U.S. EPA's IRIS Assessment of 2-Butoxyethanol: the Relationship of Noncancer to Cancer Effects
U.S. EPA's current IRIS (Integrated Risk Information System; www.epa.gov/IRIS) assessment of 2-butoxyethanol (EGBE; CASRN 11-76-2) identifies hemolytic effects in laboratory exposed animals as the critical noncancer endpoint. This noncancer (and nonlinear) endpoint forms the basis for the IRIS inhalation reference concentration (RfC) and the oral reference dose (RfD). The corresponding IRIS cancer entry for EGBE indicates that the human carcinogenic potential of EGBE cannot be determined at this time, but that "suggestive evidence" for cancer exists from laboratory animal studies (hemangiosarcoma of the liver in male mice and forestomach squamous cell papilloma or carcinoma in female mice; NTP 2000). Since the last EGBE IRIS assessment, a number of studies provide evidence that these carcinogenic effects observed in mice are nonlinear in their mode of action and may be mediated by threshold events such as EGBE initiated hemolytic effects. EPA is in the process of considering several questions relating to this issue. First, can a plausible mode of action be determined for the two types of tumors observed in mice? Second, are those mechanisms involved applicable to humans? Is so, should the mode of action be considered to result in a linear or nonlinear dose response? These questions will be addressed within the context of the Agency's new cancer guidelines, and as to how the answers might impact a revised IRIS assessment of EGBE.