Following the completion of the U.S. Environmental Protection Agency (EPA) National Center for Environmental Assessment (NCEA) state-of-the-science workshop on formaldehyde inhalation last month, the American Chemistry Council’s Formaldehyde Panel invited the co-chairs of three workshop sessions to offer their thoughts on some of the key discussions that took place.
The third co-chair we spoke with is Dr. Melvin Andersen, chief science officer and director of the Institute for Chemical Safety Sciences at the Hamner Institutes of Health Sciences.
At the EPA workshop, Dr. Andersen led a session called, “Interactions of inhaled formaldehyde at the portal of entry: toxicokinetics and comparisons to endogenous formaldehyde.”
We asked him a series of follow-up questions below:
ACC: What do you think were the three key issues discussed in your session of the workshop?
Dr. Andersen: The first session covered the biochemistry of endogenous formaldehyde, formation of DNA-reaction products with formaldehyde, and then the different types of DNA-reaction products formed by formaldehyde or by materials that form formaldehyde in the body. The key issues discussed in our session related to (1) the amounts of inhaled formaldehyde required to alter significantly the levels of DNA-formaldehyde reaction products above those present in the absence of any external exposure to inhaled formaldehyde; (2) any differences expected between rodents, non-human primates and humans; and (3) the broader question of whether formaldehyde exposures can in any way increase levels of DNA-formaldehyde reaction products in tissues distant from the portal of entry, such as the blood-forming tissues at risk for developing leukemia.
ACC: Are there any uncertainties that you believe EPA still needs to address to reach a decision on formaldehyde’s association with leukemia?
Dr. Andersen: With an intensely studied material such as formaldehyde, it is important to emphasize that we have a great deal of information about its toxicology, metabolism, role in normal cellular biochemistry, and the close association with tissue injury/cytotoxicity that accompanies the formation of nasal cancer in rats. Based on this robust body of research, we know it is astonishingly implausible that inhaled formaldehyde will increase tissue levels of endogenous formaldehyde or DNA-formaldehyde reaction products significantly in any tissues other than those at the site of contact, i.e., the nose during nasal breathing or upper airways during mouth breathing. It is very difficult to see how inhaled formaldehyde can reach and affect bone marrow or other blood forming tissues. Yet, some animal studies indicate responses in other tissues, such as the liver. One uncertainty is the manner in which inhaled formaldehyde could cause toxicity in tissues in experimental animals beyond the nose or cause cancer beyond the portals of entry in human populations. Animal studies showing systemic responses could be pursued to correlate the degree of toxicity in the nose/lungs with changes in circulating cytokines arising from the local irritation/toxicity in the nose. Even if there are systemic response associated with alterations in circulating cytokines, this response would only occur with higher exposures (> 6 ppm).
ACC: What steps are needed to integrate the information from the various sessions into a weight of evidence for the association between formaldehyde and leukemia?
Dr. Andersen: Really, everything is already in place for a weight of evidence assessment with formaldehyde. The associations with leukemia are weak; the dose measures for this association, peak exposures, are difficult to ascertain with any confidence; and, it is difficult to imagine any mechanism for formaldehyde to change tissue formaldehyde exposures at sites distant from the portal of entry. This leaves the epidemiology in limbo. On the other hand, current information can be integrated to support a weight of evidence conclusion regarding a strong non-linear mode of action, with formaldehyde acting as a threshold carcinogen, regardless of the target tissue and regardless of animal species. At this point, the assessment should focus on a concentration below which there should be no increase in pulmonary/nasal tumors. In the panel discussion, participants noted a plausible approach using a tumor BMD (benchmark dose) with a safety factor of 100.
The EPA has indicated that it plans to hold further public forums to address additional issues that can inform the revised risk assessment. The ACC Formaldehyde Panel fully supports EPA’s efforts to increase transparency and continue the discussion of the science.