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Open commentary

Establishing environmental causes of childhood cancer: a view from the IARC Monographs

Authors
  • Elisa Pasqual orcid logo (International Agency for Research on Cancer (IARC), Lyon, France)
  • Andrew Kunzmann (International Agency for Research on Cancer (IARC), Lyon, France)
  • Julia Heck orcid logo (College of Health and Public Service, University of North Texas, USA)
  • Margaret R Karagas orcid logo (Geisel School of Medicine, Dartmouth, USA)
  • Mary K Schubauer-Berigan orcid logo (International Agency for Research on Cancer (IARC), Lyon, France)

This article is a preprint and is currently undergoing peer review by UCL Open: Environment.

Abstract

In 2025, the IARC Monographs programme identified two new causes of childhood acute lymphoblastic leukaemia (ALL), with limited evidence: automotive gasoline and human cytomegalovirus (HCMV). Previously, for childhood ALL only one potential cause was identified (parental tobacco smoking, with limited evidence). The Monographs programme, throughout its history, has identified few other causes for specific childhood cancers.

Here, we aim to: i) summarize IARC Monographs classifications relevant for childhood cancer aetiology; ii) describe the evidence that contributed to the recent classifications of automotive gasoline and HCMV; iii) list agents with evidence for an association with childhood cancer that are currently prioritized for an IARC Monographs evaluation in the 2025-2029 period.

Several factors have been increasingly identified as potential external causes of childhood cancers. Methodologically, studies have been improved by including assessment of the exposure prior to diagnosis (e.g. use of geocoding methodology or stored neonatal bloodspots), which were instrumental in the automotive gasoline and HCMV classifications.

Several agents currently prioritized for IARC Monographs evaluation, mainly individual pesticides or air pollution components, present sporadic positive findings for specific childhood cancer subtypes. IARC Monographs evaluation of cannabis smoking is planned for November 2026. Sporadic positive associations for specific childhood cancer subtypes were also reported for cannabis smoking (through parental habits) in case-control studies in the 1990s and early 2000.

Studies informative for cancer hazard identification are likely those able to well define the exposure (e.g. individual pesticides), the window of exposures (e.g. in utero), and the outcome (e.g. avoiding combining childhood cancers).

Keywords: childhood cancer, epidemiology, environmental causes

Funding

  • European Union Directorate General of Employment, Social Affairs, and Inclusion.
  • National Cancer Institute (grant NIH grant R01CA033193)
Preprint Under Review
License
Creative Commons Attribution 4.0

 Open peer review from Ruth Lunn

Review
Establishing environmental causes of childhood cancer: a view from the IARC Monographs
E Pasqual, A Kunzmann, JE Heck, MR Karagas, MK Schubauer-Berigan

Pasqual and colleague present an important review of the International Agency for Research on Cancer (IARC) Monograph efforts related to childhood cancers, including current classification of environmental causes (or probable) causes and future evaluations. The incidence of childhood cancer has been increasing globally, and environmental causes remain largely unknown. Identifying environmental exposures linked to childhood cancer provides important opportunities for prevention, as many of these exposures are potentially modifiable.
The paper is informative, focused, and clearly written. In addition to presenting the IARC perspective, it also serves as a valuable resource for identifying data gaps for the research community. I offer the following comments for the author’s consideration.

Suggested Concepts to Consider
• Briefly note that the increasing incidence of childhood cancer supports a potential role for environmental factors (e.g., new or changing exposures over time), as genetic susceptibility in populations is generally more stable across generations.
• Consider mentioning environmental health disparities by socioeconomic status or race/ethnicity. For example, childhood cancer is higher in Hispanics in the United States. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/cancer-facts-and-figures-for-hispanics-and-latinos/2024/2024-2026-cancer-facts-and-figures-for-hispanics-and-latinos.pdf#:~:text=Leukemia%20incidence%20(mostly%20lymphoid%20leukemia)%20is%20higher,30%25%20higher%20than%20those%20who%20are%20White.
• In addition to the burden of cancer itself, briefly acknowledge that survivors of childhood cancer are at increased risk for subsequent chronic diseases and other adverse health outcomes, further contributing to the long-term public health burden
• Cite the following reviews on childhood cancer and briefly mention discuss whether IARC-proposed evaluations are consistent with this literature.
o Impact of the environment on childhood cancer clinical outcomes, Matayer 2025 https://www.sciencedirect.com/science/article/pii/S1538544225000756?via%3Dihub
o Causes of Childhood Cancer: A Literature Review (2014–2021)—Part 3: Environmental and Occupational Factors Emeny 2025 https://www.mdpi.com/2072-6694/17/21/3516

Balance in Discussion of Study Strengths and Limitations
I appreciate the discussion of strengths and limitations related to study design and exposure assessment; however, the discussion could be more balanced. In some instances, limitations may be understated or may depend heavily on the exposure or population under study (see example below). I agree with the statement about exposure assessment in the manuscript conclusions.
• Lines 302–307: Studies measuring pesticides in dust at diagnosis may still be subject to considerable exposure misclassification, even for persistent pesticides. Exposure can be seasonal and may vary over time. Participants with high pesticide levels at diagnosis may have had lower levels during the relevant etiologic window, unless there is evidence that exposure sources were consistent over time. Ward et al. 2023reported substantial temporal variability in glyphosate concentrations in household dust among participants with repeated samples, likely resulting in exposure misclassification, even though glyphosate may be less persistent than other pesticides. https://pmc.ncbi.nlm.nih.gov/articles/PMC10294409/
• Line 320: Biomarker studies based on a single sample may be subject to exposure misclassification, particularly for chemicals with short biological half-lives.
• Line 368: GIS-based exposure assessments that do not account for residential mobility or parental occupational exposures may also result in substantial exposure misclassification.
• Line 297: Recall bias may be less of a concern in studies assessing parental occupational exposure. Blair and Zalm (1990), in their review of pesticide studies, concluded that differential recall bias was not a major concern in many occupational exposure assessments.https://onlinelibrary.wiley.com/doi/10.1002/ajim.4700180308

Note:
This review refers to round 1 of peer review.