International Journal ofEnvironmental Researchand Public Health

Systematic Review

Benzene Exposure and Lung Cancer Risk: A Systematic Review
and Meta-Analysis of Human Studies
Manuela Chiavarini 1 , Patrizia Rosignoli 2 , Beatrice Sorbara 2 , Irene Giacchetta 3 and Roberto Fabiani 1, *
1

2

3

*

Citation: Chiavarini, M.; Rosignoli, P.;
Sorbara, B.; Giacchetta, I.; Fabiani, R.
Benzene Exposure and Lung Cancer
Risk: A Systematic Review andMeta-Analysis of Human Studies. Int.

Department of Biomedical Sciences and Public Health, Section of Hygiene, Preventive Medicine and Public
Health, Polytechnic University of the Marche Region, 60126 Ancona, Italy; m.chiavarini@staff.univpm.it
Department of Chemistry, Biology and Biotechnology, University of Perugia, 06123 Perugia, Italy;
patrizia.rosignoli@unipg.it (P.R.); b.sorbara01@gmail.com (B.S.)
Department of Medicine and Surgery, Section of Public Heath, School of Hygiene and Preventive Medicine,
University of Perugia, 06123 Perugia, Italy; irene.giacchetta@auslromagna.it
Correspondence: roberto.fabiani@unipg.it

Abstract: Lung cancer is a leading cause of death with nearly 1.8 million deaths estimated worldwide
in 2020. Although benzene is classified as a human carcinogen (Group 1) on the basis of its association
with acute myeloid/non-lymphocytic leukaemia, there is still limited evidence that it may influencelung cancer risk. This study examined the potential link between benzene exposure and risk of lungcancer using a systematic review of epidemiological studies and meta-analysis. We searched throughPubMed, Web of Science and Scopus databases up to 10 February 2023 to identify all articles on theassociation between benzene exposure and lung cancer (incidence or prevalence) and/or mortality.
We extracted the risk estimates of the highest and the lowest reported categories of benzene exposureand conducted a meta-analysis using a random-effects model. Heterogeneity and publication bias
were analysed using an I2 test and funnel plots asymmetry, respectively. Twenty-one studies were
included in the final analysis, with a total of 10,750 lung cancer cases and 2899 lung cancer deaths.
Overall, risk estimates of lung cancer prevalence and mortality in association with benzene exposure
were 1.20 (n = 14; 95% CI 1.05–1.37) and 1.15 (n = 13; 95% CI 1.02–1.30), respectively. In all cases,
heterogeneity was quite large, while no significant publication bias was observed. When only studies
that adjusted for smoking habit were selected, the risk for lung cancer increased by up to 34%(n = 9; 95% CI 1.10–1.64). Our data, which show a strong association between benzene exposureand lung cancer risk, may have important public health implications. However, further studies
are needed to identify the lung cancer risk associated with benzene exposure considering different
smoking conditions.

J. Environ. Res. Public Health 2024, 21,205. https://doi.org/10.3390/

Keywords: benzene; lung cancer; mortality; incidence; occupational exposure; meta-analysis

ijerph21020205
Academic Editor: Zongwei Ma
Received: 21 December 2023

1. Introduction

Revised: 5 February 2024

Lung cancer is the second most commonly diagnosed cancer (more than 2.2 million
new cases diagnosed in 2020) and remains the leading cause of cancer death with nearly
1.8 million deaths estimated worldwide in 2020 (18.0% of the total cancer deaths) [1].
Incidence and mortality rates of lung cancer are roughly twice higher in men than inwomen, and three to four times higher in transitioned countries than in transitioning
countries. These differences are due to the different prevalence of cigarette smoking, whichis by far the strongest risk factor for lung cancer. Indeed, in the Western world more than
80% of lung cancer cases are attributable to smoking. However, this disease is multifactorial
and other determinants may significantly influence its incidence rate [2].
Occupational exposures and air pollution in living environments contribute to the burden of lung cancer with an attributable fraction estimated in the range 5–20% [3]. Indeed,
the International Agency for Research on Cancer (IARC) classified both outdoor air pollution and particulate matter (PM) as human carcinogens (Group 1) on the base of sufficient

Accepted: 7 February 2024
Published: 9 February 2024

Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Int. J. Environ. Res. Public Health 2024, 21, 205. https://doi.org/10.3390/ijerph21020205

https://www.mdpi.com/journal/ijerph

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epidemiological evidences derived especially from lung cancer [4]. Further supporting
this evidence, a recent meta-analysis reported a significant 14% and 7% increment of lungcancer mortality in association with PM10 and PM2.5 exposure, respectively [5]. Similarly, asignificant positive association between long-term outdoor nitrogen dioxide (NO2 ) exposure and lung cancer mortality in cohort studies was observed with an increment of risk of
8% [6].
In addition to PM and NO2 , polluted air contains other gas components such asvolatile organic compounds (VOCs) which may deeply influence human health. Among
different compounds classified as VOCs, benzene is certainly the most studied in relation to
its potential human adverse effects [7]. Benzene sources in the air can be both natural andanthropogenic. In the first case, sources include emission from forest fires and volcanoes.
Anthropogenic emission of benzene include the incomplete combustion of fossil fuelssuch as crude oil and gasoline, in industrial processes and motor vehicles [8]. In addition,benzene is widely used in chemical industries both as a solvent and as a reactant due toits primary importance for the synthesis of many compounds such as plastics, resins, andother fibres. Therefore, the large global demand for benzene stood at 52.94 million tonnes
in 2020, and it is expected to reach 76.04 million tonnes by 2030 [9].
Benzene remains in the vapor phase in the air. The lifetime of benzene in air ranges
from a few hours to days and is dependent on the environmental conditions and thepresence of other pollutants. The most important mode of degradation of benzene in
the environment is through oxidation by hydroxyl radicle and its subsequent removal byrain [8]. In spite of several efforts to control benzene pollution, it remains one of the mostdangerous contaminants in urban air. The maximum desirable value under the Directive
2008/50/EC on air quality in Europe is 5 µg/m3 which refers to the annual average
concentration in urban outdoor areas [8]. Due to its high volatility, human exposure tobenzene mainly occurs via inhalation. Benzene also penetrates skin, but the degree ofdermal absorption is rather low. Consequently, the ubiquity of benzene in the environment
makes human exposure widespread and unavoidable.
As early as 2012, IARC classified benzene as carcinogenic to humans (Group 1) on thebasis of its association with acute myeloid/non-lymphocytic leukaemia [10]. Accordingly,
several meta-analyses have recently documented the association between benzene exposureand different haematological malignancies [11,12]. A further 2018 IARC monograph has
confirmed the classification of benzene on Group 1 on the basis of sufficient evidence
demonstrating its carcinogenicity toward different organs of experimental animals [13].
However, the working group reported that there is still “limited evidence that benzene
causes lung cancer” [13].
Given that several epidemiological studies have investigated the potential effect ofbenzene on the onset of lung cancer with contrasting results, the aim of this study was
to rigorously examine the literature available reporting an association between benzene
exposure and human lung cancer risk. To this end, all studies reporting both prevalence andmortality risk for lung cancer in association with benzene exposure have been considered.
We understand that this paper is the first to examine the effect of benzene exposure on lungcancer risk through a systematic review and meta-analysis.
2. Materials and Methods
In this study, the standard procedures for conducting and reporting a meta-analysis
according to the COSMOS-E (Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology) statement were followed [14]. The study protocol was
registered in the International Prospective Register of Systematic Reviews (www.crd.york.
ac.uk/PROSPERO/, registration No: CRD42023398500) (accessed on 21 February 2023).
We defined the PECO (Population, Exposure, Comparator, Outcome) questions asfollows: participants were the general population or populations exposed to benzene;
exposure was the exposure concentration of benzene; comparison subjects were thosewith the lowest benzene exposure; outcomes were lung cancer incidence or mortality [15].

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In other words, is the higher dose compared with the lower dose of benzene exposure
associated with lung cancer incidence or mortality?
2.1. Search Strategy and Data Source
A comprehensive literature search, without restrictions, was carried out until 10
February 2023 using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) (accessed on 10
February 2023), Web of Science (http://wokinfo.com/) (accessed on 10 February 2023),
and Scopus (https://www.scopus.com/) (accessed on 10 February 2023) databases to
identify all original articles on the association between benzene exposure and lung cancer(oncidence or prevalence) and/or mortality. The following key words were used: (cancer
OR tumour OR neoplasm OR “neoplastic disease” OR mortality) AND benzene ANDlung. In addition, to identify additional relevant publications, we manually examined thereference lists of the included articles and recent relevant reviews.
2.2. Selection Criteria
Of the selected articles, only those that met the following criteria were included: (i) cohort, case-control, and cross-sectional or descriptive (ecological) study design; (ii) evaluatedthe association between benzene exposure and risk of lung cancer (incidence or prevalence)and mortality; and (iii) presented odds ratio (OR), relative risk (RR), hazard ratio (HR), incidence rate ratios (IRR), and standardized incidence/mortality ratio (SIR/SMR) estimateswith 95% confidence intervals (CI). Studies that reported lung cancer risk in occupationally
exposed subjects without identifying those specifically exposed to benzene were excluded.
Independently, two authors evaluated titles and abstracts, and the studies meeting theinclusion criteria were selected for further full-text analyses. A third author helped toresolve any discrepancies after careful discussion. The publication with the highest numberof cases was selected when there were several publications of the same study. The list of
selected studies, the removal of duplicates, and the selection of studies of interest weremanaged with Zotero.
2.3. Data Extraction and Management
From each selected study, we extracted the following information: the first author’s
last name, year of publication, and country; the study design and name (if any); sample
size (incident/prevalent cases, number of cases/controls/death); age; duration of followup for cohort studies; exposure assessment method; types of lung cancer; benzene dosecomparisons; risk estimated (OR, RR, HR, IRR, SIR, SMR) with 95% confidence intervals; p
for trend (in the case of dose-response data); and variables used to adjust the risk value. If
more than one risk value was reported, we selected the one obtained by taking into accountthe greatest number of confounding factors (full-adjusted model).
2.4. Assessment of the Level of Evidence
To assess the quality of the evidence, the GRADE methodology for environmental andoccupational health studies was used [15,16]. For each study, the risk of bias was definedusing a modified version of ROBINS-I as reported previously [17,18]. The following sevenaspects were considered: confounding factors, participant selection, exposure classification,
deviation from intended exposures (change of exposure levels over time), missing data,measurement of outcomes, and the reported results selection [17,18]. At the end, we
classified the quality of evidence as follows: high, moderate, low, or very low.
2.5. Statistical Analysis
The overall effect-size statistic estimated was carried out considering the risk of lungcancer associated with the highest versus the lowest level of benzene exposure. Due tothe different techniques used in various studies to express exposure to benzene, it was notpossible to standardize the exposure parameters prior to conducting the meta-analysis. In
the case of the study that assessed benzene exposure using urinary biomarkers, similarly toInt. J. Environ. Res. Public Health 2024, 21, 205

4 of 22the other cases, we extracted the risk values for the highest quartile of exposure. The risk
values of the multivariable models were selected by considering those that took into accountthe greatest number of potential confounding variables. Due to the high heterogeneity, arandom-effects model and inverse variance weighting methods were used to calculate thesum of RR/OR and the 95% confidence intervals. An effect was considered statisticallysignificant when a two-tailed p < 0.05 was obtained. The heterogeneity across studies wasevaluated using both a chi-square-based Cochrane’s Q statistic and the I2 statistic [19]. The
I2 value can range from 0 to 25% (indicating no heterogeneity), from 25 to 50% (indicating
moderate heterogeneity), from 50 to 75% (indicating large heterogeneity), and from 75 to
100% (indicating extreme heterogeneity) [20].
Since the publication probability depends on the results obtained in the study, thedata of the meta-analysis can be influences by so-called “publication bias”. To quantify thispublication bias, we used the methods previously reported by Begg and Mazumdar [21]and by Egger et al. [22]. The graphical observation of the funnel plot asymmetry is at thecore of both methods. In the first case, the method considers the rank correlation between
the effect estimates and their sampling variances [21]. In the second case, the method
considers the intercept from the regression of standard normal deviates against precision.
The funnel plot was considered asymmetric when the intercept of Egger’s regression line
deviated from zero, with p values <0.05. When a potential bias was highlighted, a further
sensitivity analysis was conducted to assess the robustness of the combined effect estimates.
A sensitivity analysis was also performed to highlight the influence of a single study
on the overall risk estimate. One single study at a time was omitted; the results obtained
were reported. All analyses were carried out using the statistical program ProMeta version
3.0 available online from Internovi (Cesena, Italy).
3. Results
3.1. Study Selection
The primary literature search, carried out on three different databases (PubMed:n = 392, Web of Science: n = 605 and Scopus: n = 926) produced a total of 1923 items. Afterthe removal of 643 duplicates, 1280 records were selected for revision on the basis of theirtitle and abstract (Figure 1).
This procedure led us to exclude 1252 articles because they were not epidemiologicalstudies reporting data regarding the effect of benzene exposure on lung cancer risk. The
remaining twenty-eight items were read in full. From the analysis, the reference lists ofthese articles, and considering also the relevant reviews recently published, we identified
five interesting publications to include. Afterwards, 12 items did not meet the inclusion
criteria and were barred. The exclusion reasons were as follows: three studies did not report
the 95% confidence intervals; seven did not report the risk of lung cancer associated withbenzene exposure; one study reported that lung cancer death correlated with exposure tobenzene, considering only the contaminated drinking water; one study reported duplicatedresults of another further study. Therefore, at the end of the selection process, 21 studies
were selected [23–43], and used for the systematic review and meta-analysis (Figure 1).
3.2. Study Characteristics
The general characteristics of the 21 studies, published between 1983 and 2022, that
evaluated the association between benzene exposure and lung cancer risk were extracted
from the original articles (Table 1).

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Figure 1. Flow diagram of the systematic literature search on benzene exposure patterns and lungcancer risk.

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Table 1. Characteristics of the studies included in the systematic revision and meta-analysis on the association between benzene exposure and lung cancer risk.

First Author,
Year
Location
Reference

Study Design, Name
and Population
Cases/Controls
Incident Cases
Dead
Age
Follow-Up

Cheng et al., 2022
USA
[23]

CohortMultiethnic cohort
study (MEC)
Population: 97,288
Incident cases: 2796
Age: 45–75 years
Follow-up: 17 years

Residential exposure
Air-monitoring data

All types
Incidence

Exposed1 ppb increment

Men + Women (HR)
1.17 (1.02–1.34)

Age, race/ethnicity, sex, education,
marital status, smoking, family
history of lung cancer, occupation,socioeconomic status, nonsteroidal
anti-inflammatory drugs, body massindex, alcohol, physical activity,
energy intake, meat intake.

Khorrami et al., 2021
Iran
[24]

Descriptive (ecologic,
follow-up)
Population: 9,134,708
Incident cases: 1653
Age: median 65.5 years
Follow-up: 3 years

Residential exposure
Land use regression
modelsAll types
Incidence

Exposed
10 µg/m3 increment

Men + Women (IRR)
3.86 (1.55–9.60)

Age, sex, socioeconomic status, life
expectancy, smoking prevalenceUnexposedEver exposed
UnexposedEver exposed
UnexposedEver exposed
UnexposedEver exposed

Men (OR)
1.00 (Ref.)
1.35 (0.99–1.84)
1.00 (Ref.)
1.35 (0.90–2.02)
1.00 (Ref.)
1.36 (0.92–2.00)
1.00 (Ref.)
1.51 (0.88–2.56)

Age, smoking (CSI: cumulativesmoking index), respondent status,
ethnolinguistic group, years ofeducation, median household income
as well as Groups 1 and 2A
occupational carcinogens: diesel
engine emissions, crystalline silica,coke dust, coal dust, and welding
fumes.

Assessment ofExposure

Types of Lung Cancer
Incidence/
Mortality

OR/RR/HR/IRR
Benzene Exposure

CI)

All types

Warden et al., 2018
Canada[25]

Population based
case–control (Male)
Cases: 894
Age: 64.2 ± 7.8 years
Controls: 733
Age: 65.0 ± 7.6 years

Incidence
Occupational exposure
Interview: lifestyle andjob features

Adenocarcinoma
Squamous carcinoma
Small cell carcinoma

1 /SMR 2 /SIR 3 (95%

Matched or Adjusted
Variables

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Table 1. Cont.
Study Design, Name
and Population
Cases/Controls
Incident Cases
Dead
Age
Follow-Up

Assessment ofExposure

Collarile et al., 2017
Italy
[26]

Descriptive (follow-up)
Incident cases:
801 men
275 women
All age
Follow-up: 15 years

Residential exposure
Integrated approachbased on punctual
observations (local
environmental
monitoring systems)
and numericalsimulated fields

Mattei et al., 2016
France[27]

Population based
case–control (Male)ICARE 4 study
Cases: 2260
Age: 60 ± 9.1 years
Controls: 2780
Age: 58 ± 79.9 years

Occupational exposure
Interview: lifestyle
behaviours and job
featuresJob-exposure matrices(JEM)

Linet et al., 2015
China
[28]

Retrospective cohort
73,789 exposed
Dead: 351
35,504 unexposed
Dead: 119
Follow-up: 28 years
Age > 12 y at start offirst exposure

Occupational exposure
Factory and job
title-specificinformation on use ofbenzene containing
materials

All types
Mortality

Collins et al., 2015
USA
[29]

Retrospective cohort
2266 workers
Dead: 146
Follow-up: >30 years

Occupational exposure
Job-specific exposures

All types
Mortality

First Author,
Year
Location
Reference

Types of Lung Cancer
Incidence/
Mortality

All types
Incidence

All types
Incidence

OR/RR/HR/IRR
Benzene Exposure

1 /SMR 2 /SIR 3 (95%

CI)

µg/m3
<1.1
1.1–1.8>1.8

Matched or Adjusted
Variables

None

<1.1
1.1–1.8>1.8

Men (IRR)
1.00 (Ref.)
1.03 (0.87–1.22)
1.02 (0.86–1.21)
Women (IRR)
1.00 (Ref.)
1.09 (0.81–1.46)
1.12 (0.83–1.52)

Unexposed
Low
MediumHigh

Men (OR)
1.00 (Ref.)
1.29 (0.92–1.80)
1.14 (0.80–1.60)
0.97 (0.70–1.35)

Age, exposure to asbestos (CEI:
Cumulative Exposure Index),
smoking (CSI: Comprehensive
Smoking Index)

Age, sex, attained calendar year

Unexposed
ExposedMen (RR)
1.00 (Ref.)
1.5 (1.2–1.9)
Woman (RR)
1.00 (Ref.)
1.5 (0.9–2.5)

Cumulative:≥25 ppm per year

Men + Women (SMR)
1.05 (0.89–1.24)

None

Unexposed
ExposedInt. J. Environ. Res. Public Health 2024, 21, 205

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Table 1. Cont.

First Author,
Year
Location
Reference

Study Design, Name
and Population
Cases/Controls
Incident Cases
Dead
Age
Follow-Up

Assessment ofExposure

Yuan et al., 2014
China
[30]

Nested case–control
Shanghai
Cohort Study
Cases: 82
Age: 58.1 ± 5.2 years
Controls: 83
Age: 58.0 ± 5.4 years
Lifelong neversmokers

Exposure biomarker(S-phenyl mercapturicacid) in urine

All types
Incidence

Koh et al., 2014
Korea
[31]

Retrospective cohort
14,698 male
Incident cases: 5
Death: 9Age: 20–72 years
Follow-up: 4–6 years

Occupational exposure
Workers of refinery/petrochemicalcomplex

All types
Incidence
Mortality

Villeneuve et al.,2014
Canada[32]

Case–control
Cases: 445
Age: median 66 years
Controls: 948
Hospital: 523, 50 years
Population: 425
59 years

Residential exposure
Land use regression
modelInterview: lifestyle
behaviours

Types of Lung Cancer
Incidence/
Mortality

All types
Incidence

OR/RR/HR/IRR
Benzene Exposure

1 /SMR 2 /SIR 3 (95%CI)

Quartile 1
Quartile 2
Quartile 3
Quartile 4

ExposedInterquartile-Range
Increase
0.15 µg/m3

Matched or Adjusted
Variables

Men (OR)
1.00
1.03 (0.39–2.69)
1.10 (0.44–2.78)
1.57 (0.65–3.80)

Age at baseline, neighbourhood ofresidence at enrolment, years ofsample storage, urinary cotinine level
Never smokers

Men (SIR)
0.73 (0.24–1.71)
Men (SMR)
0.68 (0.31–1.29)

None

Men + Woman (OR)Population controls
1.84 (1.26–2.68)

Age, sex, pack-years of smoking,exposure to second-hand smoke,
body mass index, family history ofcancer, and neighbourhood
measures of unemployment andmedian family income

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Table 1. Cont.

First Author,
Year
Location
Reference

Study Design, Name
and Population
Cases/Controls
Incident Cases
Dead
Age
Follow-Up

Villeneuve et al.,2013
Canada[33]

Cohort“Ontario Tax Cohort
study”
29,600 men
29,150 womenDead: 1410
Age: >35 years
Follow-up: 22 years

Yuan et al., 2012
China
[34]

Nested case–control
Shanghai
Cohort Study
Cases: 343
Age: 69.4 ± 6.3 years
Controls: 392
Age: 69.1 ± 6.0 years
All Smokers

Exposure biomarkers(S-phenyl mercapturicacid) in urine

All types
Incidence

Koh et al., 2011
Korea
[35]

Retrospective cohort
8866 male
Incident cases: 8
Dead: 5
Follow-up:
Mortality 16 years
Incidence 9 years
Age: 20–74 yOccupational exposure
Work history inrefinery andpetrochemicalcompanies

All types
Incidence
Mortality

Assessment ofExposure

Residential exposure
Land use regression
model

Types of Lung Cancer
Incidence/
Mortality

All types
Mortality

OR/RR/HR/IRR
Benzene Exposure

1 /SMR 2 /SIR 3 (95%

CI)

Interquartile-Range
increase
0.13 µg/m3

Quartile 1
Quartile 2
Quartile 3
Quartile 4

ExposedMatched or Adjusted
Variables

Men + Women (RR)
1.05 (0.96–1.14)

Age, sex, family income, marital
status, census area measures ofincome, immigration, unemployment,
land use
regression estimate of NO2 . Indirect
adjustment for smoking and bodymass index.

Men (OR)
1.00
1.46 (0.91–2.35)
1.94 (1.23–3.07)
1.80 (1.14–2.85)

Age, neighbourhood of residence, andduration of biospecimen storage
before laboratory analysis, number ofcigarettes smoked per day, andnumber of years of smoking
at baseline

Men (SIR)
0.60 (0.26–1.17)
Men (SMR)
0.35 (0.11–0.83)

NoneInt. J. Environ. Res. Public Health 2024, 21, 205

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Table 1. Cont.

First Author,
Year
Location
Reference

Study Design, Name
and Population
Cases/Controls
Incident Cases
Dead
Age
Follow-Up

Assessment ofExposure

Types of Lung Cancer
Incidence/
Mortality

McHugh et al., 2010
USA
[36]

Case–control
Mexican-Americans
Cases: 38
Age: 63.8 ± 11.0 years
Controls: 51
Age: 61.5 ± 12.8 years

Occupational exposure
Self-reported
responses

All types
Incidence

Sorahan et al., 2005
UK
[37]

Cohort4740/5130 Men
352/384 Women
Incident cases: 293
Death: 294
Follow-up: 30 years

Occupational exposure
Type of industry

All types
Incidence
Mortality

Collins et al., 2003
USA
[38]

Retrospective cohort
4417 workers
Dead: 252
Follow-up: >30 years

Occupational exposure
Job type at thedifferent plants

All types
Mortality

OR/RR/HR/IRR
Benzene Exposure

1 /SMR 2 /SIR 3 (95%CI)

Matched or Adjusted
Variables

Men + Women (OR)1.00 (Ref.)
1.13 (0.69–1.86)

Age, sex, and smoking

Exposed ≥ 25 ppm

Men + Women (IRR)
1.19 (1.06–1.34)
Men + Women (SMR)
1.21 (1.07–1.35)

None>100 ppm per day

Men + Women (SMR)
1.6 (1.1–2.3)

None

Unexposed
ExposedInt. J. Environ. Res. Public Health 2024, 21, 205

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Table 1. Cont.

First Author,
Year
Location
Reference

Study Design, Name
and Population
Cases/Controls
Incident Cases
Dead
Age
Follow-Up

Assessment ofExposure

Types of Lung Cancer
Incidence/
Mortality

OR/RR/HR/IRR
Benzene Exposure

CI)

All types
Incidence

Gerin et al., 1998
Canada[39]

Population-based
case–control (Men)Cases: 857
Controls: 1349
Age: 35–70 years

Occupational exposure
Interview: lifestyle
behaviours and job
features

Adenocarcinoma

Squamous carcinoma

Small cell carcinoma

Yin et al., 1996
China
[40]

CohortMen and woman
Exposed: 74,828
38,833 men
35,995 women
Follow-up: 10.5 years
Unexposed: 35,805
20,795 men
15,010 women
Follow-up: 11.7 years
Dead: 125Occupational exposure
Type of industry

All types
Mortality

1 /SMR 2 /SIR 3 (95%

Unexposed
Low
MediumHigh
Unexposed
Low
Medium/High
Unexposed
Low
Medium/High
Unexposed
Low
Medium/High

Unexposed
ExposedUnexposed
ExposedMatched or Adjusted
Variables

Men (OR)
1.00 (Ref.)
1.1 (0.8–1.5)
0.8 (0.5–1.3)
0.7 (0.3–1.7)
1.00 (Ref.)
1.1 (0.6–1.8)
0.9 (0.4–1.9)
1.00 (Ref.)
1.3 (0.9–1.9)
1.2 (0.7–2.1)
1.00 (Ref.)
1.10 (0.6–1.9)
0.30 (0.1–0.9)

Age, family income, ethnic group,
cigarette smoking, respondent status,arsenic, asbestos, chromium VI,
nickel, crystalline silica, beryllium,
cadmium, polycyclic aromatichydrocarbons

Men (RR)
1.00 (Ref.)
1.50 (1.0–2.2)
Women (RR)
1.00 (Ref.)
1.00 (0.4–2.9)

AgeInt. J. Environ. Res. Public Health 2024, 21, 205

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Table 1. Cont.

First Author,
Year
Location
Reference

Study Design, Name
and Population
Cases/Controls
Incident Cases
Dead
Age
Follow-Up

Assessment of Exposure

Types of Lung Cancer
Incidence/
Mortality

Greenland et al., 1994
USA
[41]

Case–control
Case: 139 lung cancer
death
Control: 1202 non-cancer
death
Age: 21–90 years

Occupational exposure
Job history records

All types
Mortality

Wong 1987
USA[42]

Historical prospective
7676 Men
Dead: 47
Follow-up: 32 years

Occupational exposure
Chemical workers

All types
Mortality

Tsai et al., 1983
USA
[43]

Retrospective cohort
454 Men
Dead: 2Age: average at entry
33.8 years
Follow-up: 13 years

Occupational exposure
Workers in benzene
processes or operations

All types
Mortality

OR/RR/HR/IRR 1 /SMR
2 /SIR 3 (95% CI)

Matched or Adjusted
Variables

Men (RR)
1.00 (Ref.)
0.58 (0.31–1.07)

None

ExposedMen (SMR)
1.12 (0.90–1.39)

Age, race, sex, calendar
time

Exposed1.34 ± 1.39 ppm

Men (SMR)
0.52 (0.06–1.86)

NoneBenzene Exposure

Unexposed
Exposed

1 Incidence rate ratios; 2 standardized mortality ratios; 3 standardized incidence ratio; 4 investigation of occupational and environmental causes of

respiratory cancers.

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Eleven studies considered lung cancer incidence or prevalence [23–27,30,32,34,36,
37,39], eight studies reported lung cancer mortality [28,29,33,38,40–43], and three studies
reported both incidence or prevalence and mortality [31,35,37]. The indices used to estimate
lung cancer risk associated with benzene exposure were OR in seven studies [25,27,30,32,34,
36,39], RR in four studies [28,33,40,41]), HR in one study [23]), IRR in two studies [24,26]),
and SIR/SMR in seven studies [29,31,35,37,38,42,43]. Overall, 10,750 lung cancer cases and2899 lung cancer deaths were considered.
Very importantly, of the 21 selected studies, only 10 considered cigarette smoking as avariable to adjust lung cancer risk values [23–25,27,30,32–34,36,39].
Regarding benzene exposure, fourteen studies evaluated occupational exposure [25,27–
29,31,35–43], five evaluated residential exposure [23,24,26,32,33], and two evaluated general
exposure using a biomarker [30,34]. In particular, in eight studies the concentration ofbenzene exposure was not reported; the subjects were simply classified as unexposed andexposed [25,28,31,35,36,40–42]. In three studies the benzene exposure was expressed as
ppm [37,38,43], while in four studies the benzene exposure was reported as an increment
expressed either as ppb or µg/m3 [23,24,32,33]. Only one study reported the cumulative
benzene exposure [29], whereas the remaining five studies reported a dose-dependent lungcancer risk according to the exposure intensity and dividing the population in tertiles [26],quartiles [30,34], and different levels of exposure (low, medium, and high) [27,39].
Of the 21 selected studies, only 2 reported risk values stratified by the histologic typeof lung cancer [25,39]. Ten studies were conducted on men [25,27,30,31,34,35,39,41–43],
eight on men and women together [23,24,29,32,33,36–38], and three studies were conducted
on men and women separately [26,28,40].
Regarding the study designs, six were case-control studies, of which five consideredlung cancer disease [25,27,32,36,39] and one considered mortality [41]. In addition, twowere “nested” case-control studies that used the concentration of S-phenylmercaptic acid inurine as biomarker to estimate benzene exposure. Of these, the first study was conducted
for non-smokers [30], while the second study was conducted for smokers [34]. All theother 13 studies can be grouped as “cohort studies”; although, they were conductedwith different methodological approaches, as shown below. Six were retrospective cohort
studies [28,29,31,35,38,43], all looking at lung cancer mortality with a total of 884 deaths.
Four were cohort studies, two on lung cancer mortality [33,40], one on incidence [23], andone on both incidence and mortality [37]. The two descriptive studies were “spatial” andconsidered the lung cancer prevalence in the entire population of Tehran (Iran) [24] andMonfalcone with 13 surrounding municipalities (Italy) [26], respectively. In both studies,lung cancer risk was expressed as IRR based on 2,729 lung cancer cases. One study wasdefined as a historical prospective [42].
Finally, regarding the region, seven studies were conducted in the United States [23,29,36,38,41–43], four in Canada [25,32,33,39] and China [28,30,34,40], two in Korea [31,35],
and one each in Iran [24], Italy [26], France [27], and the United Kingdom [37].
3.3. Risk of Bias
In general, most studies considered for inclusion in the meta-analysis may be at riskof bias. In our case, 9 studies had a risk of bias that was considered “serious”, and for the
12 remaining studies, the risk of bias was “critical” (Supplementary Materials, Table S1).
The serious or critical risk of bias registered for the studies included in our meta-analysis
was primarily due to the use of an inappropriate analysis method that controlled forimportant confounding variables, which in many cases were not appropriately measured.
3.4. Meta-Analysis
The overall analysis (pooling incidence and mortality risk values) of the 21 studies
pooled together (n = 27) yielded a combined risk estimate for lung cancer in association tobenzene exposure of 1.17 (95% CI 1.08–1.28; p < 0.001). Analysing data separately resulted
in an increased risk of 20% (1.20; 95% CI 1.05–1.37; p = 0.007) (Figure 2a) and 15% (1.15; 95%

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CI 1.02–1.30; p = 0.023) (Figure 2b) for lung cancer incidence or prevalence and mortality,
respectively. Heterogeneity was quite large with an I2 of 54.19 and 56.55 for incidence andmortality, respectively (Table 2).

Figure 2. Forest plots showing the lung cancer risk expressed considering incidence and prevalence(a) [23–27,30–32,34–37,39] and mortality; (b) [28,29,31,33,35,37,38,40–43] associated with the highest
benzene exposure compared with the lowest benzene exposure.

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Table 2. Results of combined lung cancer risk estimates, heterogeneity, and publication bias, stratified
according to different variables and associated with the highest benzene exposure compared with thelowest benzene exposure 1 .
Combined Risk Estimate
ALL (n = 27) 2
Smoking
Adjusted (n = 10)
Not adjusted (n = 17)
Exposure
Residential (n = 6)
Occupational (n = 19)
Others: biomarkers (n = 2)
Sex
Men (n = 15)
Women (n = 3)
Men and Women (n = 9)
Study design
Case Control (n = 8)
Cohort (n = 19)
Continent
North America (n = 11)
Asia (n = 11)
Europe (n = 5)
INCIDENCE (n = 14)
Smoking
Adjusted (n = 9)
Not adjusted (n = 5)
Exposure
Residential (n = 5)
Occupational (n = 7)
Others: biomarkers (n = 2)
Sex
Men (n = 8)
Women (n = 1)
Men and Women (n = 5)
Study design
Case Control (n = 7)
Cohort (n = 7)
Continent
North America (n = 5)
Asia (n = 5)
Europe (n = 4)
MORTALITY (n = 13)
Smoking
Adjusted (n = 1)
Not adjusted (n = 12)
Exposure
Residential (n = 1)
Occupational (n = 12)
Others: biomarkers (n = 0)
Sex
Men (n = 7)
Women (n = 2)
Men and Women (n = 4)

Test of Heterogeneity

Publication Bias

Value (95% CI)

p

Q

I2 %

1.17 (1.08–1.28)<0.001

56.79

54.22

0.0004

0.906

0.574

1.26 (1.08–1.48)
1.13 (1.02–1.26)

0.005
0.021

24.02
32.20

62.81
50.31

0.004
0.009

0.077
0.105

0.245
0.161

1.19 (1.02–1.39)
1.14 (1.03–1.27)
1.75 (1.16–2.63)

0.030
0.015
0.007

17.10
33.16
0.07

70.76
45.71
0.00

0.004
0.016
0.788

0.051
0.052
---

0.091
0.086
---

1.07 (0.90–1.28)
1.19 (0.93–1.54)
1.20 (1.08–1.34)

0.428
0.168
0.001

32.81
1.06
22.75

57.34
0.00
64.84

0.003
0.588
0.004

0.136
0.900
0.029

0.299
0.602
0.144

1.21 (0.93–1.57)
1.15 (1.06–1.26)

0.159
0.001

17.03
38.43

58.89
53.16

0.017
0.003

0.498
0.970

0.458
0.506

1.15 (1.02–1.29)
1.23 (0.92–1.63)
1.15 (1.07–1.24)

0.022
0.157
<0.001

21.18
24.64
4.02

52.79
59.42
0.48

0.020
0.006
0.403

0.772
0.179
0.178

0.938
0.073
0.142

1.20 (1.05–1.37)

0.007

28.38

54.19

0.008

0.799

0.784

1.34 (1.10–1.64)
1.06 (0.89–1.27)

0.005
0.494

17.90
8.00

55.31
49.98

0.022
0.092

0.282
0.096

0.297
0.142

1.28 (1.02–1.61)
1.08 (0.89–1.30)
1.75 (1.16–2.63)

0.031
0.460
0.007

14.66
9.80
0.07

72.72
38.75
0.00

0.005
0.134
0.788

0.114
0.067
---

0.142
0.051
---

1.09 (0.86–1.38)

0.492

14.64

52.20

0.041

0.719

0.458

1.32 (1.09–1.60)

0.005

11.31

64.64

0.023

0.125

0.142

1.32 (1.05–1.66)
1.12 (0.96–1.32)

0.019
0.147

10.72
15.21

44.02
60.54

0.097
0.019

0.850
0.743

0.881
0.176

1.28 (1.04–1.56)
1.29 (0.64–2.59)
1.12 (1.02–1.22)

0.018
0.481
0.013

6.97
14.78
2.92

42.64
72.93
0.00

0.137
0.005
0.405

0.864
0.481
0.348

1.000
0.142
0.497

1.15 (1.02–1.30)

0.023

27.62

56.55

0.006

0.838

0.542

1.17 (1.01–1.35)

0.037

23.11

52.41

0.017

0.314

0.273

1.17 (1.01–1.35)

0.037

23.11

52.41

0.017

0.314

0.273

1.03 (0.77–1.37)
1.38 (0.87–2.17)
1.14 (1.00–1.29)

0.867
0.167
0.049

17.14
0.51
8.24

64.99
0.00
63.61

0.009
0.476
0.041

0.079
--0.4200.293--0.174p

p (Egger Test)

p (Begg Test)

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Table 2. Cont.
Combined Risk Estimate

Study design
Case Control (n = 1)
Cohort (n = 12)
Continent
North America (n = 6)
Asia (n = 6)
Europe (n = 1)

Test of Heterogeneity

Publication Bias

Value (95% CI)

p

Q

I2 %

1.17 (1.05–1.32)

0.006

23.18

52.55

0.017

0.818

0.583

1.07 (0.93–1.24)
1.21 (0.91–1.61)

0.343
0.199

9.54
9.62

47.58
48.02

0.089
0.087

0.796
0.073

0.573
0.039

p

p (Egger Test)

p (Begg Test)

1 The risk estimates were calculated using the random-effects model. 2 Amount of data used to calculate the risk.

In bold are the statistically significant risk values, and highlighted in gray are the related p values.

Additional results of the stratified analysis were performed according to smoking
status (considered as a confounding variable and used to adjust cancer risk values), typeof benzene exposure, sex, study design, and region (Table 2). When smoking status wasconsidered, the risk increased to 26% (1.26; 95% CI 1.08–1.48; p = 0.005) and 34% (1.34; 95%
CI 1.10–1.64; p = 0.005) for all studies and for incidence studies, respectively. Heterogeneity
was evident in both cases (I2 62.81 and 55.31). Stratifying the analysis according to thetype of benzene exposure (Residential/Occupational) and the increment of lung cancer
risk resulted in being statistically significant in both cases (Table 2). Furthermore, when
S-phenylmercaptic acid in urine was used as biomarker to estimate benzene exposure (onlytwo studies), a statistically significant 75% increased risk was observed (p = 0.007). On theother hand, stratification based on sex produced a significant increment of the lung cancer
risk only in the group where males and females were considered together (Table 2).
Regarding the study design, pooling together the eight case-control studies, with a
total of 4919 cases and 6336 controls, the increment of lung cancer risk (+21%) resulted inbeing not statistically significant when considering all studies, while becoming significant(+32%) when considering only the incidence and prevalence studies (1.32; 95% CI 1.05–1.66;
p = 0.019) (Table 2). In this case, heterogeneity was moderate (I2 = 44.02%, p = 0.097).
Conversely, in the case of cohort studies the increment of lung cancer risk was statisticallysignificant when considering all studies (1.15; 95% CI 1.06–1.26; p = 0.001) and mortality
studies (1.17; 95% CI 1.05–1.32; p = 0.006), but was not significant when considering theincidence and prevalence studies (1.12; 95% CI 0.96–1.32; p = 0.147) (Table 2). Again,
heterogeneity was quite high.
Finally, stratifying according to the continent where the study was conducted, statistically significant incidence results were obtained in both North America and Europe, but
not in Asia (Table 2).
3.5. Publication Bias
Considering the pooled data, and applying both the Egger and Begg tests (Table 2), andfunnel plots asymmetry, no evident publication bias could be detected for lung cancer riskreferred to in the incidence/prevalence studies (Figure 3a) and mortality studies (Figure 3b).
In the strata analysis, the Egger test suggested a significant publication bias in the case of
all studies that referred to males and females together (p = 0.029), while the Begg test gave
a positive result on mortality in Asia (p = 0.039) (Table 2). No other significant publicationbiases were observed (Table 2).

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Figure 3. Funnel plots of the meta-analysis on lung cancer incidence/prevalence (a) and mortality(b) risk.

3.6. Sensitivity Analysis
Investigation into the effect that a single study can have on the value of lung cancer
risk suggested that estimates were in some cases changed by a single study. The removalof Greenland et al. 1994 [41] and Koh et al.’s 2011 [35] studies increased the risk values,
which in some cases become statistically significant (Supplementary Material, Table S2).
In particular, the removal of Greenland et al. 1994 [41] caused the increment of pooledrisk in the case–control subgroup (1.32; 95% CI 1.05–1.66; p = 0.019), while the removal of
Koh et al. 2011 [35] caused the increment of incidence risk in the cohort subgroup (1.15;
95% CI 1.01–1.31; p = 0.037) (Supplementary Table S2). Conversely, the removal of studies
by Warden et al. 2018, Villenueve et al. 2014, and Sorahan et al. 2005 [25,32,37] caused
a decrease of lung cancer risk which becomes in some cases not statistically significant(Supplementary Material, Table S2).
4. Discussion
To the best of our knowledge, this is the first systematic review and meta-analysis
to summarize the relationships between benzene exposure and lung cancer risk. We
considered data regarding both lung cancer incidence/prevalence and mortality, andanalysed them both together and separately. We found a statistically significant association between benzene exposure and lung cancer risk in studies both considering theincidence/prevalence and mortality. In this last case, stratification based on the study
design (exclusion of the single case–control study) resulted in an increment of mortality
risk for lung cancer in the cohort studies. It should be considered, however, that these
conclusions are based on a “low” level of evidence as shown using the GRADE approach.
Although more than 80% of all new cases are attributable to smoking, lung cancer
is a multifactorial disease, which may be influenced by other important determinants.
The increment in recent years of lung cancer incidence in never smokers indicates that
other important risk factors need to be investigate [44]. Accordingly, several recent metaanalyses have suggested that different air pollutants, in particular PM10 /PM2.5 and NO2 ,also contribute significantly to the increment of lung cancer incidence and mortality [5,6].
Even more important to consider is the deleterious effects that occupational exposure(gases/fumes, vapours, dusts, fumes, and aromatic solvents) may have on the decline oflung function and cancer [45]. Our meta-analysis further support this evidence, showingthat exposure to benzene, an important compound belonging to the VOCs class and present
both in the polluted urban/industrial air and in the working place, is associated with astatistically significant 20% increment of lung cancer risk (expressed as incidence rate). Ourdata also confirm and support the latest IARC classification, which included benzene inGroup 1 as a human carcinogen, based primarily on its hematotoxic and leukemogenic

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properties [13]. The important role played by smoking on lung cancer incidence is also
evident from the data reported in the present study. In fact, the stratified analysis yielded astatistically significant 34% increase in lung cancer incidence in association with benzene
exposure only when considering studies adjusted for smoking, whereas no effect wasevident when considering studies not adjusted for smoking (Table 2). However, in theanalysis of lung cancer mortality, based mainly on data unadjusted for smoking habits, we
still observed a statistically significant increase in risk (Table 2). Unfortunately, most of themortality studies (11 of 12) did not contain information on smoking habits, making theresults not particularly reliable in this context.
As the above reported, more incisive are our results on lung cancer incidence/prevalence.
In this case, the stratified analysis according to the type of exposure (residential vs. occupational) showed a statistically significant 28% increase of risk in association with residential
benzene exposure, while a smaller (8%) and not statistically significant effect was observedfor occupational exposure. This result may be surprising because occupational benzene
exposure concentrations for workers should be higher in respect to those of residents inpolluted areas [46]. One possible explanation of this phenomenon could be related to theso called “Healthy worker” effect (HWE) which is a special type of selection bias, typicallyseen in observational studies of occupational exposures with an improper choice of comparison group (usually the general population) [47]. For instance, when SMRs are calculatedusing the general population as a reference, the values may be underestimated due tothe mortality of the occupational population. In any case, previous findings have clearly
indicated that benzene exposure in the workplace was associated with increased risk ofseveral neoplasms, including leukemia [48,49], multiple myeloma [50], and non-Hodgkin
lymphoma [51]. Workplace exposure is often complex and related to other important
carcinogens, such as other VOCs, polycyclic aromatic hydrocarbons, and heavy metals.
Therefore, for an accurate risk assessment, these variables should always be taken into
account to adjust the results. Instead, only a few studies included in this meta-analysis
considered exposure to other occupational carcinogens [25,39] as matched or adjusted
variables. Furthermore, our data may be difficult to explain due to the low number ofstudies included in the analysis. Indeed, the sensitivity analysis showed evident variationby omitting single studies. In particular, removal of the study by Koh et al., 2011, [35]resulted in a statistically significant effect on lung cancer risk (1.17; CI 1.05–1.29; p = 0.003)
associated with workplace benzene exposure.
Another important characteristic that may influence lung cancer risk in association
with benzene exposure is sex. Animal studies suggest that males have a greater susceptibility to the adverse health effects of benzene, while human studies indicate that women havea significantly higher risk of blood system effects than men in a similar situation of benzene
exposure [52]. Unfortunately, our sex-stratified analysis produced dubious results, as very
few studies on women were conducted, and a significant increase in lung cancer incidence
was only observed when studies that considered males and females together were pooled.
Regarding the biological plausibility of benzene carcinogenicity in the lungs, thiscompound has been extensively studied in the past, especially in relation to haematologicalmalignancies due to its well-known myelotoxicity. The haematotoxicity of benzene ismediated by the production of several toxic metabolites and reactive oxygen species
capable of causing DNA damage and mutations in target cells [53]. Cytogenetic damage
correlated to benzene exposure is well known. Quantitative meta-analysis have reported aclear association between occupational exposure to benzene with chromosomal aberrations(CAs) and micronuclei (MN) as markers of DNA damage [54,55]. Although the metabolismof benzene takes place mainly in the liver, the lung is also capable of metabolising it, making
it possible to form toxic metabolites directly in situ [56]. Benzene is mainly emitted in theair, so human exposure occurs mainly by inhalation, making the lung the first target for its
toxicity. Recently, a significant positive relationship between impaired lung function andoccupational exposure to benzene has been demonstrated [57].

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The present systematic review and meta-analysis has several strengths and limitations. Unlike previous meta-analyses on benzene exposure and risk of non-Hodgkin
lymphoma [12], leukemia [48], and chronic myeloid leukemia [49], which did not distinguished the incidence of the disease from the mortality for the disease, we were able toanalyse incidence/prevalence and mortality separately. In addition, our results showing theincreased risk of disease incidence were obtained from a substantial number of 10,750 lungcancer cases spread across three continents. Moreover, although we observed a consistentheterogeneity, probably due to the results from the primary studies included, no evident
publication biases were detected.
On the other hand, our results should be interpreted with caution because of several
limitations. Due to the relatively small number of studies included, our meta-analysis may
restrict the statistical power to evidence an association and may reduce the generalisability of the results. This is more evident in the stratified analysis on the same importantparameters including sex and type of benzene exposure, which produced in same cases
complicated results. Although it is well known that smoking significantly increases therisk of lung cancer, many studies reported unadjusted data for this important confounding
factor. Further studies should focus on this issue and try to identify the possible effectsof benzene exposure separately for different smoking conditions (never smoker, current
smoker, and former smoker). Another important limitation of the studies that were included is the quality of the benzene-exposure assessment. In some studies, the exposure
dose was not reported and in others, exposure estimates were reported as a slope factor(increment) making exposure assessment extremely heterogeneous. Even for studies withgood qualitative assessment of exposure, as various solvents are often used simultaneously and sometimes as components of complex mixtures, in many cases, it is difficult
to extrapolate the risk associated with individual substances. Nevertheless, there is apossibility that misclassification might have occurred in some studies. In the future, it will
be important to adjust the risk values to consider different concomitant exposure and to
more accurately identify the “exposure dose”. In addition, the indoor contribution to thebenzene exposure could be considered, and further longitudinal studies should adjust forsmoking and co-exposure in the statistical analysis.
5. Conclusions
In this study, we reviewed the available evidence showing an association between
benzene exposure and lung cancer risk. The meta-analysis has shown a significant increment of both incidence and mortality for lung cancer in benzene-exposed subjects.
Furthermore, the stratified analysis performed considering only studies that adjusted forsmoking habits indicated a marked increase in lung cancer risk in association with benzene
exposure. These data suggest that smoking is an important risk factor, which if not taken
into account may mask the effect of other less-impactful risk factors. There is, therefore, aneed for further studies aimed at identifying the lung cancer risk associated with benzene
exposure, considering different smoking conditions (never smoker, current smoker, andformer smoker).
Supplementary Materials: The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/ijerph21020205/s1, Table S1: Risk of bias assessment tool forenvironmental studies (green colour: very low risk of bias; yellow colour: low risk; orange colour:
moderate risk; red colour: high risk). Table S2: Results of sensitivity analysis on stratified data.
Author Contributions: Conceptualization: Initiated by R.F., agreed by all other authors M.C., P.R.,
B.S. and I.G.; methodology: from the literature search for meta-analysis, R.F., M.C., P.R. and I.G.;
formal analysis: meta-analysis, R.F., B.S. and M.C.; data curation: M.C., P.R., B.S. and I.G.; writing,original draft preparation, R.F., M.C. and P.R.; writing, review and editing, R.F., M.C., P.R., B.S. andI.G.; supervision, M.C. and R.F.; project administration, R.F. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.

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Institutional Review Board Statement: Not applicable.
Data Availability Statement: The data presented in this study are available on request from thecorresponding author.
Acknowledgments: All work was completed at the University of Perugia, Italy. We want to thankour home institution for their financial support.
Conflicts of Interest: The authors declare no conflict of interest.

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