Di(2-ethylhexyl) Terephthalate Research Articles

Association of Di(2-ethylhexyl) Terephthalate and Its Metabolites with Nonalcoholic Fatty Liver Disease: An Epidemiology and Toxicology Study.

As an alternative plasticizer to conventional phthalates, di(2-ethylhexyl) terephthalate (DEHTP) has attracted considerable concerns, given its widespread detection in the environment and humans. However, the potential toxicity, especially liver toxicity, posed by DEHTP remains unclear. In this study, based on the 2017-2018 National Health and Nutrition Examination Survey, two metabolites of DEHTP, i.e., mono(2-ethyl-5-hydroxyhexyl) terephthalate (MEHHTP) and mono(2-ethyl-5-carboxypentyl) terephthalate (MECPTP), were found to be present in the urine samples of nearly all representative U.S. adults. Moreover, a positive linear correlation was observed between the concentrations of the two metabolites and the risk of nonalcoholic fatty liver disease (NAFLD) in the population. Results of weighted quantile sum and Bayesian kernel machine regression indicated that MEHHTP contributed a greater weight to the risk of NAFLD in comparison with 12 conventional phthalate metabolites. In vitro experiments with hepatocyte HepG2 revealed that MEHHTP exposure could increase lipogenic gene programs, thereby promoting a dose-dependent hepatic lipid accumulation. Activation of liver X receptor α may be an important regulator of MEHHTP-induced hepatic lipid disorders. These findings provide new insights into the liver lipid metabolism toxicity potential of DEHTP exposure in the population.

Thyroid and sex hormone disrupting effects of DEHTP at different life stages of zebrafish (Danio rerio)

Di(2-ethylhexyl) terephthalate (DEHTP) is an alternative plasticizer widely used in numerous consumer products, replacing di(2-ethylhexyl) phthalate (DEHP). Hence, DEHTP has been frequently detected in the environment and humans. As a structural isomer and functional analog of DEHP, DEHTP is a suspected endocrine disruptor. Here, we evaluated thyroid-disrupting effects of DEHTP using embryo-larval and adult male zebrafish. We also investigated its sex hormone disruption potential in the adult zebrafish. After 5- and 7-days of exposure to DEHTP, significant increases in whole-body thyroid hormonal levels were observed in the larval fish. Down-regulation of several thyroid-regulating genes, including trh, tshβ, nis, and dio2, was observed, but only after 5-day exposure. Following a 21-day exposure, the adult male zebrafish exhibited a significant decrease in total triiodothyronine and an increase in thyroid-stimulating hormones. Potential changes in the deiodination of thyroid hormones, supported by the up-regulation of two deiodinases, dio1 and dio3a, along with the down-regulation of dio2, could explain the thyroid hormone changes in the adult zebrafish. Moreover, significant trends of decrease in estradiol and 11-ketotestosterone, along with increase of testosterone (T), were observed in the adult zebrafish. Up-regulation of several steroidogenic genes may explain elevated T, while exact mechanisms of action warrant further investigation. Our results demonstrate that DEHTP can cause disruptions of thyroid and sex hormones at different life stages in zebrafish.

Personal environmental exposure to plasticizers and organophosphate flame retardants using silicone wristbands and urine: Patterns, comparisons, and correlations

Plasticizers (PLs) and organophosphate flame retardants (OPFRs) are ubiquitous in the environment due to their widespread use and potential for leaching from consumer products. Environmental exposure is a critical aspect of the human exposome, revealing complex interactions between environmental contaminants and potential health effects. Silicone wristbands (SWBs) have emerged as a novel and non-invasive sampling device for assessing personal external exposure. In this study, SWBs were used as a proxy to estimate personal dermal adsorption (EDdermal) to PLs and OPFRs in Belgian participants for one week; four morning urine samples were also collected and analyzed for estimated daily intake (EDI). The results of the SWBs samples showed that all the participants were exposed to these chemicals, and the exposure was found to be highest for the legacy and alternative plasticizers (LP and AP), followed by the legacy and emerging OPFRs (LOPFR and EOPFR). In urine samples, the highest levels were observed for metabolites of diethyl phthalate (DEP), di-isobutyl phthalate (DiBP) and di-n-butyl phthalate (DnBP) among LPs and di(2-ethylhexyl) terephthalate (DEHT) for APs. Outliers among the participants indicated that there were other sources of exposure that were not identified. Results showed a significant correlation between EDdermal and EDI for DiBP, tris (2-butoxyethyl) phosphate (TBOEP) and triphenyl phosphate (TPhP). These correlations indicated their suitability for predicting exposure via SWB monitoring for total chemical exposure. The results of this pilot study advance our understanding of SWB sampling and its relevance for predicting aggregate environmental chemical exposures, while highlighting the potential of SWBs as low-cost, non-invasive personal samplers for future research. This innovative approach has the potential to advance the assessment of environmental exposures and their impact on public health.

Ongoing exposure to endocrine disrupting phthalates and alternative plasticizers in neonatal intensive care unit patients

Due to endocrine disrupting effects, di-(2-ethylhexyl) phthalate (DEHP), a plasticizer used to soften plastic medical devices, was restricted in the EU Medical Devices Regulation (EU MDR 2017/745) and gradually replaced by alternative plasticizers. Neonates hospitalized in the neonatal intensive care unit (NICU) are vulnerable to toxic effects of plasticizers. From June 2020 to August 2022, urine samples (n = 1070) were repeatedly collected from premature neonates (n = 132, 4–10 samples per patient) born at <31 weeks gestational age and/or <1500 g birth weight in the Antwerp University Hospital, Belgium. Term control neonates (n = 21, 1 sample per patient) were included from the maternity ward. Phthalate and alternative plasticizers’ metabolites were analyzed using liquid-chromatography coupled to tandem mass spectrometry. Phthalate metabolites were detected in almost all urine samples. Metabolites of alternative plasticizers, di-(2-ethylhexyl)-adipate (DEHA), di-(2-ethylhexyl)-terephthalate (DEHT) and cyclohexane-1,2-dicarboxylic-di-isononyl-ester (DINCH), had detection frequencies ranging 30–95 %. Urinary phthalate metabolite concentrations were significantly higher in premature compared to control neonates (p = 0.023). NICU exposure to respiratory support devices and blood products showed increased phthalate metabolite concentrations (p < 0.001). Phthalate exposure increased from birth until four weeks postnatally. The estimated phthalate intake exceeded animal-derived no-effect-levels (DNEL) in 10 % of samples, with maximum values reaching 24 times the DNEL. 29 % of premature neonates had at least once an estimated phthalate intake above the DNEL. Preterm neonates are still exposed to phthalates during NICU stay, despite the EU Medical Devices Regulation. NICU exposure to alternative plasticizers is increasing, though currently not regulated, with insufficient knowledge on their hazard profile.

Bioaccumulation and biotransformation of plasticisers diisononyl phthalate and di(2-ethylhexyl) terephthalate in black soldier fly larvae reared on (micro)plastic-contaminated food waste

Food waste is currently used for the production of biogas. However, a reusage of waste is preferred to follow the principles of the circular economy and consider the waste management hierarchy, which can be achieved by rearing black soldier fly (BSF) larvae on such organic waste. Nonetheless, the presence of (micro)plastics and related additive plasticisers might induce chemical safety hazards to the larval applications as feed. Therefore, the bioaccumulation and biotransformation of two plasticisers (diisononyl phthalate (DINP) and di(2-ethylhexyl) terephthalate (DEHT)) in BSF larvae reared on food waste streams contaminated with polyvinyl chloride (PVC) (micro)plastics were investigated. Results showed that BSF larvae appeared to have a moderate intake of DINP during its rearing phase of 10 days (82 - 273 ng/g), while being able to biotransform it into the primary biotransformation product monoisononyl phthalate (MINP) within 24 h. For DEHT, an uptake of 67 - 137 ng/g was measured in the BSF larvae; however, no clear biotransformation pattern was observed. In addition, while no secondary oxidative biotransformation products were found in the larvae, these were measured in the frass, leading to the hypothesis that microorganism-mediated biotransformation of plasticisers occurred. In conclusion, based on the results of this study, BSF larvae could potentially be used safely in the frame of circular economy, when reared on organic substrates contaminated with the same PVC microplastic content and sizes used.

Evaluating the risk of phthalate and non-phthalate plasticizers in dust samples from 100 Japanese houses

Phthalates are widely used as plasticizer and associated with various health issues. Recently, non-phthalate plasticizers are replacing phthalates; however, the exposure to these substances and the risk in Japan is unclear. In this study, we assessed the concentrations of phthalates, non-phthalate plasticizers, and phthalate degradation products in house dust and determined their respective exposure risks via oral and dermal routes. Twelve phthalates, seven non-phthalate plasticizers, and two degradation products were determined in the house dust obtained from 100 Japanese homes. The median concentration of di(2-ethylhexyl) phthalate (DEHP), accounting for 85 % of the total concentration of phthalates and non-phthalate plasticizers detected in this study, was 2.1 × 103 μg/g of dust. Apart from DEHP, diisononyl phthalate (DINP) and di(2-ethylhexyl) terephthalate (DEHT) were the most abundant in the house dust, accounting for 6.2 % (median: 1.7 × 102 μg/g of dust) and 6.1 % (median: 1.7 × 102 μg/g of dust) of the total concentrations, respectively. DEHP and DEHT concentrations in house dust were higher in apartment and small houses (floor area: ≤30 m2 or 31–60 m2 for DEHP and 31–60 m2 for DEHT) than in detached and large houses (floor area: ≥121 m2). Conversely, di-n-butyl phthalate (DnBP) concentrations were significantly higher in detached and large houses (floor area: ≥121 m2) than in apartment and small houses (floor area: ≤30 m2). The total hazard quotient (HQ), using the maximum concentration in house dust, revealed that oral and dermal exposure to house dust was 1.3 × 10-6–0.11 for adults (all substances) and 1.6 × 10-5–2.2 × 10-2 for preschool children (except for DnBP and DEHP), suggesting no risk. The HQs for DnBP and DEHP exposure via house dust for preschool children using the maximum values were 0.46 and 1.2, and 6.0 × 10-3 and 0.18 using the median values, indicating that risk of DEHP exposure should be exhaustively determined by considering other exposure routes that were not evaluated in this study, such as diet.

Plasticizers Used in Polyvinyl Chloride Toys (2019-2020)

We determined the fifteen types of plasticizers, including four kinds of phthalic acid esters (PAEs) used in 220 polyvinyl chloride (PVC) toys on Japanese market from 2019 to 2020. Three kinds of previously undetected types of PAEs were also detected, but not identified in this study. Di (2-ethylhexyl) terephthalate (DEHTP) was the highest detection rate in 209 soft PVC toys out of 220 toys, with 71.2% for designated toys and 88.9% for not-designated toys, respectively, showing a gradual increase from the previous reports in 2009 and 2014. On the other hand, the usages of o-acetyl tributyl citrate and adipic acid esters decreased, but the six types of PAEs prohibited to use for the designated toys in Japan were not detected in them, the usage of diisobutyl phthalate were increased. In contrast, four types of PAEs were detected in not-designated toys. Among them, the detection ratio of di (2-ethyhexyl) phthalate decreased to about 1/10. The content levels of plasticizers in per each sample were continued to keep low level from the report five years ago. These results showed that the main plasticizer used in PVC toys is DEHTP, and that the usage of other plasticizers was decreased.

Exposure Trends to the Non-phthalate Plasticizers DEHTP, DINCH, and DEHA in Children from 2012 to 2017: The Hokkaido Study.

Phthalates owing to their endocrine-disrupting effects are regulated in certain products, leading to their replacement with substitutions such as di-2-ethylhexyl terephthalate (DEHTP), 1,2-cyclohexane dicarboxylic acid di(isononyl) ester (DINCH), and di(2-ethylhexyl) adipate (DEHA). However, information on human exposure to these substitutes, especially in susceptible subpopulations such as children, is limited. Thus, we examined the levels and exposure trends of DEHTP, DINCH, and DEHA metabolites in 7 year-old Japanese school children. In total, 180 urine samples collected from 2012 to 2017 were used to quantify 10 DEHTP, DINCH, and DEHA metabolites via isotope dilution liquid chromatography with tandem mass spectrometry. DEHTP and DINCH metabolites were detected in 95.6 and 92.2% of the children, respectively, and DEHA was not detected. This study, annually conducted between 2012 and 2017, revealed a significant (p < 0.05) 5-fold increase in DEHTP metabolites and a 2-fold increase in DINCH metabolites. However, the maximum estimated internal exposures were still below the health-based guidance and toxicological reference values. Exposure levels to DEHTP and DINCH have increased considerably in Japanese school children. DEHA is less relevant. Future studies are warranted to closely monitor the increasing trend in different aged and larger populations and identify the potential health effects and sources contributing to increasing exposure and intervene if necessary.

Molecular Mechanism of Plasticizer Exudation from Polyvinyl Chloride

Plasticizers improve polymer material flexibility and durability by lowering glass transition and cold flex temperatures. While many different classes of plasticizers have been synthesized and used in various applications, several classes have been phased out due to concerns over their safety. One of the main problems that hinder the development of a new generation of efficient and safe plasticizers is the plasticizers’ migration and exudation from polymer materials, which leads to a reduction of mechanical properties and premature degradation. Here, we employed multiscale molecular dynamics, validated by experiment, to investigate the molecular mechanism of exudation of an orthophthalate plasticizer (di-2-ethylhexyl phthalate (DEHP)), non-orthophthalate plasticizers (di-n-butyl terephthalate (DnBT) and di-2-ethylhexyl terephthalate (DEHT)), and their blends from polyvinyl chloride (PVC). The results suggest that DnBT acted as an intermediary between PVC and DEHT, improving the compatibility of the plasticizer blend and reducing the degree of exudation. Specifically, it was predicted that the 70:30 wt % DnBT–DEHT blend was on par with the DEHP control system. These results also suggest that plasticizer-PVC compatibility is a stronger determinant of plasticizer exudation than the plasticizer size, diffusivity, and viscosity, given that DnBT is a smaller, more mobile, faster-diffusing, and lower-viscosity plasticizer than DEHT. Overall, our results indicate that the most important parameters that control exudation were Hansen solubility and consequently Flory–Huggins interaction parameters.

Assessment of the effects of non-phthalate plasticizer DEHT on the bivalve molluscs Mytilus galloprovincialis

Due to their uncontrolled use, plastics has become an environmental concern, not only for their varying dimension but also for the potential release of substances such as phthalates (PAEs) and non-phthalates (NPPs) into the water. Phthalates are the most common plasticizers of concern, but non-phthalate plasticizers such as di (2-ethylhexyl) terephthalate (DEHT) have also been lately found in the marine environment. Mytilus galloprovincialis is a well-known bioindicator of aquatic environments due to its ability to accumulate a wide variety of xenobiotics, including plasticizers. Hence, aim of this study was to evaluate the potential bioaccumulation and effects of the NPP DEHT on M. galloprovincialis. To this purpose, following exposure to DEHT at 1 mg/l (DEHT1) and 100 mg/l (DEHT100), its accumulation in tissues and its effects on total lipids and fatty acid (FA) composition, protein content, cell viability, ability to recover volume and changes in biomarkers of oxidative stress were assessed. Mussels were able to bioaccumulate DEHT in their tissues, with a statistically significant increase compared to the control organisms. Differences in FA composition were observed after exposure, since C16:0, C18:0, C20:5ω-3 and C22:6ω-3 were significantly decreased from control to exposed groups. As a result, total SFA, MUFA and PUFA were affected in DEHT-exposed groups. Also, total protein varied following DEHT exposure, and significantly decreased in the DEHT100-group. Considering the physiological responses, both DEHT-exposed groups lost their ability to return to the original volume of digestive gland (DG) cells. On the other hand, oxidative biomarkers in the gills and DG were not significantly affected by the DEHT exposure. Overall, this study showed for the first time that DEHT exposure differentially affect mussels, in their lipid and protein metabolism, as well as cellular parameters.

Migration of di(2-ethylhexyl) phthalate, diisononylcyclohexane-1,2-dicarboxylate and di(2-ethylhexyl) terephthalate from transfusion medical devices in labile blood products: A comparative study.

Polyvinyl chloride (PVC) plasticized with di(2-ethylhexyl) phthalate (DEHP) is a widely used material for medical transfusion devices. Not covalently bound to PVC, DEHP can migrate into blood products during storage. Recognized as an endocrine disruptor and raising concerns about its potential carcinogenicity and reprotoxicity, DEHP is gradually being withdrawn from the medical device market. Therefore, the use of alternative plasticizers, such as diisononylcyclohexane-1,2-dicarboxylate (DINCH) and di(2-ethylhexyl) terephthalate (DEHT), as potential candidates for the replacement of DEHP in medical transfusion devices has been investigated. The purpose of this study was to evaluate the quantity of PVC-plasticizers in the blood components according to their preparation, storage conditions and in function of the plasticizer. Whole blood was collected, and labile blood products (LBPs) were prepared by the buffy-coat method with a PVC blood bag plasticized either with DEHP, DINCH or DEHT. DINCH and DEHT equivalent concentrations were quantified in LBPs by liquid chromatography-tandem mass spectrometry or coupled with UV and compared to DEHP equivalent concentrations. The plasticizer equivalent concentration to which a patient is exposed during a transfusion depends on the preparation of LBPs as well as their storage conditions, that is, temperature and storage time. At day 1, for all LBPs, the migration of DEHP is 5.0 and 8.5 times greater than DINCH and DEHT, respectively. At the end of the 49 days storage period, the DEHP equivalent concentration in red blood cells concentrate is statistically higher when compared to DINCH and DEHT, with maximal values of 1.85, 1.13 and 0.86 μg/dm2 /mL, respectively. In addition to lower toxicity, transfused patients using PVC-DEHT or PVC-DINCH blood bags are less exposed to plasticizers than using PVC-DEHP bags with a ranging exposure reduction from 38.9% to 87.3%, due to lower leachability into blood components.

Effects of di-(2-ethylhexyl) terephthalate on hypothalamus-pituitary-gonad axis in adult zebrafish

Di-(2-ethylhexyl) terephthalate (DEHTP) is frequently used in food packaging and medical devices as an alternative to di-(2-ethylhexyl) phthalate (DEHP). In this study, zebrafish pairs were exposed to DEHTP for 21 d and the effects on fertility, sex hormone levels, vitellogenin levels, and transcription of genes along the hypothalamic-pituitary-gonad axis were evaluated. Results showed that mean egg numbers were significantly reduced in the 30 and 300 μg/L DEHTP groups. The adverse effects of DEHTP on hormones and gene transcripts were more prominent in males than in females. In male fish, the gonadosomatic index, hepatosomatic index, and vitellogenin concentration were significantly increased. The results of a significant decrease in testosterone (T) and an increase in the 17β-estradiol (E2)/T ratio in males exposed to 3–300 μg/L DEHTP suggest that the endocrine potential of DEHTP is similar that of DEHP. In females, genes related to gonadotropin-releasing hormone and gonadotropin were up-regulated while E2 was significantly down-regulated. These findings suggest that positive E2 feedback mechanisms in the hypothalamus and pituitary gland are activated to balance sex hormones. The effects of chronic exposure to DEHTP on the neuroendocrine system require further investigation.

Cumulative Exposure to Phthalates and Their Alternatives and Associated Female Reproductive Health: Body Burdens, Adverse Outcomes, and Underlying Mechanisms.

The global birth rate has recently shown a decreasing trend, and exposure to environmental pollutants has been identified as a potential factor affecting female reproductive health. Phthalates have been widely used as plasticizers in plastic containers, children's toys, and medical devices, and their ubiquitous presence and endocrine-disrupting potential have already raised particular concerns. Phthalate exposure has been linked to various adverse health outcomes, including reproductive diseases. Given that many phthalates are gradually being banned, a growing number of phthalate alternatives are becoming popular, such as di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH), di(2-ethylhexyl) adipate (DEHA), and di(2-ethylhexyl) terephthalate (DEHTP), and they are beginning to have a wide range of environmental effects. Studies have shown that many phthalate alternatives may disrupt female reproductive function by altering the estrous cycle, causing ovarian follicular atresia, and prolonging the gestational cycle, which raises growing concerns about their potential health risks. Herein, we summarize the effects of phthalates and their common alternatives in different female models, the exposure levels that influence the reproductive system, and the effects on female reproductive impairment, adverse pregnancy outcomes, and offspring development. Additionally, we scrutinize the effects of phthalates and their alternatives on hormone signaling, oxidative stress, and intracellular signaling to explore the underlying mechanisms of action on female reproductive health, because these chemicals may affect reproductive tissues directly or indirectly through endocrine disruption. Given the declining global trends of female reproductive capacity and the potential ability of phthalates and their alternatives to negatively impact female reproductive health, a more comprehensive study is needed to understand their effects on the human body and their underlying mechanisms. These findings may have an important role in improving female reproductive health and in turn decreasing the number of complications during pregnancy.

No effects of plasticized microplastics on the body condition and reproduction of a marine fish

Abstract This study experimentally explored the influence of periodic consumption of polystyrene (PS) microplastic fragments on the body condition and fitness of a tropical marine fish. Adult damselfish, Acanthochromis polyacanthus, were pulse fed microplastic fragments bound with one of two different common plasticizers [di-2-ethylhexyl phthalate (DEHP), di-2-ethylhexyl terephthalate (DEHT)] together with virgin-plastic and no-plastic controls. Ingestion of plastic over a 150d period had no detectable effect on growth, indices of body condition, or gonadosomatic indices. Histology of the liver showed no detrimental effects of ingesting any of the plastic treatments on hepatocyte density or vacuolation. Plastic consumption had no effect on the number of clutches produced over the breeding period, the number of eggs, or the survival of embryos. It is believed that the relatively inert nature of PS, the low amount of plasticizers leached from the fragments and fast gut through-put times meant fish were exposed to low levels of toxic compounds.

Associations of urinary metabolite concentrations of phthalates and phthalate replacements with body composition from mid-childhood to early adolescence

BackgroundPhthalates may adversely influence body composition by lowering anabolic hormones and activating peroxisome-proliferator activated receptor gamma. However, data are limited in adolescence when body mass distributions rapidly change and bone accrual peaks. Also, potential health effects of certain phthalate/replacements [e.g., di-2-ethylhexyl terephthalate (DEHTP)] have not been well studied. MethodsAmong 579 children in the Project Viva cohort, we used linear regression to evaluate associations of urinary concentrations of 19 phthalate/replacement metabolites from mid-childhood (median: 7.6 years; 2007–2010) with annualized change in areal bone mineral density (aBMD) and lean, total fat, and truncal fat mass as measured by dual-energy X-ray absorptiometry between mid-childhood and early adolescence (median: 12.8 years). We used quantile g-computation to assess associations of the overall chemical mixture with body composition. We adjusted for sociodemographics and tested for sex-specific associations. ResultsUrinary concentrations were highest for mono-2-ethyl-5-carboxypentyl phthalate [median (IQR): 46.7 (69.1) ng/mL]. We detected metabolites of most replacement phthalates in a relatively small number of participants [e.g., 28% for mono-2-ethyl-5-hydrohexyl terephthalate (MEHHTP; metabolite of DEHTP)]. Detectable (vs. non-detectable) MEHHTP was associated with less bone and greater fat accrual in males and greater bone and lean mass accrual in females [e.g., change in aBMD Z-score/year (95% CI): −0.049 (−0.085, −0.013) in males versus 0.042 (0.007, 0.076) in females; pinteraction<0.01]. Children with higher concentrations of mono-oxo-isononyl phthalate and mono-3-carboxypropyl phthalate (MCPP) had greater bone accrual. Males with higher concentrations of MCPP and mono-carboxynonyl phthalate had greater accrual of lean mass. Other phthalate/replacement biomarkers, and their mixtures, were not associated with longitudinal changes in body composition. ConclusionsConcentrations of select phthalate/replacement metabolites in mid-childhood were associated with changes in body composition through early adolescence. As use of phthalate replacements such as DEHTP may be increasing, further investigation can help better understand the potential effects of early-life exposures.

Development, testing, parameterisation, and calibration of a human PBPK model for the plasticiser, di-(2-ethylhexyl) terephthalate (DEHTP) using in silico, in vitro and human biomonitoring data.

A physiologically based pharmacokinetic model for di-(2-ethylhexyl) terephthalate (DEHTP) based on a refined model for di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the metabolism and biokinetics of DEHTP following a single oral dose of 50mg to three male volunteers. In vitro and in silico methods were used to generate parameters for the model. For example, measured intrinsic hepatic clearance scaled from in vitro to in vivo and plasma unbound fraction and tissue:blood partition coefficients (PCs) were predicted algorithmically. Whereas the development and calibration of the DPHP model was based upon two data streams, blood concentrations of parent chemical and first metabolite and the urinary excretion of metabolites, the model for DEHTP was calibrated against a single data stream, the urinary excretion of metabolites. Despite the model form and structure being identical significant quantitative differences in lymphatic uptake between the models were observed. In contrast to DPHP the fraction of ingested DEHTP entering lymphatic circulation was much greater and of a similar magnitude to that entering the liver with evidence for the dual uptake mechanisms discernible in the urinary excretion data. Further, the absolute amounts absorbed by the study participants, were much higher for DEHTP relative to DPHP. The in silico algorithm for predicting protein binding performed poorly with an error of more than two orders of magnitude. The extent of plasma protein binding has important implications for the persistence of parent chemical in venous blood-inferences on the behaviour of this class of highly lipophilic chemicals, based on calculations of chemical properties, should be made with extreme caution. Attempting read across for this class of highly lipophilic chemicals should be undertaken with caution since basic adjustments to PCs and metabolism parameters would be insufficient, even when the structure of the model itself is appropriate. Therefore, validation of a model parameterized entirely with in vitro and in silico derived parameters would need to be calibrated against several human biomonitoring data streams to constitute a data rich source chemical to afford confidence for future evaluations of other similar chemicals using the read-across approach.

Occurrence and seasonal variation of plasticizers in sediments and biota from the coast of Mahdia, Tunisia.

Plasticizers are compounds often involved in the manufacturing of plastic products. Nevertheless, the ageing of the latter generates plasticizers that generally end up in the marine environment. In fact, marine pollution by phthalate acid esters (PAEs) and their alternatives has become an environmental and health issue of serious concern, as they are largely and ubiquitously present in the environment and aquatic organisms. In the present study, four PAEs, such as diethyl phthalate (DEP), diisobutyl phthalate (DiBP), dibutyl phthalate (DBP), and di(2-ethylhexyl) phthalate (DEHP), and one non-phthalate plasticizer (NPP), namely di-2-ethylhexyl terephthalate (DEHT), are wanted in different marine compartments from the coast of Mahdia in Tunisia such as sediment, seagrass, and mussel. The most abundant and frequently detected congener was DEHT at the concentrations reached 1.181mg/kg in the sediment, 1.121mg/kg in the seagrass, and 1.86mg/kg in the mussel. This result indicates that the DEHT could emerge through the food chain and therefore bioaccumulate in marine compartments. In addition, we noticed that the seasonal variations of plasticizers were seriously affected by environmental factors including industrial and urban discharges.

Gestational Exposure to Phthalates and Phthalate Replacements in Relation to Neurodevelopmental Delays in Early Childhood.

Phthalates have been linked to changes in child neurodevelopment. However, sex-specificity has been reported inconsistently, and little is known about the impact of recent phthalate replacement chemicals. Our analysis included mother−child pairs (N = 274) from the PROTECT birth cohort in Puerto Rico. Phthalate metabolites were measured in multiple maternal urine collected during pregnancy. Neurodevelopment was measured at 6, 12, and 24 months of age using the Battelle Developmental Inventory-2nd edition (BDI), which provides scores for adaptive, personal-social, communication, motor, and cognitive domains. Multivariable linear regression was used to examine associations between phthalate metabolite concentrations and BDI scores, adjusting for maternal age, maternal education, child age, and specific gravity. Sex-specificity was assessed with sex X exposure interaction terms and stratified models. Results show that all five domains were significantly associated with mono-3-carboxypropyl phthalate (MCPP) at age 24 months, suggesting a holistic developmental delay related to this metabolite. Sex-specificity existed for all timepoints (p-interaction < 0.2), in general, showing stronger associations among boys. For example, metabolites of a recent phthalate replacement, di-2-ethylhexyl terephthalate (DEHTP), were differentially associated with the adaptive domain (boys −7.53%/IQR, 95% CI: −14.58, −0.48 vs. girls −0.85%/IQR, 95% CI: −5.08, 3.37), and the cognitive domain (boys −6.05%/IQR, 95% CI: −10.88, −1.22 vs. girls −1.93%/IQR, 95%CI: −4.14, 0.28) at 6 months. To conclude, gestational exposure to phthalates and phthalate replacements was associated with neurodevelopmental delay across multiple domains, with differences by sex and child age.

Predictors of urinary biomarker concentrations of phthalates and some of their replacements in children in the Project Viva cohort.

Some phthalates are still widely used in food packaging, toys, and personal care products, and links to adverse health have motivated substitution with replacement chemicals. Few studies have examined patterns and predictors of phthalate replacement biomarkers in children. To examine associations of sociodemographic, dietary, and urine collection characteristics with urinary concentrations of biomarkers of select phthalates and their replacements in mid-childhood. We studied 830 children ages 6-10 years in 2007-2010 in a Boston-area cohort. We quantified urinary metabolites and summed their concentrations to calculate biomarkers of the concentrations of ten parent phthalates/replacements. We used linear regression to examine mutually adjusted associations of each predictor with each phthalate biomarker. We used logistic regression to examine predictors of 1,2-cyclohexane dicarboxylic acid, diisononyl ester (DINCH) biomarker detectability. Predictor characteristics explained 25-48% of urinary biomarker variability. Di-2-ethylhexyl terephthalate (DEHTP) biomarker was higher in females (18.7% [95% CI: 0.7, 39.9]), children who consumed more meat and dairy, and samples collected from later years. DINCH biomarker was more detectable in females (odds ratio [OR] 2.1 [95% CI: 1.5, 3.0]) and samples from later years. Populations of children with increased urinary concentrations of phthalate and replacement biomarkers can be targeted for future study of sources of exposure, and identifying dietary predictors of biomarkers will directly guide future interventions. Our study uses data from a large cohort that is one of the first to measure DINCH, DEHTP, and metabolites of di-isononyl phthalate and di-isodecyl phthalate. Additionally, we evaluate predictors during mid-childhood when biomarkers might be highest. As the use of replacement phthalates increases, our study is one of the first to examine biomarker patterns and predictors among children.

Diverging trends of plasticizers (phthalates and non-phthalates) in indoor and freshwater environments—why?

BackgroundEuropean chemicals management aims to protect human health and the environment from legacy and emerging contaminants. The plasticizer market changed in response to the restriction of low molecular weight (LMW) phthalate plasticizers such as Di (2-ethylhexyl) phthalate (DEHP) due to their hazardous properties. We investigated patterns and trends of 19 regulated and emerging plasticizers in house dust from German homes and in suspended particulate matter (SPM) from major German rivers. The samples were used from the mid-2000s and late 2010s from two governmental long-term monitoring programs in Germany.ResultsWhile the sum of the respective plasticizer levels hardly changed over the study period, we observed a significant decrease of LMW phthalates in both house dust (2003/06, 80% of the ∑plasticizer concentration; 2014/17, 31%) and SPM (2005, 48%; 2017, 28%). This was accompanied by their substitution with high molecular weight (HMW) phthalates and non-phthalates. HMW phthalates increased from 19% of the ∑plasticizer concentration to 46% between the mid-2000s and the late 2010s in house dust, and from 50% to 63% in SPM samples. Diisononyl phthalate (DINP) replaced DEHP as the dominant plasticizer in both compartments. A significant tenfold increase (p < 0.05) was observed in SPM samples for Di (2-propylheptyl) phthalate (DPHP) (1–13%), compared to low levels in house dust (2014/17, 1%). Non-phthalates increased to 23% of the ∑plasticizer concentration in house dust but only to 9% in SPM (mid-2000s: house dust, < 1%; SPM, 1.5%). In recent house dust samples, Di (2-ethylhexyl) terephthalate (DEHT) had the third highest concentration of all plasticizers and contributed 18% to the total load, whereas Tris (2-ethylhexyl) trimellitate (TOTM) was one of the major non-phthalates in SPM samples.ConclusionsUnlike in the indoor environment, the substitution of LMW phthalates in the aquatic environment was characterized by a significant shift towards plasticizers with potentially hazardous properties. DPHP and TOTM were identified by European chemical regulation as potentially endocrine disrupting compounds and persistent, bioaccumulative and toxic compounds. Our data document the need for integrated chemicals management to safeguard the transition to a non-toxic environment.