Amira S. El Refay¹, Ayman F. Armaneous¹, Dina A. Salah¹, Mai Youssef¹, Ebtissam Salah¹, Mones Abu Shady¹, Nevien R. El Baroudy², Safaa Morsy³, Amr Gouda⁴ and Walaa S. Nazem⁴

¹Department of Child Health, National Research Centre, Cairo, Egypt.

²Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt.

³Department of Medical Biochemistry, National Research Centre, Cairo, Egypt

⁴Department of Biochemical Genetics, Human Genetics and Genome Research Institute.

Corresponding Author E-mail:fekreyayman@yahoo.com

DOI : https://dx.doi.org/10.13005/bpj/2959

Abstract

Background: Phthalates, which are diesters of phthalic acid, are commonly used as plasticizers and additives in various consumer products. Several phthalates have been identified as substances of high concern. Exposure to phthalate esters (PAEs) has been linked to asthma in children, but the specific impacts of PAEs on asthmatic children were not well understood. Objective: The objective of this study was to compare urinary phthalate concentrations in asthmatic and non-asthmatic children and to identify potential sources of exposure as risk factors for asthma. Methods: A case control study was conducted for 100 Egyptian children aged 8-16 years (50 asthmatics and 50 healthy controls). Asthma was identified using GINA guidelines. Socio-demographic and probable risk factors were assessed, in addition to measuring phthalate levels in urine samples using high-performance liquid chromatography. Results and conclusion: Mean urinary Mono-methyl as well as Mono-benzyl levels were highly significant in asthmatic children compared to control group (895.26ng/ mL vs 548.55 ng/mL and 13.5 ng/mL vs 2.07 ng/mL respectively) (p= 0.001). The number of asthmatic children living in houses painted with non-plastic paint was significantly lower (P<0.05) than children living in houses painted with other paints. No association between floor type and asthma was reported. The frequent use of personal care products and plastic painting of walls were identified by multiple logistic regression analysis as the highly significant predictors of asthma in the studied subjects. The declared higher levels of urinary phthalate metabolites (Mono-methyl and Mono-benzyl) in Egyptian asthmatic children may reveal the probable risk of phthalate exposure in triggering bronchial asthma.

Keywords

Egyptian Children; Environmental Risk Factors; Pediatric Asthma; Phthalate Exposure; Urinary phthalates

Download this article as: 

Copy the following to cite this article: Refay A. S. E, Armaneous A. F, Salah D. A, Youssef M, Salah E, Shady M. A, Baroudy N. R. E, Morsy S, Gouda A, Nazem W. S. Phthalate Exposure and Pediatric Asthma: A Case Control Study Among Egyptian Children. Biomed Pharmacol J 2024;17(3).

Copy the following to cite this URL: Refay A. S. E, Armaneous A. F, Salah D. A, Youssef M, Salah E, Shady M. A, Baroudy N. R. E, Morsy S, Gouda A, Nazem W. S. Phthalate Exposure and Pediatric Asthma: A Case Control Study Among Egyptian Children. Biomed Pharmacol J 2024;17(3). Available from: https://bit.ly/46pwc6R

Introduction

Bronchial asthma is a widespread chronic disease in childhood, affecting up to 20% of children worldwide with significant geographic variations in prevalence, severity, and mortality ¹. According to WHO records, asthma affected more than 339 million people globally in 2016, resulting in a significant burden of the disease globally, with approximately 10-15% of children affected.².In Egypt, the prevalence of asthma ranges between 7.7-8.2% ^3,4.  The international variations of asthma burden are still unclear, although genetic predisposition is evident. Environmental factors such as infections and exposure to environmental endotoxins may act as risk factors ⁵.

Suggested theory assumed that one potential risk factor for the raising prevalence of atopic (IgE-mediated) allergic diseases especially asthma in different countries, is exposure to constituents as environmental pollutants and plasticizers such as phthalates that act as adjuvants. Specified frequently used phthalate plasticizers, such as di-(2-ethylhexyl) phthalate, was linked to this regard ⁶. In Egypt, few studies investigated the exposure of phthalates in children and documented that plastic toys and bottled water are the main sources of exposure ^7-9.

Phthalates are plasticizers, solvents, and additives that are added to PVC (polyvinyl chloride) plastics and several personal care products. Phthalates are synthetic organic compounds that are phthalic acid diesters ¹⁰. More than 25 phthalates are used in commercial items, which raises the quality of the item they are incorporated in ¹¹.

Many commercial products may have phthalates in their consistency including: building supplies, medical devices, packages of food, makeup products, fragrances, children’s toys, shampoos, teethers, epoxy resins, decorating paint, floorboards, hair sprays, soaps, nail polishes, and cleaners ^10-12.

The production of phthalates was increased yearly worldwide from 4.7000,000 metric tons in 2006 ¹³ up to ~8 million metric tons in 2015 ¹⁴ The estimated global market of phthalates in 2020 has reached 10 billion dollars and are still widely used in plastic devices and products ¹⁵.

Exposure to phthalates in humans begins principally from eating, consumption, inhalation, and absorption through skin ^16,17. Studies in humans have assessed serum phthalate ¹⁸ and phthalate metabolites in human urine ^19,20, semen ^21,22 and breast milk ^23,24.

Although it is assumed that exposure to phthalates may prompt oxidative stress and provoke respiratory consequences, it is doubtful in what way phthalates worsen respiratory function and initiate airway inflammation in asthmatic patients  ¹⁶ .

Recent studies demonstrated the association of urinary phthalates concentration and exacerbation of asthmatic children ^15,25-27.

This study aims to compare urinary phthalates concentrations in asthmatic children with those in a control group and to identify potential sources of phthalates exposure as risk factors for asthma development.

Methods

This study was held as a case control study on children selected from those attending pulmonary clinic at Abo El Reesh Specialized Pediatric Hospital, Cairo University. Children aged between 8 and 16 years. Fifty children were selected at random out of asthmatic children with variable degrees of severity corresponding to (GINA) Guidelines ²⁸. Fifty apparently healthy children were recruited from the relatives of patients of matched age and gender, who lived in another house and/or environment through an announcement.

Ethical approval

“Ethical approval was obtained from the Medical Ethics Committee of the National Research Centre, Egypt (approval number 16-368). Written informed consent was obtained from all parents or legal guardians of the participating children. The study adhered to the International Ethical

Guidelines for Biomedical Research Involving Human Subjects ²⁹ .

Inclusion criteria and Exclusion criteria

Children diagnosed with asthma, either in remission or during an acute attack, based on clinical presentation. Exclusion criteria: Children with a history of renal, liver, thyroid, or endocrine diseases were excluded from both the case and control groups.”

Data collection and clinical examination

Data collection involved administering a questionnaire to the children and their guardians, covering socio- demographic variables and potential risk factors such as the age of the residential building, indoor environmental exposure (e.g., plastic/vinyl flooring, type of home painting), exposure to passive smoking, and the frequent use of personal care products (e.g., shampoo, hair gel/spray, lotions, toothpaste, perfumes). Both groups underwent a general and chest clinical examination. Asthma was assessed using the GINA 2019 guidelines, and chest radiographs were reviewed for the asthmatic group to verify the diagnosis. Early morning urine samples were collected from both asthmatic and control children and stored at -70°C until analysis.”

Laboratory investigations

Urinary phthalates were the definite biomarkers of phthalate exposure in previous studies ^30,31 As phthalates are metabolized to their mono-esters in few hours or maximum days. Urinary phthalate mono-esters are valuable biomarkers for evaluating human phthalate exposure ³². One spot urine sample is adequately expressive for six months exposure ³³.

Urinary creatinine was included as a covariate in all analyses as to correct dilution,  We adjusted all metabolite concentrations  for creatinine levels and was expressed as μg/g Cr.

Urine samples were thawed and sonicated for 10–15 min, then (100 μl) was loaded into a glass vial (2 ml) containing ammonium acetate (AA, 20 μl, >98%, Sigma Aldrich Laboratory, Inc., St. Louis, MO, USA), β-glucuronidase (10 μl, E.coli K12, Roche Biomedical, Mannheim, Germany), and a combination of ten isotopic 13C4) phthalate metabolite standards (100 μl. Cambridge Isotope Laboratory, Inc., Andover, MA, USA). Afterward, the samples were incubated (37℃, 90 min), a 270 μl solution (5% ACN), Merck, Darmstadt, Germany) with 0.1% formic acid (FA, Merck, Darmstadt, Germany) was added and sealed with the PTEF cap for analysis. Monoethyl phthalate, monomethyl phthalate, monobenzyl phthalate, monobutyl phthalate, and bis2ethylhexylphthalate were purchased from SigmaAldrich. β-glucuronidase was purchased from Roche. Stock solutions of standards were prepared in acetonitrile (3000ng/ml). Eleven-point calibration curve was constructed for each standard (0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256, and 1000 ng/ml). Sample preparation was done by solid-phase extraction according to the method described ²⁸ After evaporation of eluting, the residue was reconstituted in 100 µl 20% acetonitrile in water and injected.

Phthalate metabolites were assessed as an alternative of their parent compounds to lower the potential for exposure misclassification. A combination of solid phase extraction, high pressure liquid chromatography, and tandem mass spectrometry were used to measure phthalate metabolite levels using methods described by a group of researches ³⁴ .

Statistical analysis

Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) version 21 (IBM Corp., Armonk, NY, USA). Continuous variables were presented as mean ± standard deviation and compared using the student’s t- test. Categorical variables were presented as frequencies and percentages and analyzed using the two-tailed chi-square test. Odds ratios (OR), 95% confidence intervals (CI), and logistic regression analyses were conducted to identify potential risk factors and predictors of bronchial asthma. A p-value of <0.05 was considered statistically significant.

Results

Table 1 presents the descriptive data of the studied groups. The mean age of the asthmatic group was 11.78 ± 1.28 years, and the control group was 12.35 ± 1.44 years, with no significant difference between the groups. The gender distribution was similar, with 56% females and 44% males in the asthmatic group, and 60% females and 40% males in the control group, showing no significant difference. “The children with asthma had higher concentrations of some urinary phthalate metabolites than the control group. Mean Mono-methyl and Mono-benzyl levels were significantly higher in asthmatic children (895.26 ng/mL and 13.5 ng/mL) compared to the control group (548.55 ng/mL and 2.07 ng/mL, respectively; p=0.001) The mean urinary levels of the other two studied phthalate metabolites (Mono 2ethylhexyl and Mono-butyl phthalate) showed insignificant difference (p>0.05).

Table 1: Urinary phthalate metabolites level between asthmatics versus control groups

	Groups	Mean ± SD	p–value
Ag	Bronchial asthma	11.78± 1.28	0.132
	control	12.35± 1.44
Mono (2ethylhexyl) phthalate (MEHP) (ng/ml)	Bronchial asthma	61.50± 9.77	0.965
	control	60.56 ± 24.72
Mono-methyl phthalate (ng/ml)	Bronchial asthma	895.26±102.68	0.001*
	control	548.55±46.97
Mono-benzyl phthalate (ng/ml)	Bronchial asthma	13.50±17.09	0.001*
	control	2.07 ± 0.96
Mono-butyl phthalate (ng/ml)	Bronchial asthma	28.59± 9.38	0.089

*p < 0.05 is significant.

The association between asthma and potential sources of exposure was reported in table (2), where the number of asthmatic children living in houses painted with non-plastic paint was significantly lower (P=0.001) than children living in houses painted with plastic paints. The presented results showed that, the subjects exposed to passive smoking were significantly more likely to have bronchial asthma compared to those not exposed to passive smoking (p=0.001). Moreover, the subjects who frequently used personal care products were significantly more at risk of having bronchial asthma compared to those not frequently used these products (p =0.001). On the other hand, “Table 2 shows the association between asthma and potential sources of exposure. A significantly lower number of asthmatic children lived in houses painted with non-plastic paint compared to plastic paints (p = 0.001). Exposure to passive smoking was significantly associated with a higher likelihood of bronchial asthma (p = 0.001). Additionally, frequent use of personal care products significantly increased the risk of asthma (p = 0.001). However, the age of the residential building showed no association with the risk of developing asthma.”

Table 2: Exposure to potential sources of phthalate in asthmatic versus control groups

					OR	95% CI	P-value
			Bronchial asthma	control
Age of house building	≤ 10 years	Count	10	10	1.053	0.394-2.812	0.919
		% Within age of house building	50.0%	50.0%
	> 10 years	Count	38	40
		% Within age of house building	48.7%	51.3%
Painting of the wall	Non-plastic painting	Count	14	34	0.183	0.078-0.431	0.001*
		% within Painting of the wall	29.2%	70.8%
	Plastic painting	Count	36	16
		% within Painting of the wall	69.2%	30.8%
Exposure to passive smoking	yes	Count	40	23	4.696	`1.931-11.418	0.001*
		% within Exposure to passive smoking	63.5%	36.5%
	No	Count	10	27
		% within Exposure to passive smoking	27.0%	73.0%
Frequent use of personal care products (more than once / week)	yes	Count	31	5	14.358	4.842-42.579	0.001*
		% within use of personal care products	86.1%	13.9%
	No	Count	19	44
		% within use of personal care products	30.2%	69.8%

*p < 0.05 is significant, Odds ratio (OR)

Table (3) indicates no significant association between floor type and the risk of asthma, with statistically insignificant differences in the distribution of asthmatic and control subjects across different floor types (vinyl, plastic, or ceramic) (p > 0.05).

Table 3: Association between floor type and asthma using Chi-square test.

			Group		X2	p-value
			Bronchial asthma	control
Floor type	Plastic	Count	2	0	4.000	0.135
		% within Floor type	100.0%	0.0%
	Vinyl	Count	0	2
		% within Floor type	0.0%	100.0%
	Others as ceramic	Count	48	48
		% within Floor type	50.0%	50.0%

P–value is insignificant(p> 0.05)

Multiple logistic regression analysis (Table 4) showed that the age of the house, passive smoking, and floor type were not statistically significant predictors of bronchial asthma. However, plastic wall painting and frequent use of personal care products were highly significant predictors of asthma (p = 0.001). Specifically, plastic wall painting (target 1, non-plastic paint 0) was identified as a significant risk factor for bronchial asthma (p = 0.001). In contrast, the absence of frequent use of personal care products (target 1, frequent use 0) was found to be protective against bronchial asthma (B =-2.684, p = 0.001).

Table 4: Bronchial asthma Risk factors in the studied groups by multiple logistic regression analysis

	B	S.E.	p-value	OR	95% CI
Age of housebuilding          (≤ 10 years vs> 10 years)	-0.075	0.626	0.904	0.927	0.272- 3.166
Floor type (plastic and vinyl vs others)	-0.913	0.862	0.290	0.401	0.074- 2.174
Wall Painting (Non-plastic vs others)	2.233	0.618	0.001*	9.327	2.780- 31.291
Passive smoking exposure  (Yes vs no)	-0.837	0.628	0.183	0.433	0.126- 1.484
Use of personal care products     (yes vs no)	-2.684	0.698	0.001*	0.068	0.017- 0.268
Constant	4.956	3.246	0.127	142.022

B: Standard Coefficient*p < 0.05 is significant.

Discussion

The present study documented a significant association between urinary phthalate levels and asthma in children, as significantly higher concentrations of Mono-methyl and Mono-benzyl phthalate metabolites were reported in the asthmatic children than the control group. It is known that one potential contributor in aggravating atopic allergic diseases and asthma in children is exposure to substances that could affect as adjuvants. Phthalate plasticizers, such as Mono-methyl and Mono- benzyl phthalates, have been implicated in the development of asthma.  Many recent research studied the effect of phthalate exposure and development of asthma but the exposure mechanism and potential risk factors are still unclear ^35-38.

Phthalate plasticizers, such as Mono-methyl and Mono-benzyl phthalate, have been implicated in the exacerbation of asthma. These substances can act as adjuvants, aggravating atopic allergic diseases and asthma. The lack of covalent binding in some phthalate compounds leads to greater environmental exposure as they leach into the air, food, drinks, and personal care products. These compounds enter the human body through ingestion, inhalation, and skin absorption ³⁹.

Our results showed that the metabolites of phthalates were higher in asthmatic children which supports the theory that phthalate exposure may lead to or aggravate asthma. It is unclear how phthalates aggravate airway inflammation in asthmatic patients. Regular exposure to phthalates may aggravate the risk of asthma or could extend its course by peroxisome proliferator activated receptors which facilitate anti-inflammatory process in the respiratory system and immune modulation ⁴⁰. Also, increase in the proliferation of the bronchial lung muscle cells could cause airway remodeling ⁴¹ as well as in pro-inflammatory IL-6 and IL-8  production in the air way epithelial cells ⁴² which work as adjuvants by promoting macrophage production of  inflammatory cytokines and chemokines ⁴³.Moreover, Phthalate exposure induces oxidative stress that worsens respiratory outcomes. Asthma acute attacks were linked to increased oxidative stress ^{37, 39, 40} These results are in agreement with recent studies which documented high phthalate exposure in specific asthma subgroups, emphasizing its complex relationship with asthma^44,45.  

Another research documented that phthalate-induced enhancements of mast cell degranulation and eosinophilic infiltration, which are important aspects of the early inflammation phase and  especially in indoor dust in the homes of asthmatic children compared to non-asthmatic controls, indicating an association between concentrations of phthalates in indoor dust and wheezing among preschool children⁴⁶. In recent pediatric animal module study, the authors provided evidence that high-dose probiotics supplementation might play a modulating role in diethylhexyl phthalate causes of allergic asthma⁴⁷ .

Passive smoking is a well-known risk factor for childhood asthma. Tobacco smoke exposure, both direct and second-hand, significantly contributes to asthma pathogenesis in children ⁴⁸ ; tobacco smoking and exposure to negative smoking are widely acknowledged to be causative factors for asthma in children ⁴⁹.The current study investigated the passive smoking as a potential source of phthalates in asthmatic children and this is in agreement with studies that reported association between urinary phthalates in smoking mothers and health hazards .This was explained by the effect of oxidative stress caused by smoking, as a source of phthalates, on childhood asthma  ^50,51

Whether allergic reaction towards phthalates occurs due to prenatal maternal exposure, or due to post-natal infant exposure is still controversial.  Jøhnk and his colleagues ⁵² demonstrated that maternal exposure to phthalates was related to development of asthma by the first  5 years of life. In addition, Ku and Co-others  ⁵³ suggested that early postnatal exposure has the higher risk ⁵³. Moreover, a follow up study that investigated the phthalate exposure in both pre and post-natal period, proved that early phthalates exposure is linked to allergic sensitization and play a role in asthma development in the early years of childhood ⁵³.

In the current research urinary phthalate was used as an indicator of exposure. It is well known that a one spot of urine is appropriately expressive of exposure throughout a six months period and justify its use for assessment in epidemiologic studies ⁵⁴ .

In the present study, we assessed the regular exposure to products containing phthalates, and results showed that the more frequent use of personal care products was a significant predictor of asthma.^55,56.

In addition, living in homes with plastic painting of walls appeared as a significant risk factor for developing bronchial asthma⁵⁷, while those living in houses with non-plastic paint, were less likely to be asthmatics. Non-plastic painting of the wall of houses might be protective against bronchial asthma⁵⁸. Moreover, Our findings supported the theory that phthalates exposure has a role in enhancing the immune system response⁵⁹.

Limitation of the study

The results of this study cannot be generalized due to the small sample size. Additionally, the study did not account for children’s exposures in school settings, where they spend 6-8 hours daily ⁶⁰. Also, the questionnaire lacked detailed inquiry about early childhood exposures, which are critical as the early years of life are essential for the maturation of the immune and respiratory systems. Child behavior plays a significant role in the risk of exposure, as infants and toddlers who crawl on dust floors or come into direct contact with floors or house painting are more prone to developing asthma. Further research should focus on assessing exposure in school environments and raising awareness among young mothers about the risks of phthalate exposure.

Conclusion

Our study found higher urinary phthalate levels in children with asthma. Moreover Plastic wall paint and frequent use of personal care products were identified as the principal predictors of asthma. With a molecular structure like hormones, phthalates have the potential to disrupt the immune and endocrine system, leading to health concerns regarding their detrimental impacts on development. It is important to note that children are particularly vulnerable and sensitive to phthalates, particularly during the early stages of growth and development.

Acknowledgment

The author acknowledge the National Research Centre for supporting this work.

Conflict of Interest

The authors declare no conflict of interest.

Funding source

The research is funded by National Research Centre: grant no.(11010147)

References

1. Fainardi V, Saglani S. An approach to the management of children with problematic severe asthma. Acta bio-medica : Atenei Parmensis. Sep 7 2020;91(3):e2020055. doi:10.23750/abm.v91i3.9603
2. Dharmage SC, Perret JL, Custovic A. Epidemiology of Asthma in Children and Adults. Front Pediatr. 2019;7:246. doi:10.3389/fped.2019.00246
   CrossRef
3. Mohammed M, ABDELAKHER AR, SHOKRY DM, SAFAA AE. Prevalence of bronchial asthma among school aged children in Elmaraghah Center in Sohag Governorate. The Medical Journal of Cairo University. 2020;88(June):1097-1101.
   CrossRef
4. Yousef A, Imam ME-H, Mahmmoud AA, Alrifai AW. Predictors of Asthmatic Children’s Quality of Life in Damietta Governorate, Egypt. International Journal of Medical Arts. 2021;3(4):1818-1827.
   CrossRef
5. Subbarao P, Mandhane PJ, Sears MR. Asthma: epidemiology, etiology and risk factors. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. Oct 27 2009;181(9):E181-90. doi:10.1503/cmaj.080612
   CrossRef
6. Kimber I, Dearman RJ. An assessment of the ability of phthalates to influence immune and allergic responses. Toxicology. May 27 2010;271(3):73-82. doi:10.1016/j.tox.2010.03.020
   CrossRef
7. Zareh M, El-Rahim A, El-Farargy A, Gouda M. Evaluation of Phthalate Levels in Toys in Egyptian Market. Egyptian Journal of Chemistry. 2020;63(6):2395-2403.
8. Mohamed MI, Abdelsalam MH, Zohairy E, Abdel-raof NE, Aly MM, Fakher W. PHTHALATE EXPOSURE AMONG EGYPTIAN SCHOOL CHILDREN IN RELATION TO ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD). The Egyptian Journal of Forensic Sciences and Applied Toxicology. 2021;21(1):139-148.
   CrossRef
9. Zaki G, Shoeib T. Concentrations of several phthalates contaminants in Egyptian bottled water: Effects of storage conditions and estimate of human exposure. Science of The Total Environment. 2018/03/15/ 2018;618:142-150. doi:https://doi.org/10.1016/j.scitotenv.2017.10.337
   CrossRef
10. Latini G. Monitoring phthalate exposure in humans. Clinica chimica acta; international journal of clinical chemistry. Nov 2005;361(1-2):20-9. doi:10.1016/j.cccn.2005.05.003
    CrossRef
11. Wang Y, Zhu H, Kannan K. A Review of Biomonitoring of Phthalate Exposures. Toxics. Apr 5 2019;7(2)doi:10.3390/toxics7020021
    CrossRef
12. Fréry N, Santonen T, Porras SP, et al. Biomonitoring of occupational exposure to phthalates: A systematic review. International Journal of Hygiene and Environmental Health. 2020/08/01/ 2020;229:113548. doi:https://doi.org/10.1016/j.ijheh.2020.113548
    CrossRef
13. Mackintosh CE, Maldonado JA, Ikonomou MG, Gobas FAPC. Sorption of Phthalate Esters and PCBs in a Marine Ecosystem. Environmental Science & Technology. 2006/06/01 2006;40(11):3481-3488. doi:10.1021/es0519637
    CrossRef
14. Net S, Sempéré R, Delmont A, Paluselli A, Ouddane B. Occurrence, Fate, Behavior and Ecotoxicological State of Phthalates in Different Environmental Matrices. Environmental Science & Technology. 2015/04/07 2015;49(7):4019-4035. doi:10.1021/es505233b
    CrossRef
15. Wang Y, Qian H. Phthalates and Their Impacts on Human Health. Healthcare (Basel, Switzerland). May 18 2021;9(5)doi:10.3390/ healthcare9050603
    CrossRef
16. Guo Y, Kannan K. A survey of phthalates and parabens in personal care products from the United States and its implications for human exposure. Environ Sci Technol. Dec 17 2013;47(24):14442-9. doi:10.1021/es4042034
    CrossRef
17. Guo Y, Wang L, Kannan K. Phthalates and Parabens in Personal Care Products From China: Concentrations and Human Exposure. Archives of Environmental Contamination and Toxicology. 2014/01/01 2014;66(1):113-119. doi:10.1007/s00244-013-9937-x
    CrossRef
18. Specht IO, Toft G, Hougaard KS, et al. Associations between serum phthalates and biomarkers of reproductive function in 589 adult men. Environment international. May 2014;66:146-56. doi:10.1016/j.envint.2014.02.002
    CrossRef
19. Dong R, Zhou T, Zhao S, et al. Food consumption survey of Shanghai adults in 2012 and its associations with phthalate metabolites in urine. Environment international. Apr 2017;101:80-88. doi:10.1016/j.envint.2017.01.008
    CrossRef
20. Silva MJ, Samandar E, Preau JL, Jr., Reidy JA, Needham LL, Calafat AM. Quantification of 22 phthalate metabolites in human urine. Journal of chromatography B, Analytical technologies in the biomedical and life sciences. Dec 1 2007;860(1):106-12. doi:10.1016/j.jchromb.2007.10.023
    CrossRef
21. Chen Q, Yang H, Zhou N, et al. Phthalate exposure, even below US EPA reference doses, was associated with semen quality and reproductive hormones: Prospective MARHCS study in general population. Environment international. Jul 2017;104:58-68. doi:10.1016/j.envint.2017.04.005
    CrossRef
22. Nassan FL, Coull BA, Skakkebaek NE, et al. A crossover–crossback prospective study of dibutyl-phthalate exposure from mesalamine medications and semen quality in men with inflammatory bowel disease. Environment international. 2016/10/01/ 2016;95:120-130. doi:https://doi.org/10.1016/j.envint.2016.08.006
    CrossRef
23. Högberg J, Hanberg A, Berglund M, et al. Phthalate diesters and their metabolites in human breast milk, blood or serum, and urine as biomarkers of exposure in vulnerable populations. Environmental health perspectives. Mar 2008;116(3):334-9. doi:10.1289/ehp.10788
    CrossRef
24. Main KM, Mortensen GK, Kaleva MM, et al. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environmental health perspectives. Feb 2006;114(2):270-6. doi:10.1289/ehp.8075
    CrossRef
25. Hsu NY, Lee CC, Wang JY, et al. Predicted risk of childhood allergy, asthma, and reported symptoms using measured phthalate exposure in dust and urine. Indoor air. Jun 2012;22(3):186-99. doi:10.1111/j.1600-0668.2011.00753.x
    CrossRef
26. Kim Y-M, Kim J, Cheong H-K, Jeon B-H, Ahn K. Exposure to phthalates aggravates pulmonary function and airway inflammation in asthmatic children. PloS one. 2018;13(12):e0208553-e0208553. doi:10.1371/journal.pone.0208553
    CrossRef
27. Kolarik B, Naydenov K, Larsson M, Bornehag C-G, Sundell J. The association between phthalates in dust and allergic diseases among Bulgarian children. Environmental health perspectives. 2008;116(1):98-103. doi:10.1289/ehp.10498
    CrossRef
28. Reddel HK, Bateman ED, Becker A, et al. A summary of the new GINA strategy: a roadmap to asthma control. The European respiratory journal. Sep 2015;46(3):622-39. doi:10.1183/13993003.00853-2015
    CrossRef
29. Council for International Organizations of Medical Science–A nongovernmental organization in official relations with WHO. International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS. 2016;
30. Cho SC, Bhang SY, Hong YC, et al. Relationship between environmental phthalate exposure and the intelligence of school-age children. Environmental health perspectives. Jul 2010;118(7):1027-32. doi:10.1289/ehp.0901376
    CrossRef
31. Kim Y, Ha EH, Kim EJ, et al. Prenatal exposure to phthalates and infant development at 6 months: prospective Mothers and Children’s Environmental Health (MOCEH) study. Environmental health perspectives. Oct 2011;119(10):1495-500. doi:10.1289/ehp.1003178
    CrossRef
32. Koch HM, Drexler H, Angerer J. Internal exposure of nursery-school children and their parents and teachers to di(2-ethylhexyl)phthalate (DEHP). International journal of hygiene and environmental health. Jan 2004;207(1):15-22. doi:10.1078/1438-4639-00270
    CrossRef
33. Teitelbaum SL, Britton JA, Calafat AM, et al. Temporal variability in urinary concentrations of phthalate metabolites, phytoestrogens and phenols among minority children in the United States. Environmental research. Feb 2008;106(2):257-69. doi:10.1016/j.envres.2007.09.010
    CrossRef
34. Parlett LE, Calafat AM, Swan SH. Women’s exposure to phthalates in relation to use of personal care products. Journal of exposure science & environmental epidemiology. Mar 2013;23(2):197-206. doi:10.1038/jes.2012.105
    CrossRef
35. Navaranjan G, Diamond ML, Harris SA, et al. Early life exposure to phthalates and the development of childhood asthma among Canadian children. Environmental research. Jun 2021;197:110981. doi:10.1016/j.envres.2021.110981
    CrossRef
36. Tsai M-J, Kuo P-L, Ko Y-C. The association between phthalate exposure and asthma. The Kaohsiung Journal of Medical Sciences. 2012/07/01/ 2012;28(7, Supplement):S28-S36. doi:https://doi.org/10.1016/ j.kjms.2012.05.007
    CrossRef
37. Odebeatu CC, Taylor T, Fleming LE, J Osborne N. Phthalates and asthma in children and adults: US NHANES 2007-2012. Environ Sci Pollut Res Int. 2019;26(27):28256-28269. doi:10.1007/s11356-019-06003-2
    CrossRef
38. Loureiro CC, Duarte IF, Gomes J, et al. Urinary metabolomic changes as a predictive biomarker of asthma exacerbation. Journal of allergy and clinical immunology. 2014;133(1):261-263. e5.
    CrossRef
39. Dutta S, Haggerty DK, Rappolee DA, Ruden DM. Phthalate Exposure and Long-Term Epigenomic Consequences: A Review. Frontiers in genetics. 2020;11:405. doi:10.3389/fgene.2020.00405
    CrossRef
40. Bølling AK, Sripada K, Becher R, Bekö G. Phthalate exposure and allergic diseases: Review of epidemiological and experimental evidence. Environment international. Jun 2020;139:105706. doi:10.1016/j.envint.2020.105706
    CrossRef
41. Kuo PL, Hsu YL, Huang MS, Tsai MJ, Ko YC. Ginger suppresses phthalate ester-induced airway remodeling. Journal of agricultural and food chemistry. Apr 13 2011;59(7):3429-38. doi:10.1021/jf1049485
    CrossRef
42. Jepsen KF, Abildtrup A, Larsen ST. Monophthalates promote IL-6 and IL-8 production in the human epithelial cell line A549. Toxicology in vitro : an international journal published in association with BIBRA. Jun 2004;18(3):265-9. doi:10.1016/j.tiv.2003.09.008
    CrossRef
43. Nishioka J, Iwahara C, Kawasaki M, et al. Di-(2-ethylhexyl) phthalate induces production of inflammatory molecules in human macrophages. Inflammation research : official journal of the European Histamine Research Society  [et al]. Jan 2012;61(1):69-78. doi:10.1007/s00011-011-0390-x
    CrossRef
44. Hsu YT, Wu CC, Wang CC, et al. Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters. Respiratory research. Mar 23 2024;25(1):139. doi:10.1186/s12931-024-02764-8
    CrossRef
45. Jackson-Browne MS, Patti MA, Henderson NB, Hauptman M, Phipatanakul W. Asthma and Environmental Exposures to Phenols, Polycyclic Aromatic Hydrocarbons, and Phthalates in Children. Current environmental health reports. Dec 2023;10(4):469-477. doi:10.1007/s40572-023-00417-4
    CrossRef
46. Duh TH, Yang CJ, Lee CH, Ko YC. A Study of the Relationship between Phthalate Exposure and the Occurrence of Adult Asthma in Taiwan. Molecules (Basel, Switzerland). Jul 5 2023;28(13)doi:10.3390/ molecules28135230
    CrossRef
47. Lin T-J, Huang C-C, Lee M-C, et al. Effects of Lactobacillus salivarius ssp. salicinius SA-03 Supplementation on Reversing Phthalate-Induced Asthma in Mice. Nutrients. 04/13 2024;16:1160. doi:10.3390/nu16081160
    CrossRef
48. He Z, Wu H, Zhang S, et al. The association between secondhand smoke and childhood asthma: A systematic review and meta-analysis. Pediatric pulmonology. Oct 2020;55(10):2518-2531. doi:10.1002/ppul.24961
    CrossRef
49. Gopal SH, Mukherjee S, Das SK. Direct and Second Hand Cigarette Smoke Exposure and Development of Childhood Asthma. Journal of environment and health sciences. 2016;2(6)doi:10.15436/2378-6841.16.1122
    CrossRef
50. Darvishmotevalli M, Bina B, Feizi A, Ebrahimpour K, Pourzamani H, Kelishadi R. Monitoring of urinary phthalate metabolites among pregnant women in Isfahan, Iran: the PERSIAN birth cohort. Journal of environmental health science & engineering. Dec 2019;17(2):969-978. doi:10.1007/s40201-019-00412-8
    CrossRef
51. Chang J-W, Chen H-C, Hu H-Z, Chang W-T, Huang P-C, Wang I-J. Phthalate Exposure and Oxidative/Nitrosative Stress in Childhood Asthma: A Nested Case-Control Study with Propensity Score Matching. Biomedicines. 2022;10(6):1438.
    CrossRef
52. Jøhnk C, Høst A, Husby S, et al. Maternal phthalate exposure and asthma, rhinitis and eczema in 552 children aged 5 years; a prospective cohort study. Environmental Health. 2020/03/13 2020;19(1):32. doi:10.1186/s12940-020-00586-x
    CrossRef
53. Ku HY, Su PH, Wen HJ, et al. Prenatal and postnatal exposure to phthalate esters and asthma: a 9-year follow-up study of a taiwanese birth cohort. PloS one. 2015;10(4):e0123309-e0123309. doi:10.1371/journal.pone.0123309
    CrossRef
54. Wolff MS, Teitelbaum SL, McGovern K, et al. Phthalate exposure and pubertal development in a longitudinal study of US girls. Hum Reprod. 2014;29(7):1558-1566. doi:10.1093/humrep/deu081
    CrossRef
55. Dales RE, Cakmak S, Leech J, Liu L. The association between personal care products and lung function. Annals of epidemiology. Feb 2013;23(2):49-53. doi:10.1016/j.annepidem.2012.11.006
    CrossRef
56. Parks J, McCandless L, Dharma C, et al. Association of use of cleaning products with respiratory health in a Canadian birth cohort. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. Feb 18 2020;192(7):E154-e161. doi:10.1503/cmaj.190819
    CrossRef
57. Saif NT, Janecki JM, Wanner A, Colin AA, Kumar N. Pediatric Asthma Attack and Home Paint Exposure. International journal of environmental research and public health. Apr 13 2021;18(8)doi:10.3390/ijerph18084118
    CrossRef
58. Canova C, Jarvis D, Walker S, Cullinan P. Systematic review of the effects of domestic paints on asthma related symptoms in people with or without asthma. The Journal of asthma : official journal of the Association for the Care of Asthma. 09/02 2013;50doi:10.3109/ 02770903.2013.834931
    CrossRef
59. Chang JW, Chen HC, Hu HZ, Chang WT, Huang PC, Wang IJ. Phthalate Exposure and Oxidative/Nitrosative Stress in Childhood Asthma: A Nested Case-Control Study with Propensity Score Matching. Biomedicines. Jun 17 2022;10(6)doi:10.3390/biomedicines10061438
    CrossRef
60. Vesper S, Prill R, Wymer L, Adkins L, Williams R, Fulk F. Mold contamination in schools with either high or low prevelance of asthma. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. Feb 2015;26(1):49-53. doi:10.1111/pai.12324
    CrossRef