Received: 14 November 2019 Revised: 13 December 2019 Accepted: 14 December 2019

DOI: 10.1002/jat.3940

REVIEW ARTICLE

Biomarkers of exposure, effect, and susceptibility in

occupational exposure to traffic-related air pollution: A review

Natália Brucker1,2 | Sabrina Nunes do Nascimento3,4 | Letícia Bernardini2 |

Mariele Feiffer Char~
ao5 | Solange Cristina Garcia3,4

1
Department of Physiology and Pharmacology,
Federal University of Santa Maria, Santa Abstract
Maria, RS, Brazil There is a well-recognized association between environmental air pollution exposure
2
Graduate Program in Pharmacology, Federal
and several human diseases. However, the relationship between diseases related to
University of Santa Maria, Santa Maria, RS,
Brazil occupational air pollution exposure on roads and high levels of traffic-related air pol-
3
Laboratory of Toxicology (LATOX), Federal lutants (TRAPs) is less substantiated. Biomarkers are essential tools in environmental
University of Rio Grande do Sul, Porto Alegre,
RS, Brazil and occupational toxicology, and studies on new biomarkers are increasingly relevant
4
Graduate Program in Pharmaceutical due to the need to determine early biomarkers to be assessed in exposure conditions.
Sciences, Federal University of Rio Grande do
This review aimed to investigate the main advances in the biomonitoring of subjects
Sul, Porto Alegre, RS, Brazil
5
Graduate Program on Toxicology and
occupationally exposed to air pollution, as well as to summarize the biomarkers of
Analytical Toxicology, University Feevale, exposure, effect, and susceptibility. Furthermore, we discuss how biomarkers could
Novo Hamburgo, RS, Brazil
be used to complement the current application of methods used to assess occupa-
Correspondence tional exposures to xenobiotics present in air pollution. The databases used in the
Natália Brucker, Federal University of Santa
Maria, Av. Roraima, 1000, Camobi, Zip Code:
preparation of this review were PubMed, Scopus, and Science Direct. Considering
97105-900. Santa Maria, RS, Brazil. the significant deleterious effects on health associated with chronic occupational
Email: natalia.brucker@ufsm.br
exposure to xenobiotics, this topic deserves attention. As it is difficult to avoid occu-
pational exposure to TRAPs, biomonitoring should be applied as a strategy to reduce
the toxic effects of workplace exposure.

KEYWORDS

biomonitoring, occupational toxicology, toxicity, workers, xenobiotics

1 | I N T RO DU CT I O N
Numerous epidemiological studies have shown that air pollution
exposure is associated with negative health impacts, such as increased
mortality and morbidity due to respiratory and cardiovascular diseases
and cancer (Bai & Sun, 2016; Brant et al., 2014; Hamanaka & Mutlu,
2018; Lawal, 2017; Münzel et al., 2018; Ribeiro et al., 2019; Takano
et al., 2019; Wellenius et al., 2012). Air pollution is a leading cause of
deaths, responsible for 3.7 million deaths worldwide in 2012 (WHO,
2016). Besides, the International Agency for Research on Cancer
(IARC) has classified outdoor air pollution (particularly particulate
matter [PM]) as a Group I carcinogen (IARC, 2013; Lawin et al., 2018).
Vehicle exhaust emissions are dynamic mixtures of hazardous
substances that contain exhaust gas compounds such as sulfur dioxide
(SO2), nitric dioxide (NO2), carbon monoxide (CO), ozone (O3), volatile
organic compounds (VOCs; eg, benzene, acetaldehyde, 1,3-butadiene,
and formaldehyde), and PM that arise from multiple sources (Arayasiri,
Mahidol, Navasumrit, Autrup, & Ruchirawat, 2010; Burgaz, Demircigil,
Karahalil, & Karakaya, 2002; DeMarini, 2013; Knibbs & Morawska,
2012). An important fraction of air pollution is PM of <2.5 μm (PM2.5),
which contains various chemicals adsorbed to their surface that act as
efficient carriers of other pollutants (Gany et al., 2017; Huang et al.,
2012). These particles can go through the nose and enter the lower
respiratory tract, causing serious health effects when inhaled. In this
context, the United States Environmental Protection Agency (EPA)
recommends PM2.5 levels be <5 μg/m3 in the 24-h National Ambient
Air Quality Standard (NAAQS) and the WHO air quality guideline pro-
poses levels of <25 μg/m3. Moreover, the WHO has set up an Air

J Appl Toxicol. 2020;1–15. wileyonlinelibrary.com/journal/jat © 2020 John Wiley & Sons, Ltd. 1
2 BRUCKER ET AL.
Quality Guideline suggesting that annual average PM2.5 exposure
should not be >10 μg/m3 (WHO, 2016).
Today, air quality is one of the most studied themes and is
highlighted due to the deleterious effects of pollution on human
health. A recent study in China suggested that long-term exposure to
a 10 μg/m3 increase in airborne PM is associated with a 0.64-year
decrease in life expectancy (95% CI = 0.21–1.07) (Ebenstein, Fan,
Greenstone, He, & Zhou, 2017). However, there are few studies
referring to air pollution as a risk factor for diseases in urban workers
with a long-term occupational exposure to traffic-related air pollut-
ants (TRAPs). Moreover, exposures may depend on multiple factors,
including the chemical composition of the air pollutants, associated
co-pollutants, and individual susceptibility (Kleeberger, 2003; Lawin et
al., 2018; Münzel et al., 2018).
Individuals that work outdoors are exposed to different environ-
ments containing pollutants, particularly at chronic low-dose levels.
In general, these subjects engage in shift work, work long hours,
and are exposed to loud noise on urban streets (Belloc-Santaliestra,
van der Haar, & Molinero-Ruiz, 2015; Shin et al., 2013). Drivers of
cars, motorcycles, and buses in urban areas are commonly exposed
to ambient air pollution in their work (Bagryantseva et al., 2010;
Huang et al., 2012; Knibbs & Morawska, 2012; Lawin et al., 2016).
These professionals represent an important part of the labor force
in urban areas, especially in low- and middle-income countries
(Lawin et al., 2018). However, few studies are available on bio-
monitoring for the assessment of health effects related to exposure
to traffic emissions on populations exposed to urban hazard pollut-
ants in the workplace.
Biological monitoring studies are important to assess occupational
risk factors associated with exposure to environmental pollutants
(Angerer, Ewers, & Wilhelm, 2007; DeBord et al., 2015; Manno et al.,
2010; Schulte & Hauser, 2012). In this context, the present review
provides an overview of the most important advances in the bio-
monitoring of subjects occupationally exposed to air pollution, as well
as a summary of the biomarkers available for evaluating this exposure
in terms of human health effects.
For this review, a search was carried out for manuscripts written
in English using the PubMed, Scopus, and Science Direct databases.
Articles were accessed using the following search criteria: (“bio-
monitoring” OR “occupational toxicology” OR “occupational exposure”
OR “workers” OR “air pollution” OR “biomarkers” OR “biomonitoring”
OR “environmental monitoring” OR “particulate matter” OR “xenobi-
otics” OR “traffic-related air pollutants”) AND (“exposure” OR “effect”
OR “susceptibility” OR “genotoxicity” OR “oxidative stress” OR
“inflammation” OR “epigenetics” OR “polymorphisms”). Only manu-
scripts published in the last 20 years, full-text, and studies conducted
with humans were sought. A total of 244 164 records were identified
through database searching. In addition, articles were eligible for
inclusion if their aim was to study biomarkers for assessing health in
workers exposed to air pollution, except biomarkers of susceptibility
because there are few studies involving this aspect that evaluate
occupational exposure. Ultimately, 114 articles were included in the
review considering the selection criteria.
2 | OCCUPATIONAL EXPOSURE TO
T R A F F I C - R E L A T E D A I R P O L LU T I O N A N D
HE A L T H E F F E C T S
Urban areas are usually characterized by an elevated rate of air pollu-
tion through PM emitted by cars burning fossil fuel or during abrasion
processes of vehicle tires and brakes (Dröge, Müller, Scutaru, Braun, &
Groneberg, 2018; Ebenstein et al., 2017). Toxicological studies
indicate that urban traffic-related air pollution contains several com-
pounds, eg, metals and polycyclic aromatic hydrocarbons (PAHs),
which are adsorbed to the PM2.5 surfaces (HEI, 2010; Huang et al.,
2012; Ma et al., 2015). To monitor air quality, usually particle fractions
are assessed (Dröge et al., 2018). However, regardless of the particu-
late mass concentration, the composition and potential toxicity of PM
may differ greatly, depending on the origins (Ndong Ba et al., 2019).
Apart from being pollutants, these particles act as a vehicle for the
dissemination of other chemical compounds. Thus, occupational expo-
sure to air pollution rarely occurs in an isolated manner.
Outdoor air pollution can vary in time and space, and the concen-
tration of toxic agents and their physical–chemical characteristics may
influence the absorption of xenobiotics through inhalation (Dröge
et al., 2018; Ndong Ba et al., 2019). Studies reported in the litera-
ture explain that in-vehicle PM levels are often high when com-
pared to outdoor/indoor microenvironments. Gany et al. (2017)
assessed PM2.5 and black carbon levels in New York City taxi cabs
and at roadside taxi stands. This study found that taxi drivers’ in-
cab PM2.5 and black carbon levels were higher than levels found at
central site ambient air monitors. The authors suggested that air
pollution exposure among drivers likely exceeds the EPA recom-
mendation and, in general, the taxi drivers are unaware of the risks
of occupational exposures and the EPA recommendation. Yu et al.
(2017) measured fine PM (PM2.5) and ultrafine particle concentra-
tions inside and outside 17 taxis simultaneously, while they were
being driven on roadways. The authors observed that keeping win-
dows closed and the use of high-efficiency cabin air filters poten-
tially reduce PM2.5 and ultrafine particle levels inside taxis and
could protect drivers’ health.
The general population is also exposed to environmental pollut-
ants. However, individuals who remain chronically exposed for several
hours daily are more vulnerable to developing exposure-related
toxicological effects (Gany et al., 2017; Lawin et al., 2016).
Air pollution causes harmful effects on humans, leading to both
acute and chronic diseases (Feretti et al., 2019). The acute health
effects of short-term air pollution episodes appear to be small when
compared to the effects of prolonged/chronic exposure to similar
concentrations of air pollution. In other words, chronic exposure and
longer average periods of exposure to pollution are more relevant
than rare peak episodes. However, the analysis of the health effects
of temporal variations in pollution concentrations is important, as it
supports the causal interpretation of epidemiologic findings in cohort
studies (Moshammer et al., 2019). Environmental exposures to
contaminants represent a health risk for categories of workers under
frequent and prolonged exposure to vehicular emissions. Taxi drivers,
BRUCKER ET AL.
mail carriers, bus drivers, motorcyclists, trucking industry workers,
traffic controllers, traffic police officers, toll station workers, and other
vulnerable populations in urban settings are the most affected
(Arayasiri et al., 2010; Bagryantseva et al., 2010; Barth et al., 2017;
Brucker et al., 2013; Carvalho et al., 2018; Chiu et al., 2016; Hansen
et al., 2004; Huang et al., 2012; Kamal, Cincinelli, Martellini, & Malik,
2016; Li et al., 2014). Furthermore, some outdoor occupations have a
manual work component, meaning a higher than resting ventilation
rate, and probably translating into a greater dose of air pollutants
(Madureira, Brancher, Costa, Aurino de Pinho, & Teixeira, 2019).
Unlike other worker categories that perform their functions in rela-
tively comfortable and air-conditioned environments, these workers
spend hours in traffic and are exposed to climatic variations, traffic
conditions, noise, and psychosocial factors (Gany et al., 2017).
The toxic effects observed after exposure to airborne xenobiotics
could be linked to their biotransformation processes. These may pro-
mote the formation of reactive metabolites and the generation of
reactive species of oxygen and nitrogen, subsequently leading to
damaged cellular components, chronic inflammation, tumorigenesis,
autoimmune diseases, and other disease processes in the human body
(Barth et al., 2017; Brucker et al., 2013; Carvalho et al., 2018; Ma et
al., 2015; Tan et al., 2017; Zhao et al., 2013; Zheng et al., 2017). More-
over, individual characteristics such as age, gender, ethnicity, genetic
susceptibility, nutritional status, and chronic diseases should be con-
sidered because they could interfere with the severity of the toxic
effects caused by the pollutants present in the work environment
(Brucker et al., 2014; Manno et al., 2010; Yang et al., 2018).
Estévez-García, Rojas-Roa, and Rodríguez-Pulido (2013) showed
in an epidemiologic study that traffic-police officers exposed to air
pollution (n = 477) had an increased risk of developing respiratory
symptoms and signs even when the PM levels did not exceed
allowable limits for respirable particles in the workplace according
to the Association Advancing Occupational and Environmental
Health (ACGIH) standards. In contrast, Brant et al. (2014) showed
in a study with male non-smoking motorcyclists that mucociliary
clearance was decreased in 32% of the motorcyclists and 64% of
them had airway acidification, evaluated through the pH of exhaled
breath condensate, when compared with healthy adult males. San-
tos et al. (2005) showed that air pollutants might affect the cardio-
vascular system, including changes in blood pressure and heart rate
variability, in a group of non-smoking vehicular traffic controllers in
S~ao Paulo, Brazil. These symptoms could be related with exposure
to air pollution. According to Morishita et al. (2019), the effects of
combustion-derived TRAP constituents can acutely affect aortic
hemodynamics in terms of a worse cardiovascular disease
prognosis.
Additionally, cross-sectional studies have shown a positive associ-
ation between estimated long-term exposure to PM2.5 and the sub-
clinical atherosclerosis process, using carotid intima–media thickness
(CIMT), a marker of subclinical atherosclerosis. Thus, supporting the
hypothesis that chronic exposure to TRAPs influences the develop-
ment of atherosclerosis and increases the risk of coronary artery
disease (Provost, Madhloum, Int Panis, De Boever, & Nawrot, 2015).
3
However, few studies have reported this association in urban workers
with occupational exposure to xenobiotics. Brucker et al. (2014)
evaluated the possible effects of occupational exposure to air pollu-
tion on the atherosclerotic process in taxi drivers with and without
co-morbidities using CIMT measurement. The results showed that
15% of the taxi drivers without co-morbidity presented a CIMT above
the normal range, which was unexplained by the traditional risk
factors assessed in the study.
It has been established that chronic exposure to vehicular
exhausts is associated with the risk of developing respiratory prob-
lems, cardiovascular issues, infectious diseases, and cancer (Brant et
al., 2014; Estévez-García et al., 2013; Ribeiro et al., 2019). Unlike in
other studies, Torricelli et al. (2013) evaluated the Ocular Surface
Disease Index (OSDI) and conjunctival impression cytology in male
taxi drivers and traffic controllers, and found that exposure to ambient
levels of air pollution affects conjunctival goblet cell density. Previous
studies have also reported air pollution-related ocular surface
abnormalities, assessed using the Schirmer tear film break-up test
(Jung, Mehta, & Tong, 2018; Torricelli et al., 2013; Torricelli, Novaes,
Matsuda, Alves, & Monteiro, 2011).
In a recent systematic review, Dimakakou, Johnston, Streftaris,
and Cherrie (2018) highlighted the studies that investigated air
pollution as a contributor to diabetes mellitus and neurodegenerative
disease. However, there was little evidence demonstrating these
effects for workplace exposures and further research is needed to
identify the possible mechanism in occupational groups.
3 | E N V I R O N M E N T A L M O N I T O R I N G OF
EX POSURE TO AIR P OLLUTION
Environmental monitoring is applied based on the time that the
individual remains in the workplace; however, although it is relevant
to estimate the concentration of xenobiotics in the environment, it is
known that each worker is not in the same exposure condition
throughout the day (Koehler & Peters, 2015; Mostafavi et al., 2018;
Santos et al., 2016). Sometimes, studies have evaluated only station-
ary monitoring of environmental pollutants, which estimates the
concentration in a studied area, but these exposures may not be
representative of the personal exposure of the subjects. In order to
establish a better correlation with individual exposure, Santos et al.
(2016) assessed exposure to traffic-generated PM2.5 using personal
monitors on outdoor workers. The use of personal monitors seems to
be more appropriate than fixed stations for assessing daily exposure,
because it takes into account workers’ outdoor and indoor exposure
times (Mostafavi et al., 2018; Santos et al., 2016).
Furthermore, exposure assessment has been conducted by air
pollution stations, sampling pumps, and filter samplers, as it is difficult
to establish only one exposure biomarker to assess exposure to the
xenobiotic mixture present in TRAPs. Although environmental moni-
toring is valuable, the main disadvantage is its inability to reflect the
internal dose associated with personal factors (Hachesu et al., 2019;
Li et al., 2014). In this context, the application of biomonitoring has
4 BRUCKER ET AL.
several advantages over monitoring environmental air pollutants, as it
is possible to assess the uptake by an organism, taking into account
the human metabolism (Manno et al., 2010; Vilas Boas et al., 2018).
4 | BIOMARKERS THAT REPRESENT THE
EFFECTS I NDU CED BY AIR P OLLU TION
Biomarkers used in occupational human health monitoring are divided
into three classes: biomarkers of exposure, effect, and susceptibility
(DeBord et al., 2015; Lionetto, Caricato, Calisi, Giordano, & Schettino,
2013; Nordberg, 2010). Biomonitoring implies the assessment of
internal exposure to hazardous substances by measuring the
chemicals, their metabolites, or reaction products in human blood,
urine, saliva, sputum, and exhaled breath condensate (Schulte &
Hauser, 2012; DeMarini, 2013; Michalke, Rossbach, Göen,
Schäferhenrich, & Scherer, 2015), these being biomarkers of exposure.
Although biomarkers of exposure give significant information about
the interaction of pollutants with exposed workers, it is also important
to evaluate the levels of biomarkers that represent the possible
effects induced by TRAPs (DeBord et al., 2015; Hachesu et al., 2019;
Haines, Saravanabhavan, Werry, & Khoury, 2017). In addition, infor-
mation regarding personal characteristics, health status, and lifestyle
(smoking habits, passive smoking, alcohol consumption, dietary inges-
tion, sedentary lifestyle, clinical events, among others), and informa-
tion concerning the work (eg, number of years of service, number of
working hours per day, number of working days per week, use of indi-
vidual safety equipment) are important in occupational studies.
Biomonitoring to assess exposure to chemicals in the workplace
is a valuable tool to indicate the need for preventive actions to protect
workers’ health, as well as being useful for assessing adequacy and
improving protective measures, thus reducing toxic effects and
preventing the development of diseases related to these exposures. In
addition, emerging technologies in molecular biology (genomics/pro-
teomics, nanotechnology, etc) can provide greater knowledge regard-
ing environment/gene interactions and be useful in the discovery of
precocious effect biomarkers, which can be integrated with traditional
biomonitoring data to enhance the interpretation of data (Albertini et
al., 2006; Haines et al., 2017; Nordberg, 2010; WHO, 2004).
4.1 | Biomarkers of exposure to air pollution
Biomarkers of exposure are considered an important tool, as they
estimate the levels at which chemical substances are absorbed by
quantifying the toxic substances or metabolites in biological sam-
ples (Angerer et al., 2007; Haines et al., 2017). Urine and blood
samples are considered reliable, reflecting recent body burden, and
have been used to establish limit values for human biomonitoring
parameters such as biological exposure indices (Haines et al., 2017;
Michalke et al., 2015). Table 1 summarizes the main biomarkers of
exposure used to study subjects occupationally exposed to air
pollution.
Recently, Hachesu et al. (2019) demonstrated the use of phagocy-
tized carbon load in airway macrophages, obtained via sputum induc-
tion, as a biomarker of internal PM in the human body, most likely
from inhalation and relatively recently. As TRAPs contain several com-
pounds such as PAHs, VOCs, and metals, different biomarkers could
be used to assess exposure to each of the xenobiotics.
Among the different biomarkers of exposure used in occupational
studies, the quantification of urinary 1-hydroxypyrene (1-OHP), the
main metabolite of pyrene, is most frequently used for estimating
overall exposure to PAHs present in environmental pollution
(Castaño-Vinyals, D'Errico, Malats, & Kogevinas, 2004; Kamal et al.,
2016; Ciarrocca et al. (2014) showed in a meta-analysis study of out-
door workers that 1-OHP is a suitable biomarker of exposure to urban
pollution PAHs, and this biomarker has been extensively used in stud-
ies in this area. However, the excretion of 1-OHP in urine can be sig-
nificantly influenced by lifestyle and reflects PAH exposure from diet
and air, among others (Castaño-Vinyals et al., 2004; Ciarrocca et al.,
2014; Kamal et al., 2016). In another study carried out by Kamal et al.
(2016), the biomarkers α- and β-naphthol were assessed, in addition
to 1-OHP, as these biomarkers could reflect route-specific exposure
to inhalable PAHs and they are representative of exposure to low
levels of PAHs.
The biomarker of exposure assessed in the study by Yu et al.
(2017) was also 1-OHP in urine. The median 1-OHP levels in the taxi
drivers group were ~125% higher than the general USA population
median according to the National Health and Nutrition Examination
Survey (NHANES), but were lower than those in taxi drivers or other
occupational groups in Thailand, China, and Brazil (Barth et al., 2017;
Chetiyanukornkul, Toriba, Kameda, Tang, & Hayakawa, 2006; Yamano
et al., 2014).
Additionally, these workers are also exposed to VOCs in the
environment (Belloc-Santaliestra et al., 2015), and so biomarkers of
exposure to these pollutants could be evaluated. Occupational
exposure to VOCs could be assessed through the levels of urinary
biomarkers. Among VOCs, the most important one to assess in out-
door workers is benzene. Thus, as they are representative of the met-
abolic transformation of benzene, the levels of S-phenylmercapturic
acid (S-PMA), trans-trans muconic acid (t,t-MA), and catechol can be
quantified (Arayasiri et al., 2010; Ciarrocca et al., 2012; Ndong Ba et
al., 2019). Arayasiri et al. (2010) and Ciarrocca et al. (2012) assessed
the urinary biomarkers S-PMA and t,t-MA in traffic police officers and
found that the levels were significantly higher in traffic police officers
when compared with office-based police officers.
Furthermore, individuals that work at outdoor sites may also be
exposed to toxic metals present in the environment through inhala-
tion of air pollution. Thus, in biomonitoring studies, the levels of
metals in biological samples (blood, urine, nail, and hair) could be
assessed (Brucker et al., 2015; Carvalho et al., 2018). However, as
metals are ubiquitous and remain in the environment for long periods,
human exposure to metals can derive from different sources. In this
context, contaminated foods, water, and/or soil should also be consid-
ered as possible sources of exposure to these pollutants. The possible
source of exposure could be approximated based on the kinetics and
BRUCKER ET AL. 5

TABLE 1 Biomarkers of exposure used in studies that assesses subjects occupationally exposed to air pollution

Biological
Study population (N) Location Biomarker of exposure sample Results Reference
Bus drivers (30) Copenhagen, 1-OH Urine " 1-OHP Autrup et al. (1999)
Denmark
Traffic policemen (15) Ankara, Turkey 1-OH Urine " 1-OHP Burgaz et al. (2002)
Bus drivers (117) Copenhagen, 1-OH Urine " 1-OHP Hansen et al. (2004)
Denmark
Traffic policemen (10) Bangkok, 1-OH Urine " 1-OHP Chetiyanukornkul
Thailand et al. (2006)
Taxi drivers (95) Taipei, Taiwan 1-OH Urine " 1-OHP Chuang and Chang
(2007)
Traffic policemen (24) Bangkok, Benzene t,t-MA, S-PMA Blood urine " benzene blood Arayasiri et al. (2010)
Thailand and monohydroxy-butenyl t,t-MA
mercapturic acid
Bus drivers (100) Bangkok, 1-OH Urine " 1-OHP Petchpoung et al. (2011)
Thailand
Traffic policemen (62), Rome, Italy Benzene t,t-MA; S-PMA Blood urine " benzene blood, Ciarroca et al. (2012)
police drivers (22) t,t-MA and S-PMA
and roadmen (57)
Traffic conductors (91) Taipei City, 1-OHP Urine " 1-OHP Huang et al. (2012)
Taiwan
Taxi drivers (58) Porto Alegre, 1-OHP Urine " 1-OHP Brucker et al. (2013)
Brazil
Traffic policemen (110) Shanghai,China 1-OHP and BPDE-DNA Urine " 1-OHP, BPDE Li et al. (2014)
adducts
Taxi drivers (42) Porto Alegre, Trace elements Blood " Pb, Hg, As Brucker et al. (2015)
Brazil (Pb, Cd, Hg, As)
Taxi drivers (45) Porto Alegre, 1-OHP Urine " 1-OHP Barth et al. (2017)
Brazil
Traffic police officer Rawalpindi, 1-OHP, α- and β-naphthol Urine " 1-OHP, α-naph, Kamal et al. (2016)
(45) and drivers (50) Pakistan β-naph
Motorcyclists (44) Porto Alegre, Trace elements (Sb, Pt, As, Cd, Fingernail " Sb, Pt, As, Cd, Carvalho et al. (2018)
Brazil V, Mn, Co, Cr, Pb, Ni) V, Mn, Co
Bus drivers (27) and Dakar, Africa 1-OHP, t,t-MA; S-PMA Urine " 1-OHP, t,t-MA; Ndong Ba et al. (2019)
traders (30) S-PMA

Abbreviations: 1-OHP, 1-Hydroxypyrene; BPDE, benzo[a]pyrene 7,8-diol-9,10-epoxide; Pb, lead; Cd, cadmium; Hg, mercury, As, arsenic; Sb, antimony; Pt,
platinum; V, vanadium; Mn, manganese; Co, cobalt; Cr, chromium; Ni, nickel; t,t-MA, trans-trans muconic acid; S-PMA, S-phenyl-mercapturic acid.

site of the sampling (Chowdhury, Mazumder, Al-Attas, & Husain,
2016; Rehman, Fatima, Waheed, & Akash, 2018).
4.2 | Biomarkers of effect to air pollution
Biomarkers of effect are biological parameters that reflect the interac-
tion between xenobiotics and cellular, biochemical or molecular
targets. The quantification of these biomarkers could indicate the
early, reversible, or non-reversible modifications that precede progres-
sive structural or functional damage on the molecular and cellular
levels, and their application could contribute to better protect
workers’ health (Arayasiri et al., 2010; Schulte & Hauser, 2012; Zhao
et al., 2013). Among these biomarkers, the studies of occupational
exposures to air pollution have evaluated biomarkers related to
oxidative stress, the inflammation process, and genotoxicity (Chiu et
al., 2016; Göethel et al., 2014; Yang et al., 2018). Considering the
number of biomarkers of effect that can be investigated in research
on occupational exposures to air pollution, some biomarkers are
summarized in Table 2 and discussed in the following subsections.
The biomarkers of effect evaluated in these studies are generally
related to the toxic mechanisms involved in the inhalation of particu-
lates and gases. Fine airborne particles and gases are most likely to
easily enter the respiratory system upon exposure, leading to reactive
oxygen species (ROS) production and consequently macromolecule
damage, as well as activation of inflammatory mediators capable of
exacerbating lung pulmonary inflammation, the induction of increased
blood coagulability, and endothelial dysfunction (Baccarelli & Bollati,
2009; Delfino, Staimer, & Vaziri, 2011; Lawal, 2017; Niranjan &
Thakur, 2017).
6 BRUCKER ET AL.

TABLE 2 Summary of key studies on biomarkers of effect in subjects occupationally exposed to air pollution

Study population (N) Biomarkers of effect Biological sample Results Reference

Male non-smoker traffic 8-OHdG, DNA-strand breaks Blood " 8-OHdG and DNA-strand Arayasiri et al. (2010)
policemen (24) from and DNA-repair capacity breaks
Bangkok, Thailand # DNA-repair capacity
Male non-smoker bus 8-OHdG PCO, Comet assay Urine blood " 8-OHdG, PCO Bagryantseva et al.
drivers (50) and garage (2010)
men (20) from Prague,
Czech Republic
Male bus drivers (120) 8-OHdG Urine " 8-OHdG Han et al. (2010)
from Taiwan, China
Traffic conductors (91) 8-OHdG DNA strand breaks Urine blood " 8-OHdG Huang et al. (2012)
from Taipei City, " DNA strand breaks
Taiwan
Male non-smoker taxi MDA, PCO, CAT, GSH-Px, Blood " MDA, PCO, hs-CRP, Brucker et al. (2013)
drivers (29) from Porto GST, hs-CRP, IL-1β, IL-6, IL-1β, IL-6, TNF-α, IFN-γ,
Alegre, Brazil IL-10, TNF-α, IFN-γ, ox-LDL, ox-LDL-Ab, Hcy
ox-LDL, ox-LDL-Ab, Hcy, #CAT, GST, GSH-Px, IL-10
Fibrinogen
Male non-smoker traffic 8-OHdG Urine " 8-OHdG Prasad et al. (2013)
policemen (148) from
Hyderabad, India
Male non-smokers traffic hs-CRP, IgA, IgM, IgG, IgE, Blood " hs-CRP, IgM, IgG, IgE, Zhao et al. (2013)
policemen (110) from CD4, CD8 CD4
Shanghai, China # IgA, CD8
Male non-smoker airway pH Exhaled breath " airway acidification Brant et al. (2014)
motorcyclists (25) from condensate
Minas Gerais, Brazil
Male non-smoker taxi 8-OHdG Urine " 8-OHdG, % tail DNA Göethel et al. (2014)
drivers (34) from Porto MN, Comet assay Blood
Alegre, Brazil
Male non-smoker taxi Chromosome breakage Blood " chromosome aberration Taghizadeh et al.
drivers (30) from (2014)
Tehran, Iran
Male traffic police CAT, GSH, GPx Blood " GSH, GSHPx, CAT Kamal et al. (2015)
workers (15),
shopkeepers (15) and
rickshaw drivers (15)
from Lahore, Pakistan
Male non-smokers traffic Comet assay Blood " % tail DNA Ma et al. (2015)
policemen (16) from
Shenyang, China
Male non-smoker traffic Hematological, hs-CRP Blood " 8-OHdG Alteration Kamal et al. (2016)
police officer (45) and 8-OHdG Urine hematological
drivers (50) from
Rawalpindi, Pakistan
Male non-smoker taxi MDA, ICAM-1, NTPDase, Blood " ICAM-1, NTPDase, IL-1β, Barth et al. (2017)
drivers (45) from Porto IL-1β, IL-6, IL-10, TNF-α, Buccal mucosa IL-6, IL-10, TNF-α, IFN-γ
Alegre, Brazil IFN-γ comet assay MN epithelial cells " % tail DNA and MN
Male traffic policemen MDA, GSH, 8-OHdG hs-CRP, Blood " GSH, 8-OHdG, MN, % Tan et al. (2017)
(183) from Changsha IL-8, TNF-α, MN, Comet tail DNA
City, China assay
Truck drivers (60) from Global histone H3 Blood PM10 was negatively Zheng et al. (2017)
Beijing, China modifications associated with H3
changes
(Continues)
BRUCKER ET AL. 7

TABLE 2 (Continued)

Study population (N) Biomarkers of effect Biological sample Results Reference

Male motorcyclists (44) MDA, SOD, CAT Plasma " SOD, CAT, MDA, MN Carvalho et al. (2018)
from Porto Alegre, MN Buccal mucosa
Brazil epithelial cell
Male non-smoker traffic MN Buccal mucosa " MN Vilas Boas et al.
controllers (18) and epithelial cells (2018)
taxi drivers (21) from Blood
S~ao Paulo, Brazil
Male taxi drivers (104) Airway macrophages Sputum Negative correlation Hachesu et al. (2019)
from Yazd, Iran Comet assay Blood between carbon load
with comet assay
Bus drivers (27), traders 8-OHdG Urine " 8-OHdG; TNF-α, IL-1β, Ndong et al. (2019)
(30) from Dakar, Africa TNF-α, IL-1β, IL-6, IL-8 Blood IL-6, IL-8

Abbreviations: MDA, malondialdehyde; SOD, superoxide dismutase; CAT, catalase; PCO, protein carbonyl; MN, micronucleus; 8-OHdG,
8-hydroxydeoxyguanosine; hs-CRP, high-sensitivity C-reactive protein; GSH, glutathione; GSH-Px, glutathione peroxidase; GST, glutathione S-transferase;
CC16, Clara cell protein 16; ox-LDL, oxidized low-density lipoprotein; ox-LDL-Ab, auto-antibodies oxidised LDL; Hcy, homocysteine; SAA, serum amyloid
A; IL, interleukin; ICAM-1, intracellular adhesion molecule; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ; PM10: particulate matter <10 μm in
diameter.

4.2.1 | Oxidative stress biomarkers 4.2.2 | Inflammation biomarkers

Occupational exposure to air pollution induces oxidative damage,
which results from the unavailability of neutralizing antioxidant
defenses (Carvalho et al., 2018; Pradhan, Das, Meena, Nanda, &
Rajamani, 2016). Previous studies have reported increased levels of
malondialdehyde (MDA) and protein carbonyls (PCO) in the plasma of
occupationally exposed taxi drivers, bus drivers, and motorcyclists
(Bagryantseva et al., 2010; Barth et al., 2017; Brucker et al., 2013;
Carvalho et al., 2018; Petchpoung, Kaojarern, Yoovathaworn, Sura, &
Sirivarasai, 2011). Inhalation of fine PM of TRAPs promotes lipid
peroxidation by stimulating alveolar macrophages, leading to ROS
formation, which depletes antioxidant defenses (Carvalho et al., 2018;
Delfino et al., 2011; Lawal, 2017; Niranjan & Thakur, 2017; Rao,
Zhong, Brook, & Rajagopalan, 2018).
Several studies of occupationally exposed groups have shown
distinct patterns regarding antioxidant defenses. The analysis of eryth-
rocytes from subjects occupationally exposed to air pollutants showed
a decrease in catalase (CAT) and superoxide dismutase (SOD) activity
(Brucker et al., 2013), and glutathione (GSH) levels (Tan et al., 2017),
when compared to non-occupationally exposed subjects. Carvalho et
al. (2018) and Kamal, Qamar, Gulfraz, Anwar, and Malik (2015)
reported contrasting findings, which demonstrated elevated antioxi-
dants (CAT and SOD enzymatic activities) in professional motorcy-
clists and traffic police officers, respectively. These findings lead to
the hypothesis of the development of different adaptive responses to
occupational air pollution exposure, probably due to the different
levels of damage caused by free radicals, leading to oxidative stress
damage (Carvalho et al., 2018; Kamal et al., 2015). Besides chronic
exposure and the presence of additional pre-disposing factors, the
changes of endogenous molecules may overwhelm endogenous
defenses (Münzel et al., 2018).
Increased levels of reactive species of oxygen and nitrogen could
activate several signaling mechanisms such as mitogen-activated pro-
tein kinases, the antioxidant responsive element and nuclear factor κβ
(NF-κβ) cascade (Shukla et al., 2019; Wang et al., 2017). Bhargava et
al. (2018) reported that inhalation of PM initiated oxidative stress
through translocation from the lungs into the vascular tree, inducing
the release of pro-inflammatory mediators and the activation of
phosphatidylinositol 3-kinase pathways. Niranjan and Thakur (2017)
demonstrated that high levels of pollution exposure might have
systemic toxic effects, inducing the inflammatory response, including
the expression of the NF-κβ related to inflammation, and cytokines
gene expression.
Zhao et al. (2013) evaluated the inflammatory markers high-
sensitivity C-reactive protein (hs-CRP), immunoglobulins (IgA, IgG,
IgM, and IgE), and lymphocyte profiles (CD4 T cells, CD8 T cells) in
110 traffic police officers. The results showed that an increase in
PM2.5 was associated with increased hs-CRP, IgM, IgG, and IgE and
decreased CD8 and IgA levels. Considering the potential role of these
biomarkers in assessing atherosclerotic disease, these results provide
an association between PM2.5 exposure and the development and
progression of cardiovascular disease. Moreover, studies conducted
with taxi drivers have shown that these workers had high levels of
pro-inflammatory biomarkers, such as hs-CRP, interleukin 1β (IL-1β),
IL-6, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ).
Increased cytokine production could be attributed to the inflamma-
tory process induced in response to major exposure to pollutants
(Barth et al., 2017; Brucker et al., 2013; Gauer et al., 2018).
Air pollution exposure and the inflammatory process could be
responsible for vasoconstriction and endothelial dysfunction, leading
to autonomic imbalance of the nervous system (Barth et al., 2017;
8 BRUCKER ET AL.
Wang, Xiong, & Tang, 2017). Endothelial impairment appears to be
critically important in transducing signals and eventually promoting
cardiovascular disorders such as diabetes, hypertension, and athero-
sclerosis (Münzel et al., 2018). Chiu et al. (2016) and Barth et al.
(2017) demonstrated the relationship between vehicle-related air
pollutant levels in the workplace and intercellular adhesion
molecule-1 (ICAM-1) in trucking industry workers and taxi drivers,
respectively.
ICAM-1 is expressed mainly on endothelial cells under the stimu-
lation of pro-inflammatory cytokines and is a good predictor of cardio-
vascular risk. In the study of Barth et al. (2017), positive associations
were seen between environmental exposure to air pollution, assessed
by the urinary 1-OH biomarker, and an increase of the percentage of
neutrophils expressing ICAM-1 and nucleoside triphosphate
diphosphohydrolase (NTPDase) activity in the platelets of taxi drivers.
In addition, the inflammatory process seen in these workers was con-
tributing to DNA damage.
4.2.3 | Genotoxicity biomarkers
Genotoxic effects such as oxidized bases, DNA breaks, mutations,
deletions, and aneuploidy could be generated by pollutants or their
metabolites interacting with DNA. Genome instability is related to the
development of cancer (Barth et al., 2017; Knudsen et al., 1999;
Ribeiro et al., 2019; Tan et al., 2017). Biomonitoring studies have
reported DNA single-strand breaks (using comet assay), frequencies
of chromosomal aberrations, frequency of micronucleus (MN) test,
and sister chromatid exchanges as consequences of xenobiotic
exposure (Taghizadeh, Najmabadi, Kamali, & Behjati, 2014; Vilas Boas
et al., 2018).
Vilas Boas et al. (2018) assessed genotoxic effects using the buc-
cal MN cytome and cytokinesis-block MN cytome in traffic controllers
(n = 18) and taxi drivers (n = 21), who were exposed to air pollution
(PM2.5 and NO2) in the city of S~
ao Paulo, Brazil. The MN frequencies
were positively correlated with PM2.5 levels. In addition, Huang et al.
(2012) related the occurrence of DNA strand breaks in 91 traffic
conductors, evidencing that exposure to fine particles causes DNA
damage. Other studies of professional motorcyclists and taxi drivers
have indicated that occupational exposure to air pollution significantly
increased the frequency of MN in cells (Barth et al., 2017; Carvalho et
al., 2018; Göethel et al., 2014; Huang et al., 2012). More recently, a
study on taxi drivers in Iran showed a correlation between comet
assay parameters (tail intensity, tail length, tail DNA percentage, and
tail moment) and carbon load in airway macrophages. In this study,
the authors measured carbon load in the airway macrophages only
among non-smoker taxi drivers in order to ensure that it was only
attributed to air pollution. These findings are related to long-term
exposure to vehicular emissions, which contain carcinogen substances
(Hachesu et al., 2019).
In the study by Kamal et al. (2016), the biomarkers of effects
assessed were hematological parameters, C-reactive protein (CRP),
and urinary 8-hydroxydeoxyguanosine (8-OHdG). This study suggests
that traffic pollution may be associated with important health risks, as
a strong association was seen between 8-OHdG levels and bio-
markers of exposure to PAHs present in air pollution. 8-OHdG is a
product formed through an oxidative process of the DNA base
guanine (Han, Donovan, & Sung, 2010; Prasad et al., 2013). Several
studies have found that urinary levels of the 8-OHdG biomarker
increased significantly in workers exposed to air pollution and
sometimes exhibited a dose-related association with cumulative time
working outdoors (Göethel et al., 2014; Huang et al., 2012; Kamal et
al., 2016; Tan et al., 2017). Indeed, DNA damage may lead to muta-
genic processes. In this context, the MN test could also be evaluated,
as it is a good tool to assess mutagenicity in exposed groups (Bonassi,
Milic, & Neri, 2016; Vilas Boas et al., 2018).
MN frequency in peripheral blood lymphocytes or buccal mucosa
epithelial cells is a biomarker used to evaluate the amount of DNA
damage in humans after exposure to genotoxic agents and for
predicting cancer risk (Barth et al., 2017; Bonassi et al., 2016; Vilas
Boas et al., 2018). The comet assay measures the DNA damage that
can be repaired, and the results from this assay and MN frequency do
not necessarily correlate (Bonassi et al., 2016; Göethel et al., 2014).
Tan et al. (2017) evaluated DNA damage biomarkers such as 8-OHdG,
MN frequency, and tail DNA (comet assay). These biomarkers showed
a significant positive correlation with exposure time in traffic police
officers. Moreover, there is evidence that environmental stressors
initiate genetic effects (eg, epigenetic or microRNA [miRNA]),
changing signaling cascades and leading to an imbalance between
ROS production and detoxification (Münzel et al., 2018).
4.2.4 | Epigenetic changes
Epigenetic features are increasingly considered sensitive to environ-
mental exposures, and therefore could serve as an important bio-
marker for exposure effects, as they may explain the chronic effects
of xenobiotics exposure and the predisposition to several diseases
(Sanchez-Guerra et al., 2015; Shukla et al., 2019). Epigenetic modifica-
tions are flexible genomic parameters that can change genome
function under exogenous influences. To date, epigenetic changes
include DNA methylation, histone modifications, and miRNAs that
affect post-transcriptional regulation, without changes to nucleotide
sequences (Baccarelli & Bollati, 2009). Environmental factors could
influence epigenetic processes, leading to epigenetic reprogramming
and contributing to the development of several diseases (Ji et al.,
2016).
TRAPs are potential risk factors for numerous respiratory disor-
ders, including lung cancer. Alterations of DNA methylation have been
reported, including global hypomethylation and hypermethylation of
specific tumor suppressor genes, and could be considered very early
events in the development of lung cancer (Ding et al., 2017). Despite
this, there are few studies in the literature investigating the effects of
TRAPs in occupationally exposed subjects on epigenetic changes.
According to a previous study by Duan et al. (2013), exposure to
PAHs may influence DNA methylation, and global levels of DNA
BRUCKER ET AL.
methylation can be used as biomarkers of effect for subjects exposed
to them. Yang et al. (2018) investigated the effects of PAH exposure
on global levels of DNA methylation in coke oven workers and found
that high levels of urinary 1-OHP were associated with an increased
risk of hypomethylation of long interspersed nuclear element (LINE-
1). Although several toxicological studies have suggested that PAHs
inhibit DNA methylation, the exact mechanism by which PAHs and
their metabolites interfere with global DNA hypomethylation remains
unclear (Yang et al., 2018). Ding et al. (2017) revealed that exposure
to TRAPs (PM2.5 and PM10) could dose- and time-dependently affect
DNA methylation and cause histone modification in both the blood
and lung tissues of rats.
Recently, Zheng et al. (2017) evaluated the relationship between
ambient traffic-derived pollutants and histone H3 modifications in
truck drivers and indoor office workers. The authors measured four
specific histone H3 modifications: H3 lysine 9 acetylation (H3K9ac),
H3 lysine 9 trimethylation (H3K9me3), H3 lysine 27 tri-methylation
(H3K27me3), and H3 lysine 36 trimethylation (H3K36me3), in blood
leukocytes of the subjects studied. While no significant associations
were found between histone H3 modifications and general levels of
personal PM2.5 or its elemental components, the results showed that
ambient 14-day average PM10 was negatively associated with blood
levels of H3K27me3 and H3K36me3, after adjusting for potential
confounders. According to the authors, although the direct pathologi-
cal impact of their findings is presently unclear, the study provides
some scientific guidance and evidence for future air pollution studies
in humans. H3 histone can be covalently modified, eg, by acetylation,
methylation, ubiquitination, phosphorylation, and ADP ribosylation,
thus influencing chromatin structure and gene expression (Baccarelli
& Bollati, 2009).
Today, it is well established that miRNA dysregulation plays a role
in carcinogenesis. In addition, increasing evidence shows that alter-
ations in miRNA may be involved in responses to environmental
agents and pollutants that lead to various health-associated problems
(Song & Ryu, 2015). miRNAs constitute a class of small, evolutionary
conserved, noncoding RNAs critical for regulation of gene expression,
which act as modulators of gene expression programs in various
diseases, particularly in cancer, where they act through the repression
of genes that are critical for carcinogenesis (Jardim, Fry, Jaspers,
Dailey, & Diaz-Sanchez, 2009; Romero-Cordoba, Salido-Guadarrama,
Rodriguez-Dorantes, & Hidalgo-Miranda, 2014; Shahadin, Mutalib,
Latif, Greene, & Hassan, 2018). Jardim et al. (2009) showed exposure
to ambient air pollutants can disrupt miRNA expression patterns in
human airway cells, and that this may lead to gene expression changes
associated with disease initiation.
4.3 | Biomarkers of susceptibility to air pollution
Polymorphism studies can provide valuable information about the
role of individual genetic susceptibility and its relationship with
exposure to xenobiotics, which may directly influence risk factors
associated with pathologies (Prasad et al., 2013). In fact, it is known
9
that gene–environment interaction leads to the development of
diseases and represents an important area of research, because it
provides insights into disease biology, allowing for better disease
prediction and prognosis models to be built, and enabling the identi-
fication of vulnerable people (Khoury, 2017; Zhao et al., 2015). Con-
cerning exposure to PM2.5, gene–environment studies are of special
interest in the examination of cardiovascular injury (Zhao et al.,
2015). However, epidemiologic studies regarding the relationship
between occupational exposure to TRAPs and disease risks at the
individual level are limited. Table 3 summarizes the main biomarkers
of susceptibility.
Genetic polymorphisms have provided evidence that oxidative
stress plays an essential role in air pollution exposure. As the
important oxidative response mechanism is via the GSH metabolism
pathway, the polymorphisms in the genes of the glutathione
S-transferases (GSTs) superfamily have often been assessed in air pol-
lution exposure studies. GSTs are phase II detoxification enzymes,
which are important in modulating inflammatory responses and are
triggered by ROS (Bowatte et al., 2017). Among the various GST
polymorphisms, three isoenzymes, glutathione S-transferase theta 1
(GSTT1), glutathione S-transferase mu 1 (GSTM1), and glutathione S-
transferase pi 1 (GSTP1), have drawn special interest due to their
involvement in biological pathways and their role in the detoxification
of endogenous agents, including air pollution (Bowette, Lodge, Perret,
Matheson, & Dharmage, 2016; Rao et al., 2018). Knudsen et al. (1999)
investigated the influence of individual susceptibility factors on the
genotoxic effects of urban air pollution in bus drivers and postal
workers in the city of Copenhagen, Denmark. The authors concluded
that polymorphisms of major carcinogen-metabolizing enzymes,
evaluated through the GSTM1 and N-acetyltransferase 2 (NAT2)
genotypes, affect the induced or spontaneous level of chromosome
damage. Bagryantseva et al. (2010) evaluated a group of workers (bus
drivers and garage workers) exposed to environmental pollutants, and
biomarkers of oxidative damage to proteins and lipids, biomarkers of
genotoxicity, as well as susceptibility biomarkers were investigated.
The results showed that the carriers of at least one variant human
8-oxoguanine DNA glycosylase (hOGG1) (Cys) allele tended to have
higher oxidative damage to DNA than those with the wild genotype;
individuals with xeroderma pigmentosum group D23 (XPD23)
(GIn/GIn) homozygotes were more vulnerable to the induction of
DNA strand breaks; GSTM1 null variant seemed to protect DNA integ-
rity. In summary, the findings show that their genotype significantly
modified the response of occupationally exposed individuals in terms
of DNA damage.
In addition, polymorphisms in genes codifying other enzymes
involved in oxidative stress response have been studied: heme
oxygenase-1 (HMOX1), CAT, and SOD are some examples (Romieu,
Moreno-Macias, & London, 2010). Ding et al. (2014) aimed to
evaluate the transcriptomic responses by evaluating human bronchial
epithelial (HBE) cells exposed to concentrations of PM2.5 collected
from Wuhan, China. The authors showed that many genes involved in
the response to oxidative stress were significantly induced by low-
dose PM2.5, including NAD(P)H quinone dehydrogenase 1 (NQO1),
10 BRUCKER ET AL.

TABLE 3 Overview of the studies investigating biomarkers of susceptibility in subjects occupationally exposed to air pollution

Study population (N) Biomarkers of susceptibility Biological sample Result Reference

Bus drivers (81 male and Polymorphisms of genes NAT2 Whole blood (DNA) " frequency of cells with Knudsen et al.
25 female) and postal and GSTM1 chromosomal aberrations in (1999)
workers (70 male and bus drivers with GSTM1 null
31 female) from and slow acetylator NAT2
Copenhagen, Denmark genotypes
" frequency of cells
chromosomal aberration
counts related with NAT2
slow acetylators among the
postal workers
Bus drivers (50) and Polymorphisms of metabolic Mononuclear cells Variant hOGG1 (Cys) allele: Bagryantseva et al.
garagemen (20) from genes (CYP1A1, GSTM1, (DNA) higher oxidative damage to (2010)
Prague, Czech GSTP1, GSTT1, EPHX3,4); DNA; XPD23 (Gln/Gln)
Republic folic acid metabolism genes homozygotes: susceptible
(MS, MTHFR); and DNA to the induction of DNA
repair genes (XRCC1, XPD6, strand breaks; GSTM1 null
XPD23, hOGG1) variant: protect DNA
integrity
Male bus drivers (100) Polymorphisms of genes Whole blood (DNA) " 1-OHP in subjects with Petchpoung et al.
from Bangkok, CYP1A1, GSTM1, GSTP1, CYP1A1 MspI and exon 7 (2011)
Thailand and GSTT1 variants
# 1-OHP excretion in workers
with GSTP1 Val and GSTM1
null genotypes
Petrol pump workers (50) Polymorphisms of genes Whole blood (DNA) " frequency of sister Kanupriya et al.
from Haryana, India CYP2E1 and CYP1A1m2 chromatid exchanges and (2015)
tail moment in CYP2E1 and
CYP1A1m2 mutant
genotypes (homozygous
and heterozygous)
Male traffic policemen Polymorphisms of genes Whole blood (DNA) No significant interactive Zhao et al. (2015)
(110) and common CXCL3, NME7 and C5 effects of gene and PM2.5
populations (101) on lung function were
found

Abbreviations: 1-OHP, 1-Hydroxypyrene; CYP1A1, cytochrome P4501A1; CYP2E1, cytochrome P450 2E1; GSTM1, glutathione S-transferase um 1;
GSTT1, glutathione S-transferase theta 1; GSTP1, glutathione S-transferase pi 1; NAT2, N-acetyltransferase 2; EPHX3,4, epoxide hydrolase 3,4; MS,
methionine synthase; MTHFR, methylene-tetrahydrofolate; XRCC1, X-ray repair cross complementing; XPD6, xeroderma pigmentosum group D6; XPD23,
XPD group D23; hOGG1, human 8-oxoguanine DNA glycosylase; CXCL3, gene belonging to chemokine family; NME7, gene encodes a member of the
non-metastatic expressed family of nucleoside diphosphate kinases; C5, C5 complement factor.

prostaglandin-endoperoxide synthase 1 (PTGS1), glutathione peroxi-
dase 3 (GPX3), solute carrier Family 7 Member 11 (SLC7A11), BCL2
apoptosis regulator (BCL2), adrenergic beta receptor kinase 1
(ADRBK1), NADH:ubiquinone oxidoreductase core subunit
(NDUFS2), and NDUF subunit A12 (NDUFA12), and among these there
were three genes (NQO1, SLC7A11, and NDUFA12) up-regulated in
the high-dose group as well. Interestingly, NQO1 is expressed at high
levels in several human solid tumors, including lung cancer.
Enzymes involved in metabolic activation pathways of xenobi-
otics, such as cytochrome P4501A1 (CYP1A1) and enzymes involved
in DNA repair mechanisms, including 8-oxo-guanine-DNA
glycosylase/apurinic/apyrimidinic (AP) lyase, which excises 8-oxoG as
a part of the base excision repair pathway (codified by the OGG1
gene), have also been widely investigated in studies of occupational
exposure to air pollution (Bagryantseva et al., 2010; Petchpoung et al.,
2011). Since CYP1A1 and GSTs enzymes are important in the metab-
olism of PAHs, Petchpoung et al. (2011) investigated the association
between the genetic polymorphisms of these enzymes and the con-
S2 centration of 1-OHP in bus drivers in Thailand. Regarding CYP1A1, a
mutation in the 3-flanking region (CYP1A1 MspI, T6235C) and an
isoleucine/valine substitution in exon 7 (CYP1A1 exon 7, Ile462Val)
resulted in increased enzyme activities. The results showed that indi-
vidual genetic polymorphisms in CYP1A1 influenced the 1-OH con-
centration in the exposed workers. In relation to GSTs, involved in the
conjugation of PAHs or their reactive metabolites to GSH, thereby
making them readily excretable, higher urinary 1-OHP levels were
found in the GSTM1-present subjects than in the GSTM1-null subjects,
while no association was found between the biomarker of exposure
and GSTT1 polymorphisms. Regarding GSTP1, significantly decreased
urinary 1-OHP levels were observed in GSTP1 Val-variant carriers.
BRUCKER ET AL.
The polymorphism of CYP2E1, a phase I gene involved in the metabo-
lism of benzene, was associated with a significantly higher frequency
of sister chromatid exchanges and tail moment in petrol pump
workers from India (Kanupriya et al. 2015).
Inflammation is induced by several factors such as air pollution
exposure, and genetic variations may determine the intensity of an
individual's inflammatory response to environmental stimuli
(Panasevich et al., 2013). As described in the review of Ward-Caviness
(2019), the genes IL-6, TNF-α, and GSTM1 are associated with inflam-
matory markers via gene–environment interactions. Ljungman et al.
(2009) evidenced gene–environment interaction by evaluating the
genes FGB (rs1800790), encoding the fibrinogen protein (β-chain
(FGB)), and IL-6 (rs2069832), which modified the effects of air pollu-
tion on IL-6 levels in myocardial infarction survivors. Panasevich et al.
(2013) investigated the effect of modification by inflammation (IL-6,
TNF-α, FGB and Plasminogen activator inhibitor-1 [PAI-1]) gene
variants on the effect of long- or short-term air pollution exposure on
both blood marker levels and non-fatal myocardial infarction risk, and
concluded that the systemic inflammatory responses to long- and
short-term air pollution could be modified by genetic polymorphisms
in the inflammatory genes IL-6 and TNF-α in healthy subjects, and that
this has consequences for long-term myocardial infarction risk. In the
in vitro study of Ding et al. (2014), who evaluated HBE cells exposed
to different concentrations of PM2.5 collected from Wuhan, China,
various inflammatory response genes were differentially expressed
after PM2.5 exposure, including up-regulated genes (calcitonin gene-
related peptide-receptor component protein [iCRCP], bone morpho-
genetic protein 2 [BMP2], coagulation factor II thrombin receptor
[F2R], IL 10 receptor subunit β [IL10RB], MDS1 and EVI1 complex
locus [MECOM], X-C motif chemokine receptor 1 [XCR1], and neutro-
phil cytosolic factor 1 [NCF1]) and down-regulated genes (monoglyc-
eride lipase [MGLL] and macrophage migration inhibitory factor [MIF])
in the low-dose group, and up-regulated genes (CRCP, macrophage
inflammatory protein 2 [MIP-2], and PX domain containing seri-
ne/threonine kinase like [PXK]) and down-regulated genes (C-X-C
motif chemokine ligand 10 [CXCL10] and oxidized low density lipopro-
tein receptor 1 [OLR1]) in the high-dose group.
Some toxicological studies have also suggested that the associa-
tion between air pollution and diseases, such as those involving
cardiovascular and respiratory outcomes, might be modified by gene
polymorphisms. Especially in relation to GST gene polymorphisms,
recent human studies investigating the effects of air pollution expo-
sure provide evidence of interactions between these and air pollution
in respiratory diseases and allergies, despite the results being highly
heterogeneous (Bowette et al., 2016). According to Bowatte et al.
(2017), carriers of GSTT1 null may be at greater risk of respiratory dis-
ease from traffic-related air pollution. Zhao et al. (2015) analyzed the
effect of gene–PM2.5 interaction for CXC ligand 3 (CXCL3), which
belongs to the chemokine family, and C5 complement factor (C5)
genes in the respiratory system of traffic police officers. The allele and
genotype distribution of the studied genes in forced volume in 1 s
(FEV1)/forced vital capacity (FVC) ratio showed no significant
differences. Furthermore, a higher risk of acute myocardial infarction
11
was associated with vehicle air pollution exposure, and Levinsson et
al. (2014) described the effects of variants in the GSTP1 gene on the
risk of hypertension. Van Hee et al. (2010) investigated the impact of
tagged single-nucleotide polymorphisms (tagSNPs) and inferred haplo-
types in 12 candidate genes (angiotensin I converting enzyme [ACE],
adrenoceptor β2 [ADRB2], angiotensinogen [AGT], angiotensin II
receptor type 1 [AGTR1], arachidonate 15-lipoxygenase [ALOX15],
endothelin 1 [EDN1], G protein-coupled receptor kinase 4 [GRK4],
PTGS1, PTGS2, Toll-like receptor 4 [TLR4], vascular endothelial growth
factor A [VEGFA], and VEGFB) on the relationship between residential
proximity to roadways and left ventricular mass (LVM), as alterations
in the LVM is associated with cardiovascular disease risks. The
authors concluded that SNPs in two genes responsible for vascular
function, inflammation, and oxidative stress (AGTR1 and ALOX15)
modify associations between proximity to major roadways and LVM.
According to a recent review by Ward-Caviness (2019), most studies
have assessed candidate genes related to detoxification (GSTM1 and
GSTT1), inflammation (IL-6), iron processing (homeostatic iron regula-
tor [HFE]), and miRNA processing (gem nuclear organelle associated
protein 4 [GEMIN4] and DiGeorge syndrome critical region gene 8
[DGCR8]), as biomarkers of susceptibility to cardiovascular disease risk
in cases of exposure to air pollution.
5 | CONC LU SION
Considering all this evidence, the present review emphasizes the
importance of the early detection of occupational health damage and
the implementation of effective strategies to promote decreased
xenobiotics in the workplace. As it is challenging to avoid occupational
exposure to TRAPs, biomonitoring should be applied as a strategy to
reduce the damage to health from toxic effects of workplace
exposures. The novel approaches in molecular biology and the greater
sensitivity of the analytical methods are important advances to detect
early changes in biomarkers and thus prevent the development of
diseases associated with occupational exposures. The screening of
several biomarkers could be suggested as a preventive measure to
monitor drivers’ health. In addition, follow-up studies are needed to
investigate whether those individuals occupationally exposed to air
pollution have an additional risk of respiratory, cardiovascular, and
cancerous diseases. There is a clear need for more epidemiologic
studies of subjects occupationally exposed to TRAPs, especially using
the new toxicological approaches to identify early effects and genetic
susceptibility through the “omics” data, including metabolomics, pro-
teomics, epigenetics, and others, to measure and characterize biologi-
cal effects from genetic–environment interaction. Although it is well
evidenced that processes such as oxidative stress and inflammation
are involved in the pathologies associated with occupational exposure
to TRAPs, a general view of the transcriptomic responses represent
an area for future studies.
CONFLIC T OF INT ER E ST
The authors declare that they have no conflict of interest.
12
ORCID
Natália Brucker https://orcid.org/0000-0003-0632-7955
Solange Cristina Garcia https://orcid.org/0000-0003-3752-5751
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How to cite this article: Brucker N, do Nascimento SN,
Bernardini L, Char~ao MF, Garcia SC. Biomarkers of exposure,
effect, and susceptibility in occupational exposure to traffic-
related air pollution: A review. J Appl Toxicol. 2020;1–15.
https://doi.org/10.1002/jat.3940