Evaluation of mechanisms inducing thyroid toxicity and the ability of the enhanced OECD Test Guideline 407 to detect these changes.
The OECD has developed an "enhanced Test Guideline 407" (TG 407) protocol for detecting endocrine effects during the course of a 28-day testing scheme. This protocol has gone through a validation process with (anti)estrogenic and (anti)androgenic compounds and substances that affect the thyroid (thyroxine and propylthiouracil). This review investigates whether a 28-day testing scheme would show up alterations in the thyroid-related parameters of the "enhanced TG 407" (T3, T4, TSH, thyroid weight and histopathology), irrespective of the mode of action. For each mode of action, a generally accepted reference chemical was selected and an in-depth literature survey was carried out, and the chemical was evaluated for treatment-related changes of thyroid-dependent parameters. The following model chemicals were selected: ion perchlorate, blockage of iodine uptake; propylthiouracil, inhibition of thyroid hormone synthesis; excess of iodine, blockage of thyroid hormone release; pyrazole, thyroid cytotoxicity; minocycline, thyroid pigmentation; amiodarone, inhibition of TSH synthesis; diethylstilbestrol, competition for thyroid hormone binding globulin; selenium-deficient diet, inhibition of thyroxine deiodination; FD&C Red No. 3, inhibition of peripheral 5'-deiodinase; cadmium, lipid peroxidation; phenobarbital, increase in thyroxine conjugation and biliary excretion; temelastine, thyroxine accumulation. Test data for treatments lasting approximately one month were available for most of these model chemicals, and these demonstrated the expected thyroid-related changes. Thus, it can be concluded that a 28-day testing scheme allows for the detection of thyroid-disrupting chemicals. The literature data also were evaluated according to whether preference can be given to any of the thyroid-related parameters (thyroid/pituitary hormones, thyroid weight and histopathology) with regard to dose-related sensitivities. Due to different study designs (such as treatment duration, application mode, dose selection and parameters used), no clear picture emerged. Therefore, consideration should be given to all of these parameters, which should also help to define the mode of action. Overall, this literature review provides support for the contention that the newly developed "enhanced TG 407" test protocol is well suited to the detection of chemicals that affect the thyroid gland.
Cunha
G Coelho-Palermo
GC
Product Safety, BASF Aktiengesellschaft, Z 470, 67056, Ludwigshafen, Germany.
van Ravenzwaay
B
B
D000818:Animals; D017408:Guidelines as Topic; D006801:Humans; D007454:Iodides / Q000494:pharmacology; D007455:Iodine / Q000378:metabolism; D010858:Pigmentation / Q000187:drug effects; D013959:Thyroid Diseases / Q000139:chemically induced* / Q000175:diagnosis*; D013961:Thyroid Gland / Q000201:enzymology / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism; D015262:Xenobiotics / Q000494:pharmacology
D007454:Iodides; D013963:Thyroid Hormones; D015262:Xenobiotics; D007455:Iodine