EWG Original Research
Rethinking Carcinogens
New view of cancer development focuses on subtle, combined effects

By Curt DellaValle, EWG Senior Scientist

Thursday, July 16, 2015

Introduction

An ounce of prevention is worth a pound of cure. That old adage is certainly true for cancer. Despite great advances in treatments and therapies, preventing the disease from ever occurring will always be the best option.

EWG is dedicated to making cancer prevention a public health priority. And new research from the Halifax Project, a collaboration of more than 300 scientists brought together by the non-profit organization Getting to Know Cancer, shines an even brighter light on the need for prevention strategies by investigating new ways in which toxic chemicals in our environment may cause cancer. The Halifax Project’s enlightening research is featured in a special issue of the scientific journal Carcinogenesis. It’s a huge step forward for prevention.

The Halifax Project team investigated 85 common chemicals not known to be carcinogenic on their own and found that 50 can disrupt cancer-related pathways (known as the Hallmarks of Cancer) at low doses typically encountered in the environment. The researchers go on to propose that combinations of these chemicals could cause cancer by disrupting multiple pathways and overwhelming the body’s defenses. This thinking is in-line with the current understanding of cancer as a multi-step process. 

 

Executive Summary

Chemicals that disrupt cancer-related pathways can act at low doses and likely contribute to the cancer burden

More than one in three Americans will be diagnosed with cancer in their lifetimes. Along with genetics, diet, lifestyle and viruses, exposures to toxic chemicals clearly contribute to this epidemic. This means it is critical to get the science and regulation of carcinogens right, but there is growing evidence that we may be overlooking crucial aspects of how combinations of chemicals may cause cancer.

That’s the conclusion of the Halifax Project, a collaboration of researchers from around the world who have just published a series of groundbreaking papers in a special issue of the scientific journal Carcinogenesis.

Current regulatory policy focuses on identifying “complete carcinogens” – single chemicals that can cause cancer all by themselves, but the Halifax Project’s work raises the strong possibility that complete carcinogens may be only the tip of the iceberg. New research is beginning to look at chemicals that are not carcinogenic in and of themselves but can affect normal cells in ways that make them more prone to becoming cancerous. Could exposures to multiple chemicals such as these over time also have the potential to cause cancer?

This simple yet profound hypothesis is being put forward by the Halifax Project’s scientists, who were brought together by the non-profit organization Getting to Know Cancer. Their investigation of the relationship between cancer and low-dose exposures to chemical mixtures may fundamentally shift the way we think about carcinogenesis.

This idea is based on two well-accepted scientific concepts:

  1. The development of cancer is a multistep process.
  2. There is a set of aggressive characteristics and processes, called “hallmarks of cancer,” that distinguish cancer cells from normal ones.

The “hallmarks” consist of a spectrum of changes to healthy cells that allow or cause them to divide and grow uncontrollably, eventually developing into cancer. These hallmarks include such factors as the ability of a cell to replicate endlessly and avoid biologically programmed cell death.

The Halifax Project team examined toxicity data on 85 chemicals that can trigger cancer-related hallmark processes to see if they might pose a risk at exposure levels people typically encounter in day-to-day life. Among the substances were phthalates, which are common plasticizers, and several pesticides. What they found was that 59 percent of the chemicals do affect cancer hallmark processes at low doses.

Although the study investigated only a small number of chemicals, the findings suggest that many of the hundreds of substances to which people are commonly exposed to in the environment may be capable of affecting cancer-related processes in human cells.

How great are the risks associated with chemical mixtures? An analysis by the Environmental Working Group found that 23 of the 85 chemicals investigated by Halifax Project scientists have been measured at detectable levels in the bodies of people participating in the nationally representative National Health and Nutrition Examination Survey, which is conducted annually by the Centers for Disease Control and Prevention. Many questions remain, but if cancer in fact results from an accumulation of these “hallmark” processes, it would mean that exposure to multiple chemicals that act on different cellular pathways could likely cause cancer.

It is time to expand the definition of carcinogenesis beyond the idea of a single chemical acting alone. We must begin to consider how combinations of chemicals working in concert and affecting a cell’s functioning in disparate ways may result in cancer.

As the President’s Cancer Panel pointed out in its 2008-2009 annual report, federal environmental laws not only leave many known carcinogens completely unregulated, they also “fail to address the potential hazards of being exposed to combinations of chemicals”.1

This needs to change for society to have any hope of success in preventing cancer.

 

The Halifax Project: Complete vs. Partial Carcinogens

Cancer takes an enormous personal and economic toll on individuals, families and society as a whole. The numbers are startling. Nearly one in every two men and one in every three women will be diagnosed with cancer over their lifetimes.2 The evidence is now compelling that chemicals in the environment are a significant factor in the risk of developing cancer, and a new series of reports from an international scientific collaboration called the Halifax Project suggests that the risk may be greater than we realize. 

Current thinking about the known links between environmental toxics and cancer suggest that many cancers could be prevented through effective regulation and lifestyle changes. Until now, however, that has meant identifying and attempting to reduce exposures to “complete carcinogens” – chemicals that can cause cancer all by themselves. But they may only be one piece of the puzzle. What could we be missing? 

For starters, we know very little about the long-term effects of continuous low-dose exposures to a wide array of chemicals. And we know little about how those exposures might interact over time to affect the working of healthy cells.

It was with that gap in scientific knowledge in mind that the non-profit organization Getting to Know Cancer brought together researchers from around the world to investigate the combined effects of low-dose exposures to chemicals and cancer risk, in an initiative they called the “The Halifax Project.” 

Getting to Know Cancer was co-founded in 2011 by Leroy Lowe and Michael Gilbertson in Nova Scotia, Canada. The goal of the organization is to inspire new approaches to research on cancer causes and therapies. Backed by a scientific advisory board, they initiated the Halifax Project by bringing together more than 300 scientists from research institutions in 31 countries to form two teams. One team focused on new approaches to cancer therapy, while the other one investigated low-dose exposure to everyday chemicals and their role in cancer development. 

The research of the latter team, published in the scientific journal Carcinogenesis,3 shows that many common and widespread chemicals can affect cancer-related mechanisms in the body at the low doses people typically encounter in the environment. Although these chemicals are not known to cause cancer on their own, the reports present the novel idea that they can combine in ways that have synergistic carcinogenic effects. The findings suggest that it may be time for fundamental change in the way we think about chemical carcinogens.  

Cancer does not develop all at once. It happens through a series of mutations and genetic changes that collectively transform normal cells into aggressive cancer cells – the “multiple hits” model. Many chemicals that can interfere with individual cancer-related processes are not complete carcinogens, but exposure to combinations of these substances could interfere with multiple cancer-related processes, overwhelm the body’s defense mechanisms, and result in cancer. That is the underlying hypothesis the Halifax Project is exploring.

Its scientists are asking three questions: 

  1. Are there such things as partial carcinogens? 
  2. Can partial carcinogens cause adverse health effects at low doses?
  3. Can exposure to the right (or wrong) combinations of partial carcinogens have synergistic, cancer-causing effects?

In effect, they are applying the ideas of the multiple-hit model of cancer development to the concept of chemical carcinogenesis. In doing so, they may bring about a fundamental shift in the way we think about carcinogens – advancing beyond the model of single chemical “bad actors” to a model that considers the combined effects of biologically disruptive chemicals that have historically been deemed to be non-carcinogenic. 

Every day people are exposed to a chemical cocktail: volatile chemicals in the air we breathe, disinfection by-products and other contaminants in our water, numerous synthetic chemicals in the food we eat and the consumer products we buy. Most of them are present in only small amounts. The Halifax Project examined toxicity information on 85 widely used chemicals (see a full list in Appendix 1) that are not considered classically carcinogenic and found that the majority (50) were able to disrupt cancer-related mechanisms at these low doses.3

This important discovery challenges the prevailing tenet of toxicology that “the dose makes the poison,” i.e., that in small enough amounts even something known to be toxic is unlikely to hurt you. Although the Halifax Project scientists investigated only a small number of chemicals, the findings suggest that many of the hundreds of substances people are exposed to daily at low levels may be capable of affecting cancer-related processes.

 

Chemicals in Our Body

The combination of chemicals interacting with us

The logical next question is: What role do the combined effects of chemicals that interfere with cancer-related processes play in the actual development of cancer? 

This is especially important when you consider that many chemicals are known to accumulate and remain in the body for long periods of time. The National Biomonitoring Program, conducted through the Centers for Disease Control and Prevention, has found and measured 265 environmental chemicals in human blood and urine samples collected as part of the National Health and Nutrition Examination Survey (NHANES).4 We know that many of these chemicals will be present in the body at the same time, even if the exposures do not occur simultaneously.

Each year, NHANES evaluates about 5,000 adults and children from across the United States to assess the health and nutritional status of the nation. Biological samples taken as part of the survey provide a good “snapshot” of chemical exposures in the population. The Environmental Working Group found that 23 of the 85 “partial carcinogens” investigated by the Halifax Project have been detected in the blood and urine sampled from the NHANES population (Table 1). These 23 chemicals – mostly metals, plasticizers (BPA and phthalates) and pesticides – circulate in the body and are known to disrupt certain cancer-related pathways. EWG has independently measured many of these same chemicals in biological samples, including in umbilical cord blood, showing that exposure to these chemicals may be passed from a mother to her unborn child.5,6

Table 1.  Biologically disruptive chemicals investigated by the Halifax Project that have been measured in NHANES biological samples

2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE)
Acrylamide
Alloy particles (tungsten/nickel/cobalt)*
Bisphenol A (BPA)
Cadmium
Cobalt
Copper
Cotinine
DDT
Dibutyl phthalate (DBP)
Diethylhexyl phthalate (DEHP)
Hexacholorobenzene
Iron
Lead
Lindane (gamma-hexachlorohexane)
Mercury
Methoxychlor
Methylmercury
Perfluorooctane sulfonate (PFOS)
Phthalates
Polybrominated diphenyl ethers (PBDEs)
Triclosan
Tungsten

* Cobalt, nickel and tungsten measured independently in NHANES biological samples.

 

The 23 chemicals listed in Table 1 represent only those directly measured in NHANES biological samples. There are other chemicals that are quickly eliminated from the body and unlikely to be analyzed or detected in a non-specific survey such as NHANES. Just because a chemical passes quickly through the body, however, does not mean it poses no health risk. For example, the pesticide glyphosate, recently classified as probably carcinogenic by the World Health Organization, remains in the body for only a few hours after exposure. 

Chemicals can also be metabolized in the body and transformed into other substances as part of the natural process of detoxification. These metabolites are indicators that chemicals have been present and interacted with the body’s chemistry, and they, too, can be toxic. Metabolites such as atrazine mercapturate, a breakdown product of the pesticide atrazine, have been measured in biological samples but are not included in the list above. 

NHANES does not provide an exhaustive list of chemicals found in the general population. EWG’s review of the scientific literature found data on 12 of the other 62 chemicals studied by the Halifax Project that have been directly measured in humans (Table 2).7-29 The Halifax Project also lists three medications – diethylstilbestrol, phenobarbital and reserpine – and melatonin, a hormone produced by the body naturally that can also be taken as a dietary supplement. The scientific data clearly shows that chemicals in the environment end up in the body and interact in ways we don’t fully understand.   

Table 2. Additional biologically disruptive chemicals investigated by the Halifax Project that have been directly measured in biological samples.

4-Nonylphenol
Acrolein
Atrazine
Benzo(a)pyrene
Bisphenol AF
Chlorothalonil
Chlorpyrifos
Cypermethrin
Diazinon
Nickel
Nickel derived compounds*
Nitric oxide

* Measured as nickel.