Benzene: Environmental Exposureq

D Poli, Italian Workers’ Compensation Authority (INAIL), Research Center at the University of Parma, Parma, Italy
R Andreoli, University of Parma, Parma, Italy
A Mutti, University of Parma, Parma, Italy
EC Alexopoulos, Hellenic Open University, Patras, Greece
EB Bakeas, University of Athens, Athens, Greece
M Goldoni, University of Parma, Parma, Italy
© 2016 Elsevier Inc. All rights reserved.

Abbreviations
ACGIH American Conference of Governmental Industrial Hygienists
AQG Air Quality Guidelines
ATSDR Agency for Toxic Substances and Disease Registry
BEI Biological Exposure Indices
CAS Chemical Abstracts Service
CYP2E1 Cytochrome P450 2E1
DMEL Derived Minimal Effect Level
DNEL Derived No-Effect Level
EKA Values Exposure Equivalents for Carcinogenic Working Materials
EMEP European Monitoring and Evaluation Program
EPA Environmental Protection Agency
ETS Environmental Tobacco Smoke
EU European Union
GRF German Research Foundation
IARC International Agency for Research on Cancer
MAK Maximale Arbeitsplatz-Konzentration
MRL Minimal Risk Level
NADPH Nicotinamide Adenine Dinucleotide Phosphate
NATTS National Air Toxics Trend Sites
NMHC Nonmethane Hydrocarbon
NOAEL No Observed Adverse Effect Level
NQO1 Quinone Oxidoreductase-1
OSHA Occupational Safety and Health Administration
PIRG Public Interest Research Group
PNEC Predicted No Effect Concentration
POCP Photochemical Ozone Creation Potential
RfC Inhalation Reference Concentration
REACH Registration, Evaluation, Authorisation and Restriction of Chemicals
S-PMA S-Phenylmercapturic Acid
STEL Short-Term Exposure Limit
TLV Threshold Limit Value
TLV-TWA Threshold Limit Value-Total Weight Average
TRI Toxics Release Inventory
t,t-MA trans,trans-Muconic Acid
VOC Volatile Organic Compound
WHO World Health Organization.

q
Change History: October 2015. M Goldoni, D Poli, R Andreoli, A Mutti, EC Alexopoulos, EB Bakeas have extensively revised and updated all the existing
sections, except ‘Properties’ one. Section ‘International Recommended Limits’ has been added. Figure 1 has been deleted and Tables 1 and 2 have been added.

252 Encyclopedia of Environmental Health, 2nd edition, Volume 1 https://doi.org/10.1016/B978-0-12-409548-9.09582-8

 Benzene: Environmental Exposure 253

Introduction

Owing to its toxicity properties, Benzene (Chemical Abstracts Service (CAS) Registry Number 71-43-2) has become one of the most
intensely regulated substances in the world. It has been recognized as a class I carcinogenic agent by the International Agency for
Research on Cancer (IARC), as long-term exposure to high Benzene concentrations is known to cause bone marrow damage,
leukemia, and aplastic anemia. Besides of an early uncontrolled use of Benzene as a solvent, exposure to Benzene in developed
countries mainly occurs in the chemical and petroleum industry, and in urban environments, where Benzene is a ubiquitous
pollutant arising from motor vehicle emissions. In addition, tobacco smoke represents a relevant source of personal Benzene intake.
Although air quality has improved in recent decades (and particularly in the large urban areas), nearly all urban citizens still expe-
rience exceedances of European Union (EU) urban air quality standards. Road traffic is the most important contributor to urban air
pollution. Although national and EU regulations aimed at automobile emission reductions (such as the introduction of catalytic
converters or unleaded petrol) have resulted in considerably lower emissions per vehicle, the continuous expansion of the vehicle
fleet is partly offsetting these improvements. According to a EU directive entered into force on December 2000, Benzene concen-
trations in ambient air should not exceed 5 mg m
3 as a running annual average, with a long-term target of less than 1 mg m
3.

Properties

Benzene is an aromatic hydrocarbon with molecular weight 78.1 (at one atmosphere pressure and 25  C, 1 ppm Benzene is equiv-
alent to 3.26 mg m
3). It occurs as a clear or colorless to light-yellow liquid with a gasoline-like odor. Benzene (C6H6) is a colorless
liquid at room temperature (melting point 5.5  C) with a density of 0.87 g cm
3 at 20  C. It has a relatively low boiling point
(80.1  C) and a high vapor pressure (9.95 kPa at 20  C), which causes it to evaporate rapidly at room temperature. It is slightly
soluble in water (1.8 g l
1 at 25  C) and miscible with alcohol, ether, chloroform, acetone, carbon tetrachloride, carbon disulfide,
oils, and glacial acetic acid. Benzene in air exists predominately in the vapor phase, with residence times varying between a few
hours and a few days, depending on the environment, the climate, and the concentration of other pollutants. Laboratory evalua-
tions indicate that Benzene is minimally photochemically reactive in the atmosphere compared to the reactivity of other hydrocar-
bons. Reactivity can be determined by comparing the influence that different hydrocarbons have on the oxidation rate of nitric oxide
(NO) to nitrogen dioxide (NO2), or the relative degradation rate of various hydrocarbons when reacted with hydroxyl radicals
(OH$), atomic oxygen, or ozone. For example, based on the NO oxidation test, the photochemical reactivity rate of Benzene
was determined to be one-tenth that of propylene and one-third that of n-hexane. Reaction with hydroxyl radicals is the most
important means of degradation. In laboratory evaluation, Benzene is predicted to form phenols and ring cleavage products
when reacted with OH and to form quinone and ring cleavage products when reacted with aromatic hydrogen. Other products
that are predicted to form from indirect reactions with Benzene in the atmosphere include aldehydes, peroxides, and epoxides.
It can also be removed from air by rain.

Production and Use

Benzene is used primarily as a solvent in the chemical and pharmaceutical industries, as a starting material and intermediate in
the synthesis of numerous chemicals, and in gasoline. Specifically, in the United States of America, the main use of Benzene is in
the production of ethylbenzene (52% of the 2008 total Benzene demand). High percent of ethylbenzene is used in the produc-
tion of styrene, the raw material in the industry producing polystyrene and various styrene copolymers, latexes and resins.
Benzene is employed in the manufacture of cumene (22%) and therefore in phenol production. Benzene can be also used to
form several chemical intermediates: cyclohexane (nylon monomers production, 15%); nitrobenzene (aniline and other prod-
ucts production, 7%); alkylbenzene (detergent production, 2%); chlorobenzenes (engineering polymer production, 1%); and
other (1%).
The market situation for Benzene in Europe was recently analyzed by Petrochemicals Europe (http://www.petrochemistry.eu/
about-petrochemistry/facts-and-figures.html) with the following percentages in 2014: ethylbenzene 46%, cumene 27%, nitroben-
zene 13% cyclohexane 9%, other 5%.
Benzene is naturally present in petroleum products (e.g. crude oil and gasoline) and is an additive for unleaded gasoline for its
octane-enhancing and anti-knock properties. Its concentration is typically in the order of 1–2% by volume. US Environmental
Protection Agency (EPA) limits the Benzene percentage in gasoline to an average of 0.62% by volume (maximum 1.3%). The Fuels
Quality Directive (EU, 2003a) limits the Benzene content in petrol to < 1%. Several occupations deal with Benzene exposure
through petroleum derivatives: aviation, service station and shoe production workers, bus drivers, police, urban workers and fish-
ermen. EU estimated about 1 367 800 workers exposed to Benzene in 1999. 375 000 workers (2% of working population) were esti-
mated to be exposed to Benzene in Canada.
Benzene has been produced commercially from coal since 1849 and from petroleum since 1941. It is one of the main building
blocks of the petrochemical industry. It is produced domestically by five major processes: by the catalytic reforming/separation
process, from ethylene production, from toluene dealkylation or toluene disproportionation processes, from coke oven light oil
distillation at coke by-product plants, and from xylene isomerization. The global market grew from 4 million tonnes in 1960 to
over 30 million tonnes in 2000. Most of the Benzene produced is from Western Europe, North America, and Asia.
254 Benzene: Environmental Exposure

Several economic studies agree with the fact that Worldwide Benzene demand will rise of some yearly percentage points until to
2018–2020. World Benzene Production probably will exceed 50 000 Kt y
1 in 2017. The Asia-Pacific is the largest Benzene market
(> 45.0% of the World demand in 2012), and its derivatives. Asia-Pacific demand for Benzene would grow of about 4.1% y
1 from
2013 to 2018. China and Japan are the biggest consumers of Benzene in the region, while India is expected to have the fastest
growing market. In Europe, since 2007 the Benzene consumption is decreased from about 9000 Kt y
1 to about 7500 Kt y
1 in
2014, with a decreasing trend in the last 7 years (
2.4% in 2014 as compared to 2013 in Benzene production). Pyrolisis gasoline
in 2014 is still the first source of supply (54.3% of the total), followed by reformatted-based production (28.7%) and on-purpose
and coal-based production (17%). Furthermore, the overall production reached 68% of the nameplate capacity and imported
Benzene increased by 16% as compared to 2013. In the USA, Benzene production is fluctuating in the last years, and quite stable
from 2014 to 2015. However, USA accounts for about 20% of worldwide production.

Emission Sources

Emissions of Benzene to the atmosphere are due mainly to combustion processes for energy production (including motor vehicles)
and domestic heating. Since fuels are distributed from the producers to the user, evaporative processes are also responsible for the
emission of large amounts of aromatic hydrocarbons in the atmosphere. The only significant natural sources of Benzene are
biomass burning, and brush and forest fires. However, these sources are estimated in the order of 3–5% and do not affect air quality
in densely populated areas. Benzene in the atmosphere is due mainly to anthropogenic sources (more than 90%). Only in areas
where wood burning accounts for more than half of domestic energy needs, the non-anthropogenic source is substantial. The
anthropogenic sources include a variety of activities (petroleum refinery processes, gasoline marketing, and municipal solid waste
landfills), combustion sources from which Benzene is emitted as unburned compound or is formed from the thermal degradation
of other aromatic compounds (medical waste incinerators, sewage sludge incinerators, hazardous waste incineration, external
combustion of solid, liquid, and gaseous fuels in stationary sources for heat and power generation, portland cement production,
hot-mix asphalt production, open burning of biomass, scrap tires, etc.). The most significant emission sources of Benzene are the
mobile sources including on-road and off-road mobile sources, marine vessels, locomotives, aircrafts, and rocket engines. Emissions
from traffic are the largest source. Therefore, Benzene pollution is highest in densely populated areas characterized by high traffic
density. Industrial activity can contribute to ambient Benzene levels, but its contribution to the total exposure is very low.
Many studies concerning Benzene emission sources have been performed around the world. The majority of them have been
performed in a local base such as cities and industrial areas. Studies covering extended areas around the world are still limited
because national or regional emission inventories have not been established at a high level. In Europe, the contribution of main
anthropogenic sources of Benzene in the atmosphere has been evaluated. From those results it was shown that the contribution
of each source category is as follows: vehicular traffic 80–85%, petroleum refineries 0.3–1.5%, fuel distribution 2.6–6%, chemical
industry 1.3–13%, domestic heating 3–7%, and solvent use 1–4%. In the USA, according to Public Interest Research Group (PIRG),
cars, trucks, and nonroad engines released more than 250 000 tonnes of Benzene into the environment or 78% of total Benzene
emissions. In Australia, motor vehicles contribute up to 64% of total Benzene emissions. In China during 2005, an emission inven-
tory for nonmethane volatile organic compounds (NMVOCs) emissions was established. According to the results, the total Benzene
emission for that year was 0.9 Tg. The major contributions were from transportation (22%) and incomplete combustion of biomass
and commercial energy carriers (59%).
A recent WHO guideline (2010) deals with indoor sources of Benzene and the consequent exposure.
Although dependent on outdoor concentrations, climatic conditions and ventilation, Benzene in indoor air may be generated from
several activities, including building materials and furniture, attached garages, heating and cooking systems, stored solvents and
various other human activities. Specifically, constructing, remodelling and decorating activities may contribute to indoor Benzene
concentrations, because traces of Benzene are present in several materials. Therefore, new or renovated buildings may present relatively
high concentrations of indoor Benzene with further decays in time. Furthermore, attached garages and materials stored in them may
contribute up to 8 mg m
3 indoor Benzene. Each procedure of cooking and heating may be a source of Benzene, particularly in poorly
ventilated environments or when inefficient heating systems are present. Indoor Benzene can also depend on all the other human
activities using Benzene-containing products. Environmental tobacco smoke (ETS) is probably the main indoor source of Benzene.
Benzene in ETS is in the order of tens hundreds of mg per cigarette. When present, ETS account for 30–70% of total indoor Benzene.
Finally, petrochemical and petroleum industries, hazardous waste sites, industrial discharges, land disposal of Benzene wastes,
gasoline storage tanks that leak, and chemical spills release Benzene to water (surface, coastal, and even ocean) and soil and even-
tually contaminate food or water. Although Benzene in water or food contributes only a small percentage of the total daily intake in
non-smoking adults, Benzene in drinking water represents a major public health concern. It should be noted that occupational
exposure assessment is possible if the materials used are known and the occupational environment well defined. On the contrary,
the same was not possible for general population, given the variability of individual lifestyles, and indoor and outdoor environ-
mental and geographical conditions.

Outdoor, Indoor, and Personal Levels of Benzene

The concentration of Benzene in the atmosphere is a complex function of emission rates, meteorological conditions, and chemical
removal. In the atmosphere, Benzene is removed only by the reaction with OH radicals. The reaction rate of this process is
 Benzene: Environmental Exposure 255

1.2  10
12 cm
3 molecules
1 s
1, and with a 24 h average concentration of OH radicals equal to 106 mol cm
3 representative for
the troposphere, the lifetime of Benzene is nine days (in highly polluted air, the lifetime is one day). The residential time of an air
mass in a street canyon is in the order of minutes and in an urban area in the order of a few hours even in high-pressure situations
with stagnant wind velocities. Therefore, chemical removal on a local scale (within an urban area) is negligible, but on a regional
scale, chemical removal of Benzene can be important. The reactivity of Benzene, compared to that of other aromatic components, is
not so high. The POCP (photochemical ozone creation potential) value for Benzene has been calculated to be 31.7, whereas for
toluene it is 44.6. It is therefore not expected that Benzene is depleted to the same extent as other VOCs in photochemical pollution.
In fact, the ratio of toluene to Benzene is used as an important parameter to estimate aging of air masses resulting from photochem-
ical pollution. A wide range of Benzene concentrations in ambient air, both personal and area sampling, have been reported.
Although the mean levels are usually reported as not exceeding 5 parts per billion (ppb) and therefore appear not to be the cause
for concern, these studies have periodically reported much higher maximum levels of airborne Benzene that can be up to 1 ppm, or
even higher. For instance, daily average Benzene concentrations of 0.03–8.92 ppm in ambient air were recorded at different road-
side locations in Calcutta, India, in 1993, primarily due to the use of coal burning stoves. Generally, Benzene concentration values
are highest in areas of heavy motor vehicle traffic and around gasoline-filling stations.
The results from the European Monitoring and Evaluation Program (EMEP) Co-Operative Programme for Monitoring and Eval-
uation of the Long-Range Transmission of Air Pollutants for 2004 did not show clear long-term trends. Benzene was determined in
10 different rural European areas. The mean monthly values ranged from 9 to 744 ppt. The recent exposure to Benzene in Europe is
limited to a few local areas close to traffic or industrial sources in 2010–2012. Although the Air Quality Directive (EU, 2008c) sets an
annual average concentration limit value of 5 mg m
3 for outdoor Benzene, to be met by 2010, in 2012 the limit value was exceeded
at several stations in seven EU Member States. No exceedances were observed in rural environments. However, Benzene annual
concentrations were, on average, well below the limit value. Annual mean concentrations of Benzene were highest at traffic stations,
with a decrease from 2002 until 2007, reaching a plateau. Benzene concentrations at urban and rural stations showed a less sharp
decrease during the same period than traffic stations. Although < 1% of European population has been estimated to be exposed to
annual average concentration of 5 mg m
3, 10–12% is anyway exposed to levels above the WHO Air Quality Guidelines (AQG) of
1.7 mg m
3 (see below).
Toxics Release Inventory (TRI) by EPA can be consulted through TOXMAPÒ (http://toxmap-classic.nlm.nih.gov/toxmap/main/
mapIt.do?chemicalName¼Benzene), which reports a public database containing data about the outdoor emissions of Benzene in
USA showing 2013 scenarios and trends. However, in the EPA’s AiRTrend program Benzene is not specifically mentioned, although
data exist about generic VOCs. However, all the documents from National Agencies give data about airborne Benzene and several
regional air quality reports. For example, in the USA the results from 13 semiurban areas around the country during the period
1998–2000 showed that the mean concentration values of Benzene ranged from 0.12 to 1.1 ppb. Between 1999 and 2005,
a sampling campaign was conducted to identify and quantify the major species of atmospheric nonmethane hydrocarbons
(NMHCs) in 28 U.S. cities. The mean mixing ratio for Benzene was found to range between 77 and 480 ppt. The higher mixing
ratio (480 ppt) was determined in Los Angeles. According to EPA, the national average trend in Benzene levels at 107 monitoring
sites across the country suggests an average improvement of almost 17% between 2000 and 2005. A very recent study reports the
data from the EPA’s National Air Toxics Trend Sites (NATTS) network of 27 stations located in most major urban areas of the contig-
uous United States. Benzene typically ranged between 1 and 5 mg m
3.
Sources of indoor Benzene exposure are numerous, including tobacco smoke, several household products, and ambient air
entering the home through ventilation or infiltration. Tobacco combustion is a major source of indoor Benzene exposure,
with Benzene concentrations increasing by up to 50% compared with that in homes of nonsmokers. Estimates of the amount
of Benzene released by cigarette smoking range from 5.9 to 75 mg per cigarette in mainstream smoke and from 345 to 653 mg
per cigarette in side stream smoke. Several consumer products can account for up to 20% of the exposure of the total population
to Benzene.
In indoor air, the contribution of environmental tobacco smoke to concentrations of Benzene has been the subject of numerous
previous studies. Tobacco smoking is known to be a significant contributor to Benzene exposure in the general population. It has
been estimated in several studies that benzene arising from cigarette smoke increases indoor home levels of benzene up to
10 mg m
3. It is estimated that smokers receive approximately 90% of their Benzene exposure from smoking (mainstream and envi-
ronmental tobacco smoke), with an average Benzene body burden of approximately 6–10 times that of nonsmokers. However,
nonsmokers receive only approximately 10% of their Benzene exposure from environmental tobacco smoke, 6% from point sources
such as petrochemical plants or refineries, and the majority of their Benzene exposure from auto exhaust or gasoline vapor emis-
sions. In the developing countries, the combustion of solid biomass fuels indoors is one of the important sources of Benzene emis-
sions. Exposure concentration up to 75.3 mg m
3 (geometric mean values) has been determined depending on the type of fuel used.
Recent reports revealed that the use of biomass cooking stoves in Bangladesh generated a substantially higher cancer risk (more than
80 times) than the maximum risk experienced by the U.S. population from all sources of airborne Benzene and toluene.
There are some limitations in environmental sampling procedure including differences in sampling technique, the number and
type of samples, the extent of geographic and seasonal variability, and the representativeness of sites sampled. These variants have to
be taken into account in comparative studies.
Table 1 reports the levels of Benzene in different indoor environment based on the WHO Guideline 2010 and further peer-
reviewed studies. There is a general agreement in Western Countries, with peaks in public places where smoking is not forbidden
and with a general great variability depending on the multiple sources of indoor benzene previously mentioned.
256 Benzene: Environmental Exposure

Table 1 Indoor Benzene Concentration in different countries and different environments

Homes
USA 2.6–5.8
Canada 0.2–7.4
Finland 2
Urban Spain 0.5–2.4 (25th–75th percentile)
Central Europe 2–12
Europe (AIRMEX study) 1.3–6.5
Turkey 7–14
Japan 0.7–7.2
Developing Asian Countries Up to 100
Urban Africa 2.9–27
Offices
UK 0.4–4.0
Several European Countries 14.6
Restaurants 1.1–22.7
Pubs 5.1–78.8
Shopping Centres/Cinemas 0.7–15.5
Vehicles
Europe 13–42
UK 1.3–3.8
USA/Mexico 1.7–42
Asian Cities 0.5–47

Indoor benzene concentrations (mg m
3).

5 –95 percentiles or range of means of several cities/home typologies.

Table 2 Personal exposure to benzene in adults and children

UK Adults Children

1
Rural non-smokers 70–75 mg day Infants 15–20 mg day
1
Urban non-smokers 89–95 mg day
1 Children 30–40 mg day
1
Urban passive smokers 116–122 mg day
1 Infants exposed to ETS 26 mg day
1
Urban smokers >500 mg day
1 Children exposed to ETS 59 mg day
1

Overall, the daily personal intake of Benzene was estimated in several countries. To cite the data about WHO guideline, in USA, it
was estimated to be between 180 and 1300 mg day
1, with a minimal contribution of food and water (< 1%). In Canada, it was
estimated to be about 200 mg day
1 with a major contribution of indoor benzene (near 70%), followed by car-related activities
(25%) and other (ambient air, food, drink) accounting for about 5%. Cigarette smoking may contribute up to 1800 mg day
1
and passive smoking up to 50 mg day
1. Data about some European countries and children are in the same order of magnitude
(Table 2). Finally, A European study estimated a daily intake of 102 mg day
1, where indoor home or work, account for about
70% and a model of human exposure to benzene in urban environments has been recently proposed.

International Recommended Limits

For non-cancer endpoints, US-EPA chronic inhalation reference concentration (RfC) has been 0.03 mg m
3 (0.009 ppm) since
2003, calculated with the benchmark dose approach on decreasing lymphocyte count of highly exposed workers applying an uncer-
tainty factor of 300. Agency for Toxic Substances and Disease Registry (ATSDR) ToxGuideTM reports several details about Minimal
Risk Levels (MRLs) based on the dose and duration: confirming the US-EPA RfC for acute-duration inhalation exposure ( 14 days),
MRL of 0.006 ppm has been extrapolated for intermediate-duration inhalation exposure (15–364 days) and 0.003 ppm for chronic-
duration inhalation exposure ( 1 year). On the contrary, the European Chemical Bureau fixed a No Observed Adverse Effect Level
(NOAEL) of 3.2 mg m
3 (1 ppm).
For the same experimental evidences, both IARC and USEPA classified Benzene as a Group A (known human) carcinogen, inde-
pendently on the route of exposure. Considering airborne Benzene, WHO in 2010 confirmed the 2000 document. Briefly, no safe
level of exposure can be fixed and their concentrations associated with an excess lifetime risk of leukaemia of 10
4 (a case every
10 000 people), 10
5 and 10
6 are 17, 1.7 and 0.17 mg m
3, respectively. Annual average 1.7 mg m
3 was confirmed as WHO
AQG. US-EPA calculated the same risk for 1 mg m
3 airborne Benzene between 2.2 and 7.8  10
6, and 1.3–4.5 mg m
3 for an
excess lifetime risk of 10
5. The EU Directive 2008/50/EC chase the average value (2.9 mg m
3) to fix the biomonitoring guidance
value. The exposure via drinking water was also considered: the concentrations of Benzene associated with an excess lifetime risk of
 Benzene: Environmental Exposure 257

leukaemia of 10
4, 10
5 and 10
6 are 0.1, 0.01 and 0.001 mg l
1. ATSDR ToxGuideTM does not derive any acute- or intermediate-
duration oral MRLs, while A MRL of 0.0005 mg kg
1 day
1 has been proposed for chronic-duration oral exposure ( 1 year).
From occupational point of view, both Occupational Safety and Health Administration (OSHA) Threshold Limit Value-Total
Weight Average (TLV-TWA) and EU Indicative Occupational Exposure level are 3.2 mg m
3 (1 ppm, average concentration in
a working day). The maximum tolerable peak in 15-min exposure was set at 5 ppm (US-EPA). The American Conference of Govern-
mental Industrial Hygienists (ACGIH) threshold limit value (TLV) is a half (1.6 mg m
3, 0.5 ppm). The same agency indicated
a TLV Short-term exposure limit (STEL) of 2.5 ppm. On the contrary, the Maximale Arbeitsplatz-Konzentration (MAK) committee
of German Research Foundation does not indicate any reference value, as no exposure to known human carcinogens can be accept-
able or tolerable.
Finally, other European recommendations merit a mention. The German Committee for Hazardous Substances has proposed
a tolerable risk of 4:1000 and an acceptable risk of 4:10 000 (changing to 4:100 000 no later than 2018), applicable over a working
lifetime of 40 years with continuous exposure every working day. For benzene, the tolerable risk corresponds to a concentration of
1900 mg m
3, and the acceptable risk to a concentration of 200 mg m
3 (20 mg m
3 by 2018). In the Netherlands, a health based
occupational exposure limit has been recently recommended, corresponding to an airborne concentration of 700 mg m
3.

Toxicology, Metabolism, Biomarkers, and Health Effects

Absorption of Benzene varies with route of exposure. In humans, respiratory uptake has been determined to vary from approxi-
mately 47 to 80%, although dermal absorption can range from 0.05 to 0.2%. Absorption data for oral exposure in humans is
not available; however, in animals, absorption rates following oral exposure to Benzene were found to be from 90% to almost
100% and are vehicle dependent. Inhaled Benzene is readily absorbed into the blood at 40–70% of airborne doses by passive diffu-
sion through alveolar capillary membranes. Following inhalation exposure, most Benzene is excreted unchanged in exhaled air.
Human excretion of absorbed Benzene involves a biphasic urinary excretion of conjugated derivatives (sulfates and glucuronides).
Benzene should be metabolized to exert its toxicity through a complex process including mainly its oxidation by cytochrome
P450 enzymes (CYP2E1). The highly reactive intermediate is further metabolized to phenol, which may be excreted in urine
(48% as sulfate or glucuronate derivatives) or may be oxidized to p- and o-benzoquinone. The quinones may be back-reduced
to the original diols via nicotinamide adenine dinucleotide phosphate (NADPH) quinone oxidoreductase-1 (NQO1). Additional
pathways lead to trans,trans-muconic acid (t,t-MA), which is excreted in urine (up to 20% of the adsorbed dose) or to
S-phenylmercapturic acid (S-PMA) (excreted in urine; up to 1% of the absorbed dose). A very small percentage of Benzene may
also be excreted in urine non-metabolized (U-Benzene).
Some of the metabolites of Benzene are responsible for its toxicity and carcinogenicity, but it is not certain which metabolites (or
combinations of metabolites) are carcinogenic. The key toxic metabolites for cytotoxicity and the induction of leukemia are thought
to be benzoquinone, benzene oxide, and muconaldehye. Benzene metabolism also produces reactive oxygen species, which can
lead to oxidative damage to deoxyribonucleic acid (DNA) and interference with DNA repair. The formation of muconic acid
and the quinones is favored at low-exposure concentrations. The genotoxicity is thought to be clastogenic (i.e., consisting of chro-
mosomal damage) in nature rather than being caused by point mutations.
The major metabolites of Benzene interact with each other, and this may explain the nonlinear relation between administered
Benzene concentrations and internal doses of metabolites. Besides that, the specie, sex, and age could also play a role in metabolism
of Benzene. Ethanol has been shown to alter (increase the rate of metabolism and of clearance) Benzene metabolism. Co-exposure
to toluene has also been shown to lower urinary excretion of phenol and perhaps the toxicity of Benzene. Benzene conversion to
toxic metabolites may be induced by drugs (e.g., phenobarbital and alcohol) and other chemicals (e.g., chlordane and parathion).
Persons with high hemopoietic activity like children and persons with hemopoietic diseases are at increased risk.
Looking at the Benzene metabolism, IARC concluded that: ‘There is strong evidence that Benzene metabolites, acting alone or in
concert, produce multiple genotoxic effects at the level of the pluripotent haematopoietic stem cell resulting in chromosomal
changes in humans consistent with those seen in haematopoietic cancer. In multiple studies in different occupational populations
in many countries over more than three decades a variety of genotoxic changes, including chromosomal abnormalities, have been
found in the lymphocytes of workers exposed to Benzene’.
Biomarkers of Benzene exposure have been studied for potential use in assessing exposure in humans.
Benzene in blood and urine are considered reliable and valid biomarkers of exposure, as stablished by WHO in 2001. However,
they may reflect only the recent exposure due to the short half-time of Benzene. Benzene in blood is more sensitive than that in urine
and has been used to assess the background exposure on a large scale (CDC) and on different population groups, but have some
ethical concerns. Even if Benzene in urine is less sensitive and more prone to contamination than that in blood, it is used for research
purposes because the sample collection is less invasive, it correlated with air benzene levels in occupationally environments and is
easily quantifiable following standardized sampling procedures. Benzene in exhaled breath presents several limitations in the stan-
dardization of the sampling and storage of the samples, and therefore cannot be considered sufficiently reliable for applications on
a broad scale. Looking at the Benzene metabolites, S-PMA is considered the most specific one and can also easily distinguish
smokers and non-smokers. Other metabolites, mainly t,t-MA and even more phenol, catechol and hydroquinone, lack of specificity,
as products of other metabolic reactions arising from diet or other substances, and their use for airborne low exposure concentra-
tions are not recommendable (t,t-MA 0.2–0.5 ppm; phenol 0.5–5 ppm; hydroquinone 0.5 ppm; catechol 2 ppm). However, t,t-MA
has been recommended for occupational biomonitoring (ACGIH, German Research Foundation). Finally, hemoglobin and plasma
258 Benzene: Environmental Exposure

protein adducts of Benzene are promising biomarkers for less recent exposures, but unfortunately they are not sufficiently sensitive
to monitor environmental exposures.
For occupational biomonitoring, ACGIH derived Biological Exposure Indices (BEI) of 25 mg per gram of creatinine for S-PMA
and 500 mg per gram of creatinine for t,t-MA (post-shift value) in urine corresponding to TLV. German Research Foundation
(GRF) defined exposure equivalents for carcinogenic working substances (EKA values) to estimate Benzene blood, and urinary
S-PMA/t,t-MA.
For the characterization of benzene exposure at environmental levels as well as for the evaluation of health risks posed by this
exposure, the identification of suitable, specific, and sensitive biologic markers is needed but a unique biomarker is not still iden-
tified. Recently different studies suggest the contemporary use of two or more benzene exposure biomarkers, such as urinary
benzene, S-PMA and t,t-MA, to better describe the airborne benzene exposure both for occupationally subjects and in general
population.
Biomarkers of Benzene health effects are based on hematotoxicity and on indicators of genotoxicity. Hematotoxicity is
detected by alterations in complete blood counts, including hemoglobin concentration, hematocrit, erythrocyte count, leukocyte
count, and differential and platelet counts. For genotoxicity, chromosomal aberrations in bone marrow and peripheral-blood
lymphocytes and sister-chromatid exchange can be used. However, none of the biomarkers of effect are specific for Benzene.
Biomarkers of susceptibility would be very useful in helping to determine acceptable exposure concentrations for susceptible
individuals. Two genetic markers, CYP2E1 and NQO1, are associated with the variations in the ways Benzene is metabolized.
Knowledge of such genetically based variations in the response to Benzene will be important in helping to define susceptible
subpopulations.
About cancer effects, IARC emended its Monograph dedicated to Benzene in 2009 and, after some concerns, in 2012, confirm-
ing it as a class I carcinogenic agent (known for humans). It is mainly because Benzene causes acute myeloid leukaemia/acute
non-lymphocytic leukaemia, but other associations are reported: acute lymphocytic leukaemia, chronic lymphocytic leukaemia,
multiple myeloma, and non-Hodgkin lymphoma. Finally, there is sufficient evidence for the carcinogenicity of Benzene in
animals.
Although the epidemiological evidence on a causal association between Benzene and leukemia, predominantly of myeloid
origin, is considered convincing in occupational settings, there is great uncertainty of the association, if any, in the general popu-
lation. This is based on the fact that the level of exposure is much lower and there is a mixture of compounds arising from different
sources. These uncertainties are not possible to be solved either by the extrapolation to ambient concentrations of the exposure–
response curve or by physiologically based pharmacokinetic (PBPK) models that are used to correct risk assessments between
species, different routes of administration, metabolic differences, and so forth. In any case, the risk of leukemia was found to
increase at cumulative exposures greater than 50 mg m
3 year
1, with evidence of an exposure–response relationship.
A number of community studies have observed an association between the incidence of childhood leukemia and proximity to
sources of Benzene (and other hydrocarbons), such as petrochemical works and gas stations. The evidence points to an association
between childhood leukemia and exposure to mixtures that contain Benzene. Another possible but yet unclear association is child-
hood leukemia with the occupational exposure of parents to hydrocarbons. Another or acute effects are not relevant in levels of
Benzene less than 10 mg m
3, but minor symptoms and effects on circulating blood cells in humans could not be excluded in expo-
sure levels of 60 mg m
3 by inhalation or lower orally.

Preventive Actions and Research Priorities

Governmental Agencies and industry have been working for decades to lower benzene exposures by decreasing the content in gaso-
line, reducing automobile emissions, removing benzene from consumer products and by recommending that individuals stop
smoking.
In EU, the improvement of benzene knowledge about risk, kind of use and total amount marked is also due to the introduction
of Regulation EC No 1907/2006, better known as REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals).
Very recently, regulations commission regulation (EU) 2015/1494 has amended Annex XVII to Regulation (EC) No 1907/2006 of
the European Parliament and of the Council concerning REACH about benzene.
REACH is a legislation applied to all industry sectors dealing with all chemicals used in industrial processes as well as in our day-
to-day lives for example in cleaning products, paints as well as in articles such as clothes, furniture and electrical appliances. The
benefits of the introduction of REACH system were twofold: reducing risks to human health and improving environmental quality
through the better and earlier identification of the properties of chemical substances. In fact, REACH requires to all companies infor-
mation included the substance’s identification, the hazards of the substance, the potential exposure arising from the manufacture or
import, the identified uses of the substance, and the operational conditions and risk management measures applied or recommen-
ded to downstream users. Among the content developed to support this information were Derived No-Effect Levels or Derived
Minimal Effect Levels (DNELs/DMELs) for human health hazard assessment, Predicted No Effect Concentrations (PNECs) for envi-
ronmental hazard assessment, and exposure scenarios for exposure and risk assessment.
If the risks cannot be managed, authorities can restrict the use of substances in different ways (e.g. limit or ban the manufacture,
placing on the market or use of a substance) until the most hazardous substances should be substituted with less dangerous ones.
Restrictions (listed is the Annex XVII to REACH) are a tool to protect human health and the environment from unacceptable risks
posed by chemicals.
 Benzene: Environmental Exposure 259

As regard to benzene, it was prohibited its placing on the market or its use as a substance or in mixtures, in concentrations equal
to or greater than 0.1% by weight. Additionally, the natural gas placed on the market for use by consumers shall have benzene
concentration below 0.1%. The final restriction is about toys, where benzene in the free state shall not be greater than 5 mg kg
1.
This last warning is important because is focused on particular high-risk groups: infants and young children. The old and the
young, pregnant women and their fetuses, the nutritionally deprived, and individuals suffering from some diseases (especially respi-
ratory or heart diseases) are the groups who are most vulnerable to the effects of air pollution.
In fact, in a given population, not all individuals are affected equally by the same environmental hazard and substantial vari-
ations in sensitivity may occur due to age, nutritional status, genetic predisposition, and state of general health, which become
important determinants of individual vulnerability. Often, only a small subset of the population may experience high levels of
exposure to air pollution, and the doses received by the general population are so low that only vulnerable high-risk groups are
severely affected. Therefore, it is crucial to identify these high-risk groups because they will usually be the first to experience adverse
health effects as the level of the pollutant increases.
In this contest, the spread of information about lesser- known benzene sources become essential most of all in non-occupational
environment.
As we have documented in the previous paragraph, the sources of benzene are numerous and heterogeneous both in outdoor
and indoor environments. In addition, benzene was also detected in many consumer products: for example in whiteout (until to
3170 ppm), glue (1486 ppm), oil-based ballpoint pens (47 ppm), and permanent (marking) pens (2 ppm). Finally, with regard to
personal habits, benzene concentration in water pipe smoke was 6.2-fold higher than those measured in cigarette smoke and the use
of incense or other flameless products can increase benzene concentration until to 200 mg m
3 in a poorly ventilated area such as
home.
Because of these several sources, non-occupational exposure assessment becomes very difficult due the variability of individual
lifestyles, the environmental and geographical conditions. Therefore, educational programs and awareness should be developed to
communicate the information about benzene sources and health risks associated in order to take or to participate in the preventive
actions.
Additionally, to reduce risk and consequently to preserve public health, there is also need to focus the research priorities in order
to investigate the environment from a more realistic point of view and find a linkage between the biomonitoring data and the key
toxicological endpoints.
Environmental benzene exposure should be monitored routinely among populations. However, in most studies, time-
integrated measurements at fixed point monitoring stations at urban background locations area used for monitoring trends in atmo-
spheric concentrations but also to evaluate the general pollution climate. Research on personal exposures to pollutants has shown
that the measurements at fixed point monitoring stations at urban background locations may not well represent the exposures of
individual members of the general population. Even though benzene personal exposure level cannot be calculated exactly as a time-
weighted average of outdoor and indoor mean concentrations owing to large hourly urban pollution oscillations, population expo-
sure depends on time spent outdoors, indoor pollution, and transportation mean. So various exposure patterns suggest that the
strategy of fixed point monitoring is insufficient to estimate population exposure and policy makers have to take into account these
differences in establishing guidelines for ambient benzene exposure.
Additionally, the derivation of toxicologically based biomarker concentrations can be used to evaluate biomonitoring data in
a risk assessment context.
Biomonitoring data can be used in multiple ways (e.g., trend analysis, exposure assessment, dose reconstruction) and the trends
in internal concentrations as well as the impact on vulnerable populations (i.e., highly exposed or highly susceptible to effects),
must be also considered. The following questions should be considered when designing, conducting, or interpreting studies for bio-
monitoring purposes:
a) Are there sufficient and relevant toxicology data?
b) Is there a relationship between the biomarker of exposure and a known human health effect?
c) Are there pharmacokinetic data that can be useful in the risk assessment?
d) If applicable, is there evidence that remediation efforts are working?
With regard to benzene, there are some data gaps most of all the lack of knowledge of its mechanism of action. While it is generally
accepted that the metabolism of benzene is required for the major toxicities of benzene to develop (i.e. hematotoxicity and cancer),
the actual metabolite/metabolites that are responsible for this event are not known. Therefore, several benzene metabolites should
be monitored simultaneously. This may be possible at high doses in animal models, but it would be problematic to translate this to
humans at current general population or occupational exposure levels since the contribution of these metabolites from benzene is
overwhelmed by other sources (e.g. diet) as a confounding factors.
Another important limitation when evaluating benzene biomonitoring data is the relatively short biological half-life of the
biomarkers of exposure. These biomarkers reflect only very recent exposure, and serial sampling indicates there is significant
daily/weekly intra-individual variability. To overcome the limitation of the short half-life of blood benzene and urinary benzene
and S-PMA, haemoglobin and plasma protein adducts of benzene metabolites are promising biomarkers of exposure because of
their longer half-life in the body. Unfortunately, they are not sensitive enough to monitor environmental exposures.
Additionally, longer-term research is needed to link these biomonitoring data with long-term health effects, but it will probably
be impractical unless a very quick, inexpensive, sensitive, specific, non-invasive method is developed.
260 Benzene: Environmental Exposure

Thus, more research is needed on whether biomarkers of benzene exposure can predict early key events. To improve the under-
standing of biomonitoring data, a number of considerations should be taken into account: the short half-life of benzene and metab-
olites in the body; the temporal intra-individual variability of benzene and metabolites; and the conservative nature of the
toxicological benchmarks.
A deeper interpretation of existing and future biomonitoring data will require rigorous, scientific approaches to data collection,
analysis, interpretation, and application. However, researcher must define and communicate the question to be addressed in any
given biomonitoring study. For example, the data required for the assessment and interpretation of exposure trends may be different
from those necessary for the assessment of health risk. Nonetheless, the existing data gaps add to the uncertainty of the interpreta-
tion of the biomonitoring data. Filling these critical data gaps is essential to reduce these uncertainties in interpretation, thus
providing the most reliable data for public health decisions.
Therefore, to maximize application and interpretation of biomonitoring data for human health risk assessment it is recommen-
ded that future studies should be designed with some or all of the following items:
a) to improve the understanding of the predictive relationships/linkages between measures of exposure, dose, and effect;
b) to emphasize biomarker validation and precision also performing inter-laboratory comparison trials;
c) to characterize a baseline for biomarkers, and apply statistical methods to assess temporal departures from the baseline;
d) to improve understanding of the origin of the biomarker and its relationship to the disease process and/or individual, multiple,
and exogenous or endogenous exposure (establish a database of biomarker disease associations, including null and negative
studies);
e) to improve study design to better assess intra and inter-individual variability related to measures of exposure, dose, metabolism,
and effects that would influence the likelihood of observing predictive relationships between these variables and aid in iden-
tifying subpopulations that might be at greater risk;
f) to apply new technologies such as gene expression, proteomics, and protein activity profiling, both in terms of development of
potential new biomarkers and as screening tools for identifying candidates for biomonitoring.

See also: Air Quality Legislation; Hazardous (Organic) Air Pollutants; Indoor Air Pollution: Unusual Sources; Oil and Chemical Spills.

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