4. The Hallmarks of Cancer: Expanding how we search for carcinogens

How combinations of chemicals interact in our bodies is not well understood. We are repeatedly exposed to tobacco, alcohol, heavy metals and combustion by-products, which target many of the same body tissues and organs - and when combined may have the potential to dramatically increase the risk cancers.

Now scientists are rethinking how chemicals may contribute to cancer. New research from the Halifax Project suggests that mixtures of chemicals – even ones not known to be carcinogenic on their own – could cause cancer by disrupting multiple mechanisms known as the hallmarks of cancer.1,2

The hallmarks listed below are the characteristics that distinguish cancer cells – abnormal cells gone rogue, dividing and growing beyond the control of our body – from normal cells.12,13

The Hallmarks of Cancer Cells

Self-sufficient cell division—cancer cells grow and divide on their own

Insensitive to signals to stop cell division—cancer cells do not stop growing and dividing when signaled by the body

Resist cell death—cancer cell do avoid normal programmed cell death that removes old or damaged cells from the body

Limitless reproductive potential—cancer cells can replicate many more times than normal cells

Create own blood supply—cancer cells can stimulate the formation of blood vessels

Ability to invade other organs (metastasize)—cancer cells can spread from one organ to another

Ability to survive with little oxygen—cancer cells can switch to anaerobic respiration when oxygen supplies are low

Evade the immune system—cancer cells can avoid destruction by our body’s immune system

Genomic instability—cancer cell DNA is susceptible to changes in genes and gene expression

Inflammation—inflammation can promote conditions that can damage DNA

The scientists of the Halifax Project identified 85 chemicals common in the environment that are capable of disrupting hallmark pathways in the body – and the search for these types of chemicals is just beginning. What is alarming is these chemicals are not only common in the environment, they are common in people as well.

In NHANES, 34 of these hallmark-disrupting chemicals or their metabolites have been measured and detected in Americans' bodies. (Appendix C) That is significant because it means these chemicals are pervasive among the general population. Even if exposures to these chemicals do not occur simultaneously in the environment, many could still be circulating in the body at once.

The hypothesis of the Halifax Project – discussed in EWG’s Rethinking Carcinogens report1 – is that the same biological mechanisms by which many known carcinogens cause cancer can also be achieved through the combined effects of multiple chemicals.

Take the most well known carcinogen, tobacco, itself a mixture of chemicals including other known carcinogens NNN and NNK.14 Tobacco causes cancer through a multitude of hallmarks (in italics) and other biological mechanisms:

  • It causes mutations in the genes regulating cell growth, that suppress tumors and other genes that result in uncontrolled cell proliferation and genomic instability.
  • It affects receptors on cells causing resistance to cell death, increased ability for a cell to create its own blood supply and increased cellular transformations.
  • It also causes oxidative damage—free radicals that can react with and damage DNA, inflammation and DNA methylation, a chemical process that can modify how genes function.

Mechanisms of carcinogenesis for other known carcinogens similarly involve hallmark processes. Based on these mechanisms, it is a good bet that mixtures of hallmark-disrupting chemicals could have combined effects equivalent to individual carcinogens.

Here is how a mixture of chemicals we are commonly exposed to can disrupt a similar series of pathways as tobacco:

  • Bisphenol A (BPA), found in many plastics that store food and beverages, can disrupt cell proliferation and result in resistance to cell death and inflammation.
  • Heavy metals, which we can be exposed to through drinking water, some seafood and or occupational exposures, can cause genomic instability.
  • PFOS, a chemical used as a stain repellant on fabrics, can increase a cell’s ability to create its own blood supply.

That does not mean those combination of chemicals are as toxic as tobacco. They are nowhere near as powerful disrupters of those hallmark pathways, and there are many other factors involved in tobacco’s toxicity. There is no evidence yet of that particular combination of chemicals even being carcinogenic. It is merely an example of how the series of events that lead single chemicals to cause cancer could occur through exposure to mixtures of chemicals.

The potential for chemical mixtures of chemicals to cause cancer is supported by an investigation by the International Agency for Research on Cancer, part of the United Nations World Health Organization. IARC identified 10 key characteristics of mechanisms by which known carcinogens act.3 These characteristics, many of which are hallmark pathways, recognize that cancer develops in multiple stages. Many carcinogens act on multiple pathways and cause a series of biological changes in cells.

This line of thinking sets the stage for broader consideration of how chemicals contribute to cancer, rather than narrowly focusing on isolated chemicals or mechanisms. To evaluate this idea will require toxicity testing and regulatory standards that reflect the true nature of human exposure by considering the combined effects of chemicals on the body.