nature reviews cardiology https://doi.org/10.

1038/s41569-023-00873-3

Review article Check for updates

The contribution of the exposome to

the burden of cardiovascular disease
Thomas Münzel 1,2
, Mette Sørensen , Omar Hahad
3,4
, Mark Nieuwenhuijsen5,6,7 & Andreas Daiber
1,2 1,2

Abstract Sections

Large epidemiological and health impact assessment studies at the Introduction

global scale, such as the Global Burden of Disease project, indicate The need for an exposome
that chronic non-communicable diseases, such as atherosclerosis and approach

diabetes mellitus, caused almost two-thirds of the annual global deaths Assessment of the exposome
in 2020. By 2030, 77% of all deaths are expected to be caused by non- Exposome studies of
communicable diseases. Although this increase is mainly due to the cardiovascular outcomes

ageing of the general population in Western societies, other reasons Conclusions

include the increasing effects of soil, water, air and noise pollution on
health, together with the effects of other environmental risk factors
such as climate change, unhealthy city designs (including lack of
green spaces), unhealthy lifestyle habits and psychosocial stress. The
exposome concept was established in 2005 as a new strategy to study
the effect of the environment on health. The exposome describes the
harmful biochemical and metabolic changes that occur in our body
owing to the totality of different environmental exposures throughout
the life course, which ultimately lead to adverse health effects and
premature deaths. In this Review, we describe the exposome concept
with a focus on environmental physical and chemical exposures and
their effects on the burden of cardiovascular disease. We discuss
selected exposome studies and highlight the relevance of the exposome
concept for future health research as well as preventive medicine.
We also discuss the challenges and limitations of exposome studies.

1
Department of Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University, Mainz,
Germany. 2German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany. 3Danish
Cancer Society, Copenhagen, Denmark. 4Department of Natural Science and Environment, Roskilde University,
Roskilde, Denmark. 5Institute for Global Health (ISGlobal), Barcelona Biomedical Research Park (PRBB), Barcelona,
Spain. 6Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), PRBB building
(Mar Campus), Barcelona, Spain. 7CIBER Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III,
Madrid, Spain. e-mail: [email protected]

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Key points workplace, further increase the environmental contribution to DALYs

in men6 (Fig. 1). Accordingly, the environmental risks might contribute
much more to the global burden of disease than previously estimated.
•• Leading health risk factors, such as hypertension, smoking, In 2018, 5,687 published genome-wide association studies pro-
overnutrition, diabetes mellitus, air pollution, high BMI and dyslipi­ vided insights into the influence of genetics on human health and
daemia, increase the global burden of chronic non-communicable disease8. For many complex human diseases, such as cancer, cardiovas-
diseases, particularly cardiovascular diseases. cular diseases, respiratory diseases and type 2 diabetes, genetic varia-
tion explains only a modest proportion of the disease risk. For example,
•• Environmental exposures account for up to two-thirds of all chronic for 28 chronic diseases, only a mean of 18.5% of the population-attributable
non-communicable diseases, and chemical pollution alone is fraction was related to genetic predisposition9. By contrast, a large
responsible for 16% of global deaths, thereby having greater influence part of the disease burden is probably attributable to environmental
than genetic predisposition; multiple co-exposures cause additive stressors and the interplay between the genes of an individual and the
increases in the risk of cardiometabolic disease. environmental burden6. Accordingly, the statement “genetics load
the gun but environment pulls the trigger”10 (which is based on the
•• The exposome concept was established to investigate the effect of concept proposed by Olden and Wilson11) perfectly characterizes
all exposures on endogenous biochemical and functional changes and the effect of the environment on health compared with the effect of
the association with adverse health outcomes. genetic predisposition (Box 1). This postulate is supported by statistics
on cardiovascular-associated and cancer-associated deaths, among
•• Harmful exposures can increase health risks and mortality which only 0.25 (16.4%) of 1.53 million deaths in 2000 in Western Europe
synergistically with age, genetic predisposition and pre-existing could be attributed to genetic causes9. In addition, the substantial dif-
chronic diseases. ferences in disease incidence and prevalence between monozygotic
twins (who share an identical genome) suggest that other factors,
•• It is challenging to assess exposures and their effects on the internal including the environment, determine the onset of chronic disease.
environment using omics approaches and functional assays, and Nevertheless, pollution-related diseases have not earned recognition in
exposome studies that assess associations between exposure, omics the Global Action Plan for the Prevention and Control of NCDs12 nor
data and health outcomes are rare. in the United Nations (UN) sustainable development goals (SDGs)13.
Therefore, leading scientists in environmental health are calling for
•• Substantial challenges for ongoing and future exposome studies are ‘environment-wide association studies’14,15 in analogy to genome-wide
related to costs, handling of big data and multi-exposure assessment. association studies16.
In this Review, we provide a detailed description of the expo-
some concept. We discuss the most important environmental physi-
Introduction cal and chemical exposures and their consequences for the burden of
The global burden of disease has shifted from communicable, maternal, cardiovascular disease and summarize exposure assessment methods
perinatal and nutritional causes to non-communicable diseases (NCDs) and the most important biomarkers for exposome research. We discuss
such as those with atherosclerotic or metabolic sequelae, including the most relevant exposome studies related to cardiovascular diseases
ischaemic heart disease, arterial hypertension and diabetes mellitus and highlight the relevance of the exposome concept for future health
(according to data from the WHO–Global Health Observatory1 and research and preventive medicine. Finally, we highlight the challenges
the Global Burden of Disease (GBD) study2). In 2010, the leading risk and limitations of exposome studies.
factors and diseases responsible for global deaths were tobacco smok-
ing, high blood pressure, ischaemic heart disease and cerebrovascular The need for an exposome approach
disease, accounting for 55% of global mortality3–5. In 2019, the lead- Chemical pollution and global burden of disease
ing risk factors were high systolic blood pressure (causing 10.8 mil- The Lancet Commission on pollution and health concluded that chemi-
lion global deaths; 19.2% of all deaths) and tobacco smoking (causing cal pollution is currently the most important environmental cause of
8.7 million global deaths; 15.4% of all deaths)6. An overview of the lead- disease and premature death in the world12. Diseases caused by chemical
ing causes of disease and death in 2019 is provided in Fig. 1, which shows pollution were responsible for an estimated 9 million premature deaths
disability-adjusted life years (DALYs) and global deaths, and highlights in 2015 (16% of all deaths worldwide), three times more deaths than
the proportion caused by cardiovascular diseases. According to the those caused by AIDS, tuberculosis and malaria combined12. A main
2016 WHO status report, cardiovascular disease was the leading dis- pollutant is ambient air pollution, which reduces the global average life
ease category contributing to NCDs, with a percentage of >44%, fol- expectancy by 2.9 years, a reduction in life expectancy that is strikingly
lowed by cancer (22%), respiratory diseases (9%), diabetes (4%) and more extensive than the reduction caused by the traditional cardiovas-
others (21%)7. The leading risk factors for death are similar for men cular risk factor of tobacco smoking (2.2 years)17. The WHO estimates
and women6 (Fig. 1). However, the absolute numbers of deaths are that up to 12.6 million global deaths in 2012 were due to unhealthy
higher for men, and tobacco and alcohol have a greater contribution environments18,19. These numbers will most probably increase further in
to mortality and DALYs in men than in women. Three environmental future calculations given that a 2020 estimation indicates that 9 million
risk factors — air pollution, unsafe water and sanitation, and especially premature global deaths per year are due to air pollution in the form of
child and/or maternal malnutrition — contribute disproportionately particulate matter with a diameter of ≤2.5 µm (PM2.5) alone20.
more to the burden of disease (DALYs) in the general population than PM2.5 has high toxicity because these fine particulates can transmi-
other risk factors. Tobacco and alcohol use and occupational risks, such grate directly from the lung epithelium into the bloodstream, causing
as injuries and exposure to particulates, carcinogens and noise at the endothelial dysfunction, inflammation and oxidative stress in the

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Major risk factors Child and/or High fasting High plasma

for disability maternal Dietary risks plasma glucose LDL-cholesterol Unsafe water,
malnutrition Hypertension Smoking Air pollution Overnutrition level High BMI level sanitation

Attributable burden
of disease

Women DALYs (× 106) Men DALYs (× 106)

200 150 100 50 0 Health risk factors 0 50 100 150 200

High systolic blood pressure

Dietary risks
High fasting plasma glucose level
Air pollution
High BMI
Tobacco
High plasma LDL-cholesterol level
Kidney dysfunction
Child and/or maternal malnutrition
Non-optimal temperature
Unsafe water, sanitation
Unsafe sex
Low physical activity level
Alcohol use
Other environmental risks
Occupational risks
Low bone mineral density
Drug use
Intimate-partner violence
Childhood sexual abuse and bullying

7,000 6,000 5,000 4,000 3,000 2,000 1,000 0 0 1,000 2,000 3,000 4,000 5,000 6,000 7,000
Deaths (× 1,000) Deaths (× 1,000)

High fasting High plasma Child and/or

Major risk factors Dietary risks plasma glucose LDL-cholesterol Kidney maternal
for death Hypertension Smoking Overnutrition levels Air pollution High BMI level dysfunction malnutrition

Attributable burden
of disease

CVD Diabetes mellitus COPD Cancer Maternal or neonatal disorders Infection Other

Fig. 1 | Global number of deaths and DALYs in 2019 attributable to health risk of disease for the leading risk factors. Cardiovascular disease (CVD) is the major
factors according to cause and sex. The bar graphs show the global number category of sequelae for all leading risk factors, followed by respiratory disease,
of deaths and disability-adjusted life years (DALYs) in women and men in 2019 diabetes mellitus, cancer and infections. COPD, chronic obstructive pulmonary
attributable to health risk factors. The pie charts show the attributable burden disease. Based on data from ref. 6.

systemic vasculature21. PM2.5 can also enter the brain directly via the by the gradually increasing risk of all-cause and cardiovascular death
olfactory nerve, causing autonomic imbalance or activation of associated with exposure to these air pollutants, with ozone being the
the hypothalamic–pituitary–adrenal axis21. The smaller the particle, the lowest, followed by NO2, and PM2.5 being the highest23.
stronger its penetration capacity. These severe systemic adverse effects The role of air pollution as a leading health risk factor is supported
might explain why the excess mortality associated with PM2.5 exposure by the dramatic drop in the rates of cardiovascular disease and even
is around ten times higher than the excess mortality related to NO2 the extended life expectancy observed during the period of pollution-
exposure and 20 times higher than that associated with exposure to control measures before the 2008 Beijing Olympic Games24 or with
ozone22. The role of PM2.5 as a major health hazard is also supported the permanent lowering of diesel emissions by new restrictive laws

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in Tokyo25 and the USA26,27. Ambient air pollution and rising tempera- available. Environmental risk in urban areas is also influenced by the
tures due to climate change are already ranking in the top 20 of the excessive use of vehicles29 and the reduction of green spaces in favour of
risk factors for DALYs and death described in the GBD study6 (Fig. 1). road infrastructure. Both of these factors prevent the development
The GBD study estimated that diseases caused by all forms of pollu- of heart-healthy cities10,30.
tion amount to 268 million DALYs28. However, the GBD study focuses According to the data in Table 1, the primary chemical pollutants
on only a limited number of exposures for which worldwide data are contributing to global excess deaths are air, soil, water and occupa-
tional pollution31. The hazardous effects of air pollution are mediated
mainly by ambient PM2.5, those of water pollution by unsafe sources and
the hazards at the workplace primarily by particulates. Health risks
Box 1 and deaths related to soil pollution are mainly due to heavy metals,
deforestation, over-fertilization and pesticides, although nanoplastics
and microplastics also make a substantial contribution32. Although
Genetic predisposition versus lead toxicity is mainly caused by water and soil pollution, we present it
separately in Table 1 because lead is a major environmental heavy metal
environmental risk factors that enters the water and food circulation as a consequence of its use in
car batteries, water pipes and paints31, and is readily taken up by plants33
According to Olden and Wilson, “the key objective of the and, potentially, by farm animals and fish and other sources of seafood.
Environmental Genome Project is to identify alleles that confer A close relationship exists between water and soil pollution, given that
susceptibility to the adverse health effects of environmental polluted soils will contaminate surface and groundwater32. Heavy metals
agents”11. In their view, measuring the contribution of genetic and metalloids are of specific concern for their contribution to cardiovas-
predisposition and environmental conditions (exposures) is cular sequelae because they can trigger oxidative stress, inflammation
paramount to understanding the complex aetiology of chronic and sulfur-related toxicity by forming complexes with protein thiols34,35.
diseases. These contributions can be measured only by establishing Regarding the absolute number of excess deaths associated with
dose–response relationships for environmentally significant pollutants, an apparent discrepancy exists between the more conserva-
exposures or compounds in biologically relevant animal models tive calculations made using a set of extensive cohort studies or meta-
by using knockout and knock-in strains, a catalogue of the human analyses (usually from the GBD study, WHO, Global Health Observatory
gene polymorphisms that can influence human disease risk, and and European Environmental Agency) and the advanced calculations
epidemiological studies linking environmental exposure to human made using mostly up-to-date exposure–response functions and health
disease. Whereas only a few diseases are monogenic, which means data. The outcome of ‘progressive’ studies (those using the most cur-
that one gene polymorphism is enough to cause the manifestation rent exposure–response functions or most pessimistic models) can
of the disease (such as in Huntington disease), most chronic easily double the conservative values, providing a more pessimistic
diseases are polygenic, meaning that their manifestation requires picture of the environmental adverse effects on disease burden and
the presence and interaction of several gene polymorphisms. mortality. Finally, almost all chemical pollutants are associated with
However, each of these disease-triggering gene polymorphisms in adverse cardiovascular health effects such as hypertension and ischae-
polygenic conditions represents a susceptibility gene, which means mic heart disease (Table 1), stressing the importance of cardiovascular
that the gene polymorphism increases the disease risk or can cause sequelae as the driver of the detrimental effects of the exposome.
the manifestation of the disease in combination with environmental
exposures. This aspect can be studied using functional genomics Non-chemical pollution and global burden of disease
analyses of polymorphisms190 as exemplified by identifying an Transportation noise pollution. Not all established environmental risk
association between cigarette smoking and the risk of bladder factors are included in the GBD study, UN SDGs or Global Action Plan for
cancer as a function of allelic variants in NAT1 and NAT2 (ref. 191). the Prevention and Control of Non-Communicable Diseases. A striking
The individual risk of developing a chronic disease triggered by example of an overlooked risk factor in this context is transportation
environmental exposure is also secondary to the efficiency of the noise, which has consistently been associated with a higher risk of car-
unique set of environment-responsive genes of the individual; that diovascular diseases36–38. Traffic noise is a ubiquitous exposure (Fig. 2),
is, the sophisticated pathways that evolved during human evolution with >20% of the population in the EU exposed to levels exceeding the EU
to minimize biological damage arising from toxic or carcinogenic guideline value of 55 dB (ref. 39). The European Environmental Agency
environmental agents or stressors in general, including noise estimated that traffic noise causes 12,000 premature deaths and 48,000
or ultraviolet light exposure. This aspect can be assessed with cases of ischaemic heart disease per year in Europe39, particularly in cit-
toxicogenomics studies. Defining a ‘reference’ human genome ies with a high noise burden40. These numbers are likely to be an under-
sequence is vital for understanding the deviation from normal11. estimation given that the estimated number of people exposed to traffic
So far, gene–environment interactions for cardiovascular noise has been based on areas with large agglomerations of people and
disease have mostly been identified for smoking and coronary that new studies have indicated that the effect of road traffic noise on the
artery disease. However, there is also limited evidence for an effect risk of cardiovascular disease starts at values below 55 dB (refs. 37,41,42).
of gene–environment interactions on cardiovascular health and A notable reason for traffic noise not being included in the GBD study is
disease in relation to physical activity, air pollution and diet192. that worldwide traffic noise exposure data are unavailable.
Understanding the gene–environment interactions will provide
much better pathophysiological insights and help to implement Light pollution. Light pollution is a novel, ubiquitous environmental
effective healthy lifestyles and more efficient therapeutic strategies. risk factor, defined by the changes in natural night-time sky bright-
ness induced by anthropogenic sources of light43,44, which are most

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Table 1 | Contribution of major pollutants to global deaths and cardiovascular disease

Pollutant Number of deaths (95% CI) Contribution of pollutant Number of deaths (95% CI) Estimated risk of cardiovascular diseasec
(millions; conservative components (%; conservative (millions; advanced
estimates)31,a estimates)31,a estimates)b
Women Men

Air pollution 2.92 (2.53–3.33) 3.75 (3.31–4.25) PM2.5 56.8; household air 8.8 (7.1–10.4)17; 8.9 (7.5–10.3)171; Incident hypertension: HR 1.11 (1.05–1.17)
pollution 37.8; ozone 5.4 10.2 (–47.1 to 17)172 per 10 µg/m3 increment in PM2.5 level173
Water pollution 0.73 (0.40–1.26) 0.63 (0.46–0.95) Unsafe source 62.3; unsafe 1.8 (ref. 174) Prevalent hypertension: OR 2.3 (1.03–5.14)
sanitation 37.7 3.56 (ref. 175) for water with high fluoride levels176
Occupational 0.22 (0.17–0.28) 0.65 (0.54–0.79) Particulates 68.2; 1.2 (only NCDs); 1.5 (total Prevalent coronary heart disease: PR 2.20
pollution carcinogens 31.8 without injuries)177 (1.31–3.71) for occupational exposure to
pesticides178
Lead 0.35 (0.19–0.53) 0.56 (0.36–0.77) Lead acid batteries 85%179,d; Almost 1 (ref. 180) Incident ischaemic heart disease: HR 1.27
lead water pipes, other (1.01–1.59) per one SD increase in lead
sourcese levels in blood181
NCD, non-communicable disease; PM2.5, particulate matter with diameter ≤2.5 µm; PR, prevalence ratio; SD, standard deviation. aThe conservative estimation from the Institute of Health Metrics
and Evaluation was corrected for potential overlap of pollution-associated deaths. bStudies using the most current exposure–response functions or most pessimistic models. cSelected estimates
for the risk of hypertension and ischaemic heart disease associated with the different pollutants as a measure of the contribution to NCDs and the global burden of disease. dEstimated use of
lead for manufacturing today. eOther lead sources include pigments, paints, solder, lead crystal, glassware, ammunition, ceramic glazes, jewellery, toys, cosmetics and traditional medicines.

evident in big cities and large metropolitan areas. According to a 2016 increased risk of death from ischaemic heart disease, stroke or heart
report, 83% of the world’s population and >99% of the US and European failure compared with normal average temperatures52. In particular,
populations live under light-polluted skies43. A review published in among all cardiovascular-related causes of death, heart failure was
2009 provides an excellent overview of the substantial effect of light associated with the highest rate of excess deaths related to extreme
pollution on fauna and flora as well as on human NCDs45, which mainly heat or cold temperatures52.
result from poor sleep and altered circadian rhythms.
Multi-exposure to environmental risk factors
Lack of green spaces. The lack of green infrastructure in cities is The number of environmental risk factors for cardiovascular disease is
considered a major environmental stressor. A study published in 2021 increasing, and these risk factors are rarely present in isolation, espe-
established that meeting the WHO recommendation of access to green cially in densely populated and highly urbanized areas10. Although sub-
space could prevent 42,968 deaths annually, representing 2.3% of the stantial medical and societal progress has been made during the past
total deaths from natural causes and 245 years of life lost per 100,000 three decades to combat and prevent traditional cardiovascular risks
inhabitants per year46. The mechanisms for the benefits of access to factors, such as smoking, diabetes, hypercholesterolaemia, hyperten-
green space include reducing harm (such as reducing exposure to air sion and obesity, on an individual basis, environmental stressors also
pollution, noise and heat), restoring capacities (such as restoration need to be considered as crucial cardiovascular risk factors to reduce
of attention and recovery from physiological stress) and building the global burden of cardiovascular disease. The potentially additive
capacities (for example, encouraging physical activity and facilitating adverse health effects and disease burden of multi-exposure to environ-
social cohesion)47. mental stressors might substantially add to previous estimations of the
health effects of environmental risk factors that were assessed individu-
Climate change. Climate change is a major environmental risk factor ally. For example, exposure maps of light, air and noise pollution and
of concern and is associated with an increased relative risk of car- of the increase in concrete spaces and lack of green spaces in Western
diovascular disease-related death48. Cardiovascular diseases induced countries generally show a substantial colocalization of environmental
by climate change are mediated by air pollution, increased ambient risk factors, especially in highly urbanized and industrialized areas10.
temperatures, vector-borne disease and mental health disorders49. A similar co-exposure is seen for light and air pollution, with potential
Currently, the frequency of heat waves, which are responsible for additive risk profiles for cardiovascular disease53. Preclinical studies on
more deaths than any other type of extreme weather in many parts combined exposure to environmental pollutants and stressors are rare.
of the world, is increasing in conjunction with mean temperatures50. However, one study in mice suggested additive cardiovascular dam-
From 2008 to 2017, extreme heat was associated with higher all-cause age after co-exposure to particulate matter and aircraft noise (which
mortality than that seen in years with normal average temperature in induce their primary adverse effects via lung inflammation and the
the contiguous USA (which excludes Alaska and Hawaii), with a greater brain stress response, respectively) mediated by activating partially
increase noted especially among older adults51. In patients with cardio- synergistic pathological mechanisms54. In another study, co-exposure
vascular disease, particularly those with heart failure who take diuret- to particulate matter and light at night caused additive adverse effects
ics and β-blockers, the heat might result in severe volume depletion on circadian clock components and cardiometabolic parameters55.
and, potentially, cardiogenic shock52. Accordingly, a worldwide study Epidemiological studies investigating adverse health effects of
including data from 567 cities in 27 countries across 5 continents dem- colocalized environmental risk factors from a multi-exposure per-
onstrated that exposure to extreme temperatures (quantified as the spective are becoming more frequent56. A comprehensive, large-
99th percentile for heat and the 1st percentile for cold) was associated scale example is a prospective cohort study from 2022 covering all of
with an increased risk of death from any cardiovascular cause as well as Denmark, which investigated the health effects of four air pollutants

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PM2.5 (µg/m3) UFP (particles per cm3)

a 7.99–9.12
b 5,560–7,020
9.12–9.52 7,020–7,560
9.52–9.86 7,560–7,980
9.86–10.3 7,980–8,350
10.3–10.9 8,350–8770
10.9–11.2 8,770–9,250
11.2–11.4 9,250–9,920
11.4–11.5 9,920–11,100
11.5–15.7 11,100–68,900

Corine Land Cover 2000 raster

c Continuous urban fabric Land principally occupied by Intertidal flats
Discontinuous urban fabric agriculture, with substantial Water courses
Industrial or commercial units areas of natural vegetation Water bodies
Road and rail networks and Agro-forestry areas Coastal lagoons
associated land Broad-leaved forest Estuaries
Port areas Coniferous forest Sea and ocean
Airports Mixed forest
Mineral extraction sites Natural grasslands
Dump sites Moors and heathland
Construction sites Sclerophyllous vegetation
Green urban areas Transitional woodland–shrub
Sport and leisure facilities Beaches, dunes, sands
Non-irrigated arable land Bare rocks
Permanently irrigated land Sparsely vegetated areas
Fruit trees and berry plantations Burnt areas
Olive groves Glaciers and perpetual snow
Pastures Inland marshes
Annual crops associated Peat bogs
with permanent crops Salt marshes
Complex cultivation patterns Salines

d e
Ultrafine particles

NO2

Road traffic noise, most exposed facade

Road traffic noise, least exposed facade

Lack of green space, 150 m

Lack of green space, 1,000 m

Lden (dB(A)) Cumulative risk

40
50 0.98 1 1.05 1.10 1.15
60 HR (95% CI) for type 2 diabetes mellitus
70 15 0 15 km
Single-pollutant model Multi-pollutant model

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Fig. 2 | Colocalization of environmental exposures in Denmark. The maps at the most exposed facade at all residential addresses in Denmark in 2015, shown
show the annual mean levels of particulate matter with diameter ≤2.5 µm (PM2.5) as the day–evening–night noise level (Lden), an indicator based on 24-h average
(part a) and ultrafine particles (UFP) (part b) in the air in Denmark in 2000, sound levels (part d). Risk estimates for type 2 diabetes mellitus per interquartile
modelled by the Aarhus University using the Danish Eulerian Hemispheric Model range increase in exposure to air pollution, noise pollution and lack of green
and the Urban Background Model at 1 × 1 km spatial resolution186,187. Corine Land space in single-exposure and multi-exposure analyses based on a prospective
Cover map for Denmark in 2000, providing information for 44 classes of land study covering all of Denmark57 (part e). Parts a and b courtesy of Matthias Ketzel
use such as forest and arable land (part c). The European Environment Agency (unpublished data). Part c reprinted from ref. 188, CC BY 2.5. Part d courtesy of
coordinates European Union Corine Land Cover maps. Map of road traffic noise M.S. (unpublished data). Part e reprinted with permission from ref. 57, Elsevier.

(PM2.5, ultrafine particles, elemental carbon and NO2), road traffic deaths per year attributable to all forms of chemical pollution might
noise at both the most and least exposed residential facades, and lack be just the tip of the iceberg12, particularly when considering that the
of green space within 150 m and 1,000 m from the residence57 (Fig. 2). estimated 8 million premature deaths attributable to air pollution alone
All exposures were estimated using state-of-the-art exposure models are based on advanced calculations using novel exposure–response
with high spatial (address-level) and temporal resolution. The study functions20. Most of the pollutome remains poorly understood
showed that combustion-related air pollution (ultrafine particles and and comprises emerging, unquantified effects of known pollutants and
NO2), road traffic noise and lack of green space were all independently inadequately characterized health effects of emerging pollutants. This
associated with a higher risk of type 2 diabetes in a multi-exposure unknown and uncharacterized part of the pollutome is not included in
perspective (Fig. 2e). The estimated cumulative risk for all exposures the GBD study nor in other extensive, environmental health association
was higher than for any single exposure. Similar results were found for studies.
the Danish population when investigating the effects of the three types Several exposome studies assessed the exposome divided into
of exposures in relation to cardiovascular disease (M.S., unpublished various subcategories (for example, the exposure component or the
work). These results stress the importance of considering multiple health-outcome component), which might facilitate the handling of
environmental risk factors when planning cardiovascular disease data sets given that not all exposures and health effects will coincide.
prevention strategies. An example is the assessment of the occupational exposome, with
detailed consideration of multiple toxic compounds that individuals
The exposome concept are exposed to at work61. This study focused on occupational toxins and
The term ‘exposome’ was introduced in 2005 by Wild58 and describes the the subsequent development of cancer and also provided a detailed
totality of lifelong changes in human physiology and pathophysiology overview of how a specific exposome can be assessed61. Likewise, an
induced by the environment (that is, by exposure to environmental obesity exposome model was developed to evaluate the environmental
stressors16,59,60) (Fig. 3). These exposures comprise not only chemical effect of climate, sex, ethnicity and socioeconomic factors on BMI,
and physical factors, such as air pollution, noise, ultraviolet (UV) radia- adiposity and cardiometabolic health outcomes62. Other exposome
tion and climate change, but also socioeconomic and mental health approaches have investigated the effect of environmental risk factors
determinants, including the social environment and capital, exposure (external environment) and associated biomarkers (internal environ-
to viral and bacterial pathogens, and psychosocial stress. These factors ment) on the development of diabetes and its cardiovascular seque-
determine the general external environment and cannot be easily modi- lae14,63. Measuring the tumour exposome has been suggested as a robust
fied by the individual. The second component that defines the expo- basis for evaluating environmental exposures and the risk of cancer64.
some comprises lifestyle or behavioural factors, including smoking The term ‘urbanome’ describes the complexity of megacities with all the
habits, alcohol consumption, unhealthy diet, physical inactivity and exposures and their effects on people living in them65, including
use of consumer products such as cosmetics. These factors define the socioeconomic factors, green space availability, stressors and pollut-
specific external environment, which the individual can modify more ants. For example, the urbanome has been used to assess the effect of
easily than, for example, reducing air pollution and noise exposure, environmental exposures on pregnancy66.
controlling outside temperature, changing social capital or improv- The exposome can be assessed by two approaches: the top-down
ing the climate. Notably, the exposome approach moves away from approach, which determines changes in the internal environment
the one-exposure to a one-health-outcome type of analysis in favour (biomarkers), and the bottom-up approach, which assesses the external
of an analysis that considers that many exposures coincide and are environment67. In the top-down approach, the focus is on footprints of
associated with multiple health outcomes. exposure in vivo by directly quantifying exogenous compounds, pro-
Landrigan et al. coined the word ‘pollutome’ to encompass all tein adducts and reactive metabolites as well as changes in biological
forms of pollution that have the potential to harm human health12. response profiles in the host assessed by metabolomics, transcripto­
The pollutome includes chemical pollution, a crucial environmental mics or proteomics. The bottom-up approach is characterized by the
health risk, but can also include non-chemical pollutants such as light collection of comprehensive data on environmental exposures through
and noise pollution. The exposome can be divided into multiple pol- surveys, sensors or trace analytical chemistry in environmental sam-
lutomes related to specific periods of life (infancy, childhood, adoles- ples. The top-down approach enables the creation of new hypotheses
cence, adulthood and old age) or geographical locations12. Accordingly, for exposure–disease and exposure–response relationships. The
pollutomes represent temporal and spatial exposures and their bottom-up approach can help to generate new hypotheses on effects
effect on human physiology and pathophysiology. Unfortunately, we but does not necessarily investigate the effect. A complete exposome
understand only a minor part of the effects of different pollutomes on study will combine top-down and bottom-up approaches. A health
cardiometabolic health because multi-pollutant studies have not been and disease status of a person is determined by the combined effects
conducted. Therefore, the current estimate of 9 million premature of complex environmental exposures, associated biological responses

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Review article

Major exposome Genetic Pre-existing Increased cardiovascular

risk factors predisposition cardiovascular risk and morbidity
Central biochemical
disease
Smoking pathways
• Circadian clock
dysregulation
• Stress hormone
responses Plaque
Mental health and • Inflammation Thrombus
Specific external environment
societal factors • Diet • Oxidative stress
• Anxiety • Consumer products
• Psychosocial stress • Physical activity
• Loneliness • Tobacco Internal environment
• Social isolation • Water • Transcriptomics
• Proteomics Health effects and
• Metabolomics risk assessment Myocardial
infarction
General external environment
• Climate
• Traffic
Chemical pollution • Urban environment
• Air • Green spaces Stroke
• Water • Social capital
• Earth

Life course dimension

Fig. 3 | The exposome concept. The exposome describes the totality of in the transcriptome, epigenome, proteome and metabolome (and more rarely
lifelong exposures to environmental risk factors, the induced pathological by analysis of the microbiome or adductome). Alterations in central biochemical
and mechanistic changes in central biochemical pathways, and the associated pathways identified in exposome studies include dysregulation of circadian
health effects58,59. Within the general external environment, the environmental clock components that lead to impaired rhythmicity and phase shifts, the
factor with the largest effect on health is chemical pollution. Within the specific release of stress hormones (cortisol and catecholamines), production of reactive
external environment, the environmental factors with the most substantial oxygen species by mitochondria and NADPH oxidase in activated immune
effect on health are tobacco smoking and unhealthy dietary habits. The cells, inflammation with tissue infiltration of activated immune cells, and
general and specific external environment can have adverse effects on mental oxidative damage in different organs (reviewed previously10,38). Environmental
health (for example, by social isolation or work strain), but the contribution of exposures can act synergistically or additively with genetic predisposition or
environmentally triggered mental stress to the global burden of disease and pre-existing cardio­vascular disease. Environmental exposures can exacerbate
global deaths might be underestimated owing to the lack of valid exposure– detrimental cardiovascular health outcomes such as atherosclerosis, vascular
response relationship data for mental risk factors. Changes in the internal stenosis, myocardial infarction, heart failure and stroke.
environment induced by exposures are most frequently quantified by changes

and individual susceptibility over time68. Whereas the genomic com- cardiovascular damage in mice with pre-established hypertension73.
position of an individual is stable, the environmental exposures, how A study in China showed that the autonomic and vascular dysfunction
the individual responds to those exposures and how the responses induced by exposure to air pollution was higher in individuals with
ultimately manifest as health effects can vary over the life course of pre-existing heart disease and other risk factors such as inflamma-
an individual. The exposome approach involves collecting relevant tion and overweight74. Data from the MESA-Air cohort also support
information across all variables, identifying meaningful biological the presence of aggravated cardiovascular damage mediated by air
consequences, and using the information for systems analysis and pollution in patients with established heart disease and early signs of
data-driven discovery. atherosclerosis and calcification75.
As explained in detail in the Introduction, tobacco smoking and air, Moreover, the risk of plaque rupture has been shown to increase
water and soil pollution are the most important environmental risk fac- exponentially with higher air pollution levels76,77. The sum of environ-
tors (exposures) for all-cause death and cardiovascular death6 (Fig. 3). mental exposures, genetic predisposition and existing cardiovascular
Mental health and socioeconomic factors should be considered in disease causes changes in the internal environment, including altered
future exposome studies given the observed association between these gene and protein expression, leading to dysregulation of central path-
factors and cardiovascular risk69,70. However, environmental health ways such as stress hormone signalling, circadian rhythms, inflam-
studies have not characterized mental health and socioeconomic mation, oxidative stress and endothelial dysfunction, all of which
factors well. Genetic predisposition can increase the adverse health increase the risk of major adverse cardiovascular events10. The analysis
effects of environmental factors because of higher expression of sus- of all risk sources and the induced biological changes can be used for
ceptibility genes or suppression of genes related to resilience to expo- a precision medicine approach for the early diagnosis and treatment
sure-triggered organ damage11 (Box 1). Individuals with pre-existing of NCDs78.
cardiovascular disease are at a higher risk of environmentally induced Environmental risk factors are crucial in morbidity (DALYs) and
damage, as shown by field studies on traffic noise-induced cardio­ early-life and late-life mortality. The loss of healthy life years (or DALYs)
vascular complications in patients with coronary artery disease71,72. induced by chemical pollution is more pronounced in infants12 (Fig. 4).
These findings from studies in humans are supported by preclinical By contrast, the effects of chemical pollution on premature death are
data demonstrating that exposure to aircraft noise induces additive more pronounced in older adults12 (Fig. 4). The high number of DALYs

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Review article

in older adults might be attributed to lead toxicity caused by soil pol- noise, address-specific calculations using a dedicated noise exposure
lution12. The high number of DALYs in infants primarily reflects the model are necessary for obtaining high-quality exposure information,
substantial amount of life years lost when one infant dies and, likewise, including information on 3D models of buildings, noise screens, traffic
the high number of life years lived with a severe disability when one intensity and speed, and acoustic reflections. These data can be used
child develops a chronic disease in early life due to environmental to create metropolitan, national or worldwide exposure maps for
pollution79. This high number of DALYs caused by environmental pol- different environmental exposures (Fig. 5). Given that all these data
lution in infants is primarily due to ‘untrained’ defence mechanisms are usually stored for a long time, they allow inference of retrospec-
in this population, which makes them less resistant or resilient to tive associations between exposure and health outcomes going back
high doses of pollutants, for example, owing to lower body weight for decades and, in the best cases, provide a retrospective lifelong
and epigenetic reprogramming at the neonatal stage. Conversely, the exposure history of populations.
more pronounced effects of chemical pollution on mortality in old Chemical exposures from soil, water and air pollution are assessed
individuals can be attributed to the multimorbidity phenotype in older by sampling at multiple geographical positions, followed by detailed
ages. People aged >60 years usually develop multiple comorbidities, analysis (for example, mass spectrometry and atomic absorption
including cardiovascular risk factors such as diabetes and hyperten-
sion80, which makes them a more susceptible group to the adverse
health effects of environmental stressors. In addition, the lifelong Childhood Adulthood
accumulation of environmentally induced health damage also has a a 2.5

role in the higher mortality observed in older individuals81. Therefore,

these groups have been selected as the primary study population for Estimated global deaths cumulated
2.0
for major pollutants (millions)
exposome studies, given that the environmentally triggered dynamic
changes in biochemical pathways are most pronounced in these age
groups. The SDGs track death from cardiovascular disease, cancer, 1.5
diabetes and chronic respiratory diseases only in individuals aged
30–70 years. The SDGs do not track deaths in children and adolescents
and/or the contribution of chronic diseases triggered by air pollution and 1.0
other environmental factors82.

Assessment of the exposome 0.5

Assessment of environmental exposures

Several complementary methodologies, including measurements and 0.0
mathematical exposure models, can be used to assess environmental –2 0 2 4 6 8 10 12 20 30 40 50 60 70 80
exposure. These methods comprise geographical information systems Age (years)
with remote sensing, global positioning systems and geolocation tech- b 50

nologies as well as stationary, portable and personal sensors, including

mobile phone-based sensors and self-reported questionnaire assess-
40
Estimated global DALYs cumulated

ments that record personalized external exposure estimates (Fig. 5).

for major pollutants (millions)

Large-area or global exposure maps for air pollutants, night-time light

pollution43 and temperature are primarily based on satellite data (for 30
example, Copernicus pollution data (7 × 3.5 km resolution) from the
Copernicus Sentinel-5P satellite) supported by ground-based meas-
urements that are primarily from governmental sources. In the past 20
10 years, mobile and personal sensors have been widely available. These
devices can provide cross-regional exposure information by collect-
ing data via wireless transmission from the network of phone devices. 10

These data can be used to develop atmospheric models such as the high-
resolution regional Weather Research and Forecasting model coupled
0
with Chemistry (WRF-Chem) for atmospheric chemistry processes83 –2 0 2 4 6 8 10 12 20 30 40 50 60 70 80
and the low-resolution global ECHAM5/MESSy Atmospheric Chemis- Age (years)
try (EMAC) model for atmospheric chemistry–climate interactions84. Occupational + Soil + Water + Air
Both state-of-the-art models estimate concentrations of major pol-
Fig. 4 | Global deaths and DALYs for different pollutants and age groups.
lutants (such as PM2.5 and ozone) by accounting for their atmospheric
Estimated global deaths (part a) and disability-adjusted life years (DALYs)
photochemistry, emissions (natural and anthropogenic) and sinks85,86.
(part b) in 2015 that were related to exposure to different major pollution factors
Traffic-related air pollution is usually determined by a combination
(occupational, soil, water and air pollution), classified by age at death. The global
of ground-based detectors and land-use regression models compris- death and DALY values for the pollutants are presented cumulatively: occupational,
ing governmental traffic and digital ground model data as developed occupational plus soil, occupational plus soil plus water, and occupational plus soil
by the ESCAPE project using leave-one-out cross-validation87 or more plus water plus air pollution. The major environmental cause of DALYs at younger
advanced approaches using tenfold cross-validation88. These models ages is air pollution, whereas the major environmental cause of DALYs at older ages
consider the proximity of buildings to main roads, traffic streams, is soil pollution. This effect of soil pollution can largely be attributed to lead toxicity.
density and landscape characteristics. For the estimation of road traffic Data are from the 2015 Global Burden of Disease study189.

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Review article

Air pollution exposure maps PM2.5 levels in Europe

Satellite systems Map scale
Geostationary ~36,000 km
satellite
Polar 700–900 km
satellite

Aerial vehicles Map scale

Aerial photography 1–3 km
Ambulatory blood
pressure monitor
Drone 0.5 km Heart rate
NO2 levels in London sensor

Ground instruments Map scale

Volume sampler Surface

Digital sensor Surface Smartwatch

or band
Mobile
Transportation noise exposure maps by land-use regression models phone Spirometer
Smart cities
Noise pollution in the USA Positioning Intelligent sensing
(GPS, address) Sends warnings and management of
Personal or mobile sensors exposures

Personalized measurement Personalized health data Health sensors

of environmental • Blood pressure • Mobile phone
exposures • Physical activity • Smartwatch or band
• Air pollution • Pulse wave velocity • Ambulatory blood
• Noise • Nutrition pressure monitor
• UV light • Stress • Spirometer
• Artificial light at night • Sleep • Heart rate variability
• Exercise
Artifical light at night exposure maps by satellite-based Questionnaire or diary
measurements • Symptoms
• Well-being
Global artificial light at night • Photography Mobile phone
• Video technology

Routinely
monitored data
Database

Statistical analyses

Exposure–response relationship

Fig. 5 | Assessment of environmental exposures and lifestyle factors. facilitate intelligent sensing of exposures and can protect the individual from
Personal or mobile sensors enable the continuous assessment of environmental environmental hazards via early warnings sent to the individual’s mobile devices
exposures (such as air pollutants, noise, ultraviolet (UV) and artificial light at and through intelligent exposure management, for example, by advanced control
night) and health parameters (such as blood pressure, physical activity, and of traffic, waste and nocturnal illumination and by the implementation of green
sympathovagal and emotional parameters) of an individual. Personal data can spaces. The flow chart provides an example of a personalized sensor framework
also be acquired via daily questionnaires submitted via app-based software. for continuous assessment of environmental exposures and lifestyle history for
Improved exposure data from satellite, aircraft, drone and ground-based exposome studies. The exposure maps are reprinted with permission from the
measurements provide a detailed spatial and temporal exposure history in European Environment Agency (particulate matter with diameter ≤2.5 µm (PM2.5)
relation to the global positioning system (GPS) location of the target individuals. levels in Europe), the UK Department for Environment, Food and Rural Affairs,
In addition, land-use regression models allow accurate exposure estimations for © Crown 2004 (NO2 levels in London), US Department of Transportation, Bureau
air, noise or light pollution at the address level. A combination of all assessment of Transportation Statistics, National Transportation Noise Map (noise pollution
methods of exposure allows the creation of exposure maps. Smart cities can in the USA), and ref. 43, AAAS (global artificial light at night).

spectroscopy) performed mainly by governmental laboratories. The dietary habits, smoking, physical activity and other lifestyle factors,
exposure to these chemicals can also be assessed by analysis of human are assessed mainly by self-reported questionnaires16. Examples of
samples such as urine and blood16,89. questionnaires, for instance, for assessing noise-associated annoy-
Non-chemical and non-physical exposures, such as mental stress ance, sleep impairment or chronotype, and circadian rhythms, have
(from work strain, mobbing, social isolation or profound grief), been previously described and are available for use90,91.

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Personal and mobile sensors noise caused changes in the plasma proteome (measured by Olink
The rapidly evolving technology of small, wearable sensors is gen- chip) and endothelial dysfunction117. These findings are supported by
erating opportunities to measure the exposome, emotional states, results from a study in mice showing that exposure to noise induces
behaviours and physiological responses on a sufficient scale for car- plasma proteome and lipidome changes (measured by liquid chro-
diovascular health research92–94. The use of wearable sensors and global matography–mass spectrometry (LC-MS)) and microvascular dys-
positioning systems, for example, from everyday technology such function118. Both studies found that exposure to noise induced an
as smartphones, can provide detailed information on the location, inflammatory phenotype. An assessment and critical comparison of
physical activity, mode of transport, environmental exposures (such these approaches can be found in previous reviews of holistic expo-
as air pollution, noise and UV light), physiological responses (blood some approaches103,104,119 and the blood exposome89. The hierarchy
pressure and heart rate (variability), glucose levels, body temperature, and combination of these approaches were also reviewed120. The most
or galvanic skin response) and emotional status of a person95–100. This important current and potential future biomarkers are presented
information can be overlaid with information on the built environment in Table 2.
that is derived, for example, from remote sensors, to obtain detailed The different analytical work-up requirements for analysing the
insights into how multiple dimensions of the urban environment inter- exposome with LC-MS depend on the water or lipid solubility of the ana-
act to shape the health of an individual92 (Fig. 5). The feasibility of such lysed chemicals. In addition, the extremely wide concentration range
an approach was demonstrated by a study examining the use of a per- of chemicals and metabolites in the blood — ranging from 160 fmol/l
sonal sensor set to continuously measure exposures over 24 h to assess to 140 mmol/l, which represents a range of 11 orders of magnitude — is
part of the urban exposome and acute health responses97. Nevertheless, an analytical challenge89 (Fig. 6). Toxic chemicals of high concern are
many challenges remain with such an approach, including implement- heavy metals and metalloids35 as well as common toxic compounds
ing the methodology for an extended period and in larger populations, originating from industrial production processes such as bisphenols
improving the ease of wear (for example, through miniaturization and (bisphenol A), persistent organic pollutants (including pesticides such
extending battery life) and reducing costs101. In addition, the creation as dichlorodiphenyltrichloroethane), polychlorinated biphenyls,
of smart cities will help to understand the exposome and to protect and perfluoroalkyl and poly-fluoroalkyl substances (PFASs)67. Cur-
individuals from environmental hazards102 (Fig. 5 and Box 2). rent analytical methods are so sensitive that daily drug use in general

Biomarkers of the exposome

In this section, we provide a short description of the main biomarkers
for assessing exposure-triggered biochemical and functional changes
in individuals (the ‘internal’ exposome or environment) as a detailed
Box 2
description of these biomarkers is beyond the scope of this Review.
Direct determination of the presence and levels of pollutants in the Smart cities can help to
blood (such as heavy metals and pesticides) allows the drawing of con-
clusions on exposure levels of the individual and also provides infor- understand the exposome
mation on the potential biochemical reactions of these chemicals89.
These biomarkers can be measured with omics methodologies used A smart city is a place where traditional networks and services are
in genome, epigenome, transcriptome, proteome, metabolome, lipi- made more efficient using digital solutions for the benefit of its
dome, microbiome and adductome research103,104. Multiple examples inhabitants and businesses. Moreover, a smart city also helps to
of omics-based characterization of cardiovascular disease as well as understand the exposome. A smart city goes beyond the use of
exposure-triggered adverse health effects have been reported previ- digital technologies to improve resource use and reduce emissions.
ously105. In particular, redox-proteomics and phospho-proteomics A smart city means smarter urban transport networks, upgraded
provide mechanistic insights into cellular signalling; for example, as water supply and waste disposal facilities, and more efficient
shown by a study demonstrating the strong effects of the redox pro- ways to light and heat buildings. It requires a more interactive and
teome (sulfhydrome) on vascular function106 and a study that identified responsive city administration and safer public spaces to meet
novel phosphorylation targets and kinases involved in the development the needs of an ageing population. Smart cities contain many
or prevention of heart failure107. In addition, functional biomarkers sensors around the city that can be used to obtain information on
are currently being established using biochip technology, allowing the exposures that citizens experience, including, for example, the
high-throughput cell culture-based assays such as receptor activity degree of traffic, air quality, noise levels, temperature, and water
tests (for example, for androgen, oestrogen, G protein and aryl hydro- and light pollution, and where citizens spend their time and how
carbon signalling)104 and oxidative stress response reporter cell assays they move through the city. All this information can be used to
(such as for assessment of the activation of nuclear factor erythroid build the exposome and to increase the information on exposures.
2-related factor 2, a transcription factor that shows responsiveness to Feedback mechanisms can be created to improve the exposome of
most environmental stressors108). people and reduce harmful exposures. Citizen science and citizen
With a focus on specific metabolic, proteomic or transcriptomic sig- exposure kits might help to further augment the information on
natures, exposure–health association studies measure stress hormones the exosome. Citizen participation and co-creation are essential to
(catecholamines109 and cortisol110), indicators of disruption of circadian creating an acceptable and trusted smart city. In general, ethical
rhythms (melatonin111 and other factors112,113), markers of oxidative considerations should be taken into account throughout the
stress (malondialdehyde, 4-hydroxynonenal and 3-nitrotyrosine114,115) development of the smart city, including privacy issues and data
and inflammatory responses (cytokines and chemokines 35,116). protection.
A study in humans demonstrated that a one-night exposure to railway

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Table 2 | Present and future biomarkers of the exposome

Type Biomarker Type of exposome study

Pathways and functions

Circadian rhythm Melatonin111 Large human cohort
Circadian rhythm-related genes and proteins (PER1, CRY, CLOCK, BMAL, NPAS)112,113 Field study in humans
Diurnal rhythms of expression and levels of genes, proteins and metabolites that are controlled Animal models
by the circadian clock112,113
Neurohormonal Cortisol, precursors and regulators (adrenocorticotropic hormone, corticotrophin-releasing hormone)110 Large human cohort
pathways
Catecholamines (adrenaline, noradrenaline), urine stable metabolites Large human cohort
(3-methoxy-4-hydroxyphenylglycol)109
Molecules downstream of catecholamine signalling (angiotensin II, endothelin 1)35,182 Large human cohort
Inflammation Lipid peroxidation products (malondialdehyde, 4-hydroxynonenal, 8-isoprostane)54,114 Field study in humans and mice
Products of direct oxidation of proteins, nucleic acids and lipids (3-nitrotyrosine, 8-oxoguanine, Field study in humans and mice
oxidized LDL)38,54,112,114
Inflammation markers (C-reactive protein, interleukins)35,116,123,125,129,130 Large human cohort
Mitochondrial DNA copy number and mutations Large human cohort
DNA damage DNA oxidation (8-oxoguanine)38,112 Large human cohort
DNA methylation (O6-methylguanine) Large human cohort
Mutations Large human cohort
Micronuclei formation Large human cohort
Single-strand and double-strand breaks Large human cohort
Toxic compounds Heavy metals (mercury, lead, cadmium), metalloids (arsenic) 34,35,89
Large human cohort
Pesticides67,89,152–155 Large human cohort
Phthalates, bisphenols, polychlorinated aromatic compounds67,152–155 Large human cohort
DNA adducts (chemicals) 132–134
Large human cohort
Protein adducts (malondialdehyde, 4-hydroxynonenal, chemicals)115,132–134 Large human cohort
Other pathways Receptor activity assays (androgen receptor, oestrogen receptor, G protein signalling, aryl hydrocarbon)104 Large human cohort
and processes
Stress-responsive genes (NRF2, HMOX1) by reporter cell assays 108,183,184
Animal models
Functional assays (endothelial function, heart rate variability, arterial stiffness)117,135,137–140 Field study in humans
Autophagy, senescence, telomere length Animal models
Methodologies
Transcriptomics RNA sequencing103,104 Large human cohort
Single-nucleotide polymorphism-based arrays (metabochip, immunochip)103,104 Large human cohort
Epigenomics DNA methylation (EPIC, BeadChip, bisulfate sequencing)123–125 Large human cohort
Hydroxymethylation (5hmC) Large human cohort
Histone modifications Animal models
MicroRNAs126 Large human cohort
Long non-coding RNAs Large human cohort
Proteomics Protein expression 103,104
Large human cohort
Post-translational protein modifications (oxidation: 3-nitrotyrosine, S-oxo-Met, carbonylation; Field study in humans and mice
reactive aldehyde adducts: malondialdehyde, 4-hydroxynonenal)54,114
Redox and phospho-proteome106,107 Animal models, isolated cells
Lipidomics Fatty acid composition of lipid membranes (saturated versus unsaturated fatty acids) 103,104,118,185
Field study in humans and mice
Oxidized lipids (oxidized LDL, isoprostanes)114 Field study in humans
Metabolomics Lipid metabolism103,104,131 Large human cohort
Glucose metabolism 131
Large human cohort
Stress hormones (cortisol)109,110 Large human cohort
Cytokines35,116,123,125,129,130 Large human cohort
Vasoconstrictors and vasodilators (angiotensin II, endothelin 1) 35,182
Large human cohort

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Table 2 (continued) | Present and future biomarkers of the exposome

Type Biomarker Type of exposome study

Methodologies (continued)
Microbiomics Short-chain fatty acids (propionate, butyrate) Large human cohort
Toxic metabolites (trimethylamine N-oxide) Field study in humans
Beneficial (Lactobacillus) versus harmful (Campylobacter) bacterial composition by 16S rRNA Large human cohort
sequencing104

populations can be monitored in wastewater by LC-MS121,122. Although dilatation) in response to noise exposure117,137 as well as markers of
untargeted, high-resolution mass spectrometry approaches can detect thrombosis and ischaemia, blood pressure, heart rate, and brachial
>30,000 small molecules in human serum, these methods cannot reli- artery vasodilatation after inhalation of diesel particulate matter138–140.
ably measure blood concentrations of <0.1 μmol/l in a 50-μl sample89.
Considering the wide concentration range of these small molecules Exposome studies of cardiovascular outcomes
in human blood (Fig. 6), untargeted analyses might miss about 90% Selected exposome studies and relevance to cardiovascular
of pollutants and 30% of endogenous and food chemicals, including risk prediction
hormones, carcinogens and endocrine disruptors. Databases on envi- Only a few studies conducted so far fulfil the criteria for a ‘real’ compre-
ronmental toxins and their biochemical and health effects can help to hensive exposome approach that includes analyses of environmental,
promote exposome research (Box 3). lifestyle and socioeconomic exposures as well as biomarkers of expo-
For genomic analyses, arrays are now available to measure from sures and outcomes (the internal environment; assessed, for example,
500,000 to 5 million single-nucleotide polymorphisms (SNPs) in a sin- using various omics approaches) and manifest cardiovascular diseases.
gle analysis104, which is essential to determine the genotype across the These studies include the EXPOsOMICS project, a few studies from the
whole genome (for example, in comparison to a reference genome, as HELIX and PACE projects, and the European Human Exposome Network
explained in Box 1). A targeted approach to reveal the genotype related to (EHEN). Therefore, most of the available knowledge on environmental
specific biological pathways, such as the metabochip for SNPs in genes exposures in relation to the risk of cardiovascular disease originates
encoding metabolic proteins or the immunochip covering immune- from more traditional epidemiological studies.
related genes, would be cheaper than SNP-based arrays and sufficient
for most exposome studies. Epigenetic analyses can be used to identify Traditional epidemiological studies. These studies are based on few
exposome-induced changes in DNA besides alterations in the DNA exposures (such as air pollution, traffic noise and green infrastruc-
sequence, including DNA methylation patterns123–125, microRNAs (which ture) linked with either biomarkers (such as markers of inflamma-
regulate multiple cardiovascular disease pathways126) and histone modi- tion (C-reactive protein)129, stress hormones (saliva cortisol)110, DNA
fications (such as methylation or acetylation, which have a high predic- methylation123 or subclinical cardiovascular markers such as arterial
tive potential for cardiovascular diseases127,128). The epigenome changes stiffness135) or manifest cardiovascular disease in analyses adjusted for
with age, and each cell type has its own epigenome. Therefore, analysing socioeconomic status and lifestyle. Examples of important contribu-
a mix of cell populations, rather than assessment with single-cell tions to the research field using this approach include the ESCAPE and
techniques, will provide information on the so-called metagenome. ELAPSE projects. These studies used harmonized estimations of vari-
Inflammation is an essential biomarker of exposure to chemical ous air pollutants (including PM2.5 and NO2) across several European
pollutants such as heavy metals or air pollution35. The EXPOsOMICS cohorts. The results showed an association between high levels of these
consortium showed that oxidative stress and inflammation markers are pollutants and a higher risk of cardiovascular outcomes, including
associated (via DNA methylation) with the adverse effects of air pollu- cardiovascular mortality23,141,142, incidence of acute coronary and cer-
tion on cardiovascular and cerebrovascular disease125. Cohort studies ebrovascular events143–145, and hypertension146. Given that many of the
also found a significant association between plasma C-reactive protein cohorts in the ESCAPE and ELAPSE studies include biobank material,
levels (as a readout of systemic inflammation) and exposure to air pollu- the mechanistic aspects (changes in the internal environment) can be
tion129. An analysis of the HELIX cohort showed that prenatal exposure measured at later stages, which would facilitate real exposome stud-
to mercury is associated with an increased risk of non-alcoholic fatty ies in the future. The SAPALDIA consortium reported a mechanistic
liver disease and inflammation in childhood130. The EXPOsOMICS con- role of DNA methylation (with pathway enrichment in the C-reactive
sortium established an association between air pollution and cardiovas- protein cluster) for the association between traffic-related air pol-
cular disease by demonstrating a substantial dysregulation of metabolic lution and noise and cardiovascular outcomes123. The consortium
pathways using metabolomics131. Analysis of the microbiome104 and also found associations between traffic noise and arterial stiffness135.
adductomics studies (that assess adducts of chemical pollutants with A list of larger cohorts that could fulfil the requirements of a complete
DNA or proteins132–134) can also be used to detect the biological effects exposome study by using available geocoding or biobanks for internal
of exposures. The SAPALDIA study established an association between environment determination has been provided in the literature147.
arterial stiffness (a subclinical functional marker) and night-time noise
exposure, which is a well-known risk factor for cardiovascular disease135. Comprehensive exposome studies. More comprehensive exposome
Exposure–health association studies, especially field studies, have studies assessing the effects of the exposome on cardiovascular health
also measured heart rate variability136, the degree of sympathovagal are needed, but the following examples of exposome studies have
activation and endothelial function (for example, by flow-mediated reported some trends. The EXPOsOMICS project aimed to develop

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Review article

100

Cholesterol
Lead Aspirin Caffeine
90

Arsenic Trimethylamine-N-oxide

80 DDE
Homocysteine

Perfluorononanoic acid
70 γ-Tocopherol
Venlafaxine

60 Benzene
Malondialdehyde
Cumulative percent

Cotinine Acetaldehyde

50 Hexachlorocyclohexane Sulforaphane
β-Carotene
Trichloromethane
PCB 170
40
Cortisol

30 BDE 100 Simvastatin

Ethanol

20
Genistein Folic acid, vitamin D3

Aflatoxin B1 Drugs
Testosterone
10 Foods
Digoxin
OCDD Solanidine Pollutants
Endogenous
Oestradiol
0
10–7 10–6 10–5 10–4 10–3 10–2 10–1 100 101 102 103 104 105
Concentration in blood (µM)

Fig. 6 | Blood biomarkers of the exposome. a, Concentrations of small of each of the four distributions that are below a given blood concentration.
molecules and metals in human blood. Each line represents the cumulative For example, for pollutants (red line), approximately 50% of the chemicals
distribution of concentrations of chemical compounds from a particular had a blood concentration of <10–4 µmol/l, which is the blood concentration
category (drugs: n = 49; food chemicals: n = 195; pollutants: n = 94; endogenous of hexachlorocyclohexane (S. M. Rappaport, personal communication). BDE
chemicals: n = 1,223). Within each compound category, concentrations cover a 100, 2,2′,4,4′,6-pentabromodiphenyl ether; DDE, 1,1-bis-(4-chlorophenyl)-
107-fold range. Whereas the mean blood concentrations of drugs, food-derived 2,2-dichloroethene; OCDD, 1,2,3,4,6,7,8,9-octachlorooxanthrene; PCB 170,
chemicals and endogenous metabolites are 0.3–1.0 µmol/l, blood levels of 2,2′,3,3′,4,4′,5-heptachloro-1,1′-biphenyl. Adapted with permission from
pollutants are 1,000-fold lower. The cumulative percent refers to the proportion ref. 89, EHP.

a new approach to assess environmental exposures, primarily focus- focused on only early-life exposures150,151. The project defined several
ing on air pollution and water contaminants. The consortium used a cardiovascular end points (including hypertension and cardiometa-
broad range of omics techniques and estimated biomarkers (such as bolic diseases) to be studied for potential associations with blood
oxidative stress, inflammatory cytokines and adverse DNA methyla- concentrations of chemical pollutants such as PFASs and pesticide
tion patterns)124. Initial results of the EXPOsOMICS project indicated metabolites152–155. The HELIX studies also found associations between
a mechanistic role of oxidative stress and inflammation in the asso- air pollutants (NO2, PM10 and PM2.5) and higher plasma levels of IL-8
ciation between air pollution and cardiovascular and cerebrovascular and hepatocyte growth factor, whereas only NO2 was associated with
disease125. In addition, disturbance of metabolic pathways seems to be increased blood pressure156. The PACE consortium found an association
a pathological mechanism of air pollutant-mediated development of between NO2 exposure during pregnancy and differential offspring
asthma and cardiovascular disease131. The EXPOsOMICS consortium DNA methylation in mitochondria-related genes and differential
is seeking to establish multiple collaborations with other exposome methylation and expression of genes involved in antioxidant defence
projects and studies to include more cardiovascular end points and pathways157. Prenatal exposure to PM10 and PM2.5 changed the DNA
biomarkers148. methylation pattern of genes related to respiratory health158. Another
In the HBM4EU-aligned cohorts, increased exposure to PFASs example is the Generation R study, which found that maternal urine
was associated with a lower BMI in teenagers149. The HELIX project bisphenol concentrations during pregnancy were associated with

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smaller carotid intima–media thickness (an early marker of arterial Wearable sensors, mobile applications and other technologies
health) in the offspring during childhood159. provide new opportunities to assess the external exposome and
At present, the contribution of exposome studies to improving our its association with health outcomes such as disease or premature
understanding of the cardiovascular health effects and mechanisms of death163. Studying thousands of individuals over their entire lifespan
environmental exposures has been small, given that we already knew might exceed current data storage capacities and also overtax our cur-
that oxidative stress, inflammation, impaired circadian rhythm, dys- rent capacity to interpret and integrate the data to generate valuable
regulated metabolism and elevated levels of stress hormones promote insights. Therefore, clinical translation might be possible only with
cardiovascular disease. Nevertheless, hopefully, ongoing and future current systems biology or bioinformatics methods and technolo-
exposome studies will provide further insights, especially if the studies gies. Another limitation is the cost. The assessment of all biochemical
provide lifelong perspectives. changes induced by environmental exposures with the use of multi-
omics approaches (transcriptomics, proteomics, metabolomics and,
The European Human Exposome Network potentially also, epigenomics and microbiomics) makes exposome
The EHEN is the world’s largest network studying the effect of envi- studies very expensive.
ronmental exposures on health. This network is expected to provide Statistical challenges include adequate approaches for handling
substantial new knowledge in the coming years on the effects of the multiple testing in an exposome context with numerous exposures
exposome on human health over the life course. EHEN was initiated and outcomes as well as approaches for handling exposure misclas-
in 2020 with a € 106 million grant from the European Commission. The sification of various degrees across the exposures in the exposome
project consists of nine large-scale research projects, of which four analysis, which, if not accounted for, will result in differential power
projects aim to investigate the effects of the exposome on cardiovas- to detect associations depending on the precision of the exposure
cular outcomes, covering a plethora of external and internal exposures estimation164. Disentangling these highly correlated exposures is
over the life course147,160–162. The ATHLETE project will gain information difficult even when assessing only a few exposures such as noise and
on the external environment (urban, chemical, behavioural and social air pollutants. In the statistical approaches currently used in most
exposures), the internal environment (including DNA methylation, studies, the best-estimated exposure will ‘win’, although, in real life,
transcriptomics and metabolomics) and early cardiovascular mark- a combination of exposures is likely to be causing the disease. Even
ers (such as cardiac and large-vessel imaging and blood pressure) to more advanced statistical models cannot account for one exposure
investigate the effects of the exposome longitudinally from pregnancy
to adolescence, using 16 prospective birth cohorts161. The EXPANSE
project will study the effect of the urban exposome on cardiometabolic
disease by combining external exposome (such as air pollution, noise
and temperature) and health data from 55 million adult Europeans,
Box 3
using omics data from >2 million of these individuals (from birth and
adult cohorts), and performing exposome assessments for 5,000 peo- Databases of environmental
ple and screening for chemicals in 10,000 blood samples160. In birth and
adult cohorts, the LongITools project will gain information on external toxins and their biochemical
exposures (air pollution, noise, green space and built environment),
internal exposures (metabolomics, epigenomics and transcriptomics) and health effects
and cardiovascular outcomes (such as repeated blood pressure and
cardiac measurements) to elucidate molecular pathways underlying About 85,000 chemical substances are registered in the USA under
the associations between environmental exposures and cardiovascular the Toxic Substances Control Act193, and an estimated 30,000
health trajectories147. The EPHOR project will study the effects of the of these chemicals are widely available for commercial use194.
external occupational exposome (such as chemicals, particles, noise, However, few of these chemicals have recorded data on potential
strenuous physical activity, psychosocial strain and UV light) on the health effects or exposures194. A direct way of tracing chemical
risk of cardiovascular disease, using a European cohort of >20 million exposures is the analytical quantification of these compounds and
workers162. Together, these four projects will provide an unprecedented of their stable metabolites and adducts with biomolecules (such
data source to study the effects of the exposome on cardiovascular as DNA, proteins and lipids), analysed by adductomics, in blood
markers and diseases over the lifetime of individuals. or urine samples of the exposed individuals. Full coverage of the
chemical exposome will require multiple instrumental approaches
Opportunities, limitations and future directions as shown by the chemical space of 299 internal exogenous analytes
Information on the effect of environmental stressors that cause a specific routinely targeted in large population biomonitoring studies in
disease or death will be available only when the total amount of tempo- blood or urine67.
rally and spatially resolved environmental exposures can be quantified. A big step forward was the development of the Exposome-
These assessments include continuous measurement of the concen- Explorer, an online database with 692 dietary and pollutant
trations of various environmental toxins in air, water and soil to quan- biomarkers listed with multiple information about blood
tify chemical pollution, sound pressure levels for noise, temperature concentrations and biological effects195. Another resource is
changes, and the intensity of UV radiation as well as repeated question- the toxic exposome database (T3DB), comprising >3,600 toxic
naires, ideally throughout the entire lifespan of the individual, to record compounds, >2,000 of their targets and >15,000 regulated genes196.
social status and mental stress conditions. Biological and biochemical Other databases of environmental toxins, metabolites and toxic
parameters should be assessed simultaneously to correlate changes chemicals have been summarized previously197.
caused by the exposure with subsequent changes in the organism.

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Review article

being estimated more precisely than another. In addition, statistical traffic in streets; decrease heat-island effects; and provide access to
power is often limited if many exposures are evaluated (such as with green space, active travel space, and safer walking and cycling environ-
omics data), owing to multiple testing corrections and because, ments10. Another powerful way to create a healthier exposome would
for most exposures, only low-to-moderate associations with the be to adhere to the new WHO air pollution guideline for PM2.5 levels,
outcome are expected. A statistical approach to effectively deal which was reduced to 5 µg/m3 in 2021, meaning that about 99% of all
with these issues might include using factor analysis techniques to people worldwide live in areas with PM2.5 concentrations higher than
detect intercorrelations between exposure variables and thus reduce those recommended by WHO. Of note, the EU limit of PM2.5 concentra-
dimensionality and increase clustering to a more limited number of tion of 25 µg/m3 is fivefold higher than the one recommended by WHO.
underlying collective groups of co-exposures. This approach can This difference in thresholds might be crucial when considering that
also be accompanied by deep machine learning and artificial intelli- data on the relationship between exposure levels and cardiovascular
gence-supported techniques to maximize prediction performance. events suggest no lower threshold limit, with studies demonstrating
Lastly, there will be many ethical and data protection issues because a strong relationship at levels below current regulatory limits76,168,169.
geographical tracking will be required for optimal exposure assess- However, there should be a reasonable compromise between popula-
ment, making the included individuals vitreous by archiving crucial tion health benefits, socioeconomic costs and individual restrictions
personal data on a server. by air pollution legislation.
Therefore, in general, exposome research delivers an exciting
Conclusions approach to understanding the extent to which the environment is
Determining the exposome is a promising approach to understanding associated with the initiation, progression and prognosis of cardiovas-
the complex relationships between environment, behaviour, biology, cular diseases, thereby delivering a framework to explain mechanisms
genetics and disease phenotypes at the population level. The need to and exposure pathways across the life course of the individual. We
study the exposome is becoming especially important in assessing conclude with a quote from Gary W. Miller from the Mailman School
the relationship between air pollution and cardiovascular disease, the of Public Health (Columbia University): “For years, the exposome has
leading NCD category responsible for global deaths20. In the future, been a non-descript, fuzzy, and, at times, a rather unscientific idea.
the limitations of exposome studies will be overcome by technological Today, we can say that the exposome represents a new science — a new
advances that enable us to handle big data, with a decrease in the costs way of approaching how the environment influences health. Truly a
of multiomics assays and bioinformatic analyses119. Nevertheless, we new discipline. As such, the field must establish and defend its identity,
still must solve many justified ethical concerns. If we can solve these develop its core principles (i.e., the constellation), and forge a path
issues, a global and complete exposome study or environment-wide forward ( journal, society, regular meetings, websites, etc.)”170.
association studies will help to identify the effect of specific expo-
sures on our health and thereby allow targeted prevention strategies Published online: 10 May 2023
to effectively mitigate the adverse health effects of environmental
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