Implementation of USEPA RfD and SFO for improved risk assessment of organophosphate esters (organophosphate flame retardants and plasticizers)

Li, Jiafu; Zhang, Zhaozhao; Ma, Luyao; Zhang, Ying; Niu, Zhiguang

doi:10.1016/j.envint.2018.02.027

Cited by 76 publications

(26 citation statements)

References 34 publications

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“…Last, dermal exposure through the use of nail polish may result in exposures as high as 5000 ng/kg./day (Tokumura et al 2019). While our implemented dose is higher than the typical human exposure, it is lower than that in studies used to derive a nonregulatory reference dose for TPhP (70 mg/kg/day) (Li et al 2018) as well as the recently set benchmark dose of 19 mg/kg/day (NTP 2018).…”

Section: Discussionmentioning

confidence: 98%

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

et al. 2020

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Triphenyl phosphate (TPhP) is an environmental PPARγ ligand, and growing evidence suggests that it is a metabolic disruptor. We have shown previously that the structurally similar ligand, tributyltin, does not induce brite adipocyte gene expression. Here, using in vivo and in vitro models, we tested the hypothesis that TPhP is a selective PPARγ ligand, which fails to induce brite adipogenesis. C57BL/6J male mice were fed either a low or very high fat diet for 13 weeks.From weeks 7-13, mice were injected intraperitoneally, daily, with vehicle, rosiglitazone (Rosi), or TPhP (10 mg/kg). Compared to Rosi, TPhP did not induce expression of browning-related genes (e.g. Elovl3, Cidea, Acaa2, CoxIV) in mature adipocytes isolated from inguinal adipose.To determine if this resulted from an effect directly on the adipocytes, 3T3-L1 cells and primary human preadipocytes were differentiated into adipocytes in the presence of Rosi or TPhP. Rosi, but not TPhP, induced expression of brite adipocyte genes, mitochondrial biogenesis and cellular respiration. Further, Rosi and TPhP induced distinct proteomes and phosphoproteomes; Rosi enriched more regulatory pathways related to fatty acid oxidation and mitochondrial proteins.We assessed the role of phosphorylation of PPARγ in these differences in 3T3-L1 cells. Only Rosi protected PPARγ from phosphorylation at Ser273. TPhP gained the ability to stimulate brite adipocyte gene expression in the presence of the CDK5 inhibitor and in 3T3-L1 cells expressing alanine at position 273. We conclude that TPhP is a selective PPARγ modulator that fails to protect PPARγ from phosphorylation at ser273.

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Section: Discussionmentioning

confidence: 98%

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

et al. 2020

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“…The calculated HQs were always within the acceptable level (HQ <1) (U.S. EPA 2017) ( Table 2). The calculated CRs were also within the acceptable level of 10 −6 for all individual/classes of compounds, except for DEHP in both Europe and Asia (classified as within an area of concern) (Li et al 2018; U.S. EPA 2017) (Table 2). However, the exposure of the population to DEHP is expected to decrease due to its replacement with alternative plasticizers in both food processing equipment and packaging materials (Giovanoulis et al 2018), complying with a recent EU restriction because of its reproductive toxicity and endocrine disrupting properties (EC 2018).…”

Section: Evaluation Of Chemical Safety Of Edible Insectsmentioning

confidence: 63%

“…The potential risk of noncarcinogenic effects [hazard quotient (HQ)] per individual/class of compounds was calculated by dividing the total EDI (in milligrams per kilogram BW per day) by the relative oral reference dose factor (RfD, in milligrams per kilogram BW per day) ( Table 2). HQ values ≥1 indicate a potential exposure risk for the population (Li et al 2018;Poma et al 2018;Qian et al 2017; U.S. EPA 2017). The potential carcinogenic risk (CR) was calculated by multiplying the EDI (in milligrams per kilogram BW per day) by the relative oral cancer slope factor (SFO; in milligrams per kilogram BW per day) ( Table 2).…”

Section: Dietary Exposure Assessmentmentioning

confidence: 99%

“…The potential carcinogenic risk (CR) was calculated by multiplying the EDI (in milligrams per kilogram BW per day) by the relative oral cancer slope factor (SFO; in milligrams per kilogram BW per day) ( Table 2). A public screening criterion set to 1 in 1 million is used as a threshold for the CR (CR >10 −4 is considered unacceptable, 10 −6 < CR <10 −4 is an area of concern, and CR <10 −6 is acceptable) (Li et al 2018;Qian et al 2017; U.S. EPA 2017).…”

Section: Dietary Exposure Assessmentmentioning

confidence: 99%

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Occurrence of Selected Organic Contaminants in Edible Insects and Assessment of Their Chemical Safety

Poma

Yin

Tang

et al. 2019

Environ Health Perspect

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BACKGROUND: Feeding the continuously growing world population is challenging, and edible insects offer a sustainable alternative to conventional sources of animal proteins. As with any food source, the potential presence of hazardous organic chemicals, such as persistent organic pollutants (POPs), plasticizers and flame retardants (FRs), must be investigated to guarantee consumer chemical safety. OBJECTIVES: Here, we have investigated the contamination levels of several classes of organic compounds in edible insects. To evaluate their chemical safety, a dietary exposure risk assessment was then performed by combining the measured chemical contamination with the most recent food consumption data from local surveys. METHODS: Insect samples, belonging to six orders (Orthoptera, Coleoptera, Lepidoptera, Hemiptera, Odonata, Hymenoptera) were purchased from five European and three Asian countries. POPs and halogenated FRs were analyzed by gas chromatography-mass spectrometry (GC/MS) and organophosphorus FRs and plasticizers were quantified by liquid chromatography-MS/MS, according to validated protocols. RESULTS: The overall levels of chemical contamination varied greatly among the insect orders and country of purchase, but they were generally low and comparable with other commonly consumed animal products. DISCUSSION: Here we show that, besides the activities during rearing, the industrial post-harvesting handling and addition of ingredients are supplementary factors influencing the chemical load of the final insect food-product. The total estimated dietary intakes of the considered classes of compounds through insect consumption are comparable with those generally assessed in common food of animal origin worldwide and, when compared with existing reference dose values, suggest that the risk of adverse health effects from exposure to the targeted organic compounds via insect consumption is unlikely.

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“…Our in vivo dose is higher than the human average daily intake of triphenyl phosphate among 25-30 year old females (0.8 ng/kg-body weight-per day) and same age group males (1.6 ng/kg-body weight-per day) of 8 population groups in the FDA's monitoring program for chemical contaminants in the U.S. food supply (Gunderson 1988). However, our implemented dose is lower than that of studies that used a dose (70mg/kg/day) from an old in vivo TPhP exposure study in male Holtzman rats (Sutton et al 1960) to derive a non-regulatory reference dose for TPhP (Ali et al 2012;Li et al 2018). Our TPhP dose is also in the lowermiddle range of recent in vivo exposure studies as one recent study exposed C57Bl/6 dams to 0, 5, 25, or 50 mg/kg TPhP via intraperitoneal injection (Philbrook et al 2018), and National Toxicology Program (NTP) recently exposed male Harlan Sprague Dawley rats to 0, 55, 110, 220, 441, and 881 mg/kg TPHP daily for 4 days by oral gavage (National Toxicology Program 2018).…”

Section: Discussionmentioning

confidence: 99%

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Kim

Rabhi

Blum

et al. 2019

Preprint

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Background: Triphenyl phosphate (TPhP) is an environmental PPARγ ligand, and growing evidence suggests that it is a metabolic disruptor. We have shown previously that the structurally similar ligand, tributyltin, does not induce brite adipocyte gene expression.Objectives: First, we tested whether TPhP also fails to induce brite adipogenesis in vivo, in human primary preadipocytes and in 3T3 L1 cells. Second, we tested the hypothesis that TPhP is a selective PPARγ modulator that is unable to protect PPARγ from phosphorylation at serine 273.Methods: C57BL/6J male mice were fed either a low or very high fat diet for 13 weeks. From weeks 7-13, mice were injected intraperitoneally, daily, with vehicle, rosiglitazone (Rosi), or TPhP (10 mg/kg). Mature adipocytes were isolated from inguinal adipose tissue to assess adipocyte gene expression. Adipocyte genotype and phenotype were assessed in human primary preadipocytes differentiated in the presence of Rosi, or TPhP. Adipocyte gene and protein expression were determined in 3T3 L1 cells differentiated in the presence of Rosi or TPhP. Swiss 3T3 cell lines expressing wild-type PPARγ2 or PPARγ2 with alanine substitute for serine at position 273 were used to determine effects of PPARγ phosphorylation on Rosiand TPhP-induced gene expression.Results: Compared to Rosi, TPhP did not induce browning of mature adipocytes. TPhP also did not induce expression of brite adipocyte genes, mitochondrial biogenesis or cellular respiration in primary human adipocytes. Rosi and TPhP induced distinct proteomic and phosphoproteomic profiles; Rosi enriched more regulatory pathways related to fatty acid oxidation and mitochondrial proteins. Furthermore, TPhP maintained phosphorylation of PPARγ at ser273. Upon inhibition of phosphorylation at ser273, TPhP was able to induce brite adipocyte genes.Discussion: Here, we show that TPhP acts via a novel mechanism of action. TPhP disrupts brite adipocyte differentiation by failing to protect PPARγ from phosphorylation at ser273, in contrast to the therapeutic PPARγ ligand Rosi.

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Implementation of USEPA RfD and SFO for improved risk assessment of organophosphate esters (organophosphate flame retardants and plasticizers)

Cited by 76 publications

References 34 publications

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

Occurrence of Selected Organic Contaminants in Edible Insects and Assessment of Their Chemical Safety

Triphenyl phosphate is a selective PPARγ modulator that does not induce brite adipogenesis in vitro and in vivo

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