ABSTRACT
Phthalate diesters are a group of plasticizers extensively used in the manufacturing and processing of plastics. Phthalate monoesters are the primary degradation products of the diesters. Accumulation of endocrine disruptive diesters and monoesters in soil is of great concern because of the extensive use of plastic mulching and misdisposal of plastics. Accurate determination of their levels in soil is critical to assess the occurrence, exposure, and risks of phthalate diesters and monoesters. In this study, we aimed to develop a robust and environmentally friendly method for the simultaneous determination of phthalate diesters and monoesters in soil. Ultra-performance liquid chromatography coupled with electrospray tandem mass spectrometry was used for quantification, combined with accelerated solvent extraction and in-line cleanup for sample preparation. The method detection limits for the 14 diesters and 11 monoesters were in the range of 0.59 to 10.08 ng g-1 d.w. Acceptable recoveries (69%-131%) for these analytes were obtained when four deuterated analogs were used for internal calibration, and intra- and inter-day variations were less than 15%. This method was later successfully applied to five soil samples, and 8 diesters and 7 monoesters were detected with the maximum concentration up to 1142.2 ng g-1 d.w. The method developed in this study can be used for screening and accurate quantification of phthalate diesters and monoesters in soil and possibly in other environmental matrices.
Subject(s)
Phthalic Acids/analysis , Plasticizers/analysis , Soil/chemistry , Calibration , Chromatography, High Pressure Liquid/standards , Endocrine Disruptors/analysis , Endocrine Disruptors/standards , Esters/chemistry , Limit of Detection , Phthalic Acids/chemistry , Phthalic Acids/standards , Plasticizers/standards , Tandem Mass Spectrometry/standards , TemperatureABSTRACT
This manuscript presents a comprehensive analytical framework for identification and quantification of chemically diverse endocrine disrupting chemicals (EDCs) used in personal care and consumer products in diverse solid and liquid environmental matrices with an ultimate goal of evaluating public exposure to EDCs via water fingerprinting. Liquid chromatography coupled with tandem quadrupole time-of-flight mass spectrometry (UHPLC-ESI-MS/MS) was used for targeted analysis of selected EDCs as well as to identify and quantify a few metabolites using post-acquisition data mining. Solid-phase extraction (SPE) was applied to liquid matrices in order to reduce matrix effects and provide required sample concentration and ultimately, high sensitivity and selectivity of measurements. SPE recoveries in liquid samples ranged from 49 to 140% with method quantification limits not exceeding 1 ng L-1 for the majority of EDCs. Microwave-assisted extraction (MAE) was applied to solid samples and when followed by SPE, it permitted the analysis of EDCs in digested sludge. MAE/SPE recoveries varied from 11 to 186% and MQLs between 0.03 and 8.1 ng g-1 with the majority of compounds showing MQLs below 2 ng g-1. Mass error for quantifier and qualifier ions was below 5 ppm when analysing river water and effluent wastewater and below 10 ppm when analysing influent wastewater and solid samples. The method was successfully applied to environmental samples, with 33 EDCs identified and quantified in wastewater and receiving waters. In addition, several EDCs were found in digested sludge, which confirms that for a more comprehensive understanding of exposure patterns and environmental impact, analysis of solids cannot be neglected. Finally, post-acquisition data mining permitted the identification and quantification of a metabolite of BPA and the identification of a metabolite of 4-Cl-3-methylphenol. Graphical abstract á .
Subject(s)
Chromatography, High Pressure Liquid/methods , Endocrine Disruptors/analysis , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods , Water Pollutants, Chemical/analysis , Cosmetics/chemistry , Endocrine Disruptors/standards , Environmental Monitoring/methods , Fresh Water/chemistry , Limit of Detection , Reference Standards , Reproducibility of Results , Rivers/chemistry , Sewage/chemistry , Solid Phase Extraction/methods , Wastewater/chemistry , Water Pollutants, Chemical/standardsABSTRACT
Fundamental to regulatory guidelines is to identify chemicals that are implicated with adverse human health effects and inform public health risk assessors about "acceptable ranges" of such environmental exposures (e.g., from consumer products and pesticides). The process is made more difficult when accounting for complex human exposures to multiple environmental chemicals. Herein we propose a new class of nonlinear statistical models for human data that incorporate and evaluate regulatory guideline values into analyses of health effects of exposure to chemical mixtures using so-called 'desirability functions' (DFs). The DFs are incorporated into nonlinear regression models to allow for the simultaneous estimation of points of departure for risk assessment of combinations of individual substances that are parts of chemical mixtures detected in humans. These are, in contrast to published so-called biomonitoring equivalent (BE) values and human biomonitoring (HBM) values that link regulatory guideline values from in vivo studies of single chemicals to internal concentrations monitored in humans. We illustrate the strategy through the analysis of prenatal concentrations of mixtures of 11 chemicals with suspected endocrine disrupting properties and two health effects: birth weight and language delay at 2.5â¯years. The strategy allows for the creation of a Mixture Desirability Function i.e., MDF, which is a uni-dimensional construct of the set of single chemical DFs; thus, it focuses the resulting inference to a single dimension for a more powerful one degree-of-freedom test of significance. Based on the application of this new method we conclude that the guideline values need to be lower than those for single chemicals when the chemicals are observed in combination to achieve a similar level of protection as was aimed for the individual chemicals. The proposed modeling may thus suggest data-driven uncertainty factors for single chemical risk assessment that takes environmental mixtures into account.
Subject(s)
Complex Mixtures/analysis , Endocrine Disruptors/analysis , Environmental Exposure/analysis , Hazardous Substances/analysis , Models, Statistical , Birth Weight , Child, Preschool , Complex Mixtures/standards , Endocrine Disruptors/standards , Environmental Exposure/standards , Environmental Monitoring/methods , Female , Government Regulation , Hazardous Substances/standards , Humans , Infant, Newborn , Language Development Disorders/epidemiology , Male , Maternal-Fetal Exchange , Pregnancy , Risk Assessment , UncertaintyABSTRACT
The Endocrine Disruptor Screening Program (EDSP) is transitioning from traditional testing methods to integrating ToxCast/Tox21 in vitro high-throughput screening assays for identifying chemicals with endocrine bioactivity. The ToxCast high-throughput H295R steroidogenesis assay may potentially replace the low-throughput assays currently used in the EDSP Tier 1 battery to detect chemicals that alter the synthesis of androgens and estrogens. Herein, we describe an approach for identifying in vitro candidate reference chemicals that affect the production of androgens and estrogens in models of steroidogenesis. Candidate reference chemicals were identified from a review of H295R and gonad-derived in vitro assays used in methods validation and published in the scientific literature. A total of 29 chemicals affecting androgen and estrogen levels satisfied all criteria for positive reference chemicals, while an additional set of 21 and 15 chemicals partially fulfilled criteria for positive reference chemicals for androgens and estrogens, respectively. The identified chemicals included pesticides, pharmaceuticals, industrial and naturally-occurring chemicals with the capability to increase or decrease the levels of the sex hormones in vitro. Additionally, 14 and 15 compounds were identified as potential negative reference chemicals for effects on androgens and estrogens, respectively. These candidate reference chemicals will be informative for performance-based validation of in vitro steroidogenesis models.
Subject(s)
Adrenal Cortex Hormones/biosynthesis , Adrenal Cortex/drug effects , Endocrine Disruptors/toxicity , Estradiol/biosynthesis , Ovary/drug effects , Testis/drug effects , Testosterone/biosynthesis , Adrenal Cortex/cytology , Adrenal Cortex/metabolism , Adrenal Cortex Hormones/agonists , Adrenal Cortex Hormones/antagonists & inhibitors , Adrenal Cortex Hormones/metabolism , Animals , Cell Line , Cells, Cultured , Endocrine Disruptors/standards , Estradiol/agonists , Estradiol/chemistry , Estradiol/metabolism , Female , Guidelines as Topic , High-Throughput Screening Assays , Humans , Male , Osmolar Concentration , Ovary/cytology , Ovary/metabolism , Reference Standards , Small Molecule Libraries , Testis/cytology , Testis/metabolism , Testosterone/agonists , Testosterone/antagonists & inhibitors , Testosterone/metabolism , Toxicity Tests, Acute/methods , Toxicity Tests, Acute/standards , Validation Studies as TopicABSTRACT
A SETAC Pellston Workshop® "Environmental Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA)" was held in February 2016 in Pensacola, Florida, USA. The primary objective of the workshop was to provide advice, based on current scientific understanding, to regulators and policy makers; the aim being to make considered, informed decisions on whether to select an ecotoxicological hazard- or a risk-based approach for regulating a given endocrine-disrupting substance (EDS) under review. The workshop additionally considered recent developments in the identification of EDS. Case studies were undertaken on 6 endocrine-active substances (EAS-not necessarily proven EDS, but substances known to interact directly with the endocrine system) that are representative of a range of perturbations of the endocrine system and considered to be data rich in relevant information at multiple biological levels of organization for 1 or more ecologically relevant taxa. The substances selected were 17α-ethinylestradiol, perchlorate, propiconazole, 17ß-trenbolone, tributyltin, and vinclozolin. The 6 case studies were not comprehensive safety evaluations but provided foundations for clarifying key issues and procedures that should be considered when assessing the ecotoxicological hazards and risks of EAS and EDS. The workshop also highlighted areas of scientific uncertainty, and made specific recommendations for research and methods-development to resolve some of the identified issues. The present paper provides broad guidance for scientists in regulatory authorities, industry, and academia on issues likely to arise during the ecotoxicological hazard and risk assessment of EAS and EDS. The primary conclusion of this paper, and of the SETAC Pellston Workshop on which it is based, is that if data on environmental exposure, effects on sensitive species and life-stages, delayed effects, and effects at low concentrations are robust, initiating environmental risk assessment of EDS is scientifically sound and sufficiently reliable and protective of the environment. In the absence of such data, assessment on the basis of hazard is scientifically justified until such time as relevant new information is available. Integr Environ Assess Manag 2017;13:267-279. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).
Subject(s)
Endocrine Disruptors/analysis , Environmental Exposure/statistics & numerical data , Environmental Pollutants/analysis , Consensus Development Conferences as Topic , Ecotoxicology , Endocrine Disruptors/standards , Endocrine Disruptors/toxicity , Environmental Pollutants/standards , Environmental Pollutants/toxicity , Risk AssessmentABSTRACT
For ecotoxicological risk assessment, endocrine disruptors require the establishment of an endocrine mode of action (MoA) with a plausible link to a population-relevant adverse effect. Current ecotoxicity test methods incorporate mostly apical endpoints although some also include mechanistic endpoints, subcellular-through-organ level, which can help establish an endocrine MoA. However, the link between these endpoints and adverse population-level effects is often unclear. The case studies of endocrine-active substances (EAS) (tributyltin, ethinylestradiol, perchlorate, trenbolone, propiconazole, and vinclozolin) evaluated from the Society of Environmental Toxicology and Chemistry (SETAC) Pellston Workshop® "Ecotoxicological Hazard and Risk Assessment Approaches for Endocrine-Active Substances (EHRA)" were used to evaluate the population relevance of toxicity endpoints in various taxa according to regulatory endocrine-disruptor frameworks such as the Organisation for Economic Co-operation and Development (OECD) Conceptual Framework for Testing and Assessment of Endocrine Disruptors. A wide variety of potentially endocrine-relevant endpoints were identified for mollusks, fish, amphibians, birds, and mammals, although the strength of the relationship between test endpoints and population-level effects was often uncertain. Furthermore, testing alone is insufficient for assessing potential adaptation and recovery processes in exposed populations. For this purpose, models that link effects observed in laboratory tests to the dynamics of wildlife populations appear to be necessary, and their development requires reliable and robust data. As our understanding of endocrine perturbations and key event relationships improves, adverse population-level effects will be more easily and accurately predicted. Integr Environ Assess Manag 2017;13:317-330. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).
Subject(s)
Endocrine Disruptors/toxicity , Environmental Monitoring , Environmental Pollutants/toxicity , Animals , Ecotoxicology , Endocrine Disruptors/standards , Environmental Pollutants/standards , Humans , International Agencies , Mammals , Risk AssessmentABSTRACT
Reference chemicals were selected based on thyroid bioactivity in 'Tier 1' screening assays used by the U.S. EPA's Endocrine Disruptor Screening Program. Active reference chemicals had significant effects on thyroid-responsive endpoints in the amphibian metamorphosis assay, and the male and female pubertal rat assays. In the absence of thyroid weight or histopathological effects, additional published studies providing mechanistic data on thyroid activity were required for active chemicals. Inactive reference chemicals had no significant effects on thyroid-responsive endpoints in Tier 1 assays, or in amphibian or rodent studies from several online databases. The 34 reference chemicals (29 active and five inactive) will be useful for performance-based validation of alternative, high throughput screening assays for thyroid bioactivity.
Subject(s)
Biological Assay/standards , Endocrine Disruptors/standards , High-Throughput Screening Assays/standards , Thyroid Gland/drug effects , Animals , Endocrine Disruptors/toxicity , HumansABSTRACT
In view of the European Union regulations 1107/2009 and 528/2012, which say that basic substances in plant protection and biocidal products marketed in the European Union (EU) should not have an inherent capacity to cause endocrine disruption, an initiative was started to define scientific criteria for the identification of endocrine disruptors (EDs). The objectives of the EU strategy on EDs are to protect human health and the environment, to assure the functioning of the market, and to provide clear and coherent criteria for the identification of EDs that could have broad application in the EU legislation. Policy issues were to be addressed by the Ad-hoc group of Commission Services, EU Agencies and Member States established in 2010, whereas the scientific issues were to be addressed by the Endocrine Disruptors Expert Advisory Group (ED EAG), established in 2011. The ED EAG adopted the 2002 World Health Organization (WHO) definition of endocrine disruptor and agreed that for its identification it is necessary to produce convincing evidence of a biologically plausible causal link between an adverse effect and endocrine disrupting mode of action. In 2014, the European Commission proposed four ED identification criteria options and three regulatory options, which are now being assessed for socio-economic, environmental, and health impact. Slovenia supports the establishing of identification criteria and favours option 4, according to which ED identification should be based on the WHO definition with the addition of potency as an element of hazard characterisation. As for regulatory options, Slovenia favours the risk-based rather than hazard-based regulation.
Subject(s)
Endocrine Disruptors/classification , Endocrine Disruptors/standards , Environmental Exposure/standards , Guidelines as Topic , European Union , Humans , Risk Assessment , SloveniaABSTRACT
The US Environmental Protection Agency Endocrine Disruptor Screening Program (EDSP) is a tiered screening approach to determine the potential for a chemical to interact with estrogen, androgen, or thyroid hormone systems and/or perturb steroidogenesis. Use of high-throughput screening (HTS) to predict hazard and exposure is shifting the EDSP approach to (1) prioritization of chemicals for further screening; and (2) targeted use of EDSP Tier 1 assays to inform specific data needs. In this work, toxicology data for three triazole fungicides (triadimefon, propiconazole, and myclobutanil) were evaluated, including HTS results, EDSP Tier 1 screening (and other scientifically relevant information), and EPA guideline mammalian toxicology study data. The endocrine-related bioactivity predictions from HTS and information that satisfied the EDSP Tier 1 requirements were qualitatively concordant. Current limitations in the available HTS battery for thyroid and steroidogenesis pathways were mitigated by inclusion of guideline toxicology studies in this analysis. Similar margins (3-5 orders of magnitude) were observed between HTS-predicted human bioactivity and exposure values and between in vivo mammalian bioactivity and EPA chronic human exposure estimates for these products' registered uses. Combined HTS hazard and human exposure predictions suggest low priority for higher-tiered endocrine testing of these triazoles. Comparison with the mammalian toxicology database indicated that this HTS-based prioritization would have been protective for any potential in vivo effects that form the basis of current risk assessment for these chemicals. This example demonstrates an effective, human health protective roadmap for EDSP evaluation of pesticide active ingredients via prioritization using HTS and guideline toxicology information.
Subject(s)
Endocrine Disruptors/toxicity , Fungicides, Industrial/toxicity , Toxicity Tests/methods , Triazoles/toxicity , Biological Assay , Endocrine Disruptors/classification , Endocrine Disruptors/standards , Fungicides, Industrial/classification , Fungicides, Industrial/standards , Nitriles/toxicity , Triazoles/classification , Triazoles/standards , United StatesABSTRACT
BACKGROUND: Simultaneous or sequential exposure to multiple environmental stressors can affect chemical toxicity. Cumulative risk assessments consider multiple stressors but it is impractical to test every chemical combination to which people are exposed. New methods are needed to prioritize chemical combinations based on their prevalence and possible health impacts. OBJECTIVES: We introduce an informatics approach that uses publicly available data to identify chemicals that co-occur in consumer products, which account for a significant proportion of overall chemical load. METHODS: Fifty-five asthma-associated and endocrine disrupting chemicals (target chemicals) were selected. A database of 38,975 distinct consumer products and 32,231 distinct ingredient names was created from online sources, and PubChem and the Unified Medical Language System were used to resolve synonymous ingredient names. Synonymous ingredient names are different names for the same chemical (e.g., vitamin E and tocopherol). RESULTS: Nearly one-third of the products (11,688 products, 30%) contained ≥ 1 target chemical and 5,229 products (13%) contained > 1. Of the 55 target chemicals, 31 (56%) appear in ≥ 1 product and 19 (35%) appear under more than one name. The most frequent three-way chemical combination (2-phenoxyethanol, methyl paraben, and ethyl paraben) appears in 1,059 products. Further work is needed to assess combined chemical exposures related to the use of multiple products. CONCLUSIONS: The informatics approach increased the number of products considered in a traditional analysis by two orders of magnitude, but missing/incomplete product labels can limit the effectiveness of this approach. Such an approach must resolve synonymy to ensure that chemicals of interest are not missed. Commonly occurring chemical combinations can be used to prioritize cumulative toxicology risk assessments. CITATION: Gabb HA, Blake C. 2016. An informatics approach to evaluating combined chemical exposures from consumer products: a case study of asthma-associated chemicals and potential endocrine disruptors. Environ Health Perspect 124:1155-1165; http://dx.doi.org/10.1289/ehp.1510529.
Subject(s)
Consumer Product Safety , Endocrine Disruptors/toxicity , Environmental Exposure/statistics & numerical data , Asthma , Cosmetics/analysis , Endocrine Disruptors/standards , Environmental Exposure/prevention & control , Ethylene Glycols/toxicity , Humans , Parabens/toxicity , Risk AssessmentABSTRACT
BACKGROUND: A new method for the determination of four perfluoroalkyl carboxylic acids (from C5 to C8) and perfluorooctane sulfonate in human milk samples using stir-bar sorptive extraction-ultra-HPLC-MS/MS has been accurately optimized and validated. METHODOLOGY: Polydimethylsiloxane and polyethyleneglycol modified silicone materials were evaluated. DISCUSSION: Overall, polyethyleneglycol led to a better sensitivity. After optimizing experimental variables, the method was validated reaching detection limits in the range of 0.05-0.20 ng ml(-1); recovery rates from 81 to 105% and relative standard deviations fewer than 13% in all cases. The method was applied to milk samples from five randomly selected women. All samples were positive for at least one of the target compounds with concentrations ranging between 0.8 and 6.6 ng ml(-1), being the most abundant perfluorooctane sulfonate.
Subject(s)
Chromatography, High Pressure Liquid , Fluorocarbons/analysis , Milk, Human/chemistry , Adsorption , Alkanesulfonic Acids/analysis , Alkanesulfonic Acids/isolation & purification , Alkanesulfonic Acids/standards , Chromatography, High Pressure Liquid/standards , Dimethylpolysiloxanes/chemistry , Endocrine Disruptors/analysis , Endocrine Disruptors/isolation & purification , Endocrine Disruptors/standards , Female , Fluorocarbons/isolation & purification , Fluorocarbons/standards , Fractional Precipitation , Humans , Hydrogen-Ion Concentration , Limit of Detection , Quality Control , Silicones/chemistry , Sodium Chloride/chemistry , Solid Phase Extraction , Tandem Mass Spectrometry/standardsABSTRACT
Glyphosate-based herbicides (GlyBH), including Roundup, are the most widely used pesticides worldwide. Their uses have increased exponentially since their introduction on the market. Residue levels in food or water, as well as human exposures, are escalating. We have reviewed the toxic effects of GlyBH measured below regulatory limits by evaluating the published literature and regulatory reports. We reveal a coherent body of evidence indicating that GlyBH could be toxic below the regulatory lowest observed adverse effect level for chronic toxic effects. It includes teratogenic, tumorigenic and hepatorenal effects. They could be explained by endocrine disruption and oxidative stress, causing metabolic alterations, depending on dose and exposure time. Some effects were detected in the range of the recommended acceptable daily intake. Toxic effects of commercial formulations can also be explained by GlyBH adjuvants, which have their own toxicity, but also enhance glyphosate toxicity. These challenge the assumption of safety of GlyBH at the levels at which they contaminate food and the environment, albeit these levels may fall below regulatory thresholds. Neurodevelopmental, reproductive, and transgenerational effects of GlyBH must be revisited, since a growing body of knowledge suggests the predominance of endocrine disrupting mechanisms caused by environmentally relevant levels of exposure.
Subject(s)
Glycine/analogs & derivatives , Herbicides/toxicity , Pesticide Residues/toxicity , Animals , Carcinogens/analysis , Carcinogens/chemistry , Carcinogens/standards , Carcinogens/toxicity , Endocrine Disruptors/analysis , Endocrine Disruptors/chemistry , Endocrine Disruptors/standards , Endocrine Disruptors/toxicity , Glycine/analysis , Glycine/toxicity , Herbicides/analysis , Herbicides/chemistry , Herbicides/standards , Humans , Oxidative Stress/drug effects , Pesticide Residues/analysis , Pesticide Residues/chemistry , Pesticide Residues/standards , Teratogens/analysis , Teratogens/chemistry , Teratogens/standards , Teratogens/toxicity , Toxicology/methods , GlyphosateABSTRACT
Recent decades have seen an increasing interest in chemicals that interact with the endocrine system and have the potential to alter the normal function of this system in humans and wildlife. Chemicals that produce adverse effects caused by interaction with endocrine systems are termed Endocrine Disrupters (EDs). This interest has led regulatory authorities around the world (including the European Union) to consider whether potential endocrine disrupters should be identified and assessed for effects on human health and wildlife and what harmonised criteria could be used for such an assessment. This paper reviews the results of a study whereby toxicity data relating to human health effects of 98 pesticides were assessed for endocrine disruption potential using a number of criteria including the Specific Target Organ Toxicity for repeat exposure (STOT-RE) guidance values used in the European Classification, Labelling and Packaging (CLP) Regulation. Of the pesticides assessed, 27% required further information in order to make a more definitive assessment, 14% were considered to be endocrine disrupters, more or less likely to pose a risk, and 59% were considered not to be endocrine disrupters.
Subject(s)
Endocrine Disruptors/standards , Pesticides/standards , Animals , Animals, Wild , Endocrine Disruptors/toxicity , Endocrine System/drug effects , Guidelines as Topic , Humans , Pesticides/toxicity , Risk Assessment/standardsABSTRACT
Certified reference materials (CRMs) are playing an increasingly important role in national and international standardizing activities. In Japan, primary standard solutions for analyses of endocrine disrupters are supplied under the national standards dissemination system named the Japan Calibration Service System (JCSS). For the traceability on reference materials used for preparation of the primary standard solutions based on the JCSS, the National Metrology Institute of Japan, National Institute of Advanced Industrial Science and Technology (NMIJ/AIST) has developed and certified high-purity reference materials of alkylphenols as NMIJ CRMs, such as 4-n-nonylphenol, 4-tert-octylphenol, 4-n-heptylphenol, 4-tert-butylphenol, and 2,4-dichlorophenol. Thereafter, it is essential to determine the alkylphenols by using these solutions based on the JCSS for environmental monitoring and risk assessments because analytical values obtained by using the solutions can ensure the reliability and traceability of the chemical analyses.