title: Evaluation of the amphibian metamorphosis assay: exposure to the goitrogen methimazole and the endogenous thyroid hormone L-thyroxine.
abstract: The U.S. Environmental Protection Agency (U.S. EPA) has included an amphibian metamorphosis assay (AMA) to detect thyroid active chemicals in Tier 1 testing of their endocrine screening program. To understand the variability, specificity, and reliability of the key endpoints of this assay, two exposure studies with Xenopus laevis tadpoles were conducted with two known thyroid-active compounds, namely, methimazole or L-thyroxine, for a total of 21 d. In addition, various increased-flow-rate treatments were included in the exposures to evaluate the effects of physical stress on metamorphic development. The endpoints examined in the exposures were wet weight, snout-vent length, hind-limb length, developmental stage, and thyroid and gonadal histopathology. As expected, the results indicated that both methimazole and L-thyroxine were thyroid active in the AMA, hind-limb length and thyroid histopathology being the most sensitive endpoints of thyroid activity. Tadpoles that were exposed to the various physical stressors in these experiments showed no signs of altered metamorphic development, and exposure to the thyroid-active compounds had no effect on the developing gonad of X. laevis. Taken together, these results support the use of the AMA as a Tier 1 endocrine screen for detection of potential thyroid pathway activity; however, the lack of a true negative response (no-effect) during the validation process prevents a full evaluation of this assay's specificity at this time.
authors.affiliation: The Dow Chemical Company, 1803 Building, Washington Street, Midland, Michigan 48674, USA. kcoady@dow.com
authors.forename: Katherine
authors.initials: K
authors.lastname: Coady
authors.forename: Troy
authors.initials: T
authors.lastname: Marino
authors.forename: Johnson
authors.initials: J
authors.lastname: Thomas
authors.forename: Rebecca
authors.initials: R
authors.lastname: Currie
authors.forename: Gregg
authors.initials: G
authors.lastname: Hancock
authors.forename: Jackie
authors.initials: J
authors.lastname: Crofoot
authors.forename: Lindsay
authors.initials: L
authors.lastname: McNalley
authors.forename: Lisa
authors.initials: L
authors.lastname: McFadden
authors.forename: David
authors.initials: D
authors.lastname: Geter
authors.forename: Gary
authors.initials: G
authors.lastname: Klecka
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity*; D023381:Endpoint Determination; D005260:Female; D006066:Gonads / Q000187:drug effects / Q000473:pathology; D007814:Larva / Q000187:drug effects / Q000254:growth & development; D008297:Male; D008675:Metamorphosis, Biological / Q000187:drug effects*; D008713:Methimazole / Q000633:toxicity*; D013312:Stress, Physiological; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D013974:Thyroxine / Q000633:toxicity*; D014874:Water Pollutants, Chemical / Q000633:toxicity*; D014982:Xenopus laevis / Q000196:embryology*
chemical_list: D013956:Antithyroid Agents; D014874:Water Pollutants, Chemical; D008713:Methimazole; D013974:Thyroxine