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 21st 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 21st 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.
