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Nigel J. Walker,¹ Patrick W. Crockett,² Abraham Nyska,¹ Amy E. Brix,³ Michael P. Jokinen,⁴ Donald M. Sells,⁵ James R. Hailey,¹ Micheal Easterling,² Joseph K. Haseman,¹ Ming Yin,² Michael E. Wyde,¹ John R. Bucher,¹ and Christopher J. Portier¹

¹National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA; ²Constella Group, Research Triangle Park, North Carolina, USA; ³Pathology Associates--A Charles River Company, Durham, North Carolina, USA; ⁴Experimental Pathology Laboratories, Research Triangle Park, North Carolina, USA; ⁵Battelle Columbus Laboratories, Columbus, Ohio, USA

Abstract
Use of the dioxin toxic equivalency factor (TEF) approach in human risk assessments assumes that the combined effects of dioxin-like compounds in a mixture can be predicted based on a potency-adjusted dose-additive combination of constituents of the mixture. In this study, we evaluated the TEF approach in experimental 2-year rodent cancer bioassays with female Harlan Sprague-Dawley rats receiving 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) , 3,3´,4,4´,5-pentachlorobiphenyl (PCB-126) , 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) , or a mixture of the three compounds. Statistically based dose-response modeling indicated that the shape of the dose-response curves for hepatic, lung, and oral mucosal neoplasms was the same in studies of the three individual chemicals and the mixture. In addition, the dose response for the mixture could be predicted from a combination of the potency-adjusted doses of the individual compounds. Finally, we showed that use of the current World Health Organization dioxin TEF values adequately predicted the increased incidence of liver tumors (hepatocellular adenoma and cholangiocarcinoma) induced by exposure to the mixture. These data support the use of the TEF approach for dioxin cancer risk assessments. Key words: carcinogenicity, dioxin, mixtures, PCBs, persistent organochlorine pollutants, polychlorinated biphenyls, POPs, risk assessment, TEF, toxic equivalency factor. Environ Health Perspect 113:43-48 (2005) . doi:10.1289/ehp.7351 available via http://dx.doi.org/ [Online 19 October 2004]

Address correspondence to N.J. Walker, National Institute of Environmental Health Sciences, 111 Alexander Dr., Research Triangle Park, NC 27705 USA. Telephone: (919) 541-4893. Fax: (301) 451-5596. E-mail: walker3@niehs.nih.gov

We thank all those involved in the conduct of these studies, with special thanks to A. Van Birgelen Braen, D. Orzech, and M. Hejtmancik. We also thank G. Kissling and L. Fischer for critical review of the manuscript.

The authors declare they have no competing financial interests.

Received 24 June 2004 ; accepted 19 October 2004.