 1999 . בעבודה זו מוצגות הרשומו ת ממסד הנתונים בנוגע ל-1,473 צבים שנאספו בשנים 1999-2021 . הרשומות מחולקות על פי מין הצב, פיזיולוגיה )אורך, משקל, זוויג( וסוג הפגיעה. כשליש מהצבים (566 רשומות, חיים או מתים) תועדו כנפגעים ממפגעים הקשורים בפלסטיק. הפגיעותמפסולת פלסטיק מחולקות לשלושה סוגים: פגיעות פלסטיק שונות (n=115) המהוות 21% מסך הפגיעות, פגיעות דיג (n=255) מהוות 47% והפגיעות משקי פוליפרופילן (n=176) המהוות 32% . כחמישית מהצבים המטופלים ( 22% , n=123) לא שרדו . בשנים 2017-2021 נצפתה עליה חדה במספר הצבים הצעירים שנפצעו או מתו בחופי ישראל בגלל הסתבכות (צוואר וגפיים) בשקים ארוגים מפוליפרופילן. דבר זה עלול להשפיע באופן חמור על הגיוס לאוכלוסייה. לכן המרכז להצלת צבים זיהה את השקים כסכנת חיים מרכז ית עבור צבי הים הצעירים, בשלב החיים הפלאגי. שקים אלו משמשים במגוון תעשיות, אך הכתובות עליהם מציינות שייעודם במקור הוא לאריזת מזון של בעלי חיים בחקלאות ונמצאו מספר ספינות שיכולות להיות קשורות למקור השקים בים. ההסתבכויות בשקי פוליפרופילן שכיחות יותר ( 88% מצבי הים חומים, 48% מצבי הים הירוקים) במהלך חודשי הקיץ (יוני-ספטמבר) לאורך כל קו החוף של ישראל . נתיחות לאחר המוות לבדיקת נוכחות פסולת במערכות עיכול בוצעו ב- 2021 במרכז ההצלה ובחקר ימים ואגמים בשני מיני צבי ים: 6 צבי ים ירוקים ו- 15 צבי ים חומים (שנבחרו כמין המייצג באיחוד האירופי). בכל הפרטים נמצאה פסולת במערכת העיכול. בצבי הים הירוקים נמצאה כמות גבוהה בהרבה של פסולת בהשוואה לצבי הים החומים, אך ריכוז הפסולת במערכות העיכול היה גבוה יותר בצב הים החום. ריכוז הפסולת היה גבוה משמעותית בצבים הצעירים בהשוואה לבוגרים, זאת ככל הנראה כתוצאה מאזורי המחייה השונים. חוטי דיג הופיעו ב 8% מקיבות הצבים שנותחו, ייצוג גבוה משמעותית ביחס לתפוצתם בפסולת הצפה או השקופה שנוטרה באזורינו. ניטור הפסולת במערכות עיכול של צבים החל בשנת 2021 ולכן לא נאספו מספיק נתונים על מנת להבין לעומק את הקשר בין סיבת המוות לתכולת הפלסטיק במערכת העיכול. הנתונים המובאים בעבודה זו מייצגים את הנתונים שנאספו במרכז להצלת צבים בלבד וקשה להעריך את אחוז הצבים הפגועים המטופלים במרכז ההצלה מכלל האוכלוסייה. לכן ככל הנראה נתוני הדוח מספקים הערכה בחוסר של כמות הצבים הפגועים והמתים כתוצאה מפסולת ימית. ההשפעה החמורה של הפסולת הימית על צבי הים באזורינו, ובפרט הסתבכות הצבים בפסולת ימית , מחייבת המשך מעקב והבנת התנהגות הצבים והפסולת באזורנו על מנת למזער את הפגיעה העתידית .
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