In the early
1500s, the famed alchemist Paracelsus supposedly coined a phrase that has
remained an enduring principle in toxicology: “The dose makes the poison.”
The next thing to consider is, “What makes the dose?” The answer is, of course,
the level of exposure. In 1983 the National Research Council (NRC) devised a
four-step process to assess risk: hazard identification, dose-response
assessment, exposure assessment, and risk characterization. Two of those,
dose-response assessment and exposure assessment, are key to exposure science. Exposure
science is a companion field to environmental epidemiology and toxicology. The
NRC defines dose-response assessment as:
“The determination of the relationship between the
magnitude of exposure and the probability of occurrence of the health effects
in question.”
They further defined exposure assessment as:
“The determination of the extent of human exposure before
or after application of regulatory controls.”
We know we are
being exposed to many different chemicals in the environment, from the water we
drink, the food we eat, and the air we breathe. We know we are accumulating
microplastics and other chemicals that bioaccumulate in our bodies. One of the main
determinations from exposure science is to know what a threshold dose is for causing
harm. That varies considerably for different chemicals from completely safe at
all levels to completely unsafe at any level. Some chemicals accumulate in the
body or bioaccumulate, and so the dose may increase over time.
According to Wikipedia
via the NRC and others:
“Exposure science is the study of the contact between
humans (and other organisms) and harmful agents within their environment –
whether it be chemical, physical, biological, behavioural or mental stressors –
with the aim of identifying the causes and preventions of the adverse health
effects they result in.”
Below are two exposure science frameworks. The first is a general framework. The second incorporates technologies that aid exposure assessment.
In order to evaluate risk, we need to know what we are being
exposed to and at what levels. In our modern world of tens of thousands of
different chemicals, both natural and synthetic, that is no easy task. Exposure
avenues such as occupational exposures, lifestyle exposures, and relative
position to sources of contamination, ie. downwind or downstream, can be paired
with epidemiological data about exposure times and susceptibility in the
population. This susceptibility may be genetic susceptibility or predisposition
to get cancer and also includes the addition of other factors, including
lifestyle factors that can increase both total toxin exposure and susceptibility.
We know very well that airborne toxins can sicken and kill. Some act fast,
others slower. Chemical warfare is waged with poisonous gases that can kill fast.
Industry produces and manages poisonous gases as well, with the goal of
preventing exposure. Exposure to fine particulate silica dust and coal dust
leads to the debilitating incurable fatal lung diseases silicosis and black lung
disease. These diseases develop over time to a point where they can’t be
stopped. Controlling and reducing exposure is what prevents them.
Teasing
meaningful trends from fields like cancer epidemiology and finding things like
genetic biomarkers and exposure biomarkers remains a challenge and a focus.
Biomarkers are defined as “measurable indicators of biological processes or
conditions.” They are how we can tag specific exposures to specific
responses in better detail. Isolating the effects of one chemical when we are
exposed to thousands of chemicals seems a daunting task. Sometimes there are
obvious relationships. We know that mismanaged lead-acid battery recycling facilities
have released large amounts of lead dust that have sickened and killed children
and sickened adults. We know that workers at plants that make coking coal and
those who live very nearby develop diseases and often die from them. There are
numerous examples of high-exposure events that harm human and environmental health.
A lot of what we know about exposure science has come from studying
accidental or unintentional events where people or another biota were poisoned.
Unfortunately, there are also numerous attempts to try and tie questionable
exposure levels to real effects by those who advocate for stronger regulations.
There may also be attempts to dissociate possible relationships between
contaminants and effects. Thus, we need to be careful to follow science rather
than manipulative policy spin.
The Exposome
People or other
biota with higher susceptibilities would require less exposure to cause harm
than people without those susceptibilities. Designing studies to determine relationships
between susceptibility and exposure levels was seen as a need when Christopher
Paul Wild coined the term ‘exposome’ in 2005 to refer to the external,
internal, and biological response factors of exposure. It is seen as
complementary to the genome used to describe genetic factors, or transcriptome, proteome,
and metabolome to describe those respective factors. Biological response
factors may include inflammation, infection, lipid peroxidation, and oxidative
stress. His goal was to study exposure in a more systematic way. His argument
was that genetic fingerprinting through biomarkers was much further along than exposure
fingerprinting through exposure biomarkers. Just as metabolic fingerprinting
through the detection and measurement of specific metabolites yields meaningful
knowledge so should exposure fingerprinting through some expression of the
exposome. He calls these fields ‘omics technologies.’ In his own words:
“The concept of an exposome may serve to highlight this
requirement {to develop reliable exposure assessment tools} and to balance the
effort going towards characterization of the genome. An extension of the
current generation of biomarkers, together with an evaluation of the new
generation of “omics” technologies, has a crucial role to play in this regard.
However, advances will require increasing collaboration between
epidemiologists, biostatisticians, experts in bioinformatics, and laboratory
and environmental scientists.”
The exposome describes environmental exposures encountered
throughout life, and how these exposures impact biology and health. It is a way
to explore and refine exposure assessment, step 2 of the NRC’s risk assessment process.
We often need to know not just whether an environmental exposure is causing a specific
response but whether or not it is simply a contributing factor among many to a
response and at what magnitude.
Some exposure science graphics and flow charts are shown below.
In a paper
published in November 2013 in Toxicology Science authors Gary W. Miller and
Dean P. Jones set out to explore the exposome and its relationship to the biological
framework. The paper was titled: ‘The Nature of Nurture: Refining the
Definition of the Exposome.’ The authors echoed Wild when they argued that our
knowledge of nature as the genetic side of the picture was much farther along
than our knowledge of nurture, the environmental side of the picture. The human
genome is well-mapped but hopes that it would lead to widespread disease reduction
have been tempered by the gradual realization that the majority of disease
factors are not genetic. They acknowledged the need to better quantify the
environmental contributions to disease. They also noted that biology and environment,
nature and nurture, often overlap and grade into one another.
“The simple distinction between genes and environment is
blurred by knowledge that environmental exposures cause permanent genetic
changes via mutagenesis and also have long-term impact on gene expression
through epigenetic mechanisms. Importantly, epigenetic mechanisms are central
to differentiation and development, impacting genome function before birth and
throughout life.”
“The epigenome is highly reliant on nurture, ie, the
nature and timing of environmental exposures and external forces.”
Miller and Jones expanded the Wild’s exposome concept to arrive
at a more comprehensive definition:
Exposome: The cumulative measure of environmental
influences and associated biological responses throughout the lifespan,
including exposures from the environment, diet, behavior, and endogenous
processes
They explain the
need for a new science of nurture to improve our understanding of environmental
contributions to disease through mechanisms such as epigenetics and balance it
with our understanding of predisposed susceptibility to disease through
genetics.
“…exposome research can begin to provide the tangible and
quantifiable entities that medicine and public health desperately need. The
success of the Human Genome Project exposed an imbalance in the nature-nurture
interaction. Elucidating the exposome, ie, developing an integrated science of
nurture, will help fulfill the promises of the Human Genome Project.”
As a cumulative exposure idea, the exposome also encompasses
other factors such as the metabolome. The metabolome refers to the complete set
of small-molecule chemicals found within a biological sample. The end products of metabolic reactions are known as metabolites. Metabolite chemicals may be
endogenous, produced internally naturally, or exogenous, produced by consumption
typically via water, food, or air.
According to
Lindzi Wessel in a September 2019 article in Knowable Magazine, what is needed
to be known in exposomic toxicology, is:
“…which environmental exposures are the most worrying and
if there are windows of vulnerability — times of life when exposures may be
especially harmful.”
Wessel highlights the growing presence of environmental monitoring
technology with costs coming down and coverage growing. She mentions silicon
bracelets that measure exposure to various airborne contaminants. The growing
presence of satellite air monitoring can help to determine exposure levels by
comparing that data to one’s cellphone location data. Better data acquisition
very often leads to different outcomes than expected as she recounts in a few
examples, such as determining the correct allergen among different possibilities
or the risk level of an asthmatic entering a room before it was vacuumed or
just after (studies have shown that just after is worse).
Exposure scientists
want to know:
“…if certain substances are dangerous in particular
combinations, during particular times — such as during pregnancy — or to
particular groups of people.”
Our ability to collect data about both our environment and our real-time
health via sensors on our smartphones can also greatly aid our ability to assess
both exposure occurrences and exposure responses. Wessel notes:
“Signatures left over in blood, urine, teeth and even
toenails can hint at previous exposures. Blood in particular holds clues that
can let researchers work backwards to match biological changes to triggering
exposures, says Dean Jones, a biochemist at Emory University in Atlanta and
coauthor of a 2019 article about the promise of the exposome paradigm in the
Annual Review of Pharmacology and Toxicology.”
“With tens of thousands of detectable components that
hint at what the body is doing chemically, metabolites may be one possible
alphabet scientists could use to read back what’s happened internally following
various exposures.”
Another way to
link internal responses to external exposures with blood metabolites is through
examining human serum albumin, a protein that captures and removes harmful
compounds circulating in blood. The graphic below shows how this information
may be used to uncover such links.
Even if we can
link blood metabolites to toxicant exposures it remains challenging to determine
which chemical led to the specific metabolites. We have metabolite data for
tens of thousands of chemicals but there are even more for which we have no data.
Thus, there is a big data problem that needs to be solved. One method of studying the genetic
factors of disease is the genome-wide association study or GWAS. It is a
method that determines which genes vary in conjunction with a particular
disease or symptom. Wessel notes:
“In 2010, Harvard bioinformatician Chirag Patel adapted
the GWAS into an environment-wide association study {EWAS} to see how 266
environmental factors varied in step with the risk of developing type II
diabetes.”
This led to a better understanding of the combination effects
of different exposures. Wessel also notes that the GWAS methodology, still
considered imperfect, is more contained in that in the human genome about
20,000 genes code for proteins. However, we are exposed to hundreds of
thousands of different chemical compounds, both natural and synthetic, from the
environment. Thus, EWAS remains more challenging than GWAS, but it is gaining
traction.
Metabolic diseases like obesity and diabetes
are serious problems in most places in the modern world. A January 2022 paper in Environment
International highlights how biomarkers can integrate exposomics and metabolomics.
Classes of environmental toxicants such as endocrine-disrupting chemicals
(EDCs) and metabolism-disrupting chemicals (MDCs) lead to disruption in signaling
and metabolic pathways. The authors note:
“Contaminants including heavy metals and organohalogen
compounds, especially EDCs, have been repetitively associated with metabolic
disorders, whereas emerging contaminants such as perfluoroalkyl substances and
microplastics have also been found to disrupt metabolism. In addition, we found
major limitations in the effective identification of metabolic biomarkers
especially in human studies, toxicological research on the mixed effect of
environmental exposure has also been insufficient compared to the research on
single chemicals. Thus, it is timely to call for research efforts dedicated to
the study of combined effect and metabolic alterations for the better
assessment of exposomic toxicology and health risks.”
Computational
exposure science is an emerging field. According to a 2015 paper in
Environmental Health Perspectives, computational exposure science is the:
“…integration of advances in chemistry, computer science,
mathematics, statistics, and social and behavioral sciences with new and
efficient models and data collection methods to reliably and effectively
forecast real-world exposures to natural and anthropogenic chemicals in the
environment.”
It seems to me that now in the age of big data, machine
learning, and AI we could be on the cusp of a much better understanding of biological
responses to specific exposures. When I read and later reviewed Sandra Steingraber’s
book ‘Living
Downstream: An Ecologist’s Personal Investigation of Cancer and the Environment’
I noted her frustration regarding the difficulty of teasing out data about the
biological effects of exposure to environmental toxicants. Hers was a very
personal story of trying to track her own development of bladder cancer, which
has been associated with environmental exposures, early in life. She suspects
her condition was caused by or influenced by exposure to the pesticide atrazine
which was commonly used where she grew up in the farm region of Illinois. She
may never know if this is true but if we can refine our knowledge through the advancement
of exposure science perhaps people in the future in a similar situation can
know. More importantly, we may be able to predict what people will be most
susceptible to with better knowledge of not only genetics but of the sciences
of the other “omes,” or “omics” as they are sometimes referred to. Exposomics,
bioinformatics, and better and more environmental monitoring can help acquire
that knowledge, and machine learning and AI can probably help to find hidden patterns
in the data.
Computational
exposure science was given a framework and modeled in the 2015 study mentioned
above. The framework is shown below.
Another important thing noted in that paper is that there has been a dramatic increase in the number of chemicals for which probabilistic exposure assessments have been completed.
This new data can also be integrated and processed via machine learning. The problem remains the obtaining of accurate quantification of human exposures to individual chemicals, accumulated chemicals, chemical combinations, and toxic byproducts. One potential result is developing a model for each person in terms of susceptibilities that includes assessment of genetic factors, lifestyle exposures, occupational exposures, and internal data like blood metabolites.
References:
The
next omics? Tracking a lifetime of exposures to better understand disease. Lindzi
Wessel. Knowable Magazine. September 19, 2019. The
next omics? Tracking a lifetime of exposures to better understand disease |
Knowable Magazine
Exposure
science. Wikipedia. Exposure science -
Wikipedia
National
Research Council (US) Committee on the Institutional Means for Assessment of
Risks to Public Health. Wahington (DC): National Academies Press (US); 1983.
Risk Assessment in the Federal Government: Managing the Process. Front Matter | Risk
Assessment in the Federal Government: Managing the Process | The National
Academies Press
A
Discussion of Exposure Science in the 21st Century: A Vision and a Strategy. Paul
J. Lioy and Kirk R. Smith. Environmental Health Perspectives. Volume 121, Issue
4. Pages 405 – 409. January 31, 2013. A Discussion of
Exposure Science in the 21st Century: A Vision and a Strategy | Environmental
Health Perspectives | Vol. 121, No. 4
Computational
Exposure Science: An Emerging Discipline to Support 21st-Century Risk
Assessment. Peter P. Egeghy, Linda S. Sheldon, Kristin K. Isaacs, Halûk
Özkaynak, Michael-Rock Goldsmith, John F. Wambaugh, Richard S. Judson, and
Timothy J. Buckley. Environmental Health Perspectives. Volume 124, Issue 6. Pages
697 – 702. November 6, 2015. Computational
Exposure Science: An Emerging Discipline to Support 21st-Century Risk
Assessment | Environmental Health Perspectives | Vol. 124, No. 6
Complementing
the Genome with an “Exposome”: The Outstanding Challenge of Environmental
Exposure Measurement in Molecular Epidemiology. Christopher Paul Wild. Cancer
Epidemiol Biomarkers Prev (2005) 14 (8): 1847–1850. Complementing
the Genome with an “Exposome”: The Outstanding Challenge of Environmental
Exposure Measurement in Molecular Epidemiology | Cancer Epidemiology,
Biomarkers & Prevention | American Association for Cancer Research
Exposome.
Wikipedia. Exposome -
Wikipedia
A
review of environmental metabolism disrupting chemicals and effect biomarkers
associating disease risks: Where exposomics meets metabolomics. Jiachen Sun, Runcheng
Fang, Hua Wang, De-Xiang Xu, Jing Yang, Xiaochen Huang, Daniel Cozzolino, Mingliang
Fang, and Yichao Huang. Environment International Volume 158, January 2022,
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review of environmental metabolism disrupting chemicals and effect biomarkers
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The
Nature of Nurture: Refining the Definition of the Exposome. Gary W. Miller and
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Refining the Definition of the Exposome - PMC
Metabolome.
Wikipedia. Metabolome -
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Assessing
the Exposome with External Measures: Commentary on the State of the Science and
Research Recommendations. Michelle C. Turner, Mark Nieuwenhuijsen, Kim Anderson,
David Balshaw, Yuxia Cui, Genevieve Dunton, Jane A. Hoppin, Petros Koutrakis,
and Michael Jerrett. Annual Review of Public Health Volume 38, 2017. Assessing
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Exposome: Molecules to Populations. Megan M. Niedzwiecki, Douglas I. Walker,
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