When it comes to reviewing studies regarding combinations of low levels of chemical exposure and cancer risks, collaborators of the Halifax Project have raised questions that can help in the development of hypotheses – but to date, proof of cause and effect has not been presented.

The Nova Scotia-based Halifax Project is focused in part, on reviewing published scientific studies with an eye towards picking out data of the “carcinogenic potential of low dose exposures to mixtures of chemicals in the environment” and associating them to some aspect of the biological processes involved in cancer.

For the purpose of this blog, I’d like to review four key observations of the Halifax Project and offer four points to help put the Project in perspective as a thought-starter – not a conclusive body of evidence – for generating testable hypotheses about low-dose chemical exposures.

Stages of scientific inquiry

Scientific research proceeds through a process that uses knowledge, perspectives, and observations from previous investigations to pose a question in the form of a hypothesis and then to design and conduct studies to test each hypothesis.

Results from these investigations are then evaluated, hypotheses are confirmed (or not), and the knowledge gained is used to reformulate or propose new hypotheses.

It’s from this exacting approach that tremendous advances have been made by scientists in their understanding of the complex biological processes involved in the development and progression of cancer -- what Hanahan and Weinberg call the “Hallmarks of Cancer.” Scientists have uncovered an array of factors that may contribute to or cause cancer. These can include:  smoking, alcohol, radiation, viruses, natural and synthetic substances, obesity, hormones, chronic inflammation and a lack of exercise.

Four observations of the Halifax Project

From the lens of the scientific method, one can view the Halifax Project as contributing to the initial stage of a scientific inquiry.

The authors start by raising a question: can low levels of chemical exposures, in combination, be linked to significant cancer risks? Underlying this question are four observations:

•  certain chemicals can elicit responses in test systems tied to one of the hallmarks of cancer pathway; 
• humans are exposed to complex mixtures of substances;
•  testing of chemicals for carcinogenicity typically involves single substances (at high doses) and not mixtures; and
• when mixtures are evaluated, typically, we evaluate single pathways in isolation.

Four points to keep the Halifax Project in context

Keeping the complexities of the process of cancer development in mind, there are a few important points to note when reviewing some of the Project’s observations.

First, the issue of exposure to chemical mixtures is not new. Toxicologists, cancer biologists and medical researchers know that that we are exposed to a number of natural and man-made chemicals simultaneously and continuously every day. So, it comes as no surprise that chemicals can be detected in human urine and blood or that, at some dose level or concentration in specific test systems, responses can be detected when chemicals are combined.

Second, this understanding of chemicals should not lead to undue concern. Because a substance is present and has adverse effects at some dose or exposure level does not mean, or even imply, that the presence of that chemical will lead to adverse effects at all levels.   

Third, the human body is well equipped to manage exposures to low levels of chemicals. In fact, humans have always been exposed to low levels chemical mixtures. For example, an apple is a mixture of more than 150 different chemical substances; eating a fruit cocktail comprised of apples, bananas, strawberries, peaches, and pineapple, would lead to exposure to more than 400 different chemical agents. And such substances can, in certain test systems, cause responses in biological pathways.

Fourth, what matters is the amount of chemicals in the body relative to the amount that can actually cause harm. The question is not simply whether a chemical, natural or man-made, or mixtures of chemicals, are present in the body (a question of exposure), or whether chemicals can cause harm (a question of the chemical’s inherent toxicity). Instead, the answers to questions of exposure and toxicity must be considered in combination.

The Halifax Project provides a starting point for possible further study on the issue of low dose exposures to multiple chemicals with properties consistent with one or more of the hallmarks of carcinogenesis. While the articles raise questions, they do not provide the answers. 

A thought-starter for generating testable hypothesis

Publications like the current series prepared by the Halifax Project Task Force provide a first step in an overall analysis of available information. As the authors of the papers themselves state, their work has been only hypothesis-generating. These papers do not establish or provide conclusive support for the claim that low level exposures to mixtures of environmental chemicals cause cancer.

Raising a question is just the beginning of the scientific processes and provides no real proof. Proof comes incrementally, from formulating clear hypotheses and then testing these using relevant and reliable scientific methods.

The Path Forward: Building confidence in 21^st century testing tools and using these advanced methods to test hypotheses

Using modern molecular biology tools, experts are already making remarkable progress in understanding how biological pathways in cells and the body respond to different levels of chemical, physical and biological stress—whether in isolation or in a mixture. As confidence in these innovative 21^st century testing tools advances, scientists will soon be in a better position to test hypotheses like those generated from the Halifax Project.

For example, scientists have recently shown that the dynamics of key biological pathways involve complex connections – similar to the wiring in integrated electrical circuits - that give rise to thresholds, exposures below which significant biological responses are not induced. Thus, simultaneous exposure to low levels of natural or environmental chemicals does not imply that potential risks would be experienced.  At low levels of exposures, even to chemical mixtures, this type of “wiring” of the pathways underpinning cellular functions, including proliferation, differentiation, and apoptosis (pathways involved in the hallmarks of cancer) should protect against adverse effects.

Research in the molecular pathways of cancer is quite active and we are optimistic that continued strong research programs will provide greater scientific knowledge showing how the well accepted toxicological principle that the dose makes the poison operates in the integrated biological pathways that characterize the hallmarks of cancer. At ACC, our Long Range Research Initiative (LRI) is contributing to such research. The ACC LRI is focused on advancing the understanding of chemical exposure and potential links between chemical exposures, including mixtures, and adverse outcomes. This includes applying innovations in chemical safety testing, continuing the development and improvement of predictive models for generating estimates for environmentally-relevant chemical exposures, and evaluating links between chemical exposures and health and environmental outcomes.  Collaborations between LRI investigators and scientists from the academia and federal governmental agencies have been instrumental for advancing the research in chemical safety assessment, including the importance of dose response in biological pathways that characterize the hallmarks of adverse outcomes including cancer.