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The Revised IARC Monographs Preamble Fails to Meet Current Scientific Benchmarks for Evidence-Based Decision Making

Over the past few years, headlines have claimed everything from shift work to drinking “very hot” beverages can cause cancer. These alarmist headlines stemmed from the work of the International Agency for Research on Cancer (IARC) Monographs Program, which evaluates cancer hazards. The Monographs Program only examines cancer hazards (the potential of an “agent” or chemical to cause cancer) rather than cancer risks (the actually risk of developing cancer based on exposure to a cancer hazard). Many of the substances classified as cancer hazards by IARC pose a very small cancer risk, if any risk at all, to most people. But even if that risk of developing cancer from exposure to a substance is infinitesimal, once a substance is classified as a carcinogen by IARC, public policy and commercial decisions are triggered around the world.

The Monographs Program has come under significant scrutiny for the manner in which it evaluates and communicates about potential cancer hazards, detracting from IARC’s important mission of enhancing public health.

For a bit of a perspective, IARC’s warning that “very hot beverages” are “probably carcinogenic” applies, according to IARC, to beverages at “temperatures above 65 °C.” Yet in the same Monograph, IARC determined that coffee drinking is “not classifiable as to its carcinogenicity in humans.”

Recently, IARC convened experts to review the IARC Preamble, which describes the process by which IARC staff and Working Groups gather, evaluate, and determine the potential carcinogenic hazards of chemicals and agents.

ACC submitted detailed comments to IARC describing areas where improvements to the Preamble were needed. ACC emphasized that, given all the concerns raised about the Monographs Program—including lack of transparency, inadequate review of or failure to fully review all relevant scientific information, questionable practices for evaluating and integrating mechanistic data, lack of independent peer review, and conflicts of interest—the Preamble required a top-to-bottom, comprehensive review. However, IARC did not act on this recommendation.

Consequently, the revised Preamble, while making some important upgrades, still falls well short of meeting current scientific benchmarks for evidence-based decision making. Below we highlight a few of the major shortcomings and flaws:

  • IARC removed Group 4 (“probably not carcinogenic to humans”). In other words, now a chemical will be judged by IARC to be a carcinogen or, if the data is really weak, to be “not classifiable as to its carcinogenicity to humans.” Under the new rules, IARC will never conclude that an agent doesn’t pose a carcinogenic hazard – at best, no matter how much data there is to the contrary, IARC  will just say it’s not classifiable.
  • The revised Preamble still fails to require that the process start with a problem formulation containing specific, testable hypotheses.
    • Evidence-based decision making requires formulating hypotheses in advance, during the design phase, and pairing these with rigorous scientific methodology to measure and evaluate observed results.
  • The Preamble still fails to include 21st Century standards and best practices for systematic review.
    • Specifically, no guidance is provided for the objective and transparent (and reproducible) evaluation of study quality.
  • The Preamble still fails to incorporate external independent peer review of the IARC Working Group’s analysis, procedures, results and conclusions.
    • The IARC Monograph Program refuses to consider as part of an evaluation any studies that aren’t independently peer-reviewed and published, except for specific instances for pesticides and pharmaceuticals – yet it explicitly resists calls for ensuring its own Monographs be subjected to such rigorous, independent scientific peer review.
    • National Academy of Sciences reports, Cochran Reviews and other authoritative evidence-based evaluations require reports and conclusions to be subject to expert peer review (see, for example, Guiding Principles for Developing Dietary Reference Intakes Based on Chronic Disease (2017) https://www.nap.edu/download/24828#).
  • The revised Preamble still fails to use postulated modes of action (MOA) as an organizing principle for problem formulation and evaluation
    • The scientific and medical communities now know more than ever before about the ways chemicals interact with biological systems to cause effects and diseases, including cancer. Yet the approach IARC maintains in the revised Preamble largely ignores this knowledge. Specific MOAs can be postulated, as has been recommended by the International Programme for Chemical Safety (IPCS; a World Health Organization program like IARC), and then the body of evidence in support of a chemical or an agent causing cancer by one or more of such defined pathways can be objectively evaluated. Unfortunately, in the revised Preamble, IARC has largely retained the evidence evaluation framework it originally developed in the 1970s. IARC does not provide any explanation as to why it is ignoring the recommended approach of its sister WHO program, the IPCS.
    • Although the Preamble expands its discussion of mechanistic data, IARC has elected to ignore the finding that the profiles of activities in key characteristics of carcinogens cannot distinguish carcinogens from non-carcinogens. Consequently, the revised Preamble perpetuates an approach that inappropriately considers bioactivity in assays purported to measure such characteristics as mechanistic evidence of carcinogenic potential to support IARC upgrading a cancer hazard classification.
    • The revised Preamble notes that oxidative stress bioactivity needs to be cautiously interpreted. But, unfortunately, the Preamble is completely silent regarding empirical evidence that other key characteristics of carcinogens also require similar notes of caution.
  • The revised Preamble still only gives lip service to obtaining stakeholder and user input as the analysis is planned, designed, conducted and reported.
    • ACC recommended that IARC develop and implement procedures for subjecting Monographs to public comment and independent peer review before they are finalized, with the IARC Director responsible for ensuring that Monograph revisions are fully responsive to all public and peer review comments before each Monograph is published. Unfortunately, IARC failed to act on these recommendations in revising the Preamble.
    • IARC continues to relegate experts outside of academia or research institutes to observer status. This is apparently based on the belief that scientists from other organizations or affiliations inherently possess conflicts of interest. But bias and conflict of interest are not limited only to industry. Nonprofit- and government-sponsored studies may be biased, and financial conflict is not the only source of conflict of interest. Other potential conflicts include “white hat bias – bias leading to distortion of information in the service of what may be perceived to be righteous ends,” including desire for academic or public recognition.

What does this all mean?

This was a tremendous opportunity that’s been lost. IARC had the opportunity to bring its Monographs policies, practices and procedures up to the benchmarks of 21st century evidence-based decision making and it failed to do so.

As a consequence, we’ll likely continue to see IARC Monograph classifications that are scientifically flawed, generate unfounded concern and create perceptions of health risks where, at environmental levels of exposures, no significant risks actually exist.

This leaves us wondering – is IARC really concerned about protecting public health? Or is IARC failing to properly update the scientific approaches of the Monographs Program to meet present day evidence evaluation benchmarks so it can continue to make headlines under the color of authority? In which case, ask yourself, whose health and well-being are really being served?

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