At the EPA workshop, Dr. Rhomberg hosted a session entitled, “Perspectives on the application of information discussed at the workshop to assessing the potential LHP cancer hazard(s) of inhaled formaldehyde.” We asked Dr. Rhomberg a series of follow-up questions below.
ACC: What do you think were the three key issues discussed in your session?
Dr. Rhomberg: In the session on mechanisms, three key issues that were discussed are:
1. How are formaldehyde’s differences in targets and toxicity mechanisms compared to known human leukemogens to be interpreted? To what extent are there commonalities, and how does all of this help inform the weight of evidence for formaldehyde’s potential hematopoietic carcinogenicity in humans?
2. Since it appears that inhaled formaldehyde cannot get past respiratory tissues, by what means can its toxicity and reactivity in respiratory tissues affect the bone marrow precursor cells that are the targets of transformation in leukemogensis? Can the target cells move via the blood through the lungs to be exposed there, or do some toxicity products (such as cytokines from inflammation) move from respiratory tissue to the target cells in marrow? What evidence is available to support or to test different proposed mechanisms?
3. How does the formaldehyde produced naturally by metabolism in all tissues affect and interact with the processes that are invoked to support the leukemogenic potential for inhaled formaldehyde?
ACC: Are there any uncertainties that you believe EPA still needs to address to reach a decision on formaldehyde’s association with leukemia?
Dr. Rhomberg: Yes, several. In particular, a number of potential mechanisms have been proposed, but they are largely speculations at present. For instance, the suggestion of respiratory inflammation as a source of cytokines to bring about remote leukemogenic transformation needs to address how such cytokines might act, and why other inhaled inflammatory chemicals are not also leukemia causes. Reports of chromosomal changes white blood cells of exposed workers have potential artifacts and need to be independently verified.
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. Rhomberg: As I have argued in a recent paper, “integration” means more than just drawing conclusions within each realm of data (epidemiology, toxicology, mode of action) and then combining them. Instead, one should see how explanatory hypotheses are supported (or contradicted) across realms, noting how consistencies and inconsistencies both within and across realms illuminate the nature and general applicability of possible causal mechanisms. Bioassay outcomes and mechanistic data can and should inform the way epidemiologists interpret the human data. This is especially important for formaldehyde and leukemia, since rodent bioassays show no effect of inhalation on leukemia, even at high doses, human studies are inconsistent, and mechanistic studies cast doubt on the biological plausibility of many if not all mechanisms. The key is to recognize that it is the broader generalization of the explanations for particular study outcomes that makes data into evidence about causality in humans.
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.