Phthalic Acid Esters Exposure Research Articles

Toxic mechanism in Daphnia magna due to phthalic acid esters and CuO nanoparticles co-exposure: The insight of physiological, microbiomic and metabolomic profiles

Various phthalic acid esters (PAEs) such as dibutyl phthalate (DBP) and butyl benzyl phthalate (BBP) co-exist with nanopollutants in aquatic environment. In this study, Daphnia magna was exposed to nano-CuO and DBP or BBP at environmental relevant concentrations for 21-days to investigate these combined toxic effects. Acute EC50 values (48 h) of nano-CuO, DBP, and BBP were 12.572 mg/L, 8.978 mg/L, and 4.785 mg/L, respectively. Results showed that co-exposure with nano-CuO (500 μg/L) for 21 days significantly enhanced the toxicity of DBP (100 μg/L) and BBP (100 μg/L) to Daphnia magna by 18.37% and 18.11%, respectively. The activities of superoxide dismutase, catalase, and glutathione S-transferase were enhanced by 10.95% and 14.07%, 25.63% and 25.91%, and 39.93% and 35.01% in nano-CuO+DBP and nano-CuO+BBP treatments as compared to the individual exposure groups, verifying that antioxidative defense responses were activated. Furthermore, the co-exposure of nano-CuO and PAEs decreased the population richness and diversity microbiota, and changed the microbial community composition in Daphnia magna. Metabolomic analysis elucidated that nano-CuO + PAEs exposure induced stronger disturbance on metabolic network and molecular function, including amino acid, nucleotides, and lipid metabolism-related metabolic pathways, as comparison to PAEs single exposure treatments. In summary, the integration of physiological, microflora, and untargeted metabolomics analysis offers a fresh perspective into the potential ecological risk associated with nanopollutants and phthalate pollution in aquatic ecosystems.

Association of phthalate exposure with type 2 diabetes and the mediating effect of oxidative stress: A case-control and computational toxicology study

Phthalic acid esters (PAEs) are widely used as plasticizers and have been suggested to engender adverse effects on glucose metabolism. However, epidemiological data regarding the PAE mixture on type 2 diabetes (T2DM), as well as the mediating role of oxidative stress are scarce. This case-control study enrolled 206 T2DM cases and 206 matched controls in Guangdong Province, southern China. The concentrations of eleven phthalate metabolites (mPAEs) and the oxidative stress biomarker 8-hydroxy-2′-deoxyguanosine (8-OHdG) in urine were determined. Additionally, biomarkers of T2DM in paired serum were measured to assess glycemic status and levels of insulin resistance. Significantly positive associations were observed for mono-(2-ethylhexyl) phthalate (MEHP) and Mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with T2DM (P < 0.001). Restricted cubic spline modeling revealed a non-linear dose-response relationship between MEHHP and T2DM (Pnon-linear = 0.001). The Bayesian kernel machine regression and quantile g-computation analyses demonstrated a significant positive joint effect of PAE exposure on T2DM risk, with MEHHP being the most significant contributor. The mediation analysis revealed marginal evidence that oxidative stress mediated the association between the mPAEs mixture and T2DM, while 8-OHdG respectively mediated 26.88 % and 12.24 % of MEHP and MEHHP on T2DM risk individually (Pmediation < 0.05). Di(2-ethylhexyl) phthalate (DEHP, the parent compound for MEHP and MEHHP) was used to further examine the potential molecular mechanisms by in silico analysis. Oxidative stress may be crucial in the link between DEHP and T2DM, particularly in the reactive oxygen species metabolic process and glucose import/metabolism. Molecular simulation docking experiments further demonstrated the core role of Peroxisome Proliferator Activated Receptor alpha (PPARα) among the DEHP-induced T2DM. These findings suggest that PAE exposure can alter oxidative stress via PPARα, thereby increasing T2DM risk.

Risk assessment and environmental determinants of urinary phthalate metabolites in pregnant women in Southwest China.

Pregnant women are widely exposed to phthalic acid esters (PAEs) that are commonly used in most aspects of modern life. However, few studies have examined the cumulative exposure of pregnant women to a variety of PAEs derived from the living environmental conditions in China. Therefore, this study aimed to determine the urinary concentrations of nine PAE metabolites in pregnant women, examine the relationship between urinary concentrations and residential characteristics, and conduct a risk assessment analysis. We included 1,888 women who were in their third trimester of pregnancy, and we determined their urinary concentrations of nine PAE metabolites using high-performance gas chromatography-mass spectrometry. The risk assessment of exposure to PAEs was calculated based on the estimated daily intake. A linear regression model was used to analyze the relationship between creatinine-adjusted PAE metabolite concentrations and residential characteristics. The detection rate of five PAE metabolites in the study population was > 90%. Among the PAE metabolites adjusted by creatinine, the urinary metabolite concentration of monobutyl phthalate was found to be the highest. Residential factors, such as housing type, proximity to streets, recent decorations, lack of ventilation in the kitchen, less than equal to three rooms, and the use of coal/kerosene/wood/wheat straw fuels, were all significantly associated with high PAE metabolite concentrations. Due to PAE exposure, ~ 42% (n = 793) of the participants faced potential health risks, particularly attributed to dibutyl phthalate, diisobutyl phthalate, and di(2-ethyl)hexyl phthalate exposure. Living in buildings and using coal/kerosene/wood/wheat straw as domestic fuel can further increase the risks.

Dynamic variation and inhalation exposure of organophosphates esters and phthalic acid esters in face masks

The coronavirus pandemic (COVID-19) has posed a huge global health threat since December 2019. Wearing face masks is known as an effective measure for controlling the wide spread of COVID-19 and its variants. But on the other hand, face masks could be a potential source of organophosphate esters (OPEs) and phthalic acid esters (PAEs) as they are extensively added in masks. However, knowledge associated with the occurrence as well as inhalation risks of OPEs and PAEs in masks is limited. In this study, OPEs and PAEs were determined in different types of mask samples collected from the local market. OPEs and PAEs were detected in mask samples ranging from 36.7 to 855 ng/g, and from 251 to 3830 ng/g, respectively. Relatively lower OPEs and PAEs concentrations were observed in disposable mask for toddlers. Simulated inhalation experiment indicated that the mass loss of OPEs and PAEs was 136 and 3910 ng/mask in disposable masks, 71.9 and 763 ng/mask in disposable mask for toddlers, 924 and 1020 ng/mask in N95 mask after 12 h, respectively. Significantly negative correlations were exhibited between the decrement of OPEs in masks and the increment of OPEs in corresponding polyurethane foams (PUFs) during the course, elucidating OPEs released from masks could be well captured by PUFs. With regard to the variation over time, predominant OPE and PAE analogues showed semblable release and absorption tendency in mask and corresponding PUF. Inhalation exposure risk of OPEs and PAEs was estimated based on the increment of pollutants in PUF. The estimated daily intakes (EDIs), hazard index (HI) and carcinogenic risk (CR) were also calculated and they were within the threshold levels. This study provides the evidence of OPEs and PAEs releasing from the face masks during wearing and unveiled a potential source of OPEs and PAEs exposure to humans.

Dietary exposure and risk assessment of phthalic acid esters through a total diet study in Shenzhen, South China

Phthalic acid esters (PAEs) are typical endocrine disruptors which are ubiquitous contaminants. Human exposure to PAEs is through multiple routes of which the diet is recognised as the main source of daily intake. The aim of this study was to evaluate the dietary exposure to PAEs of residents in Shenzhen (China) through a total diet study and assess the potential health risk. A total of 16 different phthalate esters in samples of 12 composite food groups were determined by GC–MS. The main dietary sources of PAE exposure among adult residents in Shenzhen were potatoes (21%), eggs (21%), meat (15%) and aquatic products (14%). The median total dietary exposure to PAEs in Shenzhen residents was 7780 ng kg−1 bw d−1, and the hazard quotients (HQ) of dimethyl phthalate (DMP), diethyl phthalate (DEP), di-isobutyl phthalate (DIBP), dibutyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) were 0.09, 0.06, 0.07, 0.10 and 0.03, respectively. Therefore, the risks from dietary PAE exposure were low. However, with the increasing use of PAEs and their accumulation in the environment, the probability of PAEs entering the food chain is gradually increasing and, therefore, PAEs should be strictly controlled and regularly monitored.

Cardiorespiratory responses in healthy young adults with exposure to indoor airborne PAEs: A randomized, crossover trial of air purification.

Phthalic acid esters (PAEs) are widely used as plasticizers in industrial process and consumer products. Nowadays, PAEs are ubiquitous in the environment and are reported to be associated with cardiorespiratory diseases. However, studies about the association between indoor airborne PAEs exposure and cardiorespiratory health were limited, and the potential biological mechanism remains under-recognized. A randomized crossover trial was conducted on 57 healthy young adults in Beijing. Repeated health measurements were performed under real and sham indoor air purification with a washout interval of at least 2weeks. The concentration of indoor airborne PAEs were determined by gas chromatography-orbit ion trap mass spectrometry. Health indicators including blood pressure, lung function, airway inflammation, and circulating biomarkers reflecting blood coagulation and systematic oxidative stress were measured. Linear mixed-effect model was used to examine the between-treatment differences in health indicators, and three models including single-constituent, constituent-fine particulate matter (PM2.5) joint, and single-constituent residual model were used to estimate the association between indoor airborne PAEs and health indicators. The indoor airborne PAEs were reduced effectively under real air purification. The total indoor airborne di-2-ethylhexyl phthalate (DEHP), bis (4-Methyl-2-pentyl) phthalate (DMPP), diphenyl phthalate (DPP), and diethyl phthalate (DEP) were identified to be most significantly associated with the increase of blood pressure and airway inflammation, and decrease of lung function. A doubling increase in DEHP, DMPP, DPP, DEP was associated with the increase of 17.2% (95% CI: 3.9%, 32.2%), 11.7% (95% CI: 3.5%, 20.6%), 7.0% (95% CI: 2.4%, 11.8%), 6.0% (95% CI: 1.8%, 10.4%) in FeNO, respectively, in single-constituent residual model. Significant associations between specific total indoor airborne PAEs and increased levels of health biomarkers including oxidized low-density lipoprotein (ox-LDL), 8-isoprostane (8-isoPGF2α), and soluble P-selectin (sP-selectin) were observed. Indoor airborne PAEs may cause adverse cardiorespiratory health effects in young healthy adults, and indoor air purification could ameliorate the adverse cardiorespiratory effects.

Associations between phthalic acid esters in household dust and childhood asthma in Shanghai, China

Phthalic acid esters (PAEs) have a negative impact on human health and are widely distributed in China. As part of the China, Children, Home, Health (CCHH) study, we investigated the associations between childhood asthmatic symptoms and PAEs in settled house dust in Shanghai, China.We found that di-2-ethylhexyl phthalate (DEHP), dibutyl phthalate (DBP), and diisobutyl phthalate (DiBP) were abundant in the indoor environment. A total of 27 % of children suffered from diagnosed asthma. The Mann-Whitney U test and multiple logistic regression were used to obtain the associations between PAEs and childhood asthmatic symptoms. Stratification analysis was performed to reveal the influence of gender on the associations between PAE exposure and target symptoms. Compared with low concentrations of PAEs, high concentrations of high molecular weight PAEs (HMW-PAEs) were significantly associated with childhood diagnosed asthma (adjusted odds ratios (AORs) > 1, P < 0.05). Moreover, significantly negative associations were found between high concentrations of DiBP and current cough (AORs<1, P < 0.05). All significantly positive associations were observed among girls, and most of the associations of dimethyl phthalate (DMP) and diethyl phthalate (DEP) exposure with the studied symptoms among girls were higher than those among boys. Exposure to PAEs may be a risk factor for asthmatic symptoms in children, especially in girls.

Health risks of population exposure to phthalic acid esters through the use of plastic containers for takeaway food in China

Food delivery services have developed rapidly in China in recent years. Tens of thousands of food delivery services use hundreds of millions of plastic containers as packaging each year. This plastic packaging has the potential to cause health risks following population exposure to phthalic acid esters (PAEs) through the consumption of takeaway food in China. In this study, we used an online approach to distribute questionnaires nationwide to investigate the dietary characteristics of Chinese takeaway consumers. We collected a total of 952 valid questionnaires from 32 provinces. We also collected the main types of food packaging used in the market (n = 18). Based on the migration of PAEs to the food from the plastic packaging, we used the differentiated event frequency (EF) to calculate the chronic daily intake (CDI) of PAEs in different population. We then comprehensively evaluated the hazard quotient (HQ) and carcinogenic risk (CR) of PAE exposure in different regions and for different populations. The CDI values of different PAEs were low, at about 5.0 × 10−04–3.5 × 10−03 μg·kg−1·d−1. The amount of various PAEs released from white opaque plastic containers were relatively small, indicating that their use was relatively safe, although region, age, occupation and other factors had different degrees of impact on the CDI. The HQ was 0–0.15, and the CR was 0–1.4 × 10−08. The non-carcinogenic risks were < 1 and carcinogenic risks were < 1E-06 in all cases. Although no significant health risks were identified, we recommend that attention should still be given to the potential harm of PAEs. High food temperatures and high-fat food characteristics, as well as a higher frequency of consumption, will exacerbate the health risks. In addition, a small number of children and pregnant women also consumed food stored in the plastic food containers. The behavior of these sensitive groups should be controlled.

Typical phthalic acid esters induce apoptosis by regulating the PI3K/Akt/Bcl-2 signaling pathway in rat insulinoma cells

Di-(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) are representative phthalic acid esters (PAEs), a class of environmental endocrine disruptors used as plasticizers. PAEs exposure is associated with glucose metabolism, insulin resistance, and glucose tolerance; however, the mechanism and various PAE effects on human glucose metabolism remain largely unknown. In this study, we investigated the effects of DEHP, DBP, and their mixture on rat insulinoma (INS-1) cell apoptosis and the mechanism involved in vitro. The INS-1 cells were cultured in RPMI-1640 + 10% fetal bovine serum for 24 h and pretreated with dimethyl sulfoxide (vehicle, <0.1%), DEHP (30 μM), DBP (30 μM), and their mixture (30 μM DEHP + 30 μM DBP). The methyl-thiazolyl tetrazolium bromide test was used to measure cell viability. Hoechst 33342/propidium iodide (PI) staining and Annexin V-FITC/PI staining, 2′,7′-dichlorofluorescein diacetate assay, and glucose-induced insulin secretion assay were used to detect cell apoptosis rates, intracellular reactive oxygen species (ROS), and insulin secretion in INS-1, respectively. The mRNA expression levels of Bcl-2, Bax, Caspase 9, Caspase 8, Caspase 3, phosphoinositide 3-kinase (PI3K), and Akt were detected using real-time quantitative reverse transcription PCR; their protein expression levels were detected using western blotting. To the best of our knowledge, this study was the first to show that the combined effect of the two PAEs promotes a ROS-mediated PI3K/Akt/Bcl-2 pathway-induced pancreatic β cell apoptosis that is significantly higher than the effects of each PAE. Thus, safety standards and studies do not consider this effect as a significant oversight when blending PAEs. We assert that this must be addressed and corrected for establishing more impactful and safer standards.

Occurrence of phthalic acid esters in sediment samples from East China Sea

Phthalic acid esters (PAEs) are widely used as plasticizers in many industrial and household products. The widespread distribution of PAEs in marine environment has attracted great concerns, due to their adverse health effects on marine organisms. However, the data on the occurrence of PAEs in sediment from East China Sea is still scarce. In this study, 16 PAEs were analyzed in 67 sediment samples collected from the Hangzhou Bay, Taizhou Bay, and Wenzhou Bay. Eight PAEs were detected in collected sediment samples, and the total concentrations of detected PAEs (∑PAEs) were in the range of 654–2603 ng/g. The di(2-ethylhexyl) phthalate (DEHP) was the predominant PAE (mean 663 ng/g; accounted for mean 52% of ∑PAEs), followed by di-isobutyl phthalate (DiBP; 284 ng/g; 22%), di-n-butyl phthalate (DBP; 184 ng/g; 15%), and dimethyl phthalate (63 ng/g; 5.0%). The mean sediment concentration of ∑PAEs in the Hangzhou Bay (1623 ng/g) was higher than that in the Taizhou Bay (1282 ng/g) and Wenzhou Bay (1185 ng/g). Concentrations of diethyl phthalate, DiBP, and DBP were significantly and positively correlated with one another in sediment from Taizhou Bay and Wenzhou Bay. The estimated inventories of ∑PAEs in sediment from Hangzhou Bay, Taizhou Bay, and Wenzhou Bay were 82 tons, 28 tons, and 26 tons, respectively. Overall, this study provides the first data on the occurrence of PAEs in sediment from the East China Sea, which is necessary to conduct the PAE exposure risk assessment for the marine benthos.

Occurrence of phthalic acid esters in marine organisms from Hangzhou Bay, China: Implications for human exposure

Owing to the wide application of phthalic acid esters (PAEs) in the manufacturing of plastic products, they are ubiquitous in the marine environment. However, the occurrence of various PAEs in marine organisms from China has not been well characterized. In this study, 341 marine organism samples (including fish, shrimp, crab, and shellfish) were collected from Hangzhou Bay, China and analyzed for 16 PAEs. Further, the human PAE exposure risks raised from the consumption of marine organisms were evaluated for adults and children. In total, eight PAEs were detected in collected organism samples, with the concentration of total PAEs (∑PAEs) ranging from 64 to 2840 ng/g (mean 238 ng/g). Crab (mean 811 ng/g) samples had the highest mean concentration of ∑PAEs, followed by fish (465 ng/g), shrimp (293 ng/g), and shellfish (261 ng/g) samples. Among detected PAEs, di-isobutyl phthalate (DiBP), di-n-butyl phthalate (DBP), and di-ethylhexyl phthalate (DEHP) were the predominant PAEs, and they collectively accounted for 84–97% of the ∑PAEs concentrations in all samples. The estimated daily intakes of DiBP, DBP, and DEHP were more than one order of magnitude higher than remaining PAEs. Calculated hazard quotient values of PAEs were all <0.1, suggesting non-cancer risks for the general population through the consumption of marine organisms. Overall, for the first time, this study systematically examined the occurrence of multiple PAEs in four types of marine organisms from Hangzhou Bay, China.

Human exposure levels of PAEs in an e-waste recycling area: Get insight into impacts of spatial variation and manipulation mode

Phthalic acid esters (PAEs) are one important category of additives in plastics, which are ubiquitous products of e-waste recycling areas, where PAEs are released to the environment intensively and higher exposure level is expected for the employees. This study investigated human exposure levels of PAEs in an e-waste recycling area (Ziya Circular Economy Park (ZCEP) in Tianjin, China) with intending to explore the impacts of residence spatial variation and dismantling manipulation mode. We collected 157 urine samples from three sites around ZCEP with different distances from the core dismantling site and urinary phthalate metabolites (mPAEs) concentrations were measured and were compared among these three sites. The exposure levels of PAEs exhibited spatial variation according to the distance from the core dismantling site, and urinary median ∑mPAEs concentrations (389 ng/mL) of the employees in ZCEP were significantly higher than those of residents in Ziya town (285 ng/mL) and the downtown of Jinghai district (207 ng/mL) (p < 0.05). Moreover, PAEs exposure levels were significantly affected by the manipulation modes in the e-waste recycling area and the urinary median ∑mPAEs concentrations in the employees of family workshops (401 ng/mL) were significantly higher than those in plants with centralized management (298 ng/mL). There were obvious differences on the urinary median mPAEs concentrations between subgroups based on age, BMI, and sex; however, no significant statistical associations were found between PAEs exposure levels and these socio-demographic indices (p > 0.05). Besides, there was no correlation between exposure levels of different PAEs and their physicochemical parameters like the logKow (p > 0.05).

GC–MS determination of phthalate esters in human urine: A potential biomarker for phthalate bio-monitoring

Six phthalic acid esters (PAEs) in human urine sampled randomly from three districts (Erode, Thanjavur, and Perambalur) in Tamil Nadu State and a Union Territory (Pondicherry) in India were quantified. We determined gender-wise, age-wise and location-wise distribution of PAEs and measured estrogenic activity of urine by molecular docking. Bis(2‑ethylhexyl) phthalate (DEHP) was the predominant phthalic acid ester found and had a recovery of 104.5% (ultrasonic extraction at 15 min). Gender-wise (pregnant women: 185 ng/mL, children: 156 ng/mL, female: 151 ng/mL, and male: 138 ng/mL), age-wise (1–20 y: 157 ng/mL, 21–40 y: 156 ng/mL, and >40 y: 146 ng/mL), location-wise (urban: 154 ng/mL, and rural: 151 ng/mL), and region-wise (Erode district: 185 ng/mL, Thanjavur district: 155 ng/mL, Perambalur district: 117 ng/mL, and Pondicherry: 135 ng/mL) differences with total mean of Σ6 PAEs were found. The molecular docking study showed a high negative binding energy of PAEs with microbial receptors. Based on the results we conclude that urine could be used as an ideal biomarker to understand PAEs exposure in humans.

The effects of phthalate and nonylphenol exposure on body size and secondary sexual characteristics during puberty

Some phthalic acid esters (PAEs) and nonylphenol (NP) are endocrine-disrupting chemicals (EDCs) that are widely used in consumer products. Consequently, the general population is exposed simultaneously to both groups of chemicals. To investigate the single- and co-exposure effects of PAEs (DMP, DEP, DnBP, DiBP, BBzP, and DEHP) and NP on obesity and pubertal maturity to compare the body sizes of general adolescents with the complainants of the phthalate-tainted foods scandal that occurred in Taiwan. This study included 270 general adolescents aged 6.5-15.0 years and 38 complainants aged 6.5-8.5 years. Nine metabolites of the five PAEs and of NP were measured in urine. We used a questionnaire to evaluate pubertal maturity, measured anthropometric indices (APs) to assess body size, and collected urine samples to measure the two groups of chemicals. We found that urinary PAE metabolite concentrations (specifically, metabolites of DEP, DnBP, DiBP, and DEHP) were positively associated with the APs for abdominal obesity (including skinfold thickness, waist circumference, waist-to-height ratio, and waist-to-hip) and indicated a dose-response relationship. Mono-methyl phthalate (MMP) exposure was inversely associated with pubarche among boys. The daily intake of DEHP in general adolescents exceeded the reference doses (RfD-20 μg/kgbw/day) and tolerable daily intake (TDI-50 μg/kgbw/day) by 3.4% and 0.4%, respectively. No associations were observed between NP exposure or co-exposure and the APs or pubertal maturity. No significant differences were observed between general adolescents and the complainants with regard to weight, height, or BMI. The study suggests that PAE (specifically, DEP, DnBP, DiBP, and DEHP) exposure is associated with abdominal obesity in adolescents and that the APs for abdominal obesity are more sensitive than BMI for measuring obesity among adolescents. We suggest that the RfD and TDI for PAEs should be revised to provide sufficient protection.

Potential adverse effects of phthalic acid esters on human health: A review of recent studies on reproduction

Various phthalic acid esters (PAEs) have been used for a wide range of products. PAEs and their metabolites produce reproductive and developmental toxicities in laboratory animals. These findings have raised concern about the possibility of PAEs as contributors to reproductive and developmental adverse effects in humans. This paper focuses on PAE exposure and health effects in human populations and summarizes recent studies. The exposure data in human populations indicate that the current methodology of estimation of PAE exposure is inconsistent. It is therefore important to obtain improved data on human PAE exposure and better understanding of the toxicokinetics of PAEs in each subpopulation. Studies on health effects of PAEs in humans have remained controversial due to limitations of the study designs. Some of findings in human populations are consistent with animal data suggesting that PAEs and their metabolites produce toxic effects in the reproductive system. However, it is not yet possible to conclude whether phthalate exposure is harmful for human reproduction. Studies in human populations reviewed in this paper are useful for showing the strength of the association. It is sometimes claimed that the use of animal data for estimating human risk does not provide strong scientific support. However, because it is difficult to find alternative methods to examine the direct toxic effects of chemicals, animal studies remain necessary for risk assessment of chemicals including PAEs.