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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 HS 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 HS 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 HS in rodents by nongenotoxic, 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 HS 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 nongenotoxic compounds that can guide future research in this area. Importantly, a common MOA appears to exist for the nongenotoxic 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 results from 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.

When the United States Environmental Protection Agency (USEPA) published guidelines for carcinogen risk assessment in 1986, it provided essentially no guidance on how to consider mechanistic information. The guidelines simply pointed out that ‘‘The Agency will review each assessment as to the evidence on carcinogenesis mechanisms and other biological or statistical evidence that indicates the suitability of a particular extrapolation model.’’ (USEPA, 1986). At that time, mechanisms of carcinogenesis were largely unknown and empirically difficult to approach. Nonetheless, as mechanistic data became available, the Agency considered it in formulating science policies, e.g., alpha2u-globulin–induced rat renal tumors (USEPA, 1991) and thyroid follicular cell rodent tumors and disruption of thyroid homeostasis (USEPA, 1998) or in chemical-specific assessments, e.g., bladder tumors induced by melamine through formation of urinary calculi (USEPA, 1988). In 1996, the Agency formally proposed to make information on the mode of carcinogenic action a pivotal point of the cancer risk assessment process (USEPA, 1996). Because complete knowledge of how an agent causes cancer is unlikely to exist (certainly for the near term), the 1996 guidelines put forth the notion of understanding mode of action versus mechanism of action. The former being a less detailed biochemical description of events than is meant by mechanism of action. The mode of action is sufficient evidence to draw a reasonable working conclusion concerning the agent’s influence on key processes. The mode of action concept permits information on precursor events to be evaluated and incorporated into the risk assessment process in a realistic way. The most frequent comment about the Agency’s 1996 proposed revision of its cancer risk assessment guidelines was that more guidance was needed on how to evaluate an agent’s mode of action. A few comments raised concern that the new USEPA guidelines would not be public health protective and opposed using mode of action data. In response, in 1999, EPA incorporated a mode of action framework analysis (USEPA, 1999) in conjunction with work by the International Programme for Chemical Safety (IPCS) (SonichMullin et al., 2001). This framework provided assurance that a rigorous and transparent approach would be taken to using mode of action data in the Agency’s cancer risk assessments, and it was well received by the scientific community. The mode of action framework is derived from considerations for causality used in epidemiologic investigations, which were originally articulated by Hill (1965). The Hill criteria were later modified by the U.S. Department of Health and Human Services (USHHS, 1982) and by Faustman et al. (1997) to extend to experimental animal studies. The publication of the USEPA 1999 framework provided an important tool with which the Agency can promote and formalize the use of mode of action data in cancer assessment. Mode of action data have come into play in several ways in EPA risk assessments. It has been critical in informing the dose–response relationship below the experimental observable range of tumors, and thus it is useful in establishing more appropriate guidance levels for environmental contaminants. The Agency’s traditional linear default extrapolation procedure for modeling tumor incidence has been a longstanding and often controversial issue. The 1986 USEPA guidelines provided only one dose–response default, namely the linear extrapolation procedure. The 1999 (and 1996) guidelines advanced this issue by providing two default extrapolation approaches—one linear and and one nonlinear. Application of the nonlinear default extrapolation procedure (typically a margin of exposure analysis or determination of a reference dose/ concentration) is based on the mode of action understanding about the agent. It was acknowledged in the 1999 (1996) guidelines that ‘‘true thresholds’’ are experimentally difficult to This paper does not necessarily reflect the views and policies of the U.S. Environmental Protection Agency. The opinions expressed within this paper reflect the views of the authors. 1 To whom correspondence should be addressed. Fax: þ1-703-5147; E-mail: dellarco.vicki@epamail.epa.gov.