A National Research Council (NRC) report released on August 14, 2014 largely endorsed an earlier National Toxicology Program (NTP) review that had concluded formaldehyde is a human carcinogen. Noting the NTP program provides no criteria for determining when there is sufficient human evidence, it developed its own procedure using the expert judgment of the committee; still, the NRC panel essentially agreed with study selections and conclusions made earlier by the NTP. Importantly, nothing in the NRC committee review of the literature addressed the notable limitations, concerns or controversies of the National Cancer Institute (NCI) studies that have been previously raised by other scientists (e.g., Marsh et al, 2010). NRC’s failure to address these issues does little to resolve the controversy that already existed regarding the hazard potential of this compound. In addition, this failure would also seem to raise questions as to how the NCI studies provide strong support for either hypothesis, or allows for the elimination of concern for chance, bias, or confounding as the NRC panel stated they do. The failure to discuss the identified limitations of the observations initially reported for the NCI cohort also raises concerns for the completeness of the literature evaluation the NRC panel performed.
Regarding the current mechanistic data, the NRC acknowledged the absence of a coherent and plausible mechanism for how formaldehyde (which does not reach the bone marrow) might cause myeloid leukemia. Importantly, in its analysis of mechanistic and animal studies the NRC did not distinguish between studies that used formaldehyde and those that used formalin. The U.S. EPA has recently questioned the utility of formalin studies for assessing the effects of inhaled formaldehyde. The NRC also did not consider whether effects observed in laboratory mice were secondary to a well-documented respiratory effect that occurs when mice are exposed to irritant gases such as formaldehyde. Notably, the NRC cited one recent study using formalin (see above) and mice (see above) that appeared to mistake a blood vessel for a serious bone marrow lesion. In an interesting twist, the NTP has recently completed a formaldehyde study in mice genetically predisposed to develop leukemia and reported no signs of adverse effects—yet these findings do not appear to be referenced anywhere in the NRC report. Most strikingly, the NRC concludes that systemic delivery of formaldehyde is unlikely, but states that experimental studies provide evidence for “systemic mechanistic events”, which they suggest could be associated with irritation, inflammation, and stress at the site of contact. For nasopharyngeal cancer (NPC), the available animal and mechanistic data favor a high-dose, thresholded dose-response.
To summarize, concern for the potential cancer risk associated with high-dose formaldehyde exposure has been a debatable issue for sometime now. The epidemiology studies performed by NCI scientists represent the main studies suggesting high occupational formaldehyde exposures carries some risk of NPC and acute myeloid leukemia (AML), but these studies have been criticized for methodological shortcomings and studies in other countries have also failed to confirm the NCI findings. The NRC panel did not evaluate and discuss this issue and provides no new analysis that might help resolve the controversy surrounding formaldehyde’s potential cancer hazard. Thus, it appears this controversy may continue unabated, as may concerns for any risk assessments using slope factors derived from these controversial studies.
Drs. <a href="https://www.toxstrategies.com/people/janice-britt article source.htm” target=”new”>Britt, James and Thompson of ToxStrategies, Inc. are very familiar with all aspects of formaldehyde toxicology and risk assessment having published numerous articles on these topics in the peer reviewed scientific literature.