Crofton et al. Future work should endeavor to expand these conclusions to low-dose chronic exposures and broaden testing of mixtures to include chemi- cals from diverse classes of thyroid disruptors such as TH synthesis inhibitors. REFERENCES Agresti A. 2002. Categorical Data Analysis. 2nd ed. New York:John Wiley & Sons. Berenbaum MC. 1985. The expected effect of a combination of agents: the general solution. J Theor Biol 114(3):413–431. Birnbaum LS, Couture LA. 1988. Disposition of octa- chlorodibenzo-p-dioxin (OCDD) in male rats. Toxicol Appl Pharmacol 93(1):22–30. Brouwer A, Morse DC, Lans MC, Schuur AG, Murk AJ, Klasson- Wehler E, et al. 1998. Interactions of persistent environmen- tal organohalogens with the thyroid hormone system: mechanisms and possible consequences for animal and human health. Toxicol Ind Health 14(1–2):59–84. Capen C. 1998. Correlation of mechanistic data and histopathol- ogy in the evaluation of selected toxic endpoints of the endocrine system. Toxicol Lett 102–103:405–409. Capen CC. 1997. Mechanistic data and risk assessment of selected toxic end points of the thyroid gland. Toxicol Pathol 25(1):39–48. Casey M, Gennings C, Carter JH Jr, Moser VC, Simmons JE. 2004. Detecting interaction(s) and assessing the impact of compo- nent subsets in a chemical mixture using ﬁxed-ratio mixture ray designs. J Agric Biol Environ Stat 9(3):339–361. Connor K, Safe S, Jefcoate CR, Larsen M. 1995. Structure-depen- dent induction of CYP2B by polychlorinated biphenyl con- geners in female Sprague-Dawley rats. Biochem Pharmacol 50(11):1913–1920. Craft ES, DeVito MJ, Crofton KM. 2002. Comparative responsive- ness of hypothyroxinemia and hepatic enzyme induction in Long-Evans rats versus C57BL/6J mice exposed to TCDD- like and phenobarbital-like polychlorinated biphenyl con- geners. Toxicol Sci 68(2):372–380. Crofton KM. 2004. Developmental disruption of thyroid hormone: correlations with hearing dysfunction in rats. Risk Anal 24(6):1665–1671. Daston GP, Cook JC, Kavlock RJ. 2003. Uncertainties for endocrine disrupters: our view on progress. Toxicol Sci 74(2):245–252. Desaulniers D, Leingartner K, Musicki B, Yagminas A, Xiao GH, Cole J, et al. 2003. Effects of postnatal exposure to mixtures of non-ortho-PCBs, PCDDs, and PCDFs in prepubertal female rats. Toxicol Sci 75(2):468–480. DeVito M, Biegel L, Brouwer A, Brown S, Brucker-Davis F, Cheek AO, et al. 1999. Screening methods for thyroid hormone dis- ruptors. Environ Health Perspect 107:407–415. DeVito MJ, Birnbaum LS, Farland WH, Gasiewicz TA. 1995. Comparisons of estimated human body burdens of dioxinlike chemicals and TCDD body burdens in experimentally exposed animals. Environ Health Perspect 103:820–831. DeVito MJ, Ross DG, Dupuy AE Jr, Ferrario J, McDaniel D, Birnbaum LS. 1998. Dose-response relationships for disposi- tion and hepatic sequestration of polyhalogenated dibenzo- p -dioxins, dibenzofurans, and biphenyls following subchronic treatment in mice. Toxicol Sci 46(2):223–234. Feron VJ, Groten JP. 2002. Toxicological evaluation of chemical mixtures. Food Chem Toxicol 40(6):825–839. Gennings C, Carter WH Jr, Campain JA, Bae D, Yang RSH. 2002. Statitical analysis of interactive cytotoxicity in human epi- dermal keratinocytes following exposure to a mixture of four metals. J Agric Biol Environ Sci 7(1):58–73. Gennings C, Carter WH Jr, Carney EW, Charles GD, Gollapudi BB, Carchman RA. 2004. A novel ﬂexible approach for eval- uating fixed ratio mixtures of full and partial agonists. Toxicol Sci 80(1):134–150. Giesy JP, Verbrugge DA, Othout RA, Bowerman WW, Mora MA, Jones PD, et al. 1994. Contaminants in fishes from Great Lakes-influenced sections and above dams of three Michigan rivers. I: Concentrations of organo chlorine insec- ticides, polychlorinated biphenyls, dioxin equivalents, and mercury. Arch Environ Contam Toxicol 27(2):202–212. Guo GL, Choudhuri S, Klaassen CD. 2002. Induction proﬁle of rat organic anion transporting polypeptide 2 (oatp2) by proto- typical drug-metabolizing enzyme inducers that activate gene expression through ligand-activated transcription fac- tor pathways. J Pharmacol Exp Ther 300(1):206–212. Haddow JE, Palomaki GE, Williams J. 2002. Thyroid-stimulating- hormone concentrations and risk of hypothyroidism. Lancet 360(9350):2081–2082. Hill RN, Crisp TM, Hurley PM, Rosenthal SL, Singh DV. 1998. Risk assessment of thyroid follicular cell tumors. Environ Health Perspect 106:447–457. Hood A, Klaassen CD. 2000a. Differential effects of microsomal enzyme inducers on in vitro thyroxine (T(4)) and triiodothyro- nine (T(3)) glucuronidation. Toxicol Sci 55(1):78–84. Hood A, Klaassen CD. 2000b. Effects of microsomal enzyme inducers on outer-ring deiodinase activity toward thyroid hormones in various rat tissues. Toxicol Appl Pharmacol 163(3):240–248. Hurley PM. 1998. Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ Health Perspect 106:437–445. International Programme on Chemical Saftety. 2002. Global Assessment of the State-of-the-Science of Endocrine Disruptors. WHO/PCS/EDC/02.2 (Damstra T, Barlow S, Bergman A, Kavlock R, Van Der Kraak G, eds). Geneva: World Health Organization. Khan MA, Hansen LG. 2003. Ortho-substituted polychlorinated biphenyl (PCB) congeners (95 or 101) decrease pituitary response to thyrotropin releasing hormone. Toxicol Lett 144(2):173–182. Khan MA, Lichtensteiger CA, Faroon O, Mumtaz M, Schaeffer DJ, Hansen LG. 2002. The hypothalamo-pituitary-thyroid (HPT) axis: a target of nonpersistent ortho-substituted PCB con- geners. Toxicol Sci 65(1):52–61. Larsen BR, Turrio-Baldassarri L, Nilsson T, Iacovella N, Di Domenico A, Montagna M, et al. 1994. Toxic PCB con- geners and organochlorine pesticides in Italian human milk. Ecotoxicol Environ Saf 28(1):1–13. LeBlanc GA, Olmstead AW. 2004. Evaluating the toxicity of chemi- cal mixtures [Letter]. Environ Health Perspect 112:A729–A730. Liem AK, Furst P, Rappe C. 2000. Exposure of populations to dioxins and related compounds. Food Addit Contam 17(4):241–259. Loewe S. 1953. The problem of synergism and antagonism of combined drugs. Arzneimittelforschung 3(6):285–290. Loewe S, Muischnek H. 1926. Effect of combinations: mathemati- cal basis of problem. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 114:313–326. Longnecker MP, Wolff MS, Gladen BC, Brock JW, Grandjean P, Jacobson JL, et al. 2003. Comparison of polychlorinated biphenyl levels across studies of human neurodevelopment. Environ Health Perspect 111:65–70. Lorber M. 2002. A pharmacokinetic model for estimating expo- sure of Americans to dioxin-like compounds in the past, pre- sent, and future. Sci Total Environ 288(1–2):81–95. Martin LA. 2002. Differential effects of polychlorinated biphenyl (PCB) mixtures and congeners on the disposition of thyrox- ine (T4) in rats [PhD Dissertation]. Piscataway, NJ:Rutgers University and Robert Wood Johnson Medical School. McClain RM. 1995. Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assess- ment. Mutat Res 333(1–2):131–142. McClain RM, Levin AA, Posch R, Downing JC. 1989. The effect of phenobarbital on the metabolism and excretion of thyroxine in rats. Toxicol Appl Pharmacol 99(2):216–228. McCullagh P, Nelder JA. 1989. Generalized Linear Models. 2nd ed. London:Chapman & Hall. Morreale de Escobar G, Obregon MJ, Escobar del Rey F. 2000. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab 85(11):3975–3987. Morse DC, Groen D, Veerman M, van Amerongen CJ, Koeter HB, Smits van Prooije AE, et al. 1993. Interference of polychlori- nated biphenyls in hepatic and brain thyroid hormone metabolism in fetal and neonatal rats. Toxicol Appl Pharmacol 122(1):27–33. Oppenheimer JH, Bernstein G, Surks MI. 1968. Increased thyrox- ine turnover and thyroidal function after stimulation of hepatocellular binding of thyroxine by phenobarbital. J Clin Invest 47(6):1399–1406. Patterson DG Jr, Todd GD, Turner WE, Maggio V, Alexander LR, Needham LL. 1994. Levels of non-ortho-substituted (co- planar), mono- and di-ortho-substituted polychlorinated biphenyls, dibenzo-p-dioxins, and dibenzofurans in human serum and adipose tissue. Environ Health Perspect 102 (suppl 1):195–204. Saeed A, Hansen LG. 1997. Morphometric changes in the prepu- bertal female rat thyroid gland following acute exposure to 2,2’,4,4’-tetrachlorobiphenyl and Aroclor 1242. J Toxicol Environ Health 51(5):503–513. Schecter A, Stanley J, Boggess K, Masuda Y, Mes J, Wolff M, et al. 1994a. Polychlorinated biphenyl levels in the tissues of exposed and nonexposed humans. Environ Health Perspect 102(suppl 1):149–158. Schecter A, Startin J, Wright C, Kelly M, Papke O, Lis A, et al. 1994b. Congener-specific levels of dioxins and dibenzo- furans in U.S. food and estimated daily dioxin toxic equiva- lent intake. Environ Health Perspect 102:962–966. Tabb MM, Kholodovych V, Grun F, Zhou C, Welsh WJ, Blumberg B. 2004. Highly chlorinated PCBs inhibit the human xenobi- otic response mediated by the steroid and xenobiotic recep- tor (SXR). Environ Health Perspect 112:163–169. Teuschler L, Klaunig J, Carney E, Chambers J, Conolly R, Gennings C, et al. 2002. Support of science-based decisions concerning the evaluation of the toxicology of mixtures: a new beginning. Regul Toxicol Pharmacol 36(1):34–39. Tinwell H, Ashby J. 2004. Sensitivity of the immature rat uterotrophic assay to mixtures of estrogens. Environ Health Perspect 112:575–582. U.S. EPA (U.S. Environmental Protection Agency). 1986. Guidelines for the health risk assessment of chemical mix- tures. Fed Reg 51:34014–34025. U.S. EPA. 2000. Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures. Washington, DC:U.S. Environmental Protection Agency. Van den Berg KJ, van Raaij JA, Bragt PC, Notten WR. 1991. Interactions of halogenated industrial chemicals with transthyretin and effects on thyroid hormone levels in vivo. Arch Toxicol 65(1):15–19. Van den Berg M, Birnbaum L, Bosveld AT, Brunstrom B, Cook P, Feeley M, et al. 1998. Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. Environ Health Perspect 106:775–792. Van den Berg M, De Jongh J, Poiger H, Olson JR. 1994. The toxi- cokinetics and metabolism of polychlorinated dibenzo-p- dioxins (PCDDs) and dibenzofurans (PCDFs) and their relevance for toxicity. Crit Rev Toxicol 24(1):1–74. Vansell NR, Klaassen CD. 2002. Increase in rat liver UDP- glucuronosyltransferase mRNA by microsomal enzyme inducers that enhance thyroid hormone glucuronidation. Drug Metab Dispos 30(3):240–246. Visser TJ, Kaptein E, van Raaij JA, Joe CT, Ebner T, Burchell B. 1993. Multiple UDP-glucuronyltransferases for the glu- curonidation of thyroid hormone with preference for 3,3’,5’- triiodothyronine (reverse T3). FEBS Lett 315(1):65–68. Wade MG, Parent S, Finnson KW, Foster W, Younglai E, McMahon A, et al. 2002. Thyroid toxicity due to subchronic exposure to a complex mixture of 16 organochlorines, lead, and cadmium. Toxicol Sci 67(2):207–218. Wilson CL, Safe S. 1998. Mechanisms of ligand-induced aryl hydrocarbon receptor-mediated biochemical and toxic responses. Toxicol Pathol 26(5):657–671. Wolff J. 1998. Perchlorate and the thyroid gland. Pharmacol Rev 50(1):89–105. 1554 VOLUME 113 | NUMBER 11 | November 2005 • Environmental Health Perspectives