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.

Endocrine Disrupters and the Safety of Food Chains

“…On the other hand, the EFSA has made an important step forward, concluding that, based on the available knowledge, the most robust and conservative approach is the assumption of effect additivity: compounds that have the same effect in the same target organ (e.g., causing hypothyroidism) are assumed to act in an additive way [27]. This holds true also when pesticides eliciting the same effect have different chemical structures and molecular mechanisms [28], in agreement with a number of previous experimental data [17,18,19]. The ensuing phase in the risk assessment of multiple pesticide residues will be the identification of ‘risk drivers', i.e., those chemicals that make up most of the risk associated with a given cumulative assessment group because of their potency and/or exposure.…”

“…As already noted [17,18,19], the issue of mixture effects of ED likely extends much beyond the groups of chemicals having the same chemical structures and molecular mechanisms. Of special interest for risk managers is the presence of multiple pesticide residues in about 20% of fruits and vegetables [26].…”

“…In vitro and in vivo studies have shown that doses of ED without an effect on reproductive parameters, androgen receptor transactivation or the production and clearance of thyroxine can affect the target parameters in an additive way upon combined exposure. Interestingly, the compounds tested in the specific experimental sets had different mechanisms (e.g., aromatase inhibition or androgen receptor antagonism for reproductive effects; hormone synthesis inhibitors or hormone clearance enhancers for thyroid effects); therefore, when occurring together, ED might act in an additive way when exerting the same effects at the cell or tissue level [17,18,19]. Beyond the daily intake, several ED bioaccumulate in lipid compartments of tissues, creating a mixed ‘body burden' of contaminants of different origins, including dioxins, PCB, chlorinated pesticides and their metabolites, as well as brominated flame retardants [20].…”

Endocrine Disrupters and Food Safety

“…This long-debated issue concerns the potential additive effects of different ED present in the same foods at low levels, but interacting with the same targets, e.g., nuclear receptors [11,12,13].…”

Scientific report of the Endocrine Active Substances Task Force

“…There is also a rich literature on the experimental outcomes of combining EAS in in vitro, laboratory animal and environmental models, with some effects conforming the rules of dose addition while others appear to act synergistically (see for example Kortenkamp, 2007Kortenkamp, , 2008Christiansen et al, 2008;Flippin et al, 2009). EFSA Journal 2010;8(11):1932…”