| Thyroid-Hormone-Disrupting Chemicals: Evidence for Dose-Dependent Additivity or Synergism Kevin M. Crofton,1 Elena S. Craft,1* Joan M. Hedge,1 Chris
Gennings,2 Jane E. Simmons,3 Richard A. Carchman,2 W.
Hans Carter Jr.,2 and Michael J. DeVito3 1Neurotoxicology and 3Experimental Toxicology Divisions,
National Health and Environmental Effects Research Laboratory, Office of Research
and Development, U.S. Environmental Protection Agency, Research Triangle Park,
North Carolina, USA; 2Solveritas LLC, Richmond, Virginia, USA 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 polyyhalogenated 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. Key words: additivity, cumulative risk, polyhalogenated aromatic hydrocarbons, synergism, thyroid hormone disruptors. Environ Health Perspect 113:1549-1554 (2005) . doi:10.1289/ehp.8195 available via http://dx.doi.org/ [Online 21 July 2005]
Address correspondence to K.M. Crofton, Neurotoxicology Division, MD-105-04, National Health and Environmental Effects Laboratory, U.S. EPA, Research Triangle Park, NC 27711 USA. Telephone: (919) 541-2672. Fax: (919) 541-4849. E-mail: crofton.kevin@epa.gov *Current address: Nicholas School of the Environment and Earth Sciences, Duke University, Durham, NC 27708 USA. Supplemental Data Table 1 lists the chemicals tested, doses (µg/kg/day) , group mean serum total thyroxine (T4) concentrations expressed as percentage of control, standard deviations, and group sample sizes. These data are available on the EHP website
(http://ehp.niehs.nih.gov/docs/2005/8195/supplemental.pdf) . Raw data files can be obtained by contacting the corresponding author. We thank T. Grim at Cambridge Isotope Laboratories for help with the custom synthesis of the mixture. This work would not have been possible without the invaluable technical assistance of T. Zhou and D. Ross. G. We acknowledge G. LeBlanc and S. Padilla for commenting on a previous version of the manuscript. C.G., R.A.C., and W.H.C. were supported by U.S. EPA contract RFQ-RT-03-00298. This manuscript has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. C.G., R.A.C., and W.H.C. have a financial interest in Solveritas LLC. All other authors declare they have no competing financial interests. Received 11 April 2005 ; accepted 21 July 2005. The full version of this article is available for free in HTML or PDF formats. |
