Predictive Modeling of a Mixture of Thyroid Hormone Disrupting Chemicals That Affect Production and Clearance of Thyroxine
ABSTRACT Thyroid hormone (TH) disrupting compounds interfere with both thyroidal and extrathyroidal mechanisms to decrease circulating thyroxine (T(4)). This research tested the hypothesis that serum T(4) concentrations of rodents exposed to a mixture of both TH synthesis inhibitors (pesticides) and stimulators of T(4) clearance in the liver (polyhalogenated aromatic hydrocarbons, PHAHs) could be best predicted by an integrated addition model. Female Long-Evans rats, 23 days of age, were dosed with dilutions of a mixture of 18 PHAHs (2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin like PCBs) and a mixture of 3 pesticides (thiram, pronamide, and mancozeb) for four consecutive days. Serum was collected 24 hours after the last exposure and T(4) concentrations were measured by radioimmunoassay. Animals exposed to the highest dose of the mixture experienced a 45% decrease in serum T(4). Three additivity model predictions (dose addition, effect addition, and integrated addition) were generated based on single chemical data, and the results were compared. Effect addition overestimated the effect produced by the combination of all 21 chemicals. The results of the dose- and integrated-addition models were similar, and both provided better predictions than the effect-addition model. These results support the use of dose- and integrated additivity models in predicting the effects of complex mixtures.
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- "In connection with mixture effects, the possible endocrine disruptive effects on biological processes regulated by steroid hormones (e.g. estrogenic and anti-androgenic actions) (Rajapakse et al., 2002), and thyroid hormones (Crofton et al., 2005; Flippin et al., 2009; Kortenkamp, 2007) have been much in focus. Most mixture effect studies of EDCs have addressed estrogen receptor (ER) agonist issues. "
ABSTRACT: Environmental regulatory edicts within the EU, such as the regulatory framework for chemicals REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals), the Water Framework Directive (WFD), and the Marine Strategy Framework Directive (MSFD) focus mainly on toxicity assessment of individual chemicals although the effect of contaminant mixtures is a matter of increasing concern. This discussion paper provides an overview of the field of combined effects in aquatic ecotoxicology and addresses some of the major challenges related to assessment of combined effects in connection with environmental risk assessment (ERA) and regulation. Potentials and obstacles related to different experimental, modelling and predictive ERA approaches are described. On-going ERA guideline and manual developments in Europe aiming to incorporate combined effects of contaminants, the use of different experimental approaches for providing combined effect data, the involvement of biomarkers to characterize Mode of Action and toxicity pathways and efforts to identify relevant risk scenarios related to combined effects are discussed.Marine environmental research 11/2013; 96. DOI:10.1016/j.marenvres.2013.10.008 · 2.33 Impact Factor
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- "Inhibition of TPO activity is an accepted molecular-initiating event for a chemical-induced adverse outcome pathway of thyroid hormone disruption in rodent models (Crofton, 2008; DeVito et al., 1999; Doerge and Chang, 2002; Flippin et al., 2009; Hurley, 1998; Zoeller and Crofton, 2005). The causative link between TPO inhibition and depressed thyroid hormone concentrations has been well-established, as antihyperthyroid pharmaceuticals including methimazole (MMI) and 6-propylthiouracil (PTU) decrease systemic thyroid hormone concentrations in humans and pets with Graves' Disease (Emiliano et al., 2010; Trepanier, 2006). "
ABSTRACT: Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone, is a known target for thyroid-disrupting chemicals. In vivo toxicological evidence supporting TPO-inhibition as one molecular-initiating event that leads to thyroid disruption is derived largely from rat models; however, a significant fraction of research on the inhibition of TPO by xenobiotics has been conducted using porcine TPO. The current work tested the hypothesis that porcine and rat thyroid microsomes exposed to TPO-inhibiting chemicals would demonstrate different responses in a guaiacol oxidation assay. A primary objective of this work is to establish the degree of concordance between rat and porcine TPO inhibition data. Microsomes were isolated from both rat and pig thyroid glands, and the guaiacol oxidation assay was performed for a training set of 12 chemicals, including previously reported TPO inhibitors, thyroid-disrupting chemicals thought to perturb other targets, and several previously untested chemicals, to determine the relative TPO inhibition responses across species. Concentration-response curves were derived for methimazole (MMI), dibutylphthalate (DBP), diethylhexylphthalate (DEHP), diethylphthalate (DEP), 3,5-dimethylpyrazole-1-methanol (DPM), iopanoic acid (IOA), 2-mercaptobenzothiazole (MBT), sodium perchlorate (PERC), p-nonylphenol (PNP), 4-propoxyphenol (4POP), 6-propylthiouracil (PTU), and triclosan (TCS). MMI, PTU, MBT, DPM, 4POP, and at extremely high concentrations, PERC, inhibited TPO activity. Results demonstrated a strong qualitative concordance of response between the two species. All chemicals that inhibited TPO in porcine microsomes also inhibited TPO in rat microsomes. Hill model-derived IC50 values revealed approximate 1.5- to 50-fold differences in relative potency to MMI between species for positive chemicals. DPM, MBT, 4POP, and PTU exhibited greater relative potency to MMI using rat TPO versus porcine TPO, but rank order potency for inhibition was similar for the other test chemicals, with: PTU>MBT>DPM>4POP>PERC for rat TPO and MBT>PTU>DPM>4POP>PERC for porcine TPO. These data support the extrapolation of porcine TPO data to potential thyroid-disrupting activity in rodent models to evaluate TPO-inhibiting chemicals.Toxicology 08/2013; DOI:10.1016/j.tox.2013.08.006 · 3.75 Impact Factor
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- "While there was no deviation from additivity at the lowest doses, a greater-than-additive effect was found at the highest mixture doses. Flippin et al. (2009) tested the hypothesis that circulating T4 levels in rat exposed to a mixture of direct-TGFDs and chemicals inducing T4 clearance in the liver (PHAHs) could be best predicted by an integrated addition model. While the RA model overestimated the effect of the mixture , the CA one and the integrated addition models provided better predictions. "
ABSTRACT: Maternal thyroxine (T4) plays an essential role in fetal brain development, and even mild and transitory deficits in free-T4 in pregnant women can produce irreversible neurological effects in their offspring. Women of childbearing age are daily exposed to mixtures of chemicals disrupting the thyroid gland function (TGFDs) through the diet, drinking water, air and pharmaceuticals, what has raised the highest concern for the potential additive or synergic effects on the development of mild hypothyroxinemia during early pregnancy. Recently we demonstrated that zebrafish eleutheroembryos provide a suitable alternative model for screening chemicals impairing the thyroid hormone synthesis. The present study used the intrafollicular T4-content (IT4C) of zebrafish eleutheroembryos as integrative endpoint for testing the hypotheses that the effect of mixtures of TGFDs with a similar mode of action [inhibition of thyroid peroxidase (TPO)] were well predicted by a concentration addition concept (CA) model, whereas the response addition concept (RA) model predicted better the effect of dissimilarly acting binary mixtures of TGFDs [TPO-inhibitors and sodium-iodide symporter (NIS)-inhibitors]. However, CA model provided better prediction of joint effects than RA in five out of the six tested mixtures. The exception being the mixture MMI (TPO-inhibitor)-KClO4 (NIS-inhibitor) dosed at a fixed ratio of EC10 that provided similar CA and RA predictions and hence it was difficult to get any conclusive result. There results support the phenomenological similarity criterion stating that concept of concentration addition could be extended to mixture constituents having common apical endpoints or common adverse outcomes.Toxicology and Applied Pharmacology 04/2013; DOI:10.1016/j.taap.2013.02.015 · 3.63 Impact Factor