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ToxSci Advance Access published online on August 22, 2008
Toxicological Sciences, 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 Non-linear and Linear Approaches

Ted Simon*, Christopher R. Kirman+, Lesa L. Aylward±, Robert A. Budinsky§, J. Craig Rowlands§ and Tom F. Long+

* Ted Simon, LLC, Winston, GA 30187, simonfam{at}dscga.com.

+ The Sapphire Group, Inc., Cleveland, OH 44122. crk{at}thesapphiregroup.com

± Summit Toxicology, LLP, Falls Church, VA 22044. laylward{at}sumittoxicology.com

§ Dow Chemical Company, Midland, MI 48674 rabudinsky{at}dow.com and jcrowlands{at}dow.com

Author to whom correspondence should be addressed: Ted Simon, Ted Simon, LLC, 4184 Johnston Rd., Winston, GA 30187, Phone: 770-942-3424, simonfam{at}dscga.com

Received May 14, 2008; revision received July 31, 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) NTP 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 (LALC) and lifetime average adipose concentration (LAAC) with data from both the lifetime and 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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