Science and Law
20th December 2016

Does Carcinogenicity Classification Make Any Sense?

In a recent trial involving allegations that asbestos-contaminated talc caused the plaintiff’s mesothelioma (the Lamonica case), plaintiff counsel (Scott Frost) was having a difficult time impeaching the opinions of the defense pathologist (Dr. Mossman).

Does Carcinogenicity Classification Make Any Sense?

In a recent trial involving allegations that asbestos-contaminated talc caused the plaintiff’s mesothelioma (the Lamonica case), plaintiff counsel (Scott Frost) was having a difficult time impeaching the opinions of the defense pathologist (Dr. Mossman). After spending some time trying to impeach her opinions based on her financial payments, Frost turned to another tried and true tactic: attempt to gain the admission that talc was classified by a government agency as carcinogenic.

By attempting to gain the admission that the International Agency for Research on Cancer (IARC) had classified talc as a carcinogen, Mr. Frost was hoping that in one simple and straight forward answer he could establish a good portion of his case. Yes or no? Did they or didn’t they?

The Power of Classification

This line of cross examination is a good reminder of the power of classifying chemicals as to their carcinogenicity. It appears to be infinitely reasonable if you assume that there are world class cancer experts capable of determining, with some level of accuracy, the causes of cancer in humans. And if you build a committee, distribute the available information, gather them together for a series of meetings, it should be possible to determine with accuracy whether certain chemicals cause cancer in humans. Right?

To be sure, there are aspects of this approach that make sense. After all, non-scientists are not capable of processing detailed information about exposures (e.g., form, dose, route of administration, toxicodynamic responses, etc.) and disease endpoints (e.g., classification of disease, diagnostic criteria, etc.) and then integrating that information into a complex risk assessment and risk characterization. Is it too much to ask that experts tell us whether or not we should be concerned about specific chemicals?

IARC and Other Classification Systems

Before addressing the case against classifying chemicals as carcinogens, to provide some context I will review the IARC system and a few other commonly used classification systems.

Briefly, IARC follows what it considers to be a systematic approach in evaluating the following types of information for each agent it reviews:

  • Carcinogenicity in humans
  • Carcinogenicity in experimental animal studies
  • Mechanistic and other relevant data

From this process, IARC comes to an overall evaluation, which is its classification scheme. At the end of it’s review process, the IARC working group makes the determination as to whether the agent fits into one of the following classifications:

  • Group 1: Sufficient evidence of carcinogenicity to humans
  • Group 2a: Probably carcinogenicity to humans
  • Group 2b: Possibly carcinogenic to humans
  • Group 3: Not classifiable based on the current state of the science
  • Group 4: Probably not carcinogenic to humans

Recently, dozens of scientists who have served on IARC working groups over the last 40 years published a commentary defending the process.

The United Nations has developed criteria for a globally harmonised system of classification and labelling of chemicals (GHS) that resembles IARC’s system, although it is a bit simpler. Other US government agencies – including the National Toxicology Program, the EPA, and the CDC –have classification systems that segregate chemicals into known, probable, and unlikely carcinogens, as do European agencies such as the European Food Safety Authority (EFSA).

The Case Against Classification

Despite the longstanding and widespread nature of these classification schemes, some have argued that classifying chemicals with a simple nomenclature as to their carcinogenicity is not appropriate. A recent paper by Boobis and colleagues makes the point that these cancer classification systems are outmoded and inadequate to manage chemical risks. In their view, these classification systems have the following shortcomings:

  • They improperly conflate hazard (something that may cause harm) and risk (the probability that a particular hazard will cause harm)
  • They lead to absurd examples of classification (e.g., processed meats fall into the same category as sulfur mustard gas)
  • They lead to unintended negative consequences (e.g., health scares, economic costs, loss of beneficial products, diversion of public funds into unnecessary research)

The authors make the point that these shortcomings apply to other hazard-based assessments such as the alleged potential for so-called “endocrine disrupting chemicals” to cause reproductive toxicity.

In addition to criticisms of the classification process, others have raised serious concern about the objectivity, validity, and reliability of these classification-based assessments. They argue that IARC evaluations suffer from a process that has been coopted by politicization and cherry-picking of data.

Perhaps the most telling criticism of the classification process is the fact that different classifying bodies classify the same agents differently. Most recently, IARC classified glyphosate as a “probable human carcinogen (class 2a), while EFSA concluded that “glyphosate is unlikely to pose a carcinogenic hazard to humans and the evidence does not support classification with regard to its carcinogenic potential.”

The Future of Carcinogenicity Risk Assessment: Genetic and Molecular Approaches

With the advent of more readily available genetic and molecular techniques, there has been a trend in the scientific community to attempt to utilize these techniques to identify and classify carcinogens. One recent study systematically evaluated all IARC Group 1 carcinogens (i.e., sufficient evidence of carcinogenic in humans) to determine the following 10 key characteristics of carcinogens:

  1. Is electrophilic
  2. Is genotoxic
  3. Alters DNA repair or causes genomic instability
  4. Induces epigenetic alterations
  5. Induces oxidative stress
  6. Induces chronic inflammation
  7. Is immunosuppressive
  8. Modulates receptor-mediated effects
  9. Causes immortalization
  10. Alters cell proliferation, cell death, or nutrient supply

As you can see, many of these characteristics have to do with genetic or molecular attributes of the chemicals. This type of molecular “litmus test” to determine whether a chemical is carcinogenic is clearly far from ready for prime time. Nevertheless, it is an interesting approach that we will likely hear more about in the near future.

Specifically, epigenetic effects of toxic agents have been a major area of investigation in environmental carcinogenesis research. Chappell and colleagues recently performed a systematic review of publications reporting epigenetic effects for the 28 agents included as IARC Class 1 carcinogens. These investigators found that 12 of the 28 carcinogenic agents had studies evaluating epigenetic alterations. They believe that their results support the incorporation of epigenetic endpoints into cancer hazard assessments.

Has the IARC classification system been outdated by advancements in genomic science? Does it have reliable application to regulatory decision making?  Should there be caveats to citing classifications for litigation purposes? These are just some of the emerging questions that deserve attention today to re-establish trust in our public health policy and the courts.

Here is an infographic produced by Positive Health Wellness that highlights the complexity of determining whether common foods cause cancer.

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