Annals of Tropical Medicine and Public Health

: 2017  |  Volume : 10  |  Issue : 3  |  Page : 533--543

The application of biomarker in determining genotoxic potential of polyaromatic hydrocarbon exposure among children

Nor Ashikin Sopian, Juliana Jalaludin 
 Department of Environmental and Occupational Health, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia

Correspondence Address:
Juliana Jalaludin
Department of Environmental and Occupational Health, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang


Introduction: The quality of ambient air of industrial and urban area are often characterized by the distribution of polyaromatic hydrocarbons (PAHs) in the atmosphere. PAHs, has been associated with increasing risk of cancer especially among susceptible individual in human population such as children. Investigations of chronic health effect of PAHs can be aided with the help of biomarker application in understanding exposure, mechanism of toxicity, and level of susceptibility. Method: In this article, materials obtained from several online databases such as PubMed, Proquest, Scopus, and Science Direct from 2000 to 2015 were reviewed. The application of biomarker of PAHs exposure and effect among children living in areas with high traffic density and industrial area were summarized. From these two different environments settings, an insight into different exposure of PAHs and it association with health outcomes were given. Results: Fifteen biomarker-associated studies were reviewed. Most of the studies emphasized on the application of urinary 1-hydroxypyrene (1-OHP) and DNA adduct as biomarkers of exposure to PAHs. On the other hand, biomarker of effect was frequently represented by cytogenetic analysis. Which includes chromosomal aberrations, sister chromatid exchanges, micronuclei, comet assay parameters like tail length and percentage of DNA in tail. Conclusion: The application of biomarker in revealing the level of PAH exposure and genotoxicity among children is highly preferable. However, the biomarker itself is still considered insufficient to conclude the toxicity of PAH exposure from traffic and industrial emissions. The environmental monitoring is included in the study in order to understand the correlation of ambient PAHs and health outcomes.

How to cite this article:
Sopian NA, Jalaludin J. The application of biomarker in determining genotoxic potential of polyaromatic hydrocarbon exposure among children.Ann Trop Med Public Health 2017;10:533-543

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Sopian NA, Jalaludin J. The application of biomarker in determining genotoxic potential of polyaromatic hydrocarbon exposure among children. Ann Trop Med Public Health [serial online] 2017 [cited 2019 Jun 16 ];10:533-543
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Incomplete combustion of organic matter at high temperature releases a mixture of chemical known as namely polycyclic aromatic hydrocarbons (PAHs) It originates. These compounds are known by several names: polycyclic organic matter (POM), polynuclear aromatic hydrocarbons, polynuclear aromatics (PNAs), and polynuclear hydrocarbons.[1] from pyrogenic, petrogenic, and natural sources; the former two are the dominant anthropogenic sources of PAHs in the environment.[2],[3],[4] Nowadays, there are many of anthropogenic pyrogenic activities that contributes to atmospheric the increase of PAHs content in the atmosphere, including industrial processes, vehicle exhausts, refineries, waste incineration, and domestic heating.[5] many anthropogenic activities contribute to the atmospheric PAHs, including industrial processes, vehicle exhausts, refineries, waste incineration, and domestic heating.[4] On the other hand, the petrogenic sources are crude oil and petroleum products.[6] In nature, PAHs can be emitted from forest fires and volcanoes eruption.

Once PAHs have been emitted into the atmosphere, the fate of the compounds is determined by their physical properties and atmospheric conditions. They can exist in the gas phase or particulate phase. Compounds with high molecular weight (more than four benzene rings) tend to adsorb particulate matter, while lighter PAHs (less than four benzene rings) tend to increase in the gaseous phase until removed through precipitation.[7] The photochemical reaction between ozone and nitrogen oxides can yield derivatives of PAHs, namely oxo-PAHs and nitro-PAHs.[8] These byproducts have been frequently associated with high mutagenic potencies with positive result of famous mutagenicity test, Ames Test.[9],[10],[11],[12] Meteorologic factors play crucial roles in determining the distribution of PAHs. Most studies found that temperature, wind speed, and relative humidity have a negative correlation with concentration of PAHs.[13],[14] Strong wind speed would dilute the PAH concentrations. High temperature would increase the evaporation of particulate PAHs from the particle to gas phase, whereas low temperature would increase the condensation of gaseous PAHs to particle PAHs.

The inhalation of particle-bound PAHs is a major concern because is commonly associated with an increase in the risk of cancer, mutagenesis, and tetraogenesis.[3] The severities of PAH toxicity strongly depend on their molecular weights, as the heaviest compound tends to produce greater health effects. Due to their severe toxicity, PAHs are studied worldwide, especially studies on atmospheric PAHs in high traffic cities and on genotoxicities. Furthermore, the PAH exposures among susceptible group such as children are also highlighted in previous studies.[15],[16],[17],[18],[19] In new globalized world, children's health is precious and ought to be a vital concern for all societies. Children have been considered as one of the most vulnerable age group in human population because their physical and biologic conditions are still immature. According to Esposito et al., children that were exposed to highly-polluted environment during their early developmental stage have experience defects in lung development and lung function.[20] Moreover, active children tend to spend a lot of their time outdoors, which may increase exposure to polluted environment, especially those living in the vicinity of heavy congested road and high industrial area.[21] In addition, children generally have compromised ability of metabolizing and eliminating toxic in their body as compared to adult thus prolonged inhalation of polluted air may increase the burden of metabolism in their small bodies.[16]

To date, numerous epidemiologic studies have demonstrated that the deterioration of ambient air quality impairs children's health, both acute and chronic.[22],[23],[24],[25] While the findings of epidemiologic studies are extremely valuable in the scope of public health, but their contribution can be supported and integrated into exploiting them as biomarkers. The application biomarker is expected to improve the accuracy of assessment on exposure to toxic materials, improve the understanding of the mechanism involved, and allow the investigation of individual susceptibility through genetic polymorphism study.[26] Investigations of the chronic health effect of PAHs can be aided with the use of biomarker application in understanding the effect of exposure of toxic materials, mechanism of toxicity, and level of susceptibility.


This article reviews the role of biomarker in determining the genotoxic consequences of PAHs exposure specifically among children. A systematic search on the association of PAH-related biomarker was obtained from established online databases such as Scopus, PubMed, Proquest, and Science Direct. The literature items were retrieved based on selective keywords: “polyaromatic hydrocarbon (PAHs) and children,” “PAHs and genetic,” “PAHs and genotoxic,” “biomarker PAHs and genotoxicity,” and “genotoxicity and children.” Recent English publications of last 10 years were selected in search items. In order to understand the genotoxic outcomes of PAH exposure on children, the items were limited to original scientific papers only. Any articles that emphasized on occupational exposure and adult exposure and was written in non-English were omitted from this review. [Figure 1] demonstrates the search strategy applied in this review process.{Figure 1}


Biomarker is a common biologic tool used to detect any acute and chronic health outcome upon to environmental exposure, or in another words, it is commonly applied to represent the level of exposure considering the toxicokinetic and toxicodynamic of xenobiotic substances.[27] There are three types of biomarkers: biomarkers of exposure, biomarkers of effect, and biomarkers of susceptibility. The findings of comprehensive search strategy are abstracted and summarized in [Table 1], [Table 2], [Table 3] in terms of the numbers of respondents involved, type of biomarkers applied, the concentration of biomarkers, and significant predictors. The strengths and weaknesses of biomarker in PAH-related studies were tabulated in [Table 4].{Table 1}{Table 2}{Table 3}{Table 4}

Biomarker of PAHs exposure

The use of biomarker of exposure can be assessed using various biological fluids with the aim to assess exposure to xenobiotic substances to human body. It also allows the researcher to understand the mechanistic flow of chemical interaction in the development of a disease.[28] To date, numerous studies have focused on biomonitoring of parent compound, metabolite compound, DNA, and protein adduct as part of biomarker exposure.[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30] Through this literature survey, we found that multiple studies that emphasized on the determination one of the metabolites of PAHs, 1-hydroxy pyrene (1-OHP), among children in different environmental settings. For instance, a study of two different environmental settings in Korea showed a significant concentration of urinary 1-OHP (P< 0.0001) among children aged 11 years in an industrial city as compared to children living in a metropolitan city.[31] This finding demonstrated that children living in the vicinity of the industrial area with large steel mills have greater PAHs loading effect than children living in the proximity of heavy traffic in Korea. A similar result was reported by Lee et al., with a significant difference in the concentration of both urinary 1-OHP and creatinine-adjusted 1-OHP between 406 school children in the area near steel mill and 606 school children living in a remote area.[32] In this study, they also found a positive and significant (P< 0.05) association between concentration of particulate matter, thus supporting the fact that the high level of 1-OHP was due to environmental exposure. Another study by Alghamdi et al. reported greater concentrations of urinary 1-OHP among male children aged 10-12 years old living in the proximity of oil refinery (median = 339.3 ng/g) as compared to children living near an area with population in areas of heavy traffic (median = 278.1 ng/g) and low traffic density (median = 189.1 ng/g).[33] In addition, a study involving a younger age group of children, 3 years old, in Ukraine also reported similar findings.[34] It found that children living close to steel mills and coking facility had a higher level of 1-OHP as compared with children of urban, high traffic density areas. A comparison of different environmental settings in the aforementioned studies clearly indicated that there are higher pollutant loading in industrial areas than in heavy traffic areas.

A cross-sectional study by Sánchez-Guerra et al. demonstrated that school children in Coatzacoalcos County in Mexico were exposed to high levels of PAHs emitted from the nearby petrochemical plant.[21] In that study, 82 healthy school children aged 6-10 years old from three public elementary schools located less than 5 km from the main petrochemical plant were recruited and compared to each other according to school location. The analysis showed that subjects in the school located in west Coatzacoalcos exhibited highest 1-OHP levels with 1.26 μmol/mol creatinine (95% confidence interval [CI] 1.03-1.52) (P< 0.001) as compared with children from other schools. This condition occurred due to the direction of wind blowing from north to west, together with the heavy traffic which contributed to the highest PAH level among children studying in that particular school. Interestingly, they also found that 59% children had higher 1-OHP levels than those reported in environmentally exposed adults (0.24 μmol/mol creatinine) in the previous study.[35] The steel mill, coking, and petrochemical industry can be considered as the significant environmental sources of PAH exposure. Thus, the findings indicate that susceptible population such as children living near the mentioned industrial area may face greater health threats.

In addition, a clear comparison of PAHs levels in different traffic condition was identified by groups of studies.[16],[33],[36],[37] Heavy traffic condition has been associated with an increase in 1-OHP concentration among children, thus supporting the fact that PAHs originated from the process of incomplete combustion of vehicle exhaust. Meanwhile, children in the pristine or remote areas have low exposure to air pollutants, particularly exposure to PAHs. Interestingly, different urinary PAHs metabolites also gave similar outcomes among children. For instance, a study by Fan et al. demonstrated that four urinary monohydroxylated PAHs (OH-PAHs) including 2-hydroxynathalene (2-OHN), 2-hydroxyfluorene (2-OHF), 3-hydroxyphenanthrene (3-OHPhe), and 9-hydroxyphenanthrene (9-OHPhe) were significant biomarkers in living in high-traffic and low-traffic areas.[16] All of the monohydroxylated PAHs except (3-OHPhe) were present in higher concentrations than 1-OHP. The fascinating findings in this study revealed that metabolite PAHs present in the urine were PAHs of low molecular weight, with two- and three-ring OH-PAHs. Although high traffic density is commonly associated with high distribution of heavy molecular weight PAHs, the finding of low concentration of high molecular weight PAHs in high traffic area by Fan et al. stands for acceptable reasons.[6],[16],[38] This was could be due to the timing of which was conducted during summer. High temperature during summer caused the PAHs molecule to exist in gaseous state instead of particulate state.[39] The application of monohydroxylated PAHs plus 1-OHP can give a new color to PAHS exposure, which is able to reflect mirror whole PAHs exposure among children holistically.

On the other hand, in a study of 126 young age children in the United States, Morgan et al.[40] demonstrated findings contradictory to those by Fan et al.[16] Biomarkers of monohydroxy-PAHs like benz[a]anthracene, benzo[a]pyrene, chrysene, and indeno[1,2,3-cd]pyrene were found to be below the analytical limits of detection (0.2 ng/g) in the majority of preschool children's urine samples. Meanwhile, a median of 0.33 ng/mL urinary 1-OHP was detected in the sample population. Apart from that, 2-naphtol was a biomarker of PAHs exposure. Using high-performance liquid chromatography, Yoon et al. demonstrated that urinary 2-napthol was significantly higher among children living in industrial area than among those living in the metropolitan city of Korea, with median 21.0 and 12.3 ng/g, respectively (P< 0.001).[31] The application of this biomarker is highly recommended in emphasizing naphthalene exposure, especially in in city areas with high vehicle density and in areas with stoves burning biomass fuels.[41] Regarding sensitivity and reliability of monohydroxylated PAHs and naphthols, generally, they can be applied in determining PAHs exposure. But yet, a single biomarker of 1-OHP still remains the top choice biomarker of PAHs exposure due to the cost factor.

Biomarker of effect

Biomarkers of effect is a measurement of biochemical, physiologic, and alteration in metabolic enzymes as indicators of early pathologic changes in disease development.[42] Either enzyme, protein, or cell condition could be involved directly or indirectly in the causal pathway of a disease and therefore strongly related to disease.[43] Regarding exposure to PAHs, many biomarker epidemiologic studies were highlighted the association of PAH exposure and genotoxic outcome with genotoxic properties of PAHs.[21],[18],[17] Some of the studies highlighted that PAH exposure is associated with oxidative stress and production of the antioxidant enzyme such as superoxide dismutase.[16],[44] Genotoxicity of exposure to PAHs can be quantified by cytogenetic marker namely by chromosome aberrations (CAs), sister chromatid exchanges (SCEs) and micronuclei (MN), DNA fragmentation, or DNA damage by the comet assay in order to evaluate the early biologic effect.

In a study related to traffic pollution, Tuntawiroon et al. demonstrated that 114 Bangkok school children aged 8-13 years old were exposed to significant PAHs as measured individually with 4.13 ± 0.21 ng/m 3 as compared to Chonburi school children with 1.18 ± 0.09 ng/m 3 (P< 0.001).[37] Thus, the study explained that the potential of DNA damage among children in heavy traffic area of Bangkok is greater than that among comparative population. In that study, the genotoxicity of PAHs exposure is assessed using the comet assay with two parameters observed: tail length and olive tail moment. Both parameters were significantly higher in children living in Bangkok, with tail length of 1.93 ± 0.09 μm and olive tail moment of 0.23 ± 0.01 μm (P< 0.001). Interestingly, that study also measured the DNA repair capacity by the cytogenetic challenge assay. Cytogenetic challenge assay is used to investigate cellular activities after exposing cells to DNA-damaging agent such as radiation. In this study, Bangkok school children exhibited a significant decrease in DNA repair capacity as shown by increasing dicentric chromosomes (chromosome-type translocation) and chromosome deletions per metaphase. Ruchirawat et al. also found similar findings of genotoxicity among primary school children in heavy traffic density areas of Bangkok, Thailand, with a significant difference in olive tail moment.[45]

Contrasting to new recent study by Silva et al., children aged 5 to 11 years old in a pristine area of municipality of Santo Antônio da Patrulha, Brazil had low micronucleus frequency in buccal cells and the value complied to the reference value of general population, 0.32-1.70 % in Bonassi et al.[46],[47] In that study, all the parameters of comet assay among children's lymphocyte have greater values than those in the study by Tuntawiroon et al.[37] This could be due to different biologic sample used in the assay. It could also be because different ethnicity carries different genetic characteristics. The human biomonitoring was conducted during the spring season, with PAH concentration of 3.08 ng/m 3. From these findings, it is clear that PAH concentration of one reference area in Brazil is less pristine than the rural area of Chonburi, Thailand.[37]

As mentioned earlier, the petrochemical industry is also considered as the contributor of anthropogenic emission of PAHs. Pelallo-Martínez et al. demonstrated that children aged 6-12 years old living in the vicinity of a petrochemical plant in Mexico were exposed to various concentrations of PAHs by determining their urinary 1-OHP, which was in the range 0.2-1.26 μmol/mol creatinine.[18] Genotoxicity evaluation among respondents was performed using comet alkaline assay in leukocyte cells. In this study, DNA damage was expressed in terms of the olive tail moment and significantly correlated with urinary PAH metabolite, 1-OHP (P< 0.05). The geometric mean olive tail moment of children in this area was in the range 8.3-11.7 μm. A similar finding was reported in a study by Sánchez-Guerra et al., with greater DNA damage among children living in the vicinity of petrochemical industry area in Mexico.[21] Regarding linkage of different biomarkers used in this study, they found a positive association between 1-OHP and DNA damage among children aged 6-10 years old.

Biomarker of susceptibility

Biomarkers of susceptibility are defined as biomarker's capability or sensitivity to respond to xenobiotic substance exposure. Exposure to PAHs allowed it to be metabolized into diol-epoxides by P450 (CYP) and later undergo detoxification process by the aid of epoxide hydrolases, N-acetyltransferases, UDP-glucuronyltransferases, and glutathione S-transferases. The capacity of enzyme to metabolize and detoxify activities varies depending on individual genetic polymorphism. In this review, two related studies demonstrated the influence of genetic polymorphism on the biomarker of PAH exposure and cytogenetic effect among children. In one Mexican study by Sánchez-Guerra et al., the role of two type phase 1 enzymes (CYP1A1*2C and CYP1B1*3) and phase 2 enzymes (GSTM1*0 and GSTT1*0) were explored among 77 children aged 6-10 years old.[21] In that study, they demonstrated that the expression CYP1A1*2C polymorphism was positively associated with 1-OHP concentration, with odds ratio (OR) of 6.08 (P< 0.05). On the other hand, children who carried GSTM1*0 polymorphism had a greater risk of PAH exposure as indicated by urinary PAH metabolite with OR 5.09 (95% CI 1.26). In addition, children exposed to high levels to PAHs and carrying CYP1A1*2C polymorphism showed elevated genotoxic effect in the terms of DNA damage.

A study by Mielzynska-svach et al. reported a larger scale sampling on genes of encoding phase 1 enzymes (CYP2D6 and EPHX1), phase 2 enzymes (GSTM1, GSTP1, GSTT1, NAT2), and DNA repair proteins (XPD, XRCC1, XRCC3).[48] In that study, 87.5% of respondent carried gene encoding fast conjugator enzyme GSTP1, while 69.0% of children had extensive metabolizer gene, CYP2D6. Gene XRCC3 Met/Met, which plays a substantial role in maintaining chromosome stability and repairing DNA damage, was significantly associated with significantly higher levels of 1-OHP excretion compared with XRCC3 Thr/Met genotypes (P = 0.010). In addition, the authors also found that children with XRCC3-241 Met/Met genotype unveiled a higher number of SCEs than carriers of Thr/Met allele. Another biomarker of genotoxic effect, formation of micronuclei was conspicuously associated with GSTP1 slow conjugator enzyme instead of fast conjugator enzyme (4.23 ± 3.49 vs. 6.56 ± 5.00 MN/1,000 cells). Based on two mentioned studies, it obvious that Mexican and Polish children carry different genes responding to PAH metabolism and detoxification process.


Exposure to genotoxic substances like PAHs can cause oxidative stress, which could then lead to DNA damage and disturbances in DNA replication. Changes in DNA replication may cause mutation and may lead to carcinogenic effects. The genetic material that are damaged can be quantified with the application of genotoxic biomarker, as it is able to aid in understanding relative contribution of ambient air pollution as a risk factor for cancer and facilitate health risk assessments especially under conditions of moderate or low air pollution.[27],[49],[50] To the best of our knowledge, emission of PAHs can be easily quantified through advanced instrumentation like HPLC and gas chromatography-mass spectrometer (GC-MS). Based on the studies mentioned in this review, it is clear that particulate PAHs will always be the top choice for environmental sampling instead of gaseous PAHs, as pointed out by traffic-related studies.[34],[36],[37] Only two studies by Alghamdi et al. and Gamboa et al. demonstrated environmental PAHs sampling in both particulate and gaseous states, and these can be considered as comprehensive studies.[33],[51] In addition, these two studies elucidated the distribution of both heavy and light molecular weight PAHs in the industrial area. Surprisingly, several studies did not perform any environmental PAH sampling, which explain the exposure of PAHs as the mean of the biomarker of exposure only.

In PAH-related studies, urinary metabolites of PAHs are the most frequently and commonly used methods to assess exposure of PAHs among different population, including children. The application of urinary metabolites of PAHs was first discovered in the urine of pig in the 1980s and later underwent multiple advancements before being used in human study.[52] This metabolite is produced by the conjugation activity of metabolism of PAHs. Measurement of metabolite of PAHs in urine is highly preferable, as it is easy enough for self-collections and can be frozen for later analysis without any further processing.[52] However, this biomarker only reflects recent exposure within 1-3 days. For the study involving children, it is highly desirable, as it does not cause any impairment to children during the sample collection. In this review, the majority of studies demonstrated the application of traditional urinary PAHs metabolite, 1-OHP. Only four studies did some variation of biomarker used in their study by determining other PAHs metabolites, for instance 1-OHPG, 2-naphthol, 2-OHN, 2-OHF, 3-OHPhe, and 9-OHPhe.[16],[31],[40],[53] These metabolites could be considered as reliable biomarkers in reflecting whole exposure of PAHs among children.

A growing body of knowledge reported that genotoxicity of PAHs can be assessed in multiple genetic biomarkers like micronucleus, DNA fragmentation, CAs, and SCEs.[31],[44],[48],[54],[55] In this review, we discerned that DNA damage and micronucleus frequency in lymphocytes are the most popular choices for investigating the genotoxic effect of exposure of PAHs. Both biomarkers required meticulous observation, as both involved microscopy analysis. In other words, they required meticulous skills and competency in distinguishing cells with micronucleus and damage cells. Quantification of DNA and chromosomal damage can be performed on exfoliated buccal cell as a minimally invasive method proposed in 1983, as compared to analysis on lymphocytes and erythrocytes.[56],[57] Compared to other biologic samples, the human buccal cell is a valuable media, less invasive, and simple method to measure genetic damage in humans because buccal epithelial cells represent a preferred target population for early genotoxic events induced by carcinogen introduced via inhalation and ingestion.

The application biomarker of exposure only is considered insufficient in associating environmental exposure to PAHs with children health. To the best of our knowledge, PAHs are introduced to children's body through ingestion route as well, for instance eating smoked and grilled food or exposure to tobacco smoke. These confounding factors should be controlled before commencing any PAH-related studies through a comprehensive questionnaire on the dietary pattern. Furthermore, the bias can be minimized or controlled by matching the inclusion criteria (environmental tobacco smoke exposure, transportation, medication, type of diet of respondents) for both study and comparative groups.[37] Information on indoor exposure should not be neglected, as the indoor air pollutant source could be mosquito coil and cooking activity.[24],[25],[58],[59] In addition, cotinine analysis can be considered as an alternative to control confounding of exposure to tobacco smoke as demonstrated in a study by Pelallo-Martínez et al.[18]

The ideal of genetic epidemiologic study should understand and emphasize the interaction of environmental PAH sampling, biomarker of exposure, biomarker of effect, and biomarker of susceptibility. In this review, only two studies exhibited the interaction of three biomarkers.[21],[48] Hence, these studies can be a good reference in designing a comprehensive environmental epidemiology study. Increasing sample size should be a top priority in designing any PAH-related study, as greater sample size may minimize the variation of the biomarker.


The application of biomarker in revealing level of exposure to PAHs and genotoxicity among children is highly preferable and recommended. However, the application of biomarker itself is still considered inadequate to conclude the toxicity of exposure to PAHs from traffic and industrial emissions. The monitoring of environmental PAHs should be included in the study in order to understand the correlation between ambient PAHs and health outcomes. In addition, controlling confounding factors should be the primary concern while designing an ideal study on PAHs. The reason for conducting a perfect study is important not only for researcher but also for providing an insight into real threat of environmental PAHs on the susceptible group. The findings of PAH-related study will be a bridge in disseminating information to public on the effects of exposure to air pollutants on children's health. The basic information on children's genetic toxicity is useful to guide parents in providing healthy foods (rich in vitamin C and antioxidants) to enhance the children's defense mechanism. In addition, the information on exposure levels of air pollutant on children can be a guide to the school and parents in providing a safe and healthy environment for children, whether at school or home.

Financial support and sponsorship

This review was written in part of by Fundamental Research Grant Scheme (FRGS) funded by the Ministry of Education, Malaysia (Project code: 04-01-14-1449FR) and Universiti Putra Malaysia (Project code: GP-IPS/2016/9504000).

Conflicts of interest

There are no conflicts of interest.


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