Is exposure to formaldehyde in air causally associated with leukemia?—A hypothesis-based weight-of-evidence analysis

Abstract

Recent scientific debate has focused on the potential for inhaled formaldehyde to cause lymphohematopoietic cancers, particularly leukemias, in humans. The concern stems from certain epidemiology studies reporting an association, although particulars of endpoints and dosimetry are inconsistent across studies and several other studies show no such effects. Animal studies generally report neither hematotoxicity nor leukemia associated with formaldehyde inhalation, and hematotoxicity studies in humans are inconsistent. Formaldehyde’s reactivity has been thought to preclude systemic exposure following inhalation, and its apparent inability to reach and affect the target tissues attacked by known leukemogens has, heretofore, led to skepticism regarding its potential to cause human lymphohematopoietic cancers. Recently, however, potential modes of action for formaldehyde leukemogenesis have been hypothesized, and it has been suggested that formaldehyde be identified as a known human leukemogen. In this article, we apply our hypothesis-based weight-of-evidence (HBWoE) approach to evaluate the large body of evidence regarding formaldehyde and leukemogenesis, attending to how human, animal, and mode-of-action results inform one another. We trace the logic of inference within and across all studies, and articulate how one could account for the suite of available observations under the various proposed hypotheses. Upon comparison of alternative proposals regarding what causal processes may have led to the array of observations as we see them, we conclude that the case for a causal association is weak and strains biological plausibility. Instead, apparent association between formaldehyde inhalation and leukemia in some human studies is better interpreted as due to chance or confounding.

Keywords::

• Epidemiology
• formaldehyde
• genotoxicity
• hazard identification
• leukemia
• risk assessment

Acknowledgments

The authors would like to acknowledge Robert Golden of ToxLogic LLC and Peter de la Cruz of Keller and Heckman LLP for providing critical review of the draft manuscript.

Declaration of interest

All of the authors are employees of Gradient, a private consulting firm that provides services to both private and public organizations on toxicological and human health risk assessment issues. Individually, the authors have offered scientific testimony on formaldehyde risks to public organizations. The preparation of this review was sponsored by the Formaldehyde Council. The Council was provided the opportunity to review a draft of the paper and offer comments for consideration by the authors. The authors have sole responsibility for the content and the writing of the paper. The interpretations and views expressed in the paper are not necessarily those of the Formaldehyde Council.