U.S. EPA's IRIS assessment of 2-butoxyethanol: the relationship of noncancer to cancer effects

U.S. EPA's integrated risk information system (IRIS) assessment of 2-butoxyethanol (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 [National Toxicology Program (NTP), 2000a. Toxicology and carcinogenesis studies of 2-butoxyethanol (CAS no. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program Technical Report Series No. 484. U.S. Department of Health and Human Services, National Institutes of Health, Washington, DC]). Since the last EGBE IRIS assessment, a number of studies have provided evidence that the carcinogenic effects observed in mice are nonlinear in their mode of action and may be dependent on threshold events such as EGBE-induced 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 the mechanisms involved applicable to humans? If 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 with regard to how the answers might affect a revised IRIS assessment for EGBE.