A team of epidemiologists and toxicologists from the firm ToxStrategies has just released a state-of the-science systematic review of studies that focus on the relationship between inhaled formaldehyde and lymphohematopoietic cancers (LHP’s), including myeloid leukemia. The paper has been accepted for publication in Toxicological Sciences, the official journal of the Society of Toxicology.

This new review takes advantage of advances in the field of systematic review methodology to assess the likelihood of a causal relationship between formaldehyde and LHP cancers.

It found no evidence of systemic delivery of inhaled formaldehyde to bone marrow – where LHP cancers are formed – or blood, following inhalation of formaldehyde.  Therefore, causation is unlikely.

Meanwhile, U.S. EPA and the World Health Organizations cancer research group, The International Association for Research on Cancer, IARC (2018) have concluded that formaldehyde is a cause of LHP cancers. Other groups, including the US National Toxicology Program stop short of doing so.

Formaldehyde is made naturally in the human body and is a by-product of forest fires, cooking and automobile exhaust.   It is also widely used in industries such as composite wood products (plywood, pasteboard), embalming fluid, vaccines, medicine, adhesives, paper towels, makeup, insulation, cars, computers, furniture, cabinets and textiles.

Regulatory or legal decisions based on old or weak science can have devastating effects on these industries – including on workers and consumers.

In April 2022, the EPA released its draft Integrated Risk Information System (IRIS) report on formaldehyde. It claims, “… [there is] evidence that formaldehyde inhalation causes nasopharyngeal cancer, sinonasal cancer, and myeloid leukemia in exposed humans given appropriate exposure circumstances.”

This claim took many scientists by surprise—especially the mention of myeloid leukemia (AML), a cancer of the bone marrow and blood (and the most common type of leukemia in adults). The EPA had never before claimed that inhaled formaldehyde causes leukemia, and several scientists question if such a thing is possible, since decades of published research have demonstrated that inhaled formaldehyde does not travel past the nasal cavity and does not enter the blood or bone marrow. The EPA also failed to define the levels of exposure that would cause harm.

In the most recent release of the draft health assessment of inhaled formaldehyde on March 15, 2024, myeloid leukemia is mentioned again and EPA refers again to the draft 2022 IRIS report.

Formaldehyde has been studied and regulated for many decades. We know that at certain high levels it is a carcinogen. While the International Association for Research on Cancer (IARC) has said it is a cause of LHP cancers (blood cancers including leukemias and lymphomas) since 2012, this draft is the first time EPA has done so. At the same time, the U.S. National Toxicology Program (NTP) does not currently identify inhaled formaldehyde as a cause of LHP cancers, even though it says it is associated with them. The Center and others have criticized the EPA’s process for a lack of transparency and insufficient causal evidence in past reviews.

In response to the concerns of critics, the National Academies of Science, Engineering and Medicine (NASEM) was contracted by the EPA to conduct a new review of its formaldehyde process. Its conclusion is confusing, first praising the EPA’s process generally, then pointing out many issues and making 40 recommendations for revision. The headlines at the time seemed to reflect only the positives in the report.

(Note: The EPA had not reviewed its guidance on formaldehyde since 2011, at which time the National Research Council (part of the National Academies) had been asked by the EPA to evaluate its formaldehyde assessment process. Many drawbacks were identified in that evaluation, which resulted in NASEM being brought in again in 2023 to determine if the EPA followed the Council’s recommendations.)

In its assessment, NASEM stated:

“Overall, the report finds that EPA’s draft assessment follows the advice of prior National Academies reports and that the agency’s findings on hazard and quantitative risk are supported by the evidence identified in the document.”

But then, it goes further to state:

“The report recommends that EPA revise the document to ensure that users can find and follow the methods used in each step of its assessment for each health outcome.” 

This has not yet been satisfactorily done, as what is available on the EPA website are several documents that one must go through to locate important information. As an example, information that is presented on inhaled formaldehyde as a cause of myeloid leukemia is buried 400+ pages into a 789-page document. The Center has several questions about the systematic review that the EPA carried out on this topic, and its conclusions. We will present these questions to the EPA at the public comment session it has scheduled for May 2024.

Susan Goldhaber, MPH, describes many issues with the NASEM assessment in a blog post, where she explains a lawsuit that the American Chemistry Council is bringing against EPA and NASEM on the processes used for the formaldehyde risk assessment.

Given the issues described above, the Center for Truth in Science made the decision in 2022 to fund an independent state-of-the-science systematic review focused on the relationship between inhaled formaldehyde and LHP cancers, including myeloid leukemia. After an independent expert review of several proposals, an award was made to ToxStrategies. The work was completed by Dr. Daniele Wikoff, Melissa Vincent, MS, and a qualified team of researchers. There was no involvement from the Center in this project.

The review found no credible explanation linking inhaled formaldehyde to LHP cancers, and no evidence of formaldehyde entering the bone marrow or blood when inhaled. Additionally, it found that genotoxicity (which has been theorized as a mechanism by which formaldehyde might contribute to LHP cancers) was not found to be a plausible mode of action in this case.

More rigorous and clear than what is found in the EPA’s draft report, this systematic review was conducted with transparency and used state-of-the-science methods to assess causality, including determining study quality and identifying risk of bias. Importantly, the review team set the research questions a priori (before developing the literature search methods and conducting the search) and included a summary of evidence from multiple data streams: human, animal, and mechanistic studies.

The ToxStrategies team made the study protocol publicly available on the Center for Open Science platform before the start of the study, apprising the scientific community of their approach before the work moved forward. The process also included:

  • Critical appraisal, formal integration of evidence, and risk of bias analysis
  • Methods endorsed by both the World Health Organization and the National Toxicology Program at the U.S. National Institutes of Health (NIH)
  • Integration of NASEM’s actual recommendations to the EPA to strengthen its methods
  • Both the highly accepted GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) and Bradford Hill criteria

The publication of this systematic review adds important new evidence that must be considered in policy discussions regarding regulation of inhaled formaldehyde. The EPA’s final version of the formaldehyde risk evaluation was expected to come out in the Fall of 2023, but to date, only draft reports have been released.

The Center plans to take a deep dive into the documents released by the EPA last week. But we are concerned that this is only the tip of the proverbial iceberg. When environmental policy affects such a ubiquitous substance as formaldehyde, which is used in the making of so many products and materials affecting so many jobs and livelihoods, why do we need to fight to ensure the most rigorous science—explained in a clear, straightforward manner—be used in determining health effects?

You can find the new research publication here:  https://doi.org/10.1093/toxsci/kfae039

M J Vincent, S Fitch, L Bylsma, C Thompson, S Rogers, J Britt, D Wikoff, Assessment of associations between inhaled formaldehyde and lymphohematopoietic cancer through integration of epidemiological and toxicological evidence with biological plausibility, Toxicological Sciences, 2024;, kfae039, https://doi.org/10.1093/toxsci/kfae039 

A summary of the systematic review is here and a downloadable version is available here.