Formaldehyde as a potential human leukemogen: an assessment of biological plausibility

The International Agency for Research on Cancer (IARC, 2004) recently reevaluated the epidemiological data on formaldehyde and concluded that there was "strong but not sufficient evidence for a causal association between leukaemia and occupational exposure to formaldehyde." This conclusion was tempered since a mechanism for leukemia induction could not be identified. Chemically induced leukemia is a well-studied phenomenon with benzene and a number of cancer chemotherapeutic drugs recognized as capable of causing this effect. Abundant in vitro and in vivo data in animals and humans demonstrate that exposure to sufficient doses of these recognized leukemogens can initiate a cascade of events leading to hematopoietic toxicity and the subsequent development of leukemia. This review addresses the biological plausibility that formaldehyde might be capable of causing any type of leukemia by providing a broad overview of the scientific data that must be considered in order to support or refute a conclusion that a particular substance might be leukemogenic. Data on benzene and selected chemotherapeutic cancer drugs are used as examples and are briefly summarized to demonstrate the similar biological events thought to result in leukemogenesis. These data are compared and contrasted with the available data on formaldehyde in order to judge whether they fulfill the criteria of biological plausibility that formaldehyde would be capable of inducing leukemia as suggested by the epidemiological data. Based on the epidemiological data, it is reasonable to expect that if formaldehyde was capable of inducing leukemia, in vivo and in vitro data would offer supporting evidence for biological plausibility. In particular, there is (1) no evidence to suggest that formaldehyde reaches any target organ beyond the site of administration including the bone marrow, (2) no indication that formaldehyde is toxic to the bone marrow/hematopoietic system in in vivo or in vitro studies, and (3) no credible evidence that formaldehyde induces leukemia in experimental animals. As discussed in this review, based on the key biological events that occur in the process of chemically induced leukemia, there is inadequate biological evidence currently available to corroborate existing weak epidemiological associations. This provides an insufficient database to conclude that there is a causal relationship for formaldehyde and leukemia risk.