Associations between serum perfluoroalkyl acid (PFAA) concentrations and health related biomarkers in firefighters.

OBJECTIVES: Firefighters who used aqueous film forming foam in the past have experienced elevated exposures to perfluoroalkyl acids (PFAAs). The objective of this study was to examine the associations between clinical chemistry endpoints and serum concentrations of perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS) and perfluorooctane sulfonate (PFOS) in firefighters. Multiple linear regression was used to assess relationships between PFAA serum concentrations and biochemical markers for cardiovascular disease, kidney-, liver- and thyroid function, in a cross-sectional survey of 783 firefighters with elevated levels of PFHxS, PFHpS and PFOS in relation to the most recently reported levels in the general Australian population. Linear logistic regression was used to assess the odds ratios for selected self-reported health outcomes. Repeated measures linear mixed models were further used to assess relationships between PFAAs and biomarkers for cardiovascular disease and kidney function longitudinally in a subset of the firefighters (n = 130) where serum measurements were available from two timepoints, five years apart. In the cross-sectional analysis, higher levels of all PFAAs were significantly associated with higher levels of biomarkers for cardiovascular disease (total-cholesterol, and LDL-cholesterol). For example, doubling in PFOS serum concentration were associated with increases in total cholesterol (ß:0.111, 95% confidence interval (95%CI): 0.026, 0.195 mmol/L) and LDL-cholesterol (ß: 0.104, 95%CI:0.03, 0.178 mmol/L). Doubling in PFOA concentration, despite not being elevated in the study population, were additionally positively associated with kidney function marker urate (e.g., ß: 0.010, 95%CI; 0.004, 0.016 mmol/L) and thyroid function marker TSH (e.g., ß: 0.087, 95%CI: 0.014, 0.161 mIU/L). PFAAs were not associated with any assessed self-reported health conditions. No significant relationships were observed in the longitudinal analysis. Findings support previous studies, particularly on the association between PFAAs and serum lipids.

Exposure and Toxicity Characterization of Chemical Emissions and Chemicals in Products: Global Recommendations and Implementation in USEtox.

PURPOSE: Reducing chemical pressure on human and environmental health is an integral part of the global sustainability agenda. Guidelines for deriving globally applicable, life cycle based indicators are required to consistently quantify toxicity impacts from chemical emissions as well as from chemicals in consumer products. In response, we elaborate the methodological framework and present recommendations for advancing near-field/far-field exposure and toxicity characterization, and for implementing these recommendations in the scientific consensus model USEtox. METHODS: An expert taskforce was convened by the Life Cycle Initiative hosted by UN Environment to expand existing guidance for evaluating human toxicity impacts from exposure to chemical substances. This taskforce evaluated advances since the original release of USEtox. Based on these advances, the taskforce identified two major aspects that required refinement, namely integrating near-field and far-field exposure and improving human dose-response modeling. Dedicated efforts have led to a set of recommendations to address these aspects in an update of USEtox, while ensuring consistency with the boundary conditions for characterizing life cycle toxicity impacts and being aligned with recommendations from agencies that regulate chemical exposure. The proposed framework was finally tested in an illustrative rice production and consumption case study. RESULTS AND DISCUSSION: On the exposure side, a matrix system is proposed and recommended to integrate far-field exposure from environmental emissions with near-field exposure from chemicals in various consumer product types. Consumer exposure is addressed via submodels for each product type to account for product characteristics and exposure settings. Case study results illustrate that product-use related exposure dominates overall life cycle exposure. On the effect side, a probabilistic dose-response approach combined with a decision tree for identifying reliable points of departure is proposed for non-cancer effects, following recent guidance from the World Health Organization. This approach allows for explicitly considering both uncertainty and human variability in effect factors. Factors reflecting disease severity are proposed to distinguish cancer from non-cancer effects, and within the latter discriminate reproductive/developmental and other non-cancer effects. All proposed aspects have been consistently implemented into the original USEtox framework. CONCLUSIONS: The recommended methodological advancements address several key limitations in earlier approaches. Next steps are to test the new characterization framework in additional case studies and to close remaining research gaps. Our framework is applicable for evaluating chemical emissions and product-related exposure in life cycle assessment, chemical alternatives assessment and chemical substitution, consumer exposure and risk screening, and high-throughput chemical prioritization.

Association of endocrine active environmental compounds with body mass index and weight loss following bariatric surgery.

INTRODUCTION: The objective of this study was to study associations of a wide range of halogenated biphenyls, dibenzo-p-dioxins, dibenzofurans and diphenylethers with body mass index (BMI) and evaluate changes in their concentration following bariatric surgery. METHODS: Subcutaneous fat, visceral fat and liver tissue samples were collected from 106 patients undergoing Roux-en-Y gastric bypass surgery for weight loss or patients who were undergoing abdominal surgery for nonbariatric reasons. We measured concentrations of an extensive panel of chlorinated and brominated biphenyls, dioxins, and furans, and brominated diphenylethers in the samples. We conducted linear regression to examine associations with BMI, adjusting for age and gender. Changes in concentration for indicator chemicals were evaluated in samples collected following bariatric surgery in a small subpopulation. RESULTS: After adjustments for age and gender and correction for multiple testing, seven ortho-chlorinated biphenyls, one nonortho-chlorinated biphenyl, four PCDD/Fs and one ortho-brominated biphenyl were associated with BMI. The strongest associations between BMI and lipid-adjusted concentrations were seen with PCB-105 in subcutaneous fat (beta = 16.838 P-val = 1.45E-06) PCB-126 in visceral fat (beta = 15.067 P-val = 7.72E-06) and PCB-118 (beta = 14.101 P-val = 2.66E-05) in liver. The concentrations of sum PCBs, chlorinated toxic equivalent quantity (TEQ's) and brominated compounds increased significantly with weight loss in subcutaneous fat in a group of ten individuals resampled up to five years after bariatric surgery and substantial weight loss. CONCLUSION: We show that selected polychlorinated biphenyls PCBs and structurally related polychlorinated dibenzo-p-dioxins dibenzofurans (PCDD/Fs) were associated with BMI. Concentrations of these lipophilic compounds in subcutaneous fat increased following bariatric surgery.

Serum measures of hexabromocyclododecane (HBCDD) and polybrominated diphenyl ethers (PBDEs) in reproductive-aged women in the United Kingdom.

We investigated the serum concentrations of two brominated flame retardants (BFRs) - polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCDD) -in 59 women aged between 23 and 42 from the United Kingdom. We also collected demographic data, including age, bodyweight and height in order to test for associations with BFR levels. Temporal and global differences were also assessed using previously published data. HBCDD was detected in 68% of samples with a mean concentration of 2.2 ng/g lipid (range = <0.3-13 ng/g lipid). The dominant stereoisomer was α-HBCDD with an average contribution of 82% (0-100%) towards ΣHBCDD, was followed by γ-HBCDD (average contribution = 17%). PBDEs were detected in 95% of samples with a mean ∑PBDE (sum of BDEs -28, -47, -99, -100, -153, -154 and -183) concentration of 2.4 ng/g lipid (range = <0.4-15 ng/g lipid). BDEs -153 and -47 were the dominant congeners, contributing an average of 40% and 37% respectively, to the average ΣPBDE congener profile. Data from this study suggests that HBCDD levels decrease with age, it also suggests a positive association between bodyweight and HBCDD levels, which likewise requires a large-scale study to confirm this. The data also show that 10 years after their European ban, PBDE body burden has begun to decrease in the UK. Whilst it is too early to draw any firm conclusions for HBCDDs, they appear to be following a similar pattern to PBDEs, with levels decreasing by a factor of >2.5 since 2010. Whilst the human body burden appear to be decreasing, both PBDEs and HBCDD are still consistently detected in human serum, despite legislative action limiting their production and use. This highlights the need to continuously assess human exposure and the effectiveness of policy aimed at reducing exposure.

Pesticide metabolite concentrations in Queensland pre-schoolers - Exposure trends related to age and sex using urinary biomarkers.

This study aimed to assess pesticide concentration and composition trends associated with age and sex in Australian infants and toddlers. Individual urine samples (n = 400) were collected in 2014/5 from Queensland infants and toddlers aged 0-5 y and composited into 20 pools of 20 individual samples by age (of 5 strata) and sex. Nineteen biomarkers including organophosphate and pyrethroid pesticide metabolites, herbicides and metabolites, and an insect repellent, DEET, were measured. In total, seven organophosphate pesticide metabolites, three pyrethroid metabolites and one herbicide metabolite were detectable in >50% of the sample pools. A significant increase of concentrations of dimethyl phosphate, dimethyl dithiophosphate, diethyl thiophosphate (DETP), 3,5,6-trichloro-2-pyridinol (TCPY), 4-nitrophenol and 3-phenoxybenzoic acid with age was observed (with the p value of <0.0001 to 0.034). This suggested that exposure increases following weaning or as a result of increased dietary intake and mobility/activity. Significant age trends remained after adjustment for body weight and urine flow for DETP and TCPY (p = 0.029 and 0.016 respectively). The level of estimated "worst-case scenario" daily intake of chlorpyrifos from these pooled samples ranged from 0.40 to 1.8 µg/kg-day, which was below the Australian Acceptable Daily Intake guideline (3 µg/kg-day). This study presents the first dataset of age trends in concentrations of these pesticides for infants and toddlers and contributed to new understanding of exposure pathways and potential risks.

Biomonitoring Equivalents for interpretation of urinary iodine.

Iodine is an essential nutrient whose deficiency or excess exposure can cause adverse health effects. The primary sources of iodine exposure in the general population are iodized salt, dairy products, bread and sea food. Urinary iodine concentrations (UIC) have been measured by Canadian Health Measures Survey (CHMS) and US National Health and Nutrition Examination Survey (NHANES). The Institute of Medicine (IOM), the US Agency for Toxic Substances and Disease Registry (ATSDR) and World Health Organization (WHO) have established exposure guidance values for nutrition (IOM Estimated Average Requirement (EAR), Recommended Dietary Allowance (RDA), WHO Recommended Nutrient Intake (RNI)) and toxicity (IOM Tolerable Upper Intake Level (UL); ATSDR Minimal Risk Level (MRL), WHO International Programme on Chemical Safety (IPCS) Tolerable Daily Intake (TDI)). Using a urinary excretion fraction of 0.9, Biomonitoring Equivalents (BE) for the EAR, RDA, UL and MRL were derived for adults (60, 100, 730 and 450 µg/L, respectively) and children (50, 80, 580 and 360 µg/L, respectively). The population median UIC values from NHANES and CHMS for adults (140-181, 122-126 µg/L, respectively) and children (232, 189 µg/L, respectively) were above the criteria for assessing iodine nutrition, indicating that US and Canadian populations are likely to have adequate population iodine nutrition. The median UIC from NHANES and CHMS do not exceed BE values derived from exposure guidance values for toxicity.

Screening-level Biomonitoring Equivalents for tiered interpretation of urinary 3-phenoxybenzoic acid (3-PBA) in a risk assessment context.

3-Phenoxybenzoic acid (3-PBA) is a common metabolite of several pyrethroid pesticides of differing potency and also occurs as a residue in foods resulting from environmental degradation of parent pyrethroid compounds. Thus, 3-PBA in urine is not a specific biomarker of exposure to a particular pyrethroid. However, an approach derived from the use of Biomonitoring Equivalents (BEs) can be used to estimate a conservative initial screening value for a tiered assessment of population data on 3-PBA in urine. A conservative generic urinary excretion fraction for 3-PBA was estimated from data for five pyrethroid compounds with human data. Estimated steady-state urinary 3-PBA concentrations associated with reference doses and acceptable daily intakes for each of the nine compounds ranged from 1.7 µg/L for cyhalothrin and deltamethrin to 520 µg/L for permethrin. The lower value can be used as a highly conservative Tier 1 screening value for assessment of population urinary 3-PBA data. A second tier screening value of 87 µg/L was derived based on weighting by relative exposure estimates for the different pyrethroid compounds, to be applied as part of the data evaluation process if biomonitoring data exceed the Tier 1 value. These BE values are most appropriately used to evaluate the central tendency of population biomarker concentration data in a risk assessment context. The provisional BEs were compared to available national biomonitoring data from the US and Canada.

Monthly variation in faeces:blood concentration ratio of persistent organic pollutants over the first year of life: a case study of one infant.

Previous studies have found that the concentrations of a range of persistent organic pollutants (POPs) in faeces is linearly proportional to the POP concentrations in blood of human adults irrespective of age and gender. In order to investigate the correlation between POP concentrations in faeces and blood in infants, the monthly variation of POP concentrations in faeces over the first year of life of one infant was investigated in this study and compared to modelled blood concentrations. Faecal samples were collected from one male infant daily. The samples were pooled by month and analysed for three selected POPs (2,2('),4,4('),5,5(')-Hexachlorobiphenyl (PCB153), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and 2,2('),4,4'-tetrabromodiphenyl ether (BDE47)). The POP concentrations in faecal samples increased for the first four months by a factor of 2.9, 4.9 and 1.4 for PCB153, BDE47, and p,p'-DDE, respectively. The faecal concentrations of all POPs decreased rapidly following the introduction of formula and solid food to the diet and subsequent weaning of the infant. Further, a one-compartment model was developed to estimate the daily POP concentrations in the blood of the infant. The POP concentrations in blood were predicted to vary much less over the first year than those observed in faeces. The faeces:blood concentration ratio of selected POPs (Kfb) differed significantly (P<0.0001) between the period before and after weaning, and observed changes in Kfb are far greater than the uncertainty in the estimated Kfb. A more stable Kfb after weaning indicates the possibility of applying the stable Kfb values for non-invasive assessment of internal exposure in infants after weaning. The intra-individual variation in Kfb in infants is worthy of further investigation.

Biomonitoring Equivalents for molybdenum.

Molybdenum is an essential trace element for mammalian, plant, and other animal systems. The Institute of Medicine (IOM) has established an Estimated Average Requirement (EAR) to assure sufficient molybdenum intakes for human populations; however excessive exposures can cause toxicity. As a result, several agencies have established exposure guidance values to protect against molybdenum toxicity, including a Reference Dose (RfD), Tolerable Daily Intake (TDI) and a Tolerable Upper Intake Level (UL). Biomonitoring for molybdenum in blood or urine in the general population is being conducted by the Canadian Health Measures Survey (CHMS) and the U.S. National Health and Nutrition Examination Survey (NHANES). Using pharmacokinetic data from controlled human dosing studies, Biomonitoring Equivalents (BEs) were calculated for molybdenum in plasma, whole blood, and urine associated with exposure guidance values set to protect against both nutritional deficits and toxicity. The BEEAR values in plasma, whole blood and urine are 0.5, 0.45 and 22 µg/L, respectively. The BEs associated with toxicity range from 0.9 to 31 µg/L in plasma, 0.8-28 µg/L in whole blood and 200-7500 µg/L in urine. These values can be used to interpret molybdenum biomonitoring data from a nutritional and toxicity perspective.

California biomonitoring data: Comparison to NHANES and interpretation in a risk assessment context.

The California Environmental Biomonitoring Program (also known as Biomonitoring California) has been generating human biomonitoring data and releasing it via their website. The current Biomonitoring California program is a collection of smaller studies, targeting specific populations (e.g., fire fighters, breast cancer patients and controls, etc.). In this paper we compare the results from Biomonitoring California with those from the US National Health and Nutrition Examination Survey (NHANES). We also compare California's results with Biomonitoring Equivalents (BEs) for those compounds for which BEs exist. In general, the results from California are consistent with the biomonitoring levels found across the US via NHANES. A few notable exceptions are levels of flame retardants amongst fire fighters in California, which are higher than observed in NHANES and some persistent organic chemicals amongst a study of breast cancer patients and controls in California which are higher than in the overall adult population in NHANES. The higher levels amongst fire fighters may be a result of fire fighters being exposed to higher levels of flame retardants while fighting fires. The higher levels of the persistent organics amongst breast cancer patients is likely due to this population being older than the mean age in NHANES. Comparisons to BEs indicate that biomonitoring levels in California are all consistently below levels of concern as established by regulatory agencies.

Sources of variability in biomarker concentrations.

Human biomonitoring has become a primary tool for chemical exposure characterization in a wide variety of contexts: population monitoring and characterization at a national level, assessment and description of cohort exposures, and individual exposure assessments in the context of epidemiological research into potential adverse health effects of chemical exposures. The accurate use of biomonitoring as an exposure characterization tool requires understanding of factors, apart from external exposure level, that influence variation in biomarker concentrations. This review provides an overview of factors that might influence inter- and intraindividual variation in biomarker concentrations apart from external exposure magnitude. These factors include characteristics of the specific chemical of interest, characteristics of the likely route(s) and frequency of exposure, and physiological characteristics of the biomonitoring matrix (typically, blood or urine). Intraindividual variation in biomarker concentrations may be markedly affected by the relationship between the elimination half-life and the intervals between exposure events, as well as by variation in characteristics of the biomonitored media such as blood lipid content or urinary flow rate. Variation across individuals may occur due to differences in time of sampling relative to exposure events, physiological differences influencing urinary flow or creatinine excretion rates or blood characteristics, and interindividual differences in metabolic rate or other factors influencing the absorption or excretion rate of a compound. Awareness of these factors can assist researchers in improving the design and interpretation of biomonitoring studies.

Interpreting estrogen screening assays in the context of potency and human exposure relative to natural exposures to phytoestrogens.

While the Environmental Protection Agency and the Organization for Economic Cooperation and Development have developed validated in vitro and in vivo screening assays to measure interaction of substances with estrogen, androgen and thyroid pathway components, to date, methods to contextualize such results in terms of potencies and actual human exposures are lacking. To place endocrine screening results in the context of potency and human exposure, we propose a method that entails (1) calculating a benchmark dose for a response measured in an endocrine screen; (2) estimating the human urinary concentration (biomonitoring equivalent, BE) expected to correspond to this dose (BEBMD ); (3) deriving the exposure:activity ratio (EAR) by comparing actual urinary values from human biomonitoring studies (e.g., National Health and Nutrition Examination Survey (NHANES)) to the BEBMD . Using OECD uterotrophic assay validation studies and NHANES results, we calculated EARs for genistein (EARGEN = 6.6 × 10(-4) ) and bisphenol A (EARBPA = 8.8 × 10(-7) ). The EARGEN is more than 700-fold greater than the EARBPA . Not only can these methods be applied to additional endocrine assays and compounds, they can contribute to weight of evidence decisions regarding the need for additional endocrine screening and testing-substances with low EARs may not warrant additional testing.

Biomonitoring Equivalents for selenium.

Selenium is an essential nutrient for human health with a narrow range between essentiality and toxicity. Selenium is incorporated into several proteins that perform important functions in the body. With insufficient selenium intake, the most notable effect is Keshan disease, an endemic cardiomyopathy in children. Conversely, excessive selenium intake can result in selenosis, manifested as brittle nails and hair and gastro-intestinal disorders. As such, guidance values have been established to protect against both insufficient and excessive selenium exposures. Dietary Reference Intakes (DRIs) have been established as standard reference values for nutritional adequacy in North America. To protect against selenosis resulting from exposure to excessive amounts of selenium, several government and non-governmental agencies have established a range of guidance values. Exposure to selenium is primarily through the diet, but monitoring selenium intake is difficult. Biomonitoring is a useful means of assessing and monitoring selenium status for both insufficient and excessive exposures. However, to be able to interpret selenium biomonitoring data, levels associated with both DRIs and toxicity guidance values are required. Biomonitoring Equivalents (BEs) were developed for selenium in whole blood, plasma and urine. The BEs associated with assuring adequate selenium intake (Estimated Average Requirements - EAR) are 100, 80 and 10µg/L in whole blood, plasma and urine, respectively. The BEs associated with protection against selenosis range from 400 to 480µg/L in whole blood, 180-230µg/L in plasma, and 90-110µg/L in urine. These BE values can be used by both regulatory agencies and public health officials to interpret selenium biomonitoring data in a health risk context.

Evaluation of urinary speciated arsenic in NHANES: issues in interpretation in the context of potential inorganic arsenic exposure.

Urinary dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) are among the commonly used biomarkers for inorganic arsenic (iAs) exposure, but may also arise from seafood consumption and organoarsenical pesticide applications. We examined speciated urinary arsenic data from National Health and Nutrition Examination Survey (NHANES) 2009-2010 cycle to assess potential correlations among urinary DMA, MMA, and the organic arsenic species arsenobetaine. Urinary DMA and MMA were positively associated with urinary arsenobetaine, suggesting direct exposure to these species in seafood or metabolism of organic arsenicals to these species, although the biomonitoring data do not directly identify the sources of exposure. The magnitude of association was much larger for DMA than for MMA. The secondary methylation index (SMI, ratio of urinary DMA to MMA) observed in the NHANES program likewise is much higher in persons with detected arsenobetaine than in those without, again suggesting that direct DMA exposure is co-occurring with exposure to arsenobetaine. Urinary MMA was less correlated with organic arsenic exposures than DMA and, therefore, may be a more reliable biomarker for iAs exposure in the general US population. However, given the associations between both MMA and DMA and organic arsenic species in urine, interpretations of the urinary arsenic concentrations observed in the NHANES in the context of potential arsenic exposure should be made cautiously.

2,4-D exposure and risk assessment: comparison of external dose and biomonitoring based approaches.

Conventional chemical exposure assessment relies upon measurements or estimates of chemical concentrations in environmental media, food, or products, in combination with assumptions regarding contact rates, in order to estimate external doses (ppm in air) or intake rates of chemicals (e.g., mg/kg/day ingested). A risk assessment is conducted by comparing these external or intake dose estimates to appropriate (e.g., route-specific) exposure guidance values (e.g., Reference Dose or Reference Concentration) to assess whether exposures are exceeding levels of concern. Human biomonitoring, in which concentrations of chemicals are measured in blood or urine, is being increasingly used as an alternative or complementary exposure assessment. The Biomonitoring Equivalent, which is the translation of a Reference Dose to an equivalent concentration of a compound in blood or urine, provides a parallel means to interpret biomonitoring data in order to assess whether chemical-specific exposures exceed levels of concern. This manuscript presents a side-by-side comparison of the two approaches for assessing exposures and risks for a case study compound, 2,4-dichlorophenoxyacetic acid (2,4-D). The findings from this case study indicate that the external dose-based assessments result in estimates of exposure and resulting hazard quotients that are consistently several-fold higher than those based on biomonitoring data. These comparisons support a conclusion that exposure assessments conducted as part of the registration process for 2,4-D incorporate sufficiently conservative assumptions.

Biomonitoring Equivalents for benzene.

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews available health based risk assessments and exposure guidance values for benzene from the United States Environmental Protection Agency (US EPA), Texas Commission on Environmental Quality (TCEQ), California's Office of Environmental Health Hazard Assessment (OEHHA) and the Agency for Toxic Substances and Disease Registry (ATSDR) to derive BE values for benzene in blood and urine. No BE values were derived for any of the numerous benzene metabolites or hemoglobin and albumin adducts. Using existing physiologically based pharmacokinetic (PBPK) models, government risk assessment values were translated into corresponding benzene levels in blood assuming chronic steady-state exposures. BEs for benzene in urine were derived using measured correlations between benzene in urine with benzene in blood. The BE values for benzene in blood range from 0.04 to 1.29 µg/L, depending upon the underlying non-cancer risk assessment used in deriving the BE. Sources of uncertainty relating to both the basis for the BE values and their use in evaluation of biomonitoring data, including the transience of the biomarkers relative to exposure frequency, are discussed. The BE values derived here can be used as screening tools for evaluation of population biomonitoring data for benzene in the context of the existing risk assessment and can assist in prioritization of the potential need for additional risk assessment efforts for benzene relative to other chemicals.