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 poly-brominated 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.

Investigation of the state of the science on combined actions of chemicals in food through dissimilar modes of action and proposal for science‐based approach for performing related cumulative risk assessment

“…Other studies used the MRL (Wade et al 2002) or ADI and two studies used a measure of human levels, human serum concentrations (van Meeuwen et al 2007) or background human daily intake (Crofton et al 2005). One study used a set concentration, 1mg/kg/day ).…”

“…There is good evidence that several chemicals can work together to induce reductions in thyroid hormone levels at doses where the individual chemicals are ineffective (Crofton et al 2005). (Crofton 2008) demonstrated that chemical substances may interact with the thyroid hormone pathways at different sites and via different mechanisms.…”

“…There is experimental evidence that the concept of DA produces reliable estimations of combination effects with mixtures composed of chemicals with diverse modes of action (Christiansen et al 2009;Crofton et al 2005;Rider et al 2010).…”

Biochemical and Histopathological Effects of in Utero Di-N-Hexyl Phthalate and Di-Cyclohexyl Phthalate Exposure on the Thyroid Axes and T3, T4, TSH Hormone Levels of Male and Female Rats: at Adulthood

“…However, thyroid hormones are of special importance in fetal development. During the first part of pregnancy, the fetus relies entirely on transplacental transfer of maternal thyroid hormones and thus on a normal maternal thyroid function, but maternal thyroid homeostasis is also contributing substantially to fetal development during the remaining part of pregnancy (15,24). Thus far, only few studies in humans on thyroid disrupting effects of phthalates have been carried out, whereas their adverse effects on rat's endocrine health are better investigated.…”

Augmented atherogenesis in ApoE-null mice co-exposed to polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…For example, PCB153 (a non-dioxin-like PCB congener) and TCDD produced a remarkable synergism in the EROD enzyme activity and hepatic porphyrin level, respectively (Bannister and Safe, 1987;van Birgelen et al, 1996). A synergistic decrease in the serum total thyroxine concentrations was found when using a mixture of 18 polyhalogenated aromatic hydrocarbons (dioxins, dibenzofurans, and dioxin-like and non-dioxin-like PCB congeners) (Crofton et al, 2005). A combination of TCDD and PCBs was also found to produce synergistic effects on the CYP1A1 expression and hepatotoxicity in Sprague-Dawley rats (Wang et al, 2011).…”