title: Dose-additive carcinogenicity of a defined mixture of "dioxin-like compounds".
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.
authors.affiliation: National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27705, USA. walker3@niehs.nih.gov
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Walker
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Crockett
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
authors.forename: Amy E
authors.initials: AE
authors.lastname: Brix
authors.forename: Michael P
authors.initials: MP
authors.lastname: Jokinen
authors.forename: Donald M
authors.initials: DM
authors.lastname: Sells
authors.forename: James R
authors.initials: JR
authors.lastname: Hailey
authors.forename: Micheal
authors.initials: M
authors.lastname: Easterling
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Haseman
authors.forename: Ming
authors.initials: M
authors.lastname: Yin
authors.forename: Michael E
authors.initials: ME
authors.lastname: Wyde
authors.forename: John R
authors.initials: JR
authors.lastname: Bucher
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Portier
mesh_terms: D000818:Animals; D001681:Biological Assay; D002273:Carcinogens / Q000008:administration & dosage / Q000009:adverse effects*; D004147:Dioxins / Q000008:administration & dosage / Q000506:poisoning*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000506:poisoning; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000662:veterinary; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000662:veterinary; D009062:Mouth Neoplasms / Q000139:chemically induced* / Q000662:veterinary; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000506:poisoning; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D018570:Risk Assessment
chemical_list: D002273:Carcinogens; D004147:Dioxins; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins