Comparing the Use of Silicone Wristbands, Hand Wipes, And Dust to Evaluate Children's Exposure to Flame Retardants and Plasticizers.

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 (rs = 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.

Incidence of venous thromboembolism among patients receiving neoadjuvant chemotherapy for advanced epithelial ovarian cancer.

OBJECTIVES: Neoadjuvant chemotherapy may be considered for women with epithelial ovarian cancer who have poor performance status or a disease burden not amenable to primary cytoreductive surgery. Overlap exists between indications for neoadjuvant chemotherapy and known risk factors for venous thromboembolism, including impaired mobility, increasing age, and advanced malignancy. The objective of this study was to determine the rate of venous thromboembolism among women receiving neoadjuvant chemotherapy for epithelial ovarian cancer. METHODS: A multi-institutional, observational study of patients receiving neoadjuvant chemotherapy for primary epithelial ovarian, fallopian tube, or peritoneal cancer was conducted. Primary outcome was rate of venous thromboembolism during neoadjuvant chemotherapy. Secondary outcomes included rates of venous thromboembolism at other stages of treatment (diagnosis, following interval debulking surgery, during adjuvant chemotherapy, or during treatment for recurrence) and associations between occurrence of venous thromboembolism during neoadjuvant chemotherapy, subject characteristics, and interval debulking outcomes. Venous thromboembolism was defined as deep vein thrombosis in the upper or lower extremities or in association with peripherally inserted central catheters or ports, pulmonary embolism, or concurrent deep vein thrombosis and pulmonary embolism. Both symptomatic and asymptomatic venous thromboembolism were reported. RESULTS: A total of 230 patients receiving neoadjuvant chemotherapy were included; 63 (27%) patients overall experienced a venous thromboembolism. The primary outcome of venous thromboembolism during neoadjuvant chemotherapy occurred in 16 (7.7%) patients. Of the remaining venous thromboembolism events, 22 were at diagnosis (9.6%), six post-operatively (3%), five during adjuvant chemotherapy (3%), and 14 during treatment for recurrence (12%). Patients experiencing a venous thromboembolism during neoadjuvant chemotherapy had a longer mean time to interval debulking and were less likely to undergo optimal cytoreduction (50% vs 80.2%, p=0.02). CONCLUSIONS: Patients with advanced ovarian cancer are at high risk for venous thromboembolism while receiving neoadjuvant chemotherapy. Consideration of thromboprophylaxis may be warranted.

Infants' diminished response to DTaP vaccine is associated with exposure to organophosphate esters.

Organophosphate esters (OPEs) are commonly applied as flame retardants and plasticizers. Toxicological studies suggest exposure effects on immune endpoints, raising concerns as infants' OPE exposures are elevated compared to older children and adults due to hand-to-mouth behavior and breastfeeding. Here, we sought to evaluate the immune responsiveness of infants to a neoantigen (e.g., a newly encountered antigen) in the presence of OPE exposures. As a proxy for immune responsiveness, children were given three doses of the Diphtheria, Tetanus, and Pertussis (DTaP) vaccine as recommended, and diphtheria and tetanus antibodies were evaluated in serum samples collected when children were 12 months old (n = 84). Titers were compared, based on maximum sample overlap, to measurements of OPE metabolites in spot urine samples collected before vaccination (age 2 months, n = 73) and at the time of antibody assessment (12 months of age, n = 46). Metabolites of two chlorinated OPEs were significantly associated with diminished antibodies for diphtheria and tetanus. A metabolite of tris (1,3-dichloroisopropyl)phosphate (TDCIPP) measured at 2 months was associated with decreased diphtheria antibodies (-0.07 IU/mL per log10 increase in metabolite). One metabolite of tris(2-chloroisopropyl)phosphate (TCIPP) measured at 12 months was associated with decreased tetanus antibodies (-0.57 IU/mL per log10 increase in metabolite). These results provide some preliminary insights for OPE exposure impacts on vaccine responses in early life and may have important implications for immune health through childhood and adulthood.

Young infants' exposure to organophosphate esters: Breast milk as a potential source of exposure.

Organophosphate esters (OPEs) are applied as both flame retardants and plasticizers to a variety of consumer items such as home furnishings, construction materials, and children's products. While some assessments have characterized exposure among toddlers and young children, little is known about the OPE exposure among infants, who are a vulnerable population due to their rapid development. Here, we collected spot urine samples from 6-week-old (n = 100) and 12-month-old infants (n = 63), with about half of the infants evaluated at both ages (n = 52), to characterize OPE exposure and determine what factors contributed to higher exposures. Five of six OPE metabolites analyzed were detected frequently (>70%). Diphenyl phosphate was detected in every urine sample, while bis(2-chloro-isopropyl) phosphate (BCIPP) was the most abundant metabolite measured overall. Concentrations of bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP) and BCIPP [i.e., metabolites of tris(2-chloro-isopropyl) phosphate (TCIPP)] were significantly greater among 6-week-old infants compared to 12-month-olds, while levels of other OPE metabolites were not statistically different in the first year of life. OPE metabolites were generally correlated with one another in samples collected at each age (rs = 0.25-0.75; p < 0.05), and except BCIPHIPP, concentrations of the same metabolite were correlated over time (rs = 0.41-0.53; p < 0.05). Breastfeeding at 6 weeks of age and owning a larger number of children's products were associated with increased concentrations of urinary BDCIPP. Infants who were currently receiving breast milk had higher levels of TCIPP metabolites; urinary BCIPP concentrations were 6.2 times higher in infants receiving breast milk at 6 weeks of age, and BCIPHIPP levels were 2.2 times higher for 12-month-old infants receiving breast milk (10ß = 7.2; 95% CI: 1.6-32.1 and 10ß = 3.2; 95% CI: 1.2-8.1, respectively). Differences in the predominant TCIPP metabolite associated with breastfeeding may suggest differences in metabolism with age. Cumulatively, our results suggest levels of OPE exposure may be higher for infants than other age groups, including toddlers and older children.

Children's exposure to phthalates and non-phthalate plasticizers in the home: The TESIE study.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Children's residential exposure to organophosphate ester flame retardants and plasticizers: Investigating exposure pathways in the TESIE study.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Biomarkers of exposure to SVOCs in children and their demographic associations: The TESIE Study.

Semi-volatile organic compounds (SVOCs) are used extensively in consumer and personal care products; electronics; furniture; and building materials and are detected in most indoor environments. As a result, human exposure to mixtures of SVOCs is wide-spread. However, very few studies have measured biomarkers of exposure to multiple SVOC classes, and exposure determinants have not been thoroughly explored, particularly for young children. In this study, we investigated biomarkers of exposure to SVOCs among children (age 3-6 years), who may experience higher exposures and be more susceptible to adverse health outcomes than other age groups. We enrolled 203 participants in the Toddlers Exposure to SVOCs in Indoor Environments (TESIE) study (181 provided urine samples and 90 provided serum samples).We quantified 44 biomarkers of exposure to phthalates, organophosphate esters (OPEs), parabens, phenols, antibacterial agents and per- and polyfluoroalkyl substances (PFASs); we detected 29 of the 44 biomarkers in >95% of samples, and many biomarkers were detected at higher median concentrations than those previously reported in the U.S. general population. Demographic characteristics were associated with differences in concentrations. In general, non-Hispanic white race and higher maternal education were associated with lower concentrations, even after adjusting for other potential confounding variables. Our results suggest that outdoor temperature at the time of biospecimen collection may be a particularly important and under-evaluated predictor of biomarker concentrations; statistically significant relationships were observed between 10 biomarkers and outdoor temperature at the time of collection. A complex correlation structure was also observed among the biomarkers assessed. By and large, statistically significant correlations between biomarkers of exposure to phthalates, parabens, phenols, and OPEs were positive. Conversely, although PFASs were positively correlated with one another, they tended to be negatively correlated with other biomarkers where significant associations were observed. Taken together, our results provide evidence that the assessments of SVOC-associated health impacts should focus on chemical mixtures.

Associations between flame retardant applications in furniture foam, house dust levels, and residents' serum levels.

Polyurethane foam (PUF) in upholstered furniture frequently is treated with flame retardant chemicals (FRs) to reduce its flammability and adhere to rigorous flammability standards. For decades, a commercial mixture of polybrominated diphenyl ethers (PBDEs) called PentaBDE was commonly applied to foam to fulfill these regulations; however, concerns over toxicity, bioaccumulation, and persistence led to a global phase-out in the mid-2000s. Although PentaBDE is still detected in older furniture, other FR compounds such as tris(1,3-dichloroisopropyl) phosphate (TDCIPP) and Firemaster® 550 (FM550) have been increasingly used as replacements. While biomonitoring studies suggest exposure is widespread, the primary sources of exposure are not clearly known. Here, we investigated the relationships between specific FR applications in furniture foam and human exposure. Paired samples of furniture foam, house dust and serum samples were collected from a cohort in North Carolina, USA and analyzed for FRs typically used in PUF. In general, the presence of a specific FR in the sofa of a home was associated with an increase in the concentration of that FR in house dust. For example, the presence of PentaBDE in sofas was associated with significantly higher levels of BDE-47, a major component of PentaBDE, in house dust (10ß=6.4, p<0.001). A similar association was observed with a component of FM550, 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB), with levels that were approximately 3 times higher in house dust when FM550 was identified in the sofa foam (p<0.01). These relationships were modified by dust loading rates in the living room and the ratio of sofa size to room size. Interestingly, levels of TDCIPP and tris(1-chloro-2-isopropyl) phosphate (TCIPP) were also higher in dust with detections in sofa foam; however, these associations were not statistically significant and may suggest there are other prominent sources of these compounds in the home. In addition, the presence of PentaBDE in sofa foam was associated with significantly higher levels of BDE-47 in serum (p<0.01). These results suggest that FR applications in sofas are likely major sources of exposure to these compounds in the home.

Temporal Trends in Exposure to Organophosphate Flame Retardants in the United States.

During the past decade, use of organophosphate compounds as flame retardants and plasticizers has increased. Numerous studies investigating biomarkers (i.e., urinary metabolites) demonstrate ubiquitous human exposure and suggest that human exposure may be increasing. To formally assess temporal trends, we combined data from 14 U.S. epidemiologic studies for which our laboratory group previously assessed exposure to two commonly used organophosphate compounds, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and triphenyl phosphate (TPHP). Using individual-level data and samples collected between 2002 and 2015, we assessed temporal and seasonal trends in urinary bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and diphenyl phosphate (DPHP), the metabolites of TDCIPP and TPHP, respectively. Data suggest that BDCIPP concentrations have increased dramatically since 2002. Samples collected in 2014 and 2015 had BDCIPP concentrations that were more than 15 times higher than those collected in 2002 and 2003 (10ß = 16.5; 95% confidence interval from 9.64 to 28.3). Our results also demonstrate significant increases in DPHP levels; however, increases were much smaller than for BDCIPP. Additionally, results suggest that exposure varies seasonally, with significantly higher levels of exposure in summer for both TDCIPP and TPHP. Given these increases, more research is needed to determine whether the levels of exposure experienced by the general population are related to adverse health outcomes.