September 16, 2015

Low-dose Chemical Mixtures as Carcinogens

The effects of multiple toxins on the human body, and it means for the future of healthcare
In this study, 11 teams of toxicology experts reviewed relevant data on the chemicals in our everyday life to ascertain their carcinogenic impact according to the “hallmarks of cancer.”

In this study, 11 teams of toxicology experts reviewed relevant data on the chemicals in our everyday life to ascertain their carcinogenic impact according to the “hallmarks of cancer.” 

This paper is part of our Environmental Medicine Special Issue. Read the entire issue below.


Goodson WH 3rd, Lowe L, Carpenter DO, et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis. 2015;36 Suppl 1:S254-S296.


Eleven teams of international toxicologists and biologists reviewed relevant data on ubiquitous chemicals and their possible influence on carcinogenesis based on the “hallmarks of cancer.”1 Each team was to determine “prototypical” chemicals that are involved in the given hallmark. The 11 teams were assigned to these categories:  angiogenesis, dysregulated metabolism, evasion of antigrowth signaling, genetic instability, immune system evasion, replicative immortality, resistance to cell death, sustained proliferative signaling, tissue invasion and metastasis, tumor microenvironment, and tumor-promoting inflammation.  
Each team was tasked with determining chemical compounds that affect the given pathway and are (1) ubiquitous in the environment, (2) not known carcinogens, (3) not “lifestyle”-related (eg, fried foods, smoking), and (4) “selectively disruptive” to the assigned hallmark of cancer. The teams were further tasked to determine the level of exposure necessary to elicit effects on the given pathway and whether a linear or nonlinear relationship to the given chemical’s action exists. 

Key Findings

In total, 85 chemicals were deemed prototypical disruptors of 1 or more hallmarks of cancer. Fifty out of the 85 chemicals (59%) exerted low-dose effects (“at levels that are deemed relevant given the background levels of exposure that exist in the environment”). Fifteen of these 50 had a nonlinear dose-response pattern. Thirteen of the 85 prototypical agents (15%) had a dose-response threshold. Twenty-two of the 85 agents (26%) lacked sufficient information to define any dose-response relationship.


There is an axiom in toxicology that “the dose makes the poison.” The implication is that a chemical is innocuous until some threshold dose is reached, at which point it can have toxic effects. When considering carcinogens, this is useful for single agents that have proven thresholds (eg, arsenic, asbestos). This type of direct dose-related effect allows for classification of chemicals by carcinogenic potential.2 This singular dose-determined carcinogenic potential is relevant for occupational exposures, contaminated land/water, and other high-dose exposure scenarios. 
However, what if there is synergistic carcinogenic potential resulting from hundreds of low doses of chemicals that are going unnoticed? What if dozens of chemicals work together on multiple molecular pathways to culminate in carcinogenesis? These are very practical questions given that such exposures are the reality of our everyday existence. They are also of great relevance because cancer is a close second only to heart disease as the most common cause of death in the United States.3 Given these considerations, such questions should take on immediacy in toxicology research. However, the dominant paradigm is still based on the old axiom “the dose makes the poison.”
What if there is synergistic carcinogenic potential resulting from hundreds of low doses of chemicals that are going unnoticed? What if dozens of chemicals work together on multiple molecular pathways to culminate in carcinogenesis?  
The government-funded Agency for Toxic Substances and Disease Registry (ATSDR) has taken a stance on the role of ubiquitous chemicals and cancer causation in its publication Chemicals, Cancer and You.4 In it, the ATSDR notes, “More than 100,000 chemicals are used by Americans, and about 1,000 new chemicals are introduced each year. These chemicals are found in everyday items, such as foods, personal products, packaging, prescription drugs, and household and lawn care products.” Later in the same document is a disconcerting disconnect between these facts and ATSDR’s conclusion that “[t]hese everyday exposures are usually too small to cause health problems.” This, of course, is the old axiom of toxicology at work. 
ATSDR is an official agency whose purpose is to “increase knowledge about toxic substances, reduce the health effects of toxic exposures, and protect the public health.” Pervasive throughout its official publications is the notion that carcinogens are singular substances deemed to cause cancer at some threshold dose.5 The conclusion that combinations of low levels of chemicals are harmless is based on a lack of research, not research suggesting safety of chemical mixtures. As the adage goes, “the absence of evidence is not evidence of absence.”  
The paper reviewed here posits a means to systematically study the effects of multiple chemicals that more realistically mimics current environmental exposures. It is, essentially, a paradigm shift. Using the “hallmarks of cancer” as the framework to understand the various attributes of chemicals in relation to cancerous processes, research can investigate common environmental chemicals and discern whether a chemical affects a given pathway(s) and at what dose. This leads to a better understanding of synergistic effects on carcinogenic processes, even by chemicals considered noncarcinogens as single agents.
Of the 85 chemicals that were found to affect key pathways related to carcinogenesis, only 15% (13/85) were found to have a dose-response threshold, the classic dose threshold model of toxicity. Low-dose effects were predominant in 59% (50/85) of the compounds. The authors concluded, “Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies.”
Some of the chemicals found to disrupt key pathways that contribute to the various hallmarks include bisphenol A (BPA), phthalates, nickel, cadmium, diazinon, and malathion. Avoidance of chemical ingestion—whether from water, air, or food—is clearly the wisest option. Unfortunately, it is not a feasible option given the ubiquity of chemicals in our environment.
The paper under review was not a small undertaking. It is a result of an ambitious project that began with a consortium of scientists from many disciplines that first met in Halifax, Nova Scotia, in 2013. The meeting was hosted by the organization Getting to Know Cancer. The mission statement for Getting to Know Cancer is “To share holistic, scientific knowledge about cancer with key stakeholders who have an interest in the disease in a manner that ultimately results in societal changes that reduce the public exposure to disruptive environmental agents that can act in concert with one another to instigate cancer.”6 The gathering was sponsored by the National Institute of Environmental Health Science, a division of the National Institutes of Health.
The consortium continues its ongoing work to lay the foundation for this emerging concept, namely the “low-dose carcinogenesis hypothesis.” Perhaps the authors best summarize the utility of the paper reviewed here:
The chemicals that were selected for this review were not deemed to be the most important, and they were not selected to somehow imply (based on current information) that they are endangering us. Rather, we simply wanted to illustrate that many non-carcinogenic chemicals (that are ubiquitous in the environment) have also been shown to exert effects at low doses, which are highly relevant to the process of carcinogenesis.

Editor's note

The article reviewed here is not a clinical trial; it is a paper written by a consortium of scientists who looked at the evidence for carcinogenic potential of commonly used chemicals. We normally review only studies using human data in the Abstracts & Commentary section, but since this is such important work and represents a paradigm shift, the editorial team made an exception.

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  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
  2. World Health Organization. Agents classified by the IARC monographs, volumes 1-113. Available at: Accessed August 28, 2015.
  3. US Centers for Disease Control and Prevention. Faststats: Leading causes of death. Available at: Updated August 21, 2015. Accessed August 28, 2015. 
  4. Agency for Toxic Substances and Disease Registry, Division of Health Assessment and Consultation. Chemicals, Cancer, and You. Available at:,%20Cancer,%20and%20You%20FS.pdf.  Accessed August 28, 2015. 
  5. US Department of Health and Human Services, National Toxicology Program. Definition of carcinogenicity results. Available at: Accessed August 28, 2015.
  6. Getting to Know Cancer. Mission. Available at: Accessed August 28, 2015.