The enhancement of the subacute repeat dose toxicity test OECD TG 407 for the detection of endocrine active chemicals: comparison with toxicity tests of longer duration.
The OECD conventional 28-day repeat dose toxicity test (OECD TG 407) is widely employed in the initial hazard identification and characterization for commercial chemicals. The OECD has recently undertaken an international effort to "enhance" the conventional 28-day repeat dose toxicity test (OECD TG 407) in order to ensure that chemicals acting through (anti)estrogenic, (anti)androgenic, and (anti)thyroid mechanisms are identified. The enhancements include additional parameters based on the respective target organs from the male and female reproductive tracts, the thyroid, and circulating hormone levels. Ten chemicals with known endocrine modes of action and different potencies were administered using the "enhanced TG 407" test protocol to investigate the performance of this procedure. In the present evaluation, these "enhanced TG 407" protocol results, drawn from a report of the OECD validation studies, are compared to studies of the same or similar chemicals with longer and/or in utero exposures in order to evaluate the capability of the this "enhanced TG 407" in identifying the chemicals' mode of action. The major conclusions that can be drawn from these comparisons are: 1. The "enhanced TG 407" will reliably identify chemicals with a strong to moderate potential to act through endocrine modes of action on the gonads and the thyroid. In addition, this test method gives a first indication for the dose-related potency. 2. Substances with a low potency for an endocrine mode of action, i.e., having only marginal effects in the most comprehensive in vivo studies such as multi-generation studies, may not elicit clear endocrine-related effects in the "enhanced TG 407". In these cases, the primary or principal effects observed will be driven by other toxic actions of the test materials in the "enhanced TG 407". 3. It may be concluded from the present database that prolongation of exposure from 28 days up to 90 days is unlikely to improve the chance of detecting an endocrine-mediated effect 4. A number of higher tier studies with in utero and pubertal exposure show that prenatally exposed rats may be more sensitive to exposures to compounds with very low estrogenic or antiandrogenic potential in some cases than young adult rats as used in the "enhanced TG 407". 5. Overall, these comparisons support the use of the "enhanced TG407" for the detection of endocrine active chemicals. It is therefore recommended to fully accept the enhancements and include them in the test method for toxicological and regulatory use.