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An international workshop on "Hemangiosarcoma in Rodents: Mode-of-Action Evaluation and Human Relevance" was held in Arlington, Virginia, on December 4–5, 2008, as part of the Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) series. Government officials and researchers from around the world met to explore knowledge gaps and uncertainties related to the mode of action for the induction of hemangiosarcomas in rodents and to evaluate the potential relevance for human risk. Professor Sir Colin Berry delivered the Plenary Lecture, entitled "Trivial to Catastrophic, Necessary to Deadly: Vascular Proliferation and Malignancies in Humans and Animals." He is a Professor Emeritus of Biology at Queen Mary, University of London, United Kingdom. The two-day workshop was organized as a follow-up to a project conducted by the ILSI Health and Environmental Sciences Institute (HESI) which focused more narrowly on several knowledge gaps and uncertainties that were identified from a mode-of-action framework developed for peroxisomal proliferator-activated receptor (PPAR) agonists, many of which are known to induce hemangiosarcomas in mice. Although rarely occurring in humans, hemangiosarcomas have taken on significant importance in the evaluation of the potential human risk of a variety of chemicals, including industrial, agricultural, and pharmaceutical agents. In contrast to humans, spontaneous hemangiosarcomas are known to arise frequently in mice and less commonly in rats. In addition, numerous breeds of dogs are also known to have high incidences of spontaneous hemangiosarcomas. Possible interspecies differences were discussed including pathology, genetics, and pathobiology. For genotoxic chemicals, such as vinyl chloride and thorotrast which are known to induce hemangiosarcomas in humans, significant information is known concerning mode of action. Additional information was presented and discussed regarding DNA adducts from exogenous and endogenous sources that appear to be related to vinyl chloride, as well as possible potentiating factors in humans, such as steatohepatitis identified in vinyl chloride-exposed workers. In contrast, the numerous commercial chemicals that produce hemangiosarcomas in rodents act predominantly by non-genotoxic, proliferative mechanisms. An overall framework was presented which included a variety of modes of actions including direct and indirect actions on endothelial cells. Evidence for the possible role of adipose tissue as a source for endothelial growth factors, a possible role for bone marrow-derived endothelial precursor cells, and a potential contributing role for hypoxia were presented. Possible relationships between angiogenesis, a normal process in numerous biological phenomena, and vascular tumor induction were discussed, with many similarities identified but with some significant differences. Numerous obstacles were identified in the investigations into mode of action for hemangiosarcomas, as well as for an evaluation of the relevance of the mouse tumors to humans. These included the lack of identifiable precursor lesions, the usually late occurrence of the tumors in bioassays, and the complexities of endothelial biology. The approach in evaluating these tumors in risk assessment was presented by scientists from various government regulatory agencies, with several key issues being identified, including dose response, interspecies differences, and identification of specific modes of action. Scientists were particularly interested in the specificity and susceptibility of different rodent species and strains, including possible genetic bases for these species differences which are likely to be critical. The workshop was an opportunity for investigators from different scientific disciplines to discuss the considerable data deficiencies and uncertainties regarding the mode of action of these tumors and their human relevance. Presentations were supplemented with posters at the workshop. A report from the meeting will be prepared by the Workshop Organizing Committee and submitted for publication to Toxicological Sciences within the next few months.
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