ToxSci Advance Access published online on June 12, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp131
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Hemangiosarcoma in Rodents: Mode-of-Action Evaluation and Human Relevance2
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* University of Nebraska Medical Center, Omaha, NE, USA 68198, scohen{at}unmc.edu
Merck Research Laboratories, West Point, PA, USA 19486, richard_storer{at}merck.com
Pfizer, Inc., Ann Arbor, MI, USA 48105, kay.criswell{at}pfizer.com
ILSI Health and Environmental Sciences Institute, Washington, DC, USA 20005, ndoerrer{at}hesiglobal.org
¶ United States Environmental Protection Agency, Washington, DC, USA 20460, dellarco.vicki{at}epamail.epa.gov
|| Michigan Technology and Research Institute, Ann Arbor, MI, USA 48104, dgpegg{at}mtrinstitute.com
||| Fulcrum Pharma Developments, Inc., Ann Arbor, MI, USA 48103, zbigniew.wojcinski{at}fulcrumpharma.com
|||| National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, NC, USA 27709, malarkey{at}niehs.nih.gov
# United States Food and Drug Administration, Silver Spring, MD, USA 20993, abigail.jacobs{at}fda.hhs.gov
** Indiana University School of Medicine, Indianapolis, IN, USA 46202, jklauni{at}iupui.edu
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA 27599, james_swenberg{at}unc.edu
a Pfizer, Inc., Groton, CT, USA 06340, jon.c.cook{at}pfizer.com
1 To whom correspondence should be addressed: Nancy G. Doerrer, ILSI Health and Environmental Sciences Institute, 1156 Fifteenth St., NW, Second Floor, Washington, DC 20005. 202-659-3306 (phone), 202-659-3617 (fax); ndoerrer{at}hesiglobal.org (e-mail).
Received April 7, 2009; revision received June 2, 2009; accepted June 9, 2009
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Abstract |
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Although rarely occurring in humans, hemangiosarcomas (HS) have become important in evaluating the potential human risk of several chemicals, including industrial, agricultural, and pharmaceutical agents. Spontaneous hemangiosarcomas arise frequently in mice, less commonly in rats, and frequently in numerous breeds of dogs. This review explores knowledge gaps and uncertainties related to the mode of action (MOA) for the induction of hemangiosarcomas in rodents, and evaluates the potential relevance for human risk. For genotoxic chemicals (vinyl chloride and thorotrast), significant information is available concerning the MOA. In contrast, numerous chemicals produce hemangiosarcomas in rodents by non-genotoxic, proliferative mechanisms. An overall framework is presented, including direct and indirect actions on endothelial cells, paracrine effects in local tissues, activation of bone marrow endothelial precursor cells, and tissue hypoxia. Numerous obstacles are identified in investigations into the MOA for mouse hemangiosarcomas and the relevance of the mouse tumors to humans, including lack of identifiable precursor lesions, usually late occurrence of the tumors, and complexities of endothelial biology. This review proposes a working MOA for HS induced by non-genotoxic compounds that can guide future research in this area. Importantly, a common MOA appears to exist for the non-genotoxic induction of HS, where there appears to be a convergence of multiple initiating events (e.g., hemolysis, decreased respiration, adipocyte growth) leading to either dysregulated angiogenesis and/or erythropoiesis that produces hypoxia and macrophage activation. These later events lead to the release of angiogenic growth factors and cytokines that stimulate endothelial cell proliferation, which, if sustained, provide the milieu that can lead to HS formation.
Key Words: Hemangiosarcoma; HS; angiogenesis; endothelial cells; endothelial precursor cells; mode of action; human relevance; PPAR agonists.
2 This review summarizes the presentations and discussions from an international Workshop titled "Hemangiosarcoma in Rodents: Mode-of-Action Evaluation and Human Relevance," which was held December 4-5, 2008, in Arlington, Virginia. This Workshop was part of the Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) series, was co-sponsored by the ILSI Health and Environmental Sciences Institute (HESI), and was a follow-up to a HESI project focused on MOA for peroxisome proliferator-activated receptor (PPAR) agonists, many of which are known to induce hemangiosarcomas (HS) in mice.