A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Exploring reproductive associations of serum polybrominated diphenyl ether and hydroxylated brominated diphenyl ether concentrations among women undergoing in vitro fertilization.

STUDY QUESTION: Are serum concentrations of polybrominated diphenyl ethers (PBDEs) and hydroxylated brominated diphenyl ethers (OH-BDEs) associated with IVF endpoints? SUMMARY ANSWER: Positive associations were observed for BDE153 and several OH-BDEs with IVF endpoints. WHAT IS KNOWN ALREADY: PBDEs have been voluntarily phased out of production in the USA and EU due to their persistence and toxicity to humans and ecosystems. PBDEs have been associated with implantation failure among women undergoing IVF, yet some animal studies suggest greater toxicity from their metabolites, OH-BDEs. STUDY DESIGN, SIZE, DURATION: We evaluated a subset of 215 women (contributing 330 IVF cycles) enrolled between 2005 and 2016 in a longitudinal cohort based at Massachusetts General Hospital Fertility Center. PARTICIPANTS/MATERIALS, SETTING, METHODS: The following PBDEs were quantified: 47, 99, 100, 153 and 154 and the following OH-BDEs: 3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49. Clinical endpoints of IVF treatments were abstracted from electronic medical records. Associations of log-transformed PBDEs and OH-BDEs with IVF outcomes were assessed using multivariable generalized mixed models and cluster weighted generalized estimating equation models adjusted for lipids, age, BMI, race, year of sample collection, IVF protocol and FSH levels. Outcomes were adjusted to represent a percent change in outcome with an increase equal to the magnitude of the difference between the 75th and 25th percentiles for each specific compound (interquartile range (IQR) increase). MAIN RESULTS AND THE ROLE OF CHANCE: Detection frequencies were highest for congeners 47 and 153 (82% ≥ method detection limit (MDL)) and metabolites 3 and 5-OH-BDE47 and 4-OH-BDE49 (92% > MDL). PBDE and OH-BDE geometric mean concentrations declined by up to 80% between participants recruited in 2005 and those recruited in 2016. An IQR increase of BDE153 was associated with an increase in the probability of implantation (relative risk (RR) = 1.26, 95% CI: 1.16, 1.36), clinical pregnancy (RR = 1.32, 95% CI: 1.19, 1.46) and live birth (RR = 1.34; 95% CI: 1.15, 1.54). An IQR increase in 3 and 5-OH-BDE47 was associated with increased probabilities of implantation (RR = 1.52; 95% CI: 1.11, 2.09), clinical pregnancy (RR = 1.66; 95% CI: 1.17, 2.36), and live birth (RR = 1.61; 95% CI: 1.07, 2.40). When models were stratified by race (White (86%)/Other race (14%)), associations remained positive for White women, yet inverse associations were observed for Other race women. An IQR increase in BDE47 was associated with a 46% decreased probability of clinical pregnancy (95% CI: 0.31, 0.95) for Other race women. LIMITATIONS, REASONS FOR CAUTION: Despite the long half-lives of PBDEs and OH-BDEs, exposure misclassification is possible for women who underwent multiple treatment cycles over several months or years. It is also possible another medium, such as follicular fluid would be optimal to characterize exposure. We also tested associations for multiple congeners and metabolites with multiple outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Detections of serum concentrations of PBDEs and OH-BDEs were highest in the early years of the study and suggests that the phase-out of these compounds has contributed to a decrease in exposure. The negative associations found for PBDEs and IVF outcomes among other race women suggests the potential for racial disparity. Potential racial disparities in PBDE exposure and exploration of alternative flame retardants with reproductive health outcomes should be the focus of future investigations. STUDY FUNDING/COMPETING INTEREST(S): Funding for this research was supported by the National Institutes of Environmental Health Sciences (NIEHS) [R01 ES009718, ES022955, ES000002 and 009718T32ES007069]. The authors have no conflicts of interest.

The association of urinary phosphorous-containing flame retardant metabolites and self-reported personal care and household product use among couples seeking fertility treatment.

BACKGROUND: Phosphorous-containing flame-retardants (PFRs) are widely detected. They are used both as a flame retardant as well as plasticizer. METHODS: A subset of 230 women and 229 men were recruited from Massachusetts General Hospital fertility clinic between 2005 and 2015. At each visit, participants completed a questionnaire of personal care product (PCP) and household product (HP) use. Metabolites [bis(1,3-dichloro-2-propyl) phosphate, diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate and bis(1-chloro-2-propyl) phosphate] were measured in urine (1-5 samples; n = 638 women, n = 335 men). Associations were assessed using generalized mixed models, adjusted for SG, age, BMI, smoking, education, and season. RESULTS: In women, moisturizer (60%), nail polish remover (77%), and nail polish (134%) use were associated (p < 0.05) with an increase in DPHP concentrations, while ip-PPP concentrations increased 21-27% with conditioner, cosmetics, deodorant, and hair product use. Mouthwash and vinyl glove use were associated with a respective 31% and 92% increase in DPHP among men. CONCLUSIONS: Our exploratory analysis suggests PFRs may be used as a plasticizer in consumer products, and nail polish use contributes to internal DPHP exposure. Further research is needed to understand how PFRs are used in these products and how it relates to exposure.

Organophosphate flame-retardant metabolite concentrations and pregnancy loss among women conceiving with assisted reproductive technology.

OBJECTIVE: To evaluate whether urinary concentrations of organophosphate flame retardant (PFR) metabolites are associated with pregnancy loss among women conceiving with assisted reproductive technology (ART). DESIGN: Prospective preconception cohort of subfertile women. SETTING: Academic hospital fertility center in Boston, Massachusetts. PATIENT(S): A total of 155 women conceiving 179 pregnancies with ART. INTERVENTION(S): None. Mean exposure to each of five PFR metabolites was estimated by averaging the specific-gravity adjusted natural log concentrations from two urine samples collected during the ART cycle of conception. MAIN OUTCOME MEASURE(S): Adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for biochemical and total pregnancy loss (all losses <20 weeks' gestation) by quartiles of PFR metabolite concentrations were estimated using a repeated measures log-binomial model, accounting for multiple pregnancies per woman. RESULT(S): Of the 179 pregnancies, 31% ended in pregnancy loss (12% in biochemical loss). Among the three metabolites with high detection frequency [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), and isopropylphenyl phenyl phosphate (ip-PPP)], an increased risk of biochemical loss was observed for women with DPHP concentrations in the fourth vs. first quartile (RR 1.64; 95% CI 0.61-4.39). Also found was an elevated risk of biochemical pregnancy loss among women in the highest quartile of the molar sum of urinary PFR metabolites compared with the lowest (RR 1.89; 95% CI 0.64-5.58). Urinary concentrations of ip-PPP and BDCIPP were not associated with either outcome. CONCLUSION(S): Among subfertile women, urinary DPHP metabolite concentrations measured during the ART cycle of conception may be associated with early pregnancy loss. Although this study is uniquely designed to investigate early markers of pregnancy success and maintenance, the small sample size likely contributed to imprecision. Given their increasing use as replacement chemicals for traditional flame retardants, exposure to PFRs may increase, and more studies will be needed to investigate their potential to impact pregnancy and reproduction.

The association between urinary concentrations of phosphorous-containing flame retardant metabolites and semen parameters among men from a fertility clinic.

BACKGROUND: The use of PFRs has steadily increased as brominated compounds have been or are being phased out. Human exposure is widespread and animal studies have shown adverse impacts on male reproduction, but human data are lacking. OBJECTIVE: To study the associations between urinary concentrations of phosphorous-containing flame retardant (PFR) metabolites and semen parameters. METHODS: A subset of 220 men from an existing longitudinal cohort of couples were recruited from Massachusetts General Hospital fertility clinic between 2005 and 2015. Semen parameters included sperm count, concentration, motility, and morphology; some men had samples measured from multiple clinic visits (up to five visits; n = 269 semen samples). Metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP) and bis(1-chloro-2-propyl) phosphate (BCIPP)] were measured in urine samples (between one and five urine samples per participant; n = 355 urine samples). Semen parameters were evaluated continuously and dichotomized for models. Metabolites were assessed for associations with semen parameters as continuous and categorized into quartiles using multivariable generalized mixed models, adjusted for specific gravity, age, BMI, smoking, and abstinence period. RESULTS: Metabolites BDCIPP, DPHP, and ip-PPP were detected in a high proportion of urine samples (85%, 86%, and 65% respectively). Concentrations varied by season of collection, particularly for BDCIPP where samples collected in the summer were approximately 2-fold higher than concentrations of other seasons (p < 0.0001). The odds of having a sperm count less than 39 mil/ejaculate decreased by 20% for increasing BDCIPP concentrations (p = 0.04). When regressing semen parameters on PFR metabolite quartiles, some negative associations were observed for individual quartiles among sample volume and morphology, but overall associations were weak and inconsistent. CONCLUSION: Detection rates were high for BDCIPP, DPHP, and ip-PPP. We did not observe consistent associations between PFR metabolites and semen parameters. Due to the high prevalence of exposure, further investigation of other potential health effects should be conducted.

Paternal urinary concentrations of organophosphate flame retardant metabolites, fertility measures, and pregnancy outcomes among couples undergoing in vitro fertilization.

BACKGROUND: Use of organophosphate flame retardants (PFRs) has increased over the past decade following the phase out of some brominated flame retardants, leading to increased human exposure. We recently reported that increasing maternal PFR exposure is associated with poorer pregnancy outcomes among women from a fertility clinic. Because a small epidemiologic study previously reported an inverse association between male PFR exposures and sperm motility, we sought to examine associations of paternal urinary concentrations of PFR metabolites and their partner's pregnancy outcomes. METHODS: This analysis included 201 couples enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. In both the male and female partner, we measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP) and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). The sum of the molar concentrations of the urinary PFR metabolites was calculated. We used multivariable generalized linear mixed models to evaluate the association of urinary concentrations of paternal PFR metabolites with IVF outcomes, accounting for multiple in vitro fertilization (IVF) cycles per couple. Models were adjusted for year of IVF treatment cycle, primary infertility diagnosis, and maternal urinary PFR metabolites as well as paternal and maternal age, body mass index, and race/ethnicity. RESULTS: Detection rates were high for paternal urinary concentrations of BDCIPP (84%), DPHP (87%) and ip-PPP (76%) but low for tb-PPP (12%) and zero for BCIPP (0%). We observed a significant 12% decline in the proportion of fertilized oocytes from the first to second quartile of male urinary ΣPFR and a 47% decline in the number of best quality embryos from the first to third quartile of male urinary BDCIPP in our adjusted models. An 8% decline in fertilization was observed for the highest compared to lowest quartile of urinary BDCIPP concentrations (95% CI: 0.01, 0.12, p-trend=0.06). CONCLUSIONS: Using IVF as a model to investigate human reproduction and pregnancy outcomes, we found that paternal urinary concentrations of BDCIPP were associated with reduced fertilization. In contrast to previously reported findings for the female partners, the paternal urinary PFR metabolites were not associated with the proportion of cycles resulting in successful implantation, clinical pregnancy, and live birth. These results indicate that paternal preconception exposure to TDCIPP may adversely impact successful oocyte fertilization, whereas female preconception exposure to ΣPFRs may be more relevant to adverse pregnancy outcomes.

Urinary Concentrations of Organophosphate Flame Retardant Metabolites and Pregnancy Outcomes among Women Undergoing in Vitro Fertilization.

BACKGROUND: Evidence from animal studies suggests that exposure to organophosphate flame retardants (PFRs) can disrupt endocrine function and impair embryo development. However, no epidemiologic studies have been conducted to evaluate effects on fertility and pregnancy outcomes. OBJECTIVES: We evaluated associations between urinary concentrations of PFR metabolites and outcomes of in vitro fertilization (IVF) treatment among couples recruited from an academic fertility clinic. METHODS: This analysis included 211 women enrolled in the Environment And Reproductive Health (EARTH) prospective cohort study (2005-2015) who provided one or two urine samples per IVF cycle. We measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). Molar concentrations of the urinary PFR metabolites were summed. We used multivariable generalized linear mixed models to evaluate the association of the PFR metabolites with IVF outcomes, accounting for multiple IVF cycles per woman. RESULTS: Detection frequencies were high for BDCIPP (87%), DPHP (94%), and ip-PPP (80%), but low for tb-PPP (14%) and BCIPP (0%). We observed decreased success for several IVF outcomes across increasing quartiles of both summed and individual PFR metabolites (DPHP and ip-PPP) in our adjusted multivariable models. Significant declines in adjusted means from the lowest to highest quartile of ΣPFR were observed for the proportion of cycles resulting in successful fertilization (10% decrease), implantation (31%), clinical pregnancy (41%), and live birth (38%). CONCLUSIONS: Using IVF to investigate human reproduction and pregnancy outcomes, we found that concentrations of some urinary PFR metabolites were negatively associated with proportions of successful fertilization, implantation, clinical pregnancy, and live birth. https://doi.org/10.1289/EHP1021.

Influence of storage vial material on measurement of organophosphate flame retardant metabolites in urine.

Use of organophosphate flame retardants (PFRs) has increased over the past decade with the phase out of polybrominated diphenyl ethers. Urinary metabolites of PFRs are used as biomarkers of exposure in epidemiologic research, which typically uses samples collected and stored in polypropylene plastic cryovials. However, a small study suggested that the storage vial material may influence reported concentrations. Therefore, we aimed to examine the influence of the storage vial material on analytical measurement of PFR urinary metabolites. Using urine samples collected from participants in the Environment and Reproductive Health (EARTH) Study, we analyzed the PFR metabolites in duplicate aliquots that were stored in glass and plastic vials (n = 31 pairs). Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP) and isopropyl-phenyl phenyl phosphate (ip-PPP) were detected in 98%, 97% and 87% of duplicates. We observed high correlations between glass-plastic duplicates for BDCIPP (rs = 0.95), DPHP (rs = 0.79) and ip-PPP (rs = 0.82) (p < 0.0001). Urinary ip-PPP was an average of 0.04 ng/ml (p = 0.04) higher among samples stored in glass, with a mean relative difference of 14%. While this difference is statistically significant, it is small in magnitude. No differences were observed for BDCIPP or DPHP, however future research should seek to reduce the potential for type II error (false negatives). We conclude that storing urine samples in polypropylene plastic cryovials may result in slightly reduced concentrations of urinary ip-PPP relative to storage in glass vials and future research should seek to increase the sample size, reduce background variability and consider the material of the urine collection cup.

Contribution of breast milk and formula to arsenic exposure during the first year of life in a US prospective cohort.

Arsenic is a carcinogen that can also affect the cardiac, respiratory, neurological and immune systems. Children have higher dietary arsenic exposure than adults owing to their more restricted diets and greater intake per unit body mass. We evaluated the potential contributions of breast milk and formula to arsenic exposure throughout the first year of life for 356 infants in the prospective New Hampshire Birth Cohort Study (NHBCS) using infant diets reported by telephone at 4, 8 and 12 months of age; measured household water arsenic concentrations; and literature data. Based on our central-tendency models, population-wide geometric mean (GM) estimated arsenic exposures in the NHBCS were relatively low, decreasing from 0.1 µg/kg/day at 4 months of age to 0.07 µg/kg/day at 12 months of age. At all three time points, exclusively formula-fed infants had GM arsenic exposures ~8 times higher than exclusively breastfed infants owing to arsenic in both tap water and formula powder. Estimated maximum exposures reached 9 µg/kg/day among exclusively formula-fed infants in households with high tap water arsenic (80 µg/l). Overall, modeled arsenic exposures via breast milk and formula were low throughout the first year of life, unless formula was prepared with arsenic-contaminated tap water.

Temporal variability of polybrominated diphenyl ether (PBDE) serum concentrations over one year.

Polybrominated diphenyl ethers (PBDEs) are flame retardant chemicals used in consumer products. They are common contaminants in human serum and associated with adverse health effects. Our objectives were to characterize PBDE serum concentrations in a New England cohort and assess temporal variability of this exposure biomarker over a one-year period. We collected three repeated measurements at six-month intervals from 52 office workers from the greater Boston (MA, United States) area from 2010 to 2011. The intraclass correlation coefficient for BDEs 28, 47, 99, 100, and 153 ranged from 0.87 to 0.99, indicating that a single serum measurement can reliably estimate exposure over a one-year period. This was true for both lipid adjusted and nonlipid adjusted concentrations. The kappa statistics, quantifying the level of agreement of categorical exposure classification, based on medians, tertiles, or quartiles ranged from 0.67 to 0.90. Some congeners showed nonsignificant increases from sampling round 1 (winter) to round 2 (summer) and significant decreases from round 2 to round 3 (winter). This study highlights the high reliability of a single serum PBDE measurement for use in human epidemiologic studies.

Predictors of tris(1,3-dichloro-2-propyl) phosphate metabolite in the urine of office workers.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is a flame retardant widely used in furniture containing polyurethane foam. It is a carcinogen, endocrine disruptor, and potentially neurotoxic. Our objectives were to characterize exposure of adult office workers (n=29) to TDCPP by measuring its primary metabolite, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), in their urine; measuring TDCPP in dust from their homes; offices and vehicles; and assessing possible predictors of exposure. We identified TDCPP in 99% of dust (GM=4.43µg/g) and BDCPP in 100% of urine samples (GM=408pg/mL). Concentrations of TDCPP were significantly higher in dust from vehicles (GM=12.5µg/g) and offices (GM=6.06µg/g) than in dust from the main living area (GM=4.21µg/g) or bedrooms (GM=1.40µg/g) of worker homes. Urinary BDCPP concentrations among participants who worked in a new office building were 26% of those who worked in older buildings (p=0.01). We found some evidence of a positive trend between urinary BDCPP and TDCPP in office dust that was not observed in the other microenvironments and may be related to the timing of urine sample collection during the afternoon of a workday. Overall our findings suggest that exposure to TDCPP in the work environment is one of the contributors to the personal exposure for office workers. Further research is needed to confirm specific exposure sources (e.g., polyurethane foam), determine the importance of exposure in other microenvironments such as homes and vehicles, and address the inhalation and dermal exposure pathways.