title: Thyroid-hormone-disrupting chemicals: evidence for dose-dependent additivity or synergism.
abstract: Endocrine disruption from environmental contaminants has been linked to a broad spectrum of adverse outcomes. One concern about endocrine-disrupting xenobiotics is the potential for additive or synergistic (i.e., greater-than-additive) effects of mixtures. A short-term dosing model to examine the effects of environmental mixtures on thyroid homeostasis has been developed. Prototypic thyroid-disrupting chemicals (TDCs) such as dioxins, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers have been shown to alter thyroid hormone homeostasis in this model primarily by up-regulating hepatic catabolism of thyroid hormones via at least two mechanisms. Our present effort tested the hypothesis that a mixture of TDCs will affect serum total thyroxine (T4) concentrations in a dose-additive manner. Young female Long-Evans rats were dosed via gavage with 18 different polyhalogenated aromatic hydrocarbons [2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin-like PCBs] for 4 consecutive days. Serum total T4 was measured via radioimmunoassay in samples collected 24 hr after the last dose. Extensive dose-response functions (based on seven to nine doses per chemical) were determined for individual chemicals. A mixture was custom synthesized with the ratio of chemicals based on environmental concentrations. Serial dilutions of this mixture ranged from approximately background levels to 100-fold greater than background human daily intakes. Six serial dilutions of the mixture were tested in the same 4-day assay. Doses of individual chemicals that were associated with a 30% TH decrease from control (ED30), as well as predicted mixture outcomes were calculated using a flexible single-chemical-required method applicable to chemicals with differing dose thresholds and maximum-effect asymptotes. The single-chemical data were modeled without and with the mixture data to determine, respectively, the expected mixture response (the additivity model) and the experimentally observed mixture response (the empirical model). A likelihood-ratio test revealed statistically significant departure from dose additivity. There was no deviation from additivity at the lowest doses of the mixture, but there was a greater-than-additive effect at the three highest mixtures doses. At high doses the additivity model underpredicted the empirical effects by 2- to 3-fold. These are the first results to suggest dose-dependent additivity and synergism in TDCs that may act via different mechanisms in a complex mixture. The results imply that cumulative risk approaches be considered when assessing the risk of exposure to chemical mixtures that contain TDCs.
authors.affiliation: Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. crofton.kevin@epa.gov
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Crofton
authors.forename: Elena S
authors.initials: ES
authors.lastname: Craft
authors.forename: Joan M
authors.initials: JM
authors.lastname: Hedge
authors.forename: Chris
authors.initials: C
authors.lastname: Gennings
authors.forename: Jane E
authors.initials: JE
authors.lastname: Simmons
authors.forename: Richard A
authors.initials: RA
authors.lastname: Carchman
authors.forename: W Hans
authors.initials: WH
authors.lastname: Carter
authors.forename: Michael J
authors.initials: MJ
authors.lastname: DeVito
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000633:toxicity; D000072338:Dibenzofurans, Polychlorinated; D004357:Drug Synergism; D052244:Endocrine Disruptors / Q000633:toxicity*; D005260:Female; D008954:Models, Biological; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans; D018570:Risk Assessment; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013974:Thyroxine / Q000097:blood
chemical_list: D001572:Benzofurans; D000072338:Dibenzofurans, Polychlorinated; D052244:Endocrine Disruptors; D000072317:Polychlorinated Dibenzodioxins; D011078:Polychlorinated Biphenyls; D013974:Thyroxine