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ToxSci Advance Access originally published online on August 22, 2008
Toxicological Sciences 2008 106(2):519-537; doi:10.1093/toxsci/kfn176
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Estimates of Cancer Potency of 2,3,4,7,8-Pentachlorodibenzofuran Using Both Nonlinear and Linear Approaches

Ted Simon*,1, Christopher R. Kirman{dagger}, Lesa L. Aylward{ddagger}, Robert A. Budinsky§, J. Craig Rowlands§ and Tom F. Long{dagger}

* Ted Simon, LLC, Winston, Georgia 30187 {dagger} The Sapphire Group, Inc., Cleveland, Ohio 44122 {ddagger} Summit Toxicology, LLP, Falls Church, Virginia 22044 § Dow Chemical Company, Midland, Michigan 48674

1 To whom correspondence should be addressed at Ted Simon, LLC, 4184 Johnston Road, Winston, GA 30187. Fax: 770-942-3424. E-mail: ted{at}tedsimon-toxicology.com.

Received May 14, 2008; accepted August 14, 2008


  Abstract

Cancer potency estimates were derived for 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) using data collected from the recently published National Toxicology Program bioassay in female Sprague-Dawley rats. By using a toxicokinetic model for 4-PeCDF, the dose-response relationship for combined liver tumors (hepatocellular adenomas and cholangiocarcinomas) in rats was assessed in terms of lifetime average liver concentration and lifetime average adipose concentration with data from both the lifetime and the stop-exposure components of the bioassay. Benchmark dose modeling was performed to estimate tissue concentrations at two points of departure (EC10 and EC01 and their 95% upper and lower confidence limits). The same toxicokinetic model with human input values was then used to back-extrapolate human equivalent doses that corresponded to the internal tissue concentration measures at the points of departure. Information regarding the cancer mode of action was used to support the development of several toxicity criterion values based on a nonlinear method, e.g., reference dose or tolerable daily intake. Nonlinear estimates of toxicity criteria based on observed noncancer toxic events as possible precursors to tumor formation were also derived and were similar in value to those based on combined liver tumors. For comparison purposes, linear estimates of cancer potency were also derived.

Key Words: dioxin; 2,3,4,7,8-pentachlorodibenzofuran; dose-response; cancer potency factor; reference dose; tumor promotion.


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T. Simon, L. L. Aylward, C. R. Kirman, J. C. Rowlands, and R. A. Budinsky
Estimates of Cancer Potency of 2,3,7,8-Tetrachlorodibenzo(p)dioxin Using Linear and Nonlinear Dose-Response Modeling and Toxicokinetics
Toxicol. Sci., December 1, 2009; 112(2): 490 - 506.
[Abstract] [Full Text] [PDF]


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