title: 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.
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Flippin
authors.forename: J M
authors.initials: JM
authors.lastname: Hedge
authors.forename: M J
authors.initials: MJ
authors.lastname: DeVito
authors.forename: G A
authors.initials: GA
authors.lastname: Leblanc
authors.forename: K M
authors.initials: KM
authors.lastname: Crofton
mesh_terms: D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D010575:Pesticides / Q000737:chemistry / Q000633:toxicity*; D011237:Predictive Value of Tests; D051381:Rats; D020318:Rats, Long-Evans; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013974:Thyroxine / Q000096:biosynthesis* / Q000097:blood / Q000378:metabolism*
chemical_list: D052244:Endocrine Disruptors; D010575:Pesticides; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D013974:Thyroxine