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Journal of Orthopaedic Research :... Apr 2018Plasticizer di(2-ethylhexyl)phthalate (DEHP) can leach from medical devices such as blood storage bags and the tubing. Recently, epidemiological studies showed that...
Plasticizer di(2-ethylhexyl)phthalate (DEHP) can leach from medical devices such as blood storage bags and the tubing. Recently, epidemiological studies showed that phthalate metabolites levels in the urine are associated with low bone mineral density (BMD) in older women. The detailed effect and mechanism of DEHP on osteoblastogenesis and adipogenesis, and bone loss remain to be clarified. Here, we investigated the effect and mechanism of DEHP and its active metabolite mono(2-ethylhexyl)phthalate (MEHP) on osteoblastogenesis and adipogenesis. The in vitro study showed that osteoblast differentiation of bone marrow stromal cells (BMSCs) was significantly and dose-dependently decreased by DEHP and MEHP (10-100 µM) without cytotoxicity to BMSCs. The mRNA expressions of alkaline phosphatase, Runx2, osteocalcin (OCN), Wnt1, and β-catenin were significantly decreased in DEHP- and MEHP-treated BMSCs during differentiation. MEHP, but not DEHP, significantly increased the adipocyte differentiation of BMSCs and PPARγ mRNA expression. Both DEHP and MEHP significantly increased the ratios of phosphorylated β-catenin/β-catenin and inhibited osteoblastogenesis, which could be reversed by Wnt activator lithium chloride and PPARγ inhibitor T0070907. Moreover, exposure of mice to DEHP (1, 10, and 100 mg/kg) for 8 weeks altered BMD and microstructure. In BMSCs isolated from DEHP-treated mice, osteoblastogenesis and Runx2, Wnt1, and β-catenin expression were decreased, but adipogenesis and PPARγ expression were increased. These findings suggest that DEHP and its metabolite MEHP exposure may inhibit osteoblastogenesis and promote adipogenesis of BMSCs through the Wnt/β-catenin-regulated and thus triggering bone loss. PPARγ signaling may play an important role in MEHP- and DEHP-induced suppression of osteogenesis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1124-1134, 2018.
Topics: Adipogenesis; Animals; Cell Survival; Diethylhexyl Phthalate; Gene Expression; Male; Mesenchymal Stem Cells; Mice, Inbred ICR; Osteoblasts; Osteogenesis; PPAR gamma; Plasticizers; Wnt Signaling Pathway
PubMed: 28921615
DOI: 10.1002/jor.23740 -
Environmental Science & Technology Nov 2018In the 2000s, nail polish manufacturers started promoting "3-Free" products, phasing out three widely publicized toxic chemicals: toluene, formaldehyde, and dibutyl...
In the 2000s, nail polish manufacturers started promoting "3-Free" products, phasing out three widely publicized toxic chemicals: toluene, formaldehyde, and dibutyl phthalate (DnBP). However, DnBP was sometimes replaced by another endocrine-disrupting plasticizer, triphenyl phosphate (TPHP). Many new " n-Free" labels have since appeared, without any standardization on which n chemicals are excluded. This study aimed to compare measured plasticizer content against nail polish labels. First, we summarized definitions of labels. Then, we measured 12 phthalate and 10 organophosphate plasticizers in 40 nail polishes from 12 brands selected for popularity and label variety. We found labels ranging from 3- to 13-Free; 10-Free was the most inconsistently defined (six definitions). Our samples contained TPHP and bis(2-ethylhexyl) phthalate (DEHP) at up to 7940 and 331 μg/g, respectively. The 5- to 13-Free samples had lower TPHP levels than unlabeled or 3-Free samples (median <0.002 vs 3730 μg/g, p < 0.001). The samples that did not contain TPHP had higher DEHP levels (median 68.5 vs 1.51 μg/g, p < 0.05). We measured plasticizers above 100 μg/g in five brands that did not disclose them and in two that excluded them in labels. This study highlights inconsistencies in nail polish labels and identifies TPHP and DEHP as ingredient substitutes for DnBP.
Topics: Diethylhexyl Phthalate; Organophosphates; Phthalic Acids; Plasticizers; Poland
PubMed: 30302996
DOI: 10.1021/acs.est.8b04495 -
Environmental Science and Pollution... Jul 2013Emerging contaminants in wastewater and sewage sludge spread on agricultural soil can be transferred to the human food web directly by uptake into food crops or...
Emerging contaminants in wastewater and sewage sludge spread on agricultural soil can be transferred to the human food web directly by uptake into food crops or indirectly following uptake into forage crops. This study determined uptake and translocation of the organophosphates tris(1-chloro-2-propyl) phosphate (TCPP) (log Kow 2.59), triethyl-chloro-phosphate (TCEP) (log Kow 1.44), tributyl phosphate (TBP) (log Kow 4.0), the insect repellent N,N-diethyl toluamide (DEET) (log Kow 2.18) and the plasticiser N-butyl benzenesulfonamide (NBBS) (log Kow 2.31) in barley, wheat, oilseed rape, meadow fescue and four cultivars of carrot. All species were grown in pots of agricultural soil, freshly amended contaminants in the range of 0.6-1.0 mg/kg dry weight, in the greenhouse. The bioconcentration factors for root (RCF), leaf (LCF) and seed (SCF) were calculated as plant concentration in root, leaf or seed over measured initial soil concentration, both in dry weight. The chlorinated flame retardants (TCEP and TCPP) displayed the highest bioconcentration factors for leaf and seed but did not show the same pattern for all crop species tested. For TCEP, which has been phased out due to toxicity but is still found in sewage sludge and wastewater, LCF was 3.9 in meadow fescue and 42.3 in carrot. For TCPP, which has replaced TCEP in many products and also occurs in higher residual levels in sewage sludge and wastewater, LCF was high for meadow fescue and carrot (25.9 and 17.5, respectively). For the four cultivars of carrot tested, the RCF range for TCPP and TCEP was 10-20 and 1.7-4.6, respectively. TCPP was detected in all three types of seeds tested (SCF, 0.015-0.110). Despite that DEET and NBBS have log Kow in same range as TCPP and TCEP, generally lower bioconcentration factors were measured. Based on the high translocation of TCPP and TCEP to leaves, especially TCPP, into meadow fescue (a forage crop for livestock animals), ongoing risk assessments should be conducted to investigate the potential effects of these compounds in the food web.
Topics: Animal Feed; Crops, Agricultural; DEET; Daucus carota; Environmental Monitoring; Flame Retardants; Food Chain; Food Contamination; Hordeum; Organophosphates; Plant Roots; Plasticizers; Risk Assessment; Seeds; Sewage; Soil; Soil Pollutants; Sulfonamides; Triticum
PubMed: 23250727
DOI: 10.1007/s11356-012-1363-5 -
Environment International Dec 2014Phthalates and bisphenol A (BPA) are ubiquitous in our environment. These chemicals have been characterized as endocrine disruptors that can cause functional impairment...
Phthalates and bisphenol A (BPA) are ubiquitous in our environment. These chemicals have been characterized as endocrine disruptors that can cause functional impairment of development and reproduction. Processed and packaged foods are among the major sources of human exposure to these chemicals. No previous report showing the levels of these chemicals in food items purchased in Norway is available. The aim of the present study was to determine the concentration of ten different phthalates and BPA in foods and beverages purchased on the Norwegian market and estimate the daily dietary exposure in the Norwegian adult population. Commonly consumed foods and beverages in Norway were purchased in a grocery store and analysed using gas- and liquid chromatography coupled with mass spectrometry. Daily dietary exposures to these chemicals in the Norwegian adult population were estimated using the latest National dietary survey, Norkost 3 (2010-2011). This study showed that phthalates and BPA are found in all foods and beverages that are common to consume in Norway. The detection frequency of phthalates in the food items varied from 11% for dicyclohexyl phthalate (DCHP) to 84% for di-iso-nonyl phthalate (DiNP), one of the substitutes for bis(2-ethylhexyl) phthalate (DEHP). BPA was found in 54% of the food items analysed. Among the different phthalates, the highest concentrations were found for DEHP and DiNP in the food items. Estimated dietary exposures were also equally high and dominated by DEHP and DiNP (400-500 ng/kg body weight (bw)/day), followed by di-iso-butyl phthalate (DiBP), di-n-butyl phthalate (DnBP), di-n-octyl phthalate (DnOP) and di-iso-decyl phthalate (DiDP) (30-40 ng/kg bw/day). Dimethyl phthalate (DMP), diethylphthalate (DEP) and DCHP had the lowest concentrations and the exposures were around 10-20 ng/kg bw/day. Estimated dietary exposure to BPA was 5 ng/kg bw/day. In general, levels of phthalates and BPA in foods and beverages from the Norwegian market are comparable to other countries worldwide. Grain and meat products were the major contributors of exposure to these chemicals in the Norwegian adult population. The estimated dietary exposures to these chemicals were considerably lower than their respective tolerable daily intake (TDI) values established by the European Food Safety Authority (EFSA).
Topics: Adult; Benzhydryl Compounds; Beverages; Diet; Environmental Exposure; Food Analysis; Humans; Norway; Phenols; Phthalic Acids; Plasticizers
PubMed: 25173060
DOI: 10.1016/j.envint.2014.08.005 -
PloS One 2023Phthalate plasticizers are incorporated into plastics to make them soft and malleable, but are known to leach out of the final product into their surroundings with...
Exposure to the non-phthalate plasticizer di-heptyl succinate is less disruptive to C57bl/6N mouse recovery from a myocardial infarction than DEHP, TOTM or related di-octyl succinate.
Phthalate plasticizers are incorporated into plastics to make them soft and malleable, but are known to leach out of the final product into their surroundings with potential detrimental effects to human and ecological health. The replacement of widely-used phthalate plasticizers, such as di-ethylhexyl phthalate (DEHP), that are of known toxicity, by the commercially-available alternative Tris(2-ethylhexyl) tri-mellitate (TOTM) is increasing. Additionally, several newly designed "green" plasticizers, including di-heptyl succinate (DHPS) and di-octyl succinate (DOS) have been identified as potential replacements. However, the impact of plasticizer exposure from medical devices on patient recovery is unknown and, moreover, the safety of TOTM, DHPS, and DOS is not well established in the context of patient recovery. To study the direct effect of clinically based chemical exposures, we exposed C57bl/6 N male and female mice to DEHP, TOTM, DOS, and DHPS during recovery from cardiac surgery and assessed survival, cardiac structure and function, immune cell infiltration into the cardiac wound and activation of the NLRP3 inflammasome. Male, but not female, mice treated in vivo with DEHP and TOTM had greater cardiac dilation, reduced cardiac function, increased infiltration of neutrophils, monocytes, and macrophages and increased expression of inflammasome receptors and effectors, thereby suggesting impaired recovery in exposed mice. In contrast, no impact was detected in female mice and male mice exposed to DOS and DHPS. To examine the direct effects in cells involved in wound healing, we treated human THP-1 macrophages with the plasticizers in vitro and found DEHP induced greater NLRP3 expression and activation. These results suggest that replacing current plasticizers with non-phthalate-based plasticizers may improve patient recovery, especially in the male population. In our assessment, DHPS is a promising possibility for a non-toxic biocompatible plasticizer.
Topics: Male; Humans; Mice; Animals; Plasticizers; Diethylhexyl Phthalate; Succinic Acid; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Myocardial Infarction; Succinates; Mice, Inbred Strains
PubMed: 37440506
DOI: 10.1371/journal.pone.0288491 -
International Journal of Hygiene and... Jun 2024Phthalates and the substitute plasticizer DINCH belong to the first group of priority substances investigated by the European Human Biomonitoring Initiative (HBM4EU) to... (Review)
Review
Phthalates and the substitute plasticizer DINCH belong to the first group of priority substances investigated by the European Human Biomonitoring Initiative (HBM4EU) to answer policy-relevant questions and safeguard an efficient science-to-policy transfer of results. Human internal exposure levels were assessed using two data sets from all European regions and Israel. The first collated existing human biomonitoring (HBM) data (2005-2019). The second consisted of new data generated in the harmonized "HBM4EU Aligned Studies" (2014-2021) on children and teenagers for the ten most relevant phthalates and DINCH, accompanied by a quality assurance/quality control (QA/QC) program for 17 urinary exposure biomarkers. Exposures differed between countries, European regions, age groups and educational levels. Toxicologically derived Human biomonitoring guidance values (HBM-GVs) were exceeded in up to 5% of the participants of the HBM4EU Aligned Studies. A mixture risk assessment (MRA) including five reprotoxic phthalates (DEHP, DnBP, DiBP, BBzP, DiNP) revealed that for about 17% of the children and teenagers, health risks cannot be excluded. Concern about male reproductive health emphasized the need to include other anti-androgenic substances for MRA. Contaminated food and the use of personal care products were identified as relevant exposure determinants paving the way for new regulatory measures. Time trend analyses verified the efficacy of regulations: especially for the highly regulated phthalates exposure dropped significantly, while levels of the substitutes DINCH and DEHTP increased. The HBM4EU e-waste study, however, suggests that workers involved in e-waste management may be exposed to higher levels of restricted phthalates. Exposure-effect association studies indicated the relevance of a range of endpoints. A set of HBM indicators was derived to facilitate and accelerate science-to-policy transfer. Result indicators allow different groups and regions to be easily compared. Impact indicators allow health risks to be directly interpreted. The presented results enable successful science-to-policy transfer and support timely and targeted policy measures.
Topics: Humans; Phthalic Acids; Plasticizers; Biological Monitoring; Europe; Environmental Pollutants; Adolescent; Child; Environmental Exposure; Male; Risk Assessment; Female; Adult; Environmental Monitoring
PubMed: 38631089
DOI: 10.1016/j.ijheh.2024.114378 -
Toxicological Sciences : An Official... Feb 2023Two organophosphate esters used as flame retardants and plasticizers, triphenyl phosphate (TPHP) and isopropylated phenyl phosphate (IPP), have been detected in...
Reproductive and developmental toxicity following exposure to organophosphate ester flame retardants and plasticizers, triphenyl phosphate and isopropylated phenyl phosphate, in Sprague Dawley rats.
Two organophosphate esters used as flame retardants and plasticizers, triphenyl phosphate (TPHP) and isopropylated phenyl phosphate (IPP), have been detected in environmental samples around the world. Human exposure primarily occurs via oral ingestion with reported higher concentrations in children. Currently, there are no data to evaluate potential risk from exposure to either TPHP or IPP during fetal development. These short-term perinatal studies in rats provide preliminary toxicity data for TPHP and IPP, including information on transfer to fetus/offspring and across the pup blood-brain barrier. In separate experiments, TPHP or IPP were administered via dosed feed at concentrations 0, 1000, 3000, 10 000, 15 000, or 30 000 ppm to time-mated Hsd:Sprague Dawley SD rats from gestation day (GD) 6 through postnatal day (PND) 28; offspring were provided dosed feed at the same concentration as their dam (PND 28-PND 56). TPHP- and IPP-related toxicity resulted in removal of both 30 000 ppm groups on GD 12 and 15 000 ppm IPP group after parturition. Body weight and organ weights were impacted with exposure in remaining dams. Reproductive performance was perturbed at ≥10 000 ppm TPHP and all IPP exposure groups. In offspring, both TPHP- and IPP-related toxicity was noted in pups at ≥10 000 ppm as well as reduction in bodyweights, delays in pubertal endpoints, and/or reduced cholinesterase enzyme activity starting at 1000 ppm TPHP or IPP. Preliminary internal dose assessment indicated gestational and lactational transfer following exposure to TPHP or IPP. These findings demonstrate that offspring development is sensitive to 1000 ppm TPHP or IPP exposure.
Topics: Pregnancy; Female; Child; Rats; Animals; Humans; Rats, Sprague-Dawley; Flame Retardants; Plasticizers; Organophosphates; Phosphates; Esters
PubMed: 36562586
DOI: 10.1093/toxsci/kfac135 -
Reproductive Toxicology (Elmsford, N.Y.) Jun 2022Widespread use of phthalates as solvents and plasticizers leads to everyday human exposure. The mechanisms by which phthalate metabolites act as ovarian toxicants are...
Widespread use of phthalates as solvents and plasticizers leads to everyday human exposure. The mechanisms by which phthalate metabolites act as ovarian toxicants are not fully understood. Thus, this study tested the hypothesis that the phthalate metabolites monononyl phthalate (MNP), monoisononyl phthalate (MiNP), mono(2-ethylhexyl) phthalate (MEHP), monobenzyl phthalate (MBzP), monobutyl phthalate (MBP), monoisobutyl phthalate (MiBP), and monoethyl phthalate (MEP) act through peroxisome proliferator-activated receptors (PPARs) in mouse granulosa cells. Primary granulosa cells were isolated from CD-1 mice and cultured with vehicle control (dimethyl sulfoxide) or MNP, MiNP, MEHP, MBzP, MBP, MiBP, or MEP (0.4-400 μM) for 24 h. Following culture, qPCR was performed for known PPAR targets, Fabp4 and Cd36. Treatment with the phthalate metabolites led to significant changes in Fabp4 and Cd36 expression relative to control in dose-dependent or nonmonotonic fashion. Primary granulosa cell cultures were also transfected with a DNA plasmid containing luciferase expressed under the control of a consensus PPAR response element. MNP, MiNP, MEHP, and MBzP caused dose-dependent changes in expression of luciferase, indicating the presence of functional endogenous PPAR receptors in the granulosa cells that respond to phthalate metabolites. The effects of phthalate metabolites on PPAR target genes were inhibited in most of the cultures by co-treatment with the PPAR-γ inhibitor, T0070907, or with the PPAR-α inhibitor, GW6471. Collectively, these data suggest that some phthalate metabolites may act through endogenous PPAR nuclear receptors in the ovary and that the differing structures of the phthalates result in different levels of activity.
Topics: Animals; Environmental Exposure; Environmental Pollutants; Female; Mice; Ovary; PPAR alpha; PPAR gamma; Phthalic Acids; Plasticizers
PubMed: 35421560
DOI: 10.1016/j.reprotox.2022.04.002 -
Environmental Health Perspectives Oct 2021To date, the toxicity of organophosphate esters has primarily been studied regarding their use as pesticides and their effects on the neurotransmitter...
BACKGROUND
To date, the toxicity of organophosphate esters has primarily been studied regarding their use as pesticides and their effects on the neurotransmitter acetylcholinesterase (AChE). Currently, flame retardants and plasticizers are the two largest market segments for organophosphate esters and they are found in a wide variety of products, including electronics, building materials, vehicles, furniture, car seats, plastics, and textiles. As a result, organophosphate esters and their metabolites are routinely found in human urine, blood, placental tissue, and breast milk across the globe. It has been asserted that their neurological effects are minimal given that they do not act on AChE in precisely the same way as organophosphate ester pesticides.
OBJECTIVES
This commentary describes research on the non-AChE neurodevelopmental toxicity of organophosphate esters used as flame retardants and plasticizers (OPEs). Studies in humans, mammalian, nonmammalian, and models are presented, and relevant neurodevelopmental pathways, including adverse outcome pathways, are described. By highlighting this scientific evidence, we hope to elevate the level of concern for widespread human exposure to these OPEs and to provide recommendations for how to better protect public health.
DISCUSSION
Collectively, the findings presented demonstrate that OPEs can alter neurodevelopmental processes by interfering with noncholinergic pathways at environmentally relevant doses. Application of a pathways framework indicates several specific mechanisms of action, including perturbation of glutamate and gamma-aminobutyric acid and disruption of the endocrine system. The effects may have implications for the development of cognitive and social skills in children. Our conclusion is that concern is warranted for the developmental neurotoxicity of OPE exposure. We thus describe important considerations for reducing harm and to provide recommendations for government and industry decision makers. https://doi.org/10.1289/EHP9285.
Topics: Acetylcholinesterase; Child; Environmental Monitoring; Esters; Female; Flame Retardants; Humans; Organophosphates; Placenta; Plasticizers; Pregnancy
PubMed: 34612677
DOI: 10.1289/EHP9285 -
The Kaohsiung Journal of Medical... Jul 2012
Topics: Animals; Drug Contamination; Endocrine Disruptors; Environmental Exposure; Food Contamination; Humans; Plasticizers; Quantum Dots
PubMed: 22871599
DOI: 10.1016/j.kjms.2012.05.002