The Hitchhiker’s Guide to an IARC Monograph Conclusion: Don’t Panic

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The answer “42” that IARC has for everything is “carcinogenic” because its declarations are limited to: carcinogenic, probably or possibly carcinogenic to humans, or “I don’t know”. The program’s statements are met with understandable concern, sometimes bordering on panic, because almost everything it examines is considered to be at some level “carcinogenic to humans”. Over the years, the IARC has labeled red meat, pickled foods and salted fish, carpentry, night work, cell phone use and, most recently, firefighting as possible, probable or definitely carcinogenic. How will we respond to these statements appropriately? Stop using my cell phone? Resign? Give up meat? If this is the case, you will also have to give up bread and many fruits and vegetables, as they contain substances considered carcinogenic by the IARC system. Moreover, when the IARC classified coffee and hot beverages as “possibly carcinogenic” and then reclassified coffee several years later as “unclassifiable” (meaning “I don’t know”), should I start drinking coffee again and stop drinking hot tea?

It wouldn’t be strange to start worrying about all this and wondering if, in fact, we are all doomed. But as another famous phrase from The Hitchhiker’s Guide to the Galaxy tells us, “Don’t panic.”

The IARC monographs program was established in the early 1970s as our understanding of cancer and its causes grew. At the time, it was assumed that carcinogenicity was a fairly simple binary problem – either a substance caused cancer or it did not – and that the number of carcinogens was relatively limited. It soon became apparent that this was too simplistic, to say the least. As scientists tested more and more substances, they discovered that at least half were probable or possible carcinogens, and that these substances exist not only in many fruits and vegetables that make up a healthy diet , but also in about 60% of life-saving drugs. on the market today. They also found that in many cases, the excessive doses given to laboratory animals during carcinogenicity testing likely in themselves caused cancer simply by overwhelming biological systems.

Not surprisingly, the IARC monographs program systematically finds just about anything that can cause cancer. Of the nearly 1,000 substances and lifestyle hazards they evaluated, they found only one (1) that definitely did not cause cancer.

But if the answer to the question “Does a substance cause cancer?” is always “yes or I don’t know”, what practical value does that have? It’s kind of a “42” answer.

In The Hitchhiker’s Guide, scientists who had waited seven thousand years for “the answer” were understandably disappointed by the computer’s response. But as Deep Thought pointed out in its own defense, the question they asked wasn’t very specific.

Perhaps like these scientists, the IARC monographs program needs to be more specific with its questions and the context of those questions. Instead of the simplistic question “Does a substance cause cancer?” they should ask questions like, “At what dose does this cause cancer?” (in other words, how powerful right?) Is anyone likely to be exposed to this dose? Is it even possible, outside of a laboratory, to consume or be exposed to enough of a substance to cause cancer? They might also ask a few other questions – questions that all other regulators in the world naturally ask – such as “is the effect specific to the route of exposure?”, “what is the mode of action ?” (that’s to say, How? ‘Or’ What does it cause cancer), and does this same mode of action apply to humans, not just laboratory animals? (See the list of publications at the end of this article for peer-reviewed ideas on better ways to understand carcinogenesis, testing, interpretation, and classification of potentially carcinogenic substances and occupations.) If the answer to all of these questions suggests that a substance poses a hazard, appropriate measures, ranging from outright bans to limitations on use, can be taken to ensure safety.

If the agent is another scenario such as behavior, infectious agent, occupation or lifestyle choice, then one would imagine that the research program of IARC or other institutions would conduct further research to confirm the conclusion of the monograph program and, if confirmed, institute a program to determine public health improvements to prevent carcinogenic effects.

Asking the wrong questions can lead to an answer equivalent to Deep Thought’s “42” and the elimination of helpful, even life-saving substances or professions. However, regardless of the answer to the question asked, even if it is the wrong question, remember: “Don’t panic.

The IARC Monographs program needs to have a conversation to make its statements more useful. The upcoming IARC Scientific Workshop on Assessing Bias in Cancer Risk Identification in October 2022 would be a good place to start this conversation.

Authors and affiliations:

  • Samuel M. CohenMD, PhD, Havlik-Wall Professor of Oncology, University of Nebraska College of Medicine
  • Penny Fenner CrispPhD, former Director of the Environmental and Health Review Division of the United States Environmental Protection Agency, Office of Pollution Prevention and Toxic Substances.
  • Alan BoobisPhD, Emeritus Professor of Toxicology, Imperial College London, former Editor, now Emeritus Editor, of Food and Chemical Toxicology.
  • Angelo MorettoMD, PhD, Professor of Occupational Medicine, University of Padua, Italy and Director, Occupational Health Unit and Postgraduate School in Occupational Health, University Hospital of Padua.

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Supporting published and peer-reviewed research includes:

Boobis AR, Cohen SM, Dellarco VL, Doe JE, Fenner-Crisp PA, Moretto A, Pastoor TP, Schoeny RS, Seed JG, Wolf DC. Carcinogenicity classification systems based on hazard identification have become obsolete and serve neither science nor society. Regul Toxicol Pharmacol. 2016 Dec;82:158-166. doi: 10.1016/j.yrtph.2016.10.014. Epub 2016 October 22. PMID: 27780763.

Wolf DC, Cohen SM, Boobis AR, Dellarco VL, Fenner-Crisp PA, Moretto A, Pastoor TP, Schoeny RS, Seed JG, Doe JE. Chemical carcinogenicity revisited 1: A unified theory of carcinogenicity based on contemporary knowledge. Regul Toxicol Pharmacol. April 2019;103:86-92. doi: 10.1016/j.yrtph.2019.01.021. Epub 2019 January 8. PMID: 30634023.

Doe JE, Boobis AR, Dellarco V, Fenner-Crisp PA, Moretto A, Pastoor TP, Schoeny RS, Seed JG, Wolf DC. Chemical Carcinogenicity Revisited 2: Current knowledge of carcinogenesis shows that categorization as carcinogenic or non-carcinogenic is not scientifically credible. Regul Toxicol Pharmacol. 2019 Apr;103:124-129. doi: 10.1016/j.yrtph.2019.01.024. Published online January 18, 2019. PMID: 30660801.

Samuel M. Cohen, Alan R. Boobis, Vicki L. Dellarco, John E. Doe, Penelope A. Fenner-Crisp, Angelo Moretto, Timothy P. Pastoor, Rita S. Schoeny, Jennifer G. Seed, Douglas C. Wolf , Chemical carcinogenicity revisited 3: Risk assessment of carcinogenic potential based on the current state of knowledge of carcinogenesis in humansRegulatory Toxicology and Pharmacology, Volume 103, 2019Pages 100-105, ISSN 0273-2300, https://doi.org/10.1016/j.yrtph.2019.01.017.

· Doe, JE, Boobis, AR, Cohen, SM et al. The codification of hazard and its impact on the hazard/risk controversy. Arch Toxicol 95, 3611–3621 (2021). https://doi.org/10.1007/s00204-021-03145-6

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