Hormone receptor activities of complex mixtures of known and suspect chemicals in personal silicone wristband samplers worn in office buildings.

Humans are exposed to increasingly complex mixtures of hormone-disrupting chemicals from a variety of sources, yet, traditional research methods only evaluate a small number of chemicals at a time. We aimed to advance novel methods to investigate exposures to complex chemical mixtures. Silicone wristbands were worn by 243 office workers in the USA, UK, China, and India during four work shifts. We analyzed extracts of the wristbands for: 1) 99 known (targeted) chemicals; 2) 1000+ unknown chemical features, tentatively identified through suspect screening; and 3) total hormonal activities towards estrogen (ER), androgen (AR), and thyroid hormone (TR) receptors in human cell assays. We evaluated associations of chemicals with hormonal activities using Bayesian kernel machine regression models, separately for targeted versus suspect chemicals (with detection ≥50%). Every wristband exhibited hormonal activity towards at least one receptor: 99% antagonized TR, 96% antagonized AR, and 58% agonized ER. Compared to men, women were exposed to mixtures that were more estrogenic (180% higher, adjusted for country, age, and skin oil abundance in wristband), anti-androgenic (110% higher), and complex (median 836 detected chemical features versus 780). Adjusted models showed strong associations of jointly increasing chemical concentrations with higher hormonal activities. Several targeted and suspect chemicals were important co-drivers of overall mixture effects, including chemicals used as plasticizers, fragrance, sunscreen, pesticides, and from other or unknown sources. This study highlights the role of personal care products and building microenvironments in hormone-disrupting exposures, and the substantial contribution of chemicals not often identifiable or well-understood to those exposures.

Assessing Indoor Dust Interference with Human Nuclear Hormone Receptors in Cell-Based Luciferase Reporter Assays.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), organophosphate esters (OPEs), and polybrominated diphenyl ethers (PBDEs) are hormone-disrupting chemicals that migrate from building materials into air and dust. OBJECTIVES: We aimed to quantify the hormonal activities of 46 dust samples and identify chemicals driving the observed activities. METHODS: We evaluated associations between hormonal activities of extracted dust in five cell-based luciferase reporter assays and dust concentrations of 42 measured PFAS, OPEs, and PBDEs, transformed as either raw or potency-weighted concentrations based on Tox21 high-throughput screening data. RESULTS: All dust samples were hormonally active, showing antagonistic activity toward peroxisome proliferator-activated receptor (PPARγ2) (100%; 46 of 46 samples), thyroid hormone receptor (TRß) (89%; 41 samples), and androgen receptor (AR) (87%; 40 samples); agonist activity on estrogen receptor (ERα) (96%; 44 samples); and binding competition with thyroxine (T4) on serum transporter transthyretin (TTR) (98%; 45 samples). Effects were observed with as little as 4µg of extracted dust. In regression models for each chemical class, interquartile range increases in potency-weighted or unknown-potency chemical concentrations were associated with higher hormonal activities of dust extracts (potency-weighted: ΣPFAS-TRß, ↑28%, p<0.05; ΣOPEs-TRß, ↑27%, p=0.08; ΣPBDEs-TRß, ↑20%, p<0.05; ΣPBDEs-ERα, ↑7.7%, p=0.08; unknown-potency: ΣOPEs-TTR, ↑34%, p<0.05; ΣOPEs-AR, ↑13%, p=0.06), adjusted for chemicals with active, inactive, and unknown Tox21 designations. DISCUSSION: All indoor dust samples exhibited hormonal activities, which were associated with PFAS, PBDE, and OPE levels. Reporter gene cell-based assays are relatively inexpensive, health-relevant evaluations of toxic loads of chemical mixtures that building occupants are exposed to. https://doi.org/10.1289/EHP8054.

Dibutyl-phthalate exposure from mesalamine medications and serum thyroid hormones in men.

BACKGROUND: Dibutyl phthalate (DBP) is an endocrine disruptor and used in some medication coatings, such as mesalamine for treatment inflammatory bowel disease (IBD). OBJECTIVES: To determine whether high-DBP from some mesalamine medications alters thyroid function. METHODS: Seventy men with IBD, without thyroid disease or any radiation history participated in a crossover-crossback prospective study and provided up to 6 serum samples (2:baseline, 2:crossover, 2:crossback). Men on non-DBP mesalamine (background exposure) at baseline crossed-over to DBP-mesalamine (high exposure) then crossed-back to non-DBP mesalamine (B1HB2-arm) and vice versa for men on DBP-mesalamine at baseline (H1BH2-arm). Serum concentrations of total triiodothyronine (T3), total thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb). RESULTS: After crossover in B1HB2-arm (26 men, 134 samples), T3 decreased 10% (95% confidence interval (CI): 14%,-5%), T3/T4 ratio decreased 8% (CI: 12%,-3%), TPOAb, and TgAb concentrations decreased, 11% (-20%, -2%) and 15% (-23%, -5%), respectively; after crossback, they increased. When men in the H1BH2-arm (44 men, 193 samples) crossed-over, T3 decreased 7% (CI: -11%, -2%) and T3/T4 ratio decreased 6% (CI: -9%, -2%). After crossback, only TgAb increased and FT4 decreased. CONCLUSIONS: High-DBP novel exposure or removal from chronic high-DBP exposure could alter elements of the thyroid system, and most probably alters the peripheral T4 conversion to T3 and thyroid autoimmunity, consistent with thyroid disruption. After exposure removal, these trends were mostly reversed.

Application of a ternary HP-ß-CD-complex approach to improve the dissolution performance of a poorly soluble weak acid under biorelevant conditions.

Over the last decades the poor solubility of new drugs has become an important issue, with one of the main challenges being to develop oral dosage forms with acceptable bioavailability for such compounds. The specific purpose of our study was to combine the advantages of cyclodextrins with those of solid dispersion approaches to improve the bioavailability of poorly soluble weak acids. Glyburide, an antidiabetic, was used as a model drug. First, binary drug inclusion complexes were prepared with 2-hydroxypropyl-ß-cyclodextrin. Next, solid glyburide dispersions were prepared with polyvinylpyrrolidone (PVP) and a relatively new hydrophilic copolymer, Kollicoat IR. Finally, to check for potential synergistic effects of the two types of excipients, ternary inclusion complexes were formulated by keeping the 1:2 drug:CD ratio constant but varying the polymer concentration (5-20%). The formulations were analyzed by differential scanning calorimetry and subjected to solubility and dissolution experiments in compendial and biorelevant media. The results of the study clearly indicate that all formulations result in better in vitro performance of the drug. Best results were obtained with the ternary inclusion complexes containing 10% Kollicoat IR or 20% PVP K30. This formulation approach, particularly with the new polymer, appears to be promising in terms of enhancing the bioavailability of BCS class II drugs.

Environmental chemicals targeting thyroid.

Thyroid hormones (THs) are required for normal brain and somatic development and for the proper regulation of physiology in both children and adults. Thyroid function is controlled by the dynamic interrelationships between the hypothalamus, the pituitary and the thyroid. These dynamic relationships maintain circulating levels of THs within a narrow range under normal conditions. Normally, there is likely to be a tight relationship between changes in circulating levels of THs and changes in TH action in various target tissues. This relationship is maintained by tissue-level mechanisms that include TH metabolism and transport. Environmental chemicals that interfere with TH signaling mechanisms (Endocrine Disrupting Chemicals, EDCs) may produce adverse effects both in the individual and in a population. Because of the complex nature of the regulation of thyroid function and TH action, the consequences of EDC exposure is also likely to be complex and our ability to understand these effects as well as to screen for potential EDCs must consider this complexity. Specifically, if there are chemicals in the environment that directly interfere with TH action through their receptors but do not affect circulating TH levels, they would not be identified as thyroid toxicants by currently applied screening methods or by epidemiological studies. The goal of this review is therefore to identify the issues that must be clearly resolved before effective risk assessment can be performed.

Improving glyburide solubility and dissolution by complexation with hydroxybutenyl-beta-cyclodextrin.

OBJECTIVES: Glyburide, an important drug for type 2 diabetes, has extremely poor aqueous solubility and resulting low bioavailability. This study describes the ability of hydroxybutenyl-beta-cyclodextrin (HBenBCD) to form complexes with glyburide, with enhanced solubility and dissolution rate in vitro. METHOD: Glyburide and glyburide-HBenBCD were evaluated in various test media known to simulate human gastrointestinal conditions in the fasted and fed states, respectively. KEY FINDINGS: At approximately 14 wt% drug load, in the presence of HBenBCD, an almost 400-fold increase in glyburide aqueous solubility was observed. In the presence of HBenBCD, glyburide solubility was also significantly improved in all physiologically relevant test media. Subsequent dissolution experiments confirmed the solubility study results; the dissolution rate and total amount of drug released were significantly increased. CONCLUSIONS: Complexation with HBenBCD may be an effective way to increase the bioavailability of glyburide.

Thyroid hormone, brain development, and the environment.

Thyroid hormone is essential for normal brain development. Therefore, it is a genuine concern that thyroid function can be altered by a very large number of chemicals routinely found in the environment and in samples of human and wildlife tissues. These chemicals range from natural to manufactured compounds. They can produce thyroid dysfunction when they are absent from the diet, as in the case of iodine, or when they are present in the diet, as in the case of thionamides. Recent clinical evidence strongly suggests that brain development is much more sensitive to thyroid hormone excess or deficit than previously believed. In addition, recent experimental research provides new insight into the developmental processes affected by thyroid hormone. Based on the authors' research focusing on the ability of polychlorinated biphenyls to alter the expression of thyroid hormone-responsive genes in the developing brain, this review provides background information supporting a new way of approaching risk analysis of thyroid disruptors.