Combined Chronic Toxicity/Carcinogenicity Studies (OECD TG 451-3)

745. These assays determine the general toxicity (OECD TG 452 and TG 453) and carcinogenicity (OECD TG 451 and TG 453) of chemicals in laboratory animals after exposure for a period lasting most of the lifespan. Route of administration may be oral, dermal or inhalation, although oral via diet is the most common. OECD TG 453 was revised in September 2009 and replaced OECD TG 451 (older studies may have used OECD TG 451). General toxicity studies usually have a duration of 12 months whilst carcinogenicity studies usually have a duration of 18 or 24 months depending on the species tested. They provide information on major toxic effects, target organ toxicity and carcinogenicity. Although they have not been validated for the detection of endocrine disruptors (EDs), they contain many endpoints that are suitable for the determination of endocrine effects. Organ weights are not always included in the carcinogenicity phases of these studies as neoplastic changes may confound them, but they are generally determined at 12 months. A comparison can be made with validation of the OECD TG 407 (28-Day Oral Toxicity Study) for endocrine endpoints (OECD, 2006) where substances that were moderate and strong EDs for (anti)estrogenicity and (anti)androgenicity (e.g. ethinylestradiol and flutamide) and weak and strong modulators of thyroid hormone-related effects (e.g. propylthiouracil, T4 and methyl testosterone) were detected. Steroidogenesis inhibition was also detected although only one (potent) chemical was used in the validation study (CGS 18320B). OECD TG 453 and TG 452 are likely to be more sensitive than OECD TG 407 because of the extended dosing period and the larger number of animals per group (20 or 50 rodents per sex per group for chronic or carcinogenicity studies respectively compared with 5 in OECD TG 407). OECD TG 453 and TG 452, however, do not contain some sensitive endpoints (e.g. thyroid hormones, estrous cyclicity) that may be included in OECD TG 407.