Since the phase-out of pentaBDE in the early 2000s, replacement flame-retardant mixtures including Firemaster 550 (FM 550), Firemaster 600 (FM 600), and organophosphate aryl ester technical mixtures ...have been increasingly used to treat polyurethane foam in residential upholstered furniture. These mixtures contain isomers of isopropylated and tert-butylated triarylphosphate esters (ITPs and TBPPs), which have similar or greater neuro- and developmental toxicity compared to BDE 47 in high-throughput assays. Additionally, human exposure to ITPs and TBPPs has been demonstrated to be widespread in several recent studies; however, the relative composition of these mixtures has remained largely uncharacterized. Using available authentic standards, the present study quantified the contribution of individual ITP and TBPP isomers in four commercial flame retardant mixtures: FM 550, FM 600, an ITP mixture, and a TBPP mixture. Findings suggest similarities between FM 550 and the ITP mixture, with 2-isopropylphenyl diphenyl phosphate (2IPPDPP), 2,4-diisopropylphenyl diphenyl phosphate (24DIPPDPP), and bis(2-isopropylphenyl) phenyl phosphate (B2IPPPP) being the most prevalent ITP isomers in both mixtures. FM 600 differed from FM 550 in that it contained TBPP isomers instead of ITP isomers. These analytes were also detected and quantified in a house dust standard reference material, SRM 2585, demonstrating their environmental relevance.
Organophosphate esters (OPEs) are applied as additive flame retardants, and along with phthalates, are also used as plasticizers in consumer products. As such, human exposure is common and chronic. ...Deployed as personal passive samplers, silicone wristbands have been shown to detect over a thousand industrial and consumer product chemicals; however, few studies have evaluated chemical concentrations with their corresponding biomarkers of exposure, especially in children. Further, little is known about how well the wristbands predict individual exposure compared to existing validated external exposure tools such as indoor air, dust, and hand wipes. Here, we analyzed wristbands worn by children (ages 3–6) for 18 OPEs and 10 phthalates and compared them to corresponding urinary biomarkers. In wristbands, 13 of 18 OPEs and all phthalates were detected in >80% of wristbands, and 6 OPEs and 4 phthalates were significantly associated with corresponding urinary metabolites (r s = 0.2–0.6, p < 0.05). When compared to paired hand wipes and house dust, wristbands were found to have similar or greater correlation coefficients with respective urinary biomarkers. These results suggest that wristbands can serve as effective and quantitative assessment tools for evaluating personal exposure to some OPEs and phthalates, and for certain chemicals, may provide a better exposure estimate than indoor dust.
Phthalates and their potential replacements, including non-phthalate plasticizers, are ubiquitous in home environments due to their presence in building materials, plastics, and personal care ...products. As a result, exposure to these compounds is universal. However, the primary pathways of exposure and understanding which products in the home are associated most strongly with particular exposures are unclear.
We sought to investigate the relationships between phthalates and non-phthalate plasticizers in paired samples of house dust, hand wipes, and their corresponding metabolites in children's urine samples (n = 180). In addition, we compared product use or presence of materials in the household against all compounds to investigate the relationship between product use or presence and exposure.
Children aged 3–6 years provided hand wipe and urine samples. Questionnaires were completed by mothers or legal guardians to capture product use and housing characteristics, and house dust samples were collected from the main living area during home visits.
Phthalates and non-phthalate replacements were detected frequently in the environmental matrices. All urine samples had at least 13 of 19 phthalate or non-phthalate replacement metabolites present. Hand wipe mass and dust concentrations of diisobutyl phthalate, benzyl butyl phthalate (BBP), bis(2-ethylhexyl) phthalate, and di-isononyl phthalate were significantly associated with their corresponding urinary metabolites (rs = 0.18–0.56, p < 0.05). Bis(2-ethylhexyl) terephthalate (DEHTP) in dust was also significantly and positively correlated with its urinary metabolites (rs = 0.33, p < 0.001). Vinyl flooring was most significantly and positively associated with particular phthalate exposures (indicated by concentrations in environmental matrices and urinary biomarkers). In particular, children who lived in homes with 100% vinyl flooring had urinary concentrations of monobenzyl phthalate, a BBP metabolite, that were 15 times higher than those of children who lived in homes with no vinyl flooring (p < 0.0001). Levels of BBP in hand wipes and dust were 3.5 and 4.5 times higher, respectively, in those homes with 100% vinyl flooring (p < 0.0001 for both).
This paper summarizes one of the most comprehensive phthalate and non-phthalate plasticizer investigation of potential residential exposure sources conducted in North America to date. The data presented herein provide evidence that dermal contact and hand-to-mouth behaviors are important sources of exposure to phthalates and non-phthalate plasticizers. In addition, the percentage of vinyl flooring is an important consideration when examining residential exposures to these compounds.
•Plasticizers were frequently detected in children’s hand wipes, dust, and urine.•Phthalates in hand wipes and house dust were correlated with metabolites in urine.•The metabolite of BBP was higher in children who lived in homes with 100% vinyl floors.•DEHTP was more abundant than DEHP in house dust and child hand wipes.
Biomarkers remain the gold standard for assessing chemical exposure. However, silicone wristbands may provide some added benefits for characterizing personal exposures compared to single biomarker ...measurements, such as decreased costs, noninvasive sampling, and increased ease of analysis. Previously, we validated their use in characterizing exposure to organophosphate flame retardants (PFRs). However, it is unclear whether these results would extend to chemicals like polybrominated diphenyl ethers (PBDEs), which biomagnify and have longer half-lives than PFRs in the body. This study sought to determine if accumulation of PBDEs on wristbands was correlated to serum biomarkers. Adult participants (n = 30) provided serum samples and wore wristbands for 7 days. PBDEs and 6 novel brominated flame retardants (BFRs) were measured on wristbands, and serum samples were analyzed for PBDE biomarkers. Like most PBDE congeners, 5 of 6 novel BFRs were frequently detected on wristbands (≥90% of bands). In particular, decabromodiphenyl ethane (DBDPE) was detected in all wristbands in this study and was significantly correlated with BDE-209, suggesting a similar source and exposure pathway. Wristband levels of BDE-47, -99, -100, and -153 were significantly and positively associated with respective serum biomarkers (r s = 0.39–0.57, p < 0.05). This study demonstrates that silicone wristbands can accurately detect personal PBDE exposures.
Organophosphate ester (OPE) flame retardants and plasticizers, consumer product additives with widespread human exposure, were evaluated for their effect on the activity of purified human liver ...carboxylesterase (hCE1). Four of the 15 OPEs tested had IC50 values lower than 100 nM, including triphenyl phosphate (TPHP), 2-ethylhexyl diphenyl phosphate (EHDPHP), 4-isopropylphenyl diphenyl phosphate (4IPPDPP), and 4-tert-butylphenyl diphenyl phosphate (4tBPDPP), as did 4 of the commercial flame retardant mixtures tested. Because hCE1 is critical for the activation of imidapril, an angiotensin-converting enzyme-inhibitor prodrug prescribed to treat hypertension, the most potent inhibitors, TPHP and 4tBPDPP, and an environmentally relevant mixture (house dust) were further evaluated for their effect on imidapril bioactivation in vitro. TPHP and 4tBPDPP were potent inhibitors of hCE1-mediated imidapril activation (Ki = 49.0 and 17.9 nM, respectively). House dust extracts (100 µg/ml) also caused significant reductions (up to 33%) in imidapril activation. Combined, these data suggest that exposure to OPEs may affect pharmacotherapy.
•Paired hand wipe, wristband, house dust and urine samples were analyzed for phenols.•Exposure matrices and urinary biomarkers were positively correlated.•Triclosan in dust, wristbands and hand wipes ...was correlated with urinary biomarkers.•Lotion use was associated with ethyl, methyl, and propylparaben biomarkers.
Environmental phenols, such as parabens, bisphenol A, and triclosan, are ubiquitous in indoor environments because of their use in packaging, plastics, personal care products, and as anti-microbials. The primary pathways of exposure, as well as habits and behaviors that may lead to greater exposure, are still unclear.
Herein, we investigate the relationships between phenols found in residential environments by comparing levels in paired samples of house dust and hand wipes with children’s urine. In addition, phenols were analyzed in a novel exposure tool, the silicone wristbands, to investigate which external matrix best correlates with individual exposure based on urinary phenol biomarkers.
Children aged 3–6 years in central North Carolina, United States, provided paired hand wipe (n = 202), wristband (n = 76), and spot urine samples (n = 180), while legal guardians completed questionnaires on habits and behaviors. House dust samples (n = 186) were collected from the main living area during home visits completed between 2014 and 2016.
Environmental phenols were detected frequently in all matrices investigated. Ethyl, methyl, and propylparaben levels observed in hand wipes, dust, and on wristbands were significantly correlated to their associated urinary biomarkers. In addition, intra-paraben correlations were noted, with biomarkers of ethyl, methyl, and propylparabens generally positively and significantly correlated, which suggests co-application of parabens in products. Triclosan levels in dust were positive and significantly correlated with levels in hand wipes and wristbands and with urinary concentrations, suggesting non-personal care product sources may be important in children’s overall triclosan exposure. Generally, chemicals on wristbands were more highly correlated with urinary biomarkers than with chemicals in hand wipes or house dust. In addition, more frequent lotion use was positively associated with urinary concentrations of paraben biomarkers.
Our results suggest that the home environment is an important source of exposure which has been under-investigated for some environmental phenols (e.g., triclosan in house dust). Associations between wristbands and biomarkers of exposure, which were stronger than for hand wipes and house dust, suggest that silicone wristbands may provide a suitable exposure assessment tool for some phenols.
Over the past few years, human exposure to per- and polyfluoroalkyl substances (PFAS) has garnered increased attention. Research has focused on PFAS exposure via drinking water and diet, and fewer ...studies have focused on exposure in the indoor environment. To support more research on the latter exposure pathway, we conducted a study to evaluate PFAS in indoor dust. Dust samples from 184 homes in North Carolina and 49 fire stations across the United States and Canada were collected and analyzed for a suite of PFAS using liquid and gas chromatography–mass spectrometry. Fluorotelomer alcohols (FTOHs) and di-polyfluoroalkyl phosphoric acid esters (diPAPs) were the most prevalent PFAS in both fire station and house dust samples, with medians of approximately 100 ng/g dust or greater. Notably, perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate, perfluorononanoic acid, and 6:2 diPAP were significantly higher in dust from fire stations than from homes, and 8:2 FTOH was significantly higher in homes than in fire stations. Additionally, when comparing our results to earlier published values, we see that perfluoroalkyl acid levels in residential dust appear to decrease over time, particularly for PFOA and PFOS. These results highlight a need to better understand what factors contribute to PFAS levels in dust and to understand how much dust contributes to overall human PFAS exposure.
Objective:
The aim of this article is to assess available data regarding use of nivolumab/relatlimab for adult and pediatric patients 12 years of age and older with unresectable or metastatic ...melanoma.
Data Sources:
A search of PubMed conducted from August 2019 to August 2022 with the search terms Opdualag, nivolumab AND relatlimab, and BMS-986016 resulted in 14 publications.
Study Selection and Data Extraction:
Relevant clinical trials written in English language were analyzed.
Data Synthesis:
Nivolumab/relatlimab was approved by the Food and Drug Administration following results of a phase 1/2 trial and phase 2/3 RELATIVITY-047 trial. Nivolumab/relatlimab demonstrated a median progression free survival (PFS) of 10.1 months in the first-line setting without new safety signals. The PFS benefits appear greatest in those with programmed cell death-ligand 1 (PD-L1) <1% and lymphocyte activation gene-3 (LAG-3) ≥1%. Adverse effects commonly experienced were immune related in nature and require early identification and prompt management. Grade 3 or 4 adverse effects occurred in 18.9% of patients.
Relevance to Patient Care and Clinical Practice:
For patients 12 years of age and older with unresectable or metastatic melanoma, nivolumab/relatlimab offers a new first-line treatment option. Evaluation of PD-L1 expression along with concomitant use of medications with potential interactions should be evaluated when deciding if nivolumab/relatlimab is the most appropriate treatment option.
Conclusions:
Nivolumab/relatlimab adds an additional first-line treatment option demonstrating promising improved PFS for patients with unresectable or metastatic melanoma, particularly those with PD-L1 <1% and/or LAG 3 ≥1%. Additional uses of nivolumab/relatlimab may be on the horizon as further clinical trials are ongoing.
Following the phase-out of polybrominated diphenyl ethers (PBDEs), organophosphate esters (OPEs) have been increasingly used in consumer products and building materials for their flame retardant and ...plasticizing properties. As a result, human exposure to these chemicals is widespread as evidenced by common detection of their metabolites in urine. However, little is known about the major exposure pathways, or factors that influence children's exposure to OPEs. Furthermore, little data is available on exposure to the novel aryl OPEs.
To examine predictors of children's internal exposure, we assessed relationships between OPEs in house dust and on hand wipes and levels of their corresponding metabolites in paired urine samples (n = 181). We also examined associations between urinary metabolites and potential covariates, including child's age and sex, mother's educational attainment and race, and average outdoor air temperature.
Children aged 3 to 6 years provided urine and hand wipe samples. Mothers or legal guardians completed questionnaires, and a house dust sample was taken from the main living area during home visits. Alkyl chlorinated and aryl OPEs were measured in dust and hand wipes, and composite urine samples were analyzed for several metabolites.
Tris(2-chloroethyl) phosphate (TCEP), tris(2-chloroisopropyl) phosphate (TCIPP), tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), 2-ethylhexyl diphenyl phosphate (EHDPHP), triphenyl phosphate (TPHP), and 2-isopropylphenyl diphenyl phosphate (2IPPDPP) were detected frequently in hand wipes and dust (>80%), indicating that these compounds were near-ubiquitous in indoor environments. Additionally, bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP), bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), mono-isopropyl phenyl phenyl phosphate (ip-PPP), and mono-tert-butyl phenyl phenyl phosphate (tb-PPP) were detected in >94% of tested urine samples, signifying that TESIE participants were widely exposed to OPEs. Contrary to PBDEs, house dust OPE concentrations were generally not correlated with urinary OPE metabolite levels; however, hand wipe levels of OPEs were associated with internal dose. For example, children with the highest mass of TDCIPP on hand wipes had BDCIPP levels that were 2.73 times those of participants with the lowest levels (95% CI: 1.67, 4.48, p < 0.0001). Of the variables examined, hand wipe level was the most consistent and strongest predictor of OPE urinary metabolite concentrations. Outdoor air temperature was also a significant predictor of urinary BDCIPP concentrations, with a 1 °C increase in temperature corresponding to a 4% increase in urinary BDCIPP (p < 0.0001).
OPE exposures are highly prevalent, and data provided herein further substantiate hand-to-mouth contact and dermal absorption as important pathways of OPE exposure, especially for young children.
•Exposure to organophosphate flame retardants and plasticizers was measured in children.•OPEs were measured in paired samples of handwipes, house dust and urine.•Handwipe levels of OPEs were more strongly associated with urine than house dust.•Average outdoor air temperature was a significant predictor of urinary BDCIPP.
Purpose
To examine the impact of diabetes (type 2) and glycemic control on healthcare-related outcomes (healthcare utilization, adverse effects, and treatment modifications) in non-metastatic breast ...cancer (NMBC) patients during chemotherapy treatment.
Methods
This was a retrospective study of 243 NMBC patients (stages 1–3) with/without diabetes receiving neoadjuvant or adjuvant cytotoxic chemotherapy. The primary study endpoint was to compare healthcare utilization between NMBC patients with and without diabetes. Secondary study endpoints included adverse events and chemotherapy treatment modifications. Additional analyses were conducted to compare these health-related outcomes by glycemic control status.
Results
NMBC patients with diabetes had higher utilization of emergency department (ED) services
(
52% vs. 33%,
p
= 0.013) and a higher frequency of unplanned inpatient admissions (35% vs. 19%,
p
= 0.014). Additionally, NMBC patients with diabetes had a higher incidence of infection and treatment modifications. NMBC patients, regardless of diabetes diagnosis, who had poor glycemic control, specifically hyperglycemia (per random blood glucose), during the study period also had increased healthcare utilization, adverse effects, and treatment modifications. Patients with a baseline HbA1c ≥ 7 had a greater number of ED visits and a higher incidence of infection than those without diabetes.
Conclusion
Diabetes and glycemic control may impact the health-related outcomes of NMBC patients. Additional studies are needed to confirm these findings and determine optimal monitoring and management strategies for NMBC patients with diabetes and/or poor glycemic control during cytotoxic chemotherapy.
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