Polycyclic Aromatic Hydrocarbons

Polycyclic Aromatic Hydrocarbons

C H A P T E R 29 Polycyclic Aromatic Hydrocarbons Leah D. Banks1, Kelly L. Harris1, Kenneth J. Harris1, Jane A. Mantey1, Darryl B. Hood2, Anthony E. ...

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C H A P T E R

29 Polycyclic Aromatic Hydrocarbons Leah D. Banks1, Kelly L. Harris1, Kenneth J. Harris1, Jane A. Mantey1, Darryl B. Hood2, Anthony E. Archibong3, Aramandla Ramesh1 1

Department of Biochemistry, Cancer Biology, Neuroscience & Pharmacology, Meharry Medical College, Nashville, TN, United States; 2College of Public Health, Ohio State University, Columbus, OH, United States; 3Department of Microbiology, Immunology & Physiology, Meharry Medical College, Nashville, TN, United States

INTRODUCTION Cancer risk assessment based on the 2-year rodent tumor bioassay is becoming obsolete because of the complexities associated with polycyclic aromatic hydrocarbon (PAH) exposures from occupational, dietary, and environmental settings. In addition to the costs and time factors involved, the relationship at best infers the relationship between the measured event (PAH exposure) and the tumor response. This approach, however, misses several endpoints that represent the various causal pathways involved in carcinogenesis. Additionally, the bioassay results could predict risk in the case of individuals but not at a population level. Therefore, to predict “at risk populations” from PAH exposure, appropriate biomarkers need to be employed for rapid screening of vulnerable populations and deploy appropriate preventive measures. Biomarkers are cellular, biochemical, or molecular alterations that are measureable in biological media such as human tissues, cells, or fluids (Hulka, 1990). This definition has been extended to embrace biological parameters that could be measured and evaluated as an indicator of normal biological and pathogenic processes (Naylor, 2003). Biomarkers could be indicators of exposure, effect, or susceptibility (Links et al., 1995). These three categories of biomarkers are explained below (Links and Groopman, 2010). In the context of toxicology, biomarker of exposure indicates previous exposure to an environmental toxicant. This biomarker could be an exogenous chemical and interactive product (formed between a toxicant and endogenous compound) that could change the identity or status of target molecule. On the other hand, the biomarker of effect reports the nature and magnitude of biological

Biomarkers in Toxicology, Second Edition https://doi.org/10.1016/B978-0-12-814655-2.00029-3

(functional) response on exposure to an environmental pollutant. The third category, biomarker of susceptibility, outlines the heightened sensitivity of a subpopulation to the effects of a xenobiotic. Biomarkers have power to be indispensable tools for preventing environmentally induced disease. The rising incidence of human exposure to persistent environmental pollutants necessitated use of biomarkers for disease detection and prevention at an early stage (Suk and Wilson, 2002). One such family of compounds that garnered a great deal of interest in the last century is PAHs. Being products of incomplete combustion they are prevalent in several environmental media (IARC, 2010; Ramesh et al., 2004, 2011, 2012) and through long-range atmospheric transport are carried over to places far away from point source areas (Shen et al., 2012). In addition, these toxicants are released from automobile exhaust, cigarette smoke, and industrial emissions. Several diseases such as cancer (lung, breast, colon, prostate), neurotoxicity, atherosclerosis, and infertility have been attributed to PAH exposure (IARC, 2010; Ramesh et al., 2011). Over the years, several biomarkers have been employed to detect susceptible populations from PAH-induced diseases. Some of the commonly employed biomarkers of PAH exposure, effect, and susceptibility are presented schematically in Fig. 29.1.

BIOMARKERS OF EXPOSURE Hydroxylated Metabolites As products of incomplete combustion, PAHs are prevalent in the environment, and exposure of people to PAHs in domestic, outdoor, and occupational settings

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Exposure •Sources -Occupational -Ambient air -Dietary -Smoking

Internal dose •Urinary biomarkers -1-OHPY -3-hydro benzo(a)pyrene -Urinary mutagenicity

Biologically effective dose •DNA adducts -bulky/PAH-DNA adducts -BP-tetrol(DNA adducts) -8-oxo-dG adducts

•Protein adducts

Early biological effect •Cytogenetic end-points -CA -SCE -MN -HPRT mutation frequency -GPA mutation frequency

-albumin adducts -hemoglobin adducts

•DNA strand breaks, UDS FIGURE 29.1 Overview of PAH exposures and biomarkers. 1-OH-PY, 1-hydroxypyrene; 8-oxo-dG, 8-oxo-20 -deoxyguanosine; CA, chromosome aberrations; GPA, glycophorin A; HPRT, hypoxanthine-guanine phosphoribosyltransferase; MN, micronuclei; PAH, polycyclic aromatic hydrocarbon; SCE, sister chromatid exchange. Adopted from Gyorffy E., Anna, L., Kova´cs, K., et al., 2008. Correlation between biomarkers of human exposure to genotoxins with focus on carcinogen-DNA adducts. Mutagenesis 23, 1e18; with permission from Oxford University Press, UK.

is inevitable. Hydroxylated metabolites of PAHs (OHPAHs) generated through biotransformation have widely been used as biomarkers of exposure. Urinary concentrations of these metabolites have been employed in several studies. It is reported that urinary 1hydroxypyrene (1-OHP) concentrations are higher for outdoor workers exposed to polluted air in urban setting than their unexposed counterparts (Ciarrocca et al., 2014). Similar observations were made in volunteers experimentally exposed to wood smoke (Li et al., 2016). Interestingly, the urinary concentrations of 1nitropyrene are elevated in the United StateseMexico border residents, who tend to cross the border frequently, which is indicative of the higher urban pollution south of the border (Galaviz et al., 2017). Increased concentrations of 1-OHP glucuronide were reported in inner city Baltimore children from the home of cigarette smokers and children who more time spent outdoors (Peters et al., 2017). Children and elderly residents living near emission sources such as oil refineries and coalfired power plants were also found to have elevated urinary concentrations of 1-OHP (Chen et al., 2017). Furthermore, restaurant workers exposed to fumes from repeated frying oil and restaurant waste oil were found to have higher urinary concentrations of 1-OHP (Ke et al., 2016). Another instance of occupation exposure to PAHs was reported in metallurgy workers in aluminum electrode production plant, who had high levels of urinary PAHs, the half-lives of which were estimated to range from 12 to 18 h (Lutier et al., 2016).

DNA Adducts PAHs undergo biotransformation. As a result of this process, highly reactive metabolites are generated, which interact with cellular DNA and form PAH-DNA adducts. Measurement of these adducts serve an important purpose of human biomonitoring for exposure to

PAH carcinogenesis and are also used as tools in molecular epidemiology studies (Farmer et al., 2003; Perera, 2000, 2011). PAH-DNA adducts have been used as biomarkers to assess human exposure to mixtures of toxicants in Poland (Perera, 2000). Peripheral blood samples collected from residents of high-exposure regions revealed an association between environmental pollution and significant increases in levels of PAH-DNA adduct, sister chromatid exchanges (SCEs), chromosomal aberrations, and c-ras oncogene expression. Another molecular epidemiology study that deserves mention was conducted by Taioli et al. (2007). The PAH-DNA adducts and oxidative DNA damage was measured in PAH-exposed populations from Prague (Czech Republic), Kosice (Slovakia), and Sofia (Bulgaria). The occupationally exposed individuals (policeman and bus drivers) were subjected to personal exposure monitoring, and the exposure of general population was monitored by measuring the levels of carcinogenic PAHs (c-PAHs) in ambient air. In the occupational category, policemen were exposed to PAHs to a greater extent than bus drivers. The average personal exposure to c-PAHs was found to be highest in Bulgaria, followed by Slovakia and the Czech Republic. Further studies in this direction were undertaken by the SRAM research group in the Czech Republic (Rossner et al., 2013a). This study compared exposure of general public to contaminated air in Ostrava, a heavily polluted region, and Prague, a relatively clean region. The bulky PAH-DNA adducts in peripheral blood lymphocytes were used as biomarkers. A significant correlation between personal exposure to benzo(a)pyrene and BaP-DNA adduct levels were found in subjects from Ostrava, but not Prague. Several analytical techniques have been employed for detection and quantitation of PAH-DNA adducts. The sources, types of samples used for analysis, and the methods used are summarized in Table 29.1.

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BIOMARKERS OF EXPOSURE

TABLE 29.1

Sample Matrices and Methods Employed for Biomonitoring of Polycyclic Aromatic Hydrocarbon (PAH) DNA Adducts in Susceptible Populations

Exposure Route

Biological Matrix

Population

Analytical Method

References

Inhalation (cigarette smoke)

White blood cells

Healthy smokers and nonsmokers

Enzyme linked immunosorbent assay (ELISA)

Perera et al. (1987)

Inhalation (cigarette smoke)

White blood cells

Lung cancer patients

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van Schooten et al. (1992)

Inhalation (cigarette smoke)

Peripheral leukocytes

Lung cancer patients

ELISA

Tang et al. (1995)

Inhalation (cigarette smoke)

Oral cavity (mouth floor and buccal mucosa)

Healthy subjects

Immunoperoxidase assay

Besaratinia et al. (2000)

Inhalation (cigarette smoke)

White blood cells

Smokers

Immunoassay

Funck-Brentano et al. (2006)

Inhalation (cigarette smoke)

Cervical mucosa

HPV-infected patients

Chemiluminescence assay

Pratt et al. (2007)

Inhalation (environmental tobacco smoke)

Maternal and umbilical cord blood

Pregnant mothers

?

Perera et al. (2007)

Inhalation (polluted air)

Placenta

Pregnant women from chemical and radioactive polluted areas

Chemiluminescence immune assay

Obolenskaya et al. (2010)

Inhalation (occupational)

White blood cells

Coke oven workers

ELISA

van Schooten et al. (1990)

Inhalation (occupational)

White blood cells

Iron foundry workers

ELISA

Santella et al. (1993)

Inhalation (occupational)

Peripheral blood lymphocytes

Aluminum plant workers

ELISA

Schoket et al. (1999)

Inhalation (occupational)

Peripheral blood lymphocytes

Coke oven workers

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P-postlabeling High performance liquid chromatography (HPLC)

Brescia et al. (1999)

Inhalation (occupational)

Lymphocytes

Coke oven, aluminum plant workers, chimney sweeps

HPLC

Pavanello et al. (1999)

Dermal (coal tar)

White blood cells

Psoriasis patients

ELISA

Santella et al. (1995)

Dietary (charbroiled beef eaters)

White blood cells

Fire fighters who consumed barbecued food

ELISA

Rothman et al. (1993)

Dietary (charbroiled beef eaters)

White blood cells

Healthy subjects

ELISA

Kang et al. (1995)

Dietary (red meat eaters)

Leukocytes

Nonsmokers

Chemiluminescence assay

Gunter et al. (2007)

None specified

Colon tissue

Colon cancer patients

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Al-Saleh et al. (2008)

None specified

Breast tissue

Breast cancer

ELISA

Sagiv et al. (2009) Al-Saleh et al. (2010)

P-postlabeling

P-postlabeling

None specified

Follicular cells

Infertile women

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None specified

Spermatozoa

Infertile men

Immunofluorescence assay

Ji et al. (2010)

None specified

Prostate

General population

Immunohistochemistry

Tang et al. (2013)

P-postlabeling

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Protein Adducts The formation of protein adducts is fundamentally similar to that of DNA adducts, i.e., reaction of a diol epoxide metabolite with a protein molecule (Autrup et al., 1999). Because of this property, protein adducts have been used as surrogates for DNA adducts, as metabolites of PAH carcinogens bind to both DNA and protein with similar dose-response kinetics (Poirier et al., 2000; Links and Groopman, 2010). Of all the proteins, hemoglobin and albumin have become the proteins of choice for molecular dosimetry studies. The characteristics that made protein adducts preferable over DNA adducts are that protein adducts are relatively more stable and are not removed by repair processes unlike DNA. Although protein adducts, when compared with DNA adducts, are considered as precise dosimeters (Links and Groopman, 2010), interpretation of results from protein adduct studies is limited by the techniques employed, which vary highly among laboratories (Castan˜o-Vinyals et al., 2004). Additionally, compared with DNA adducts, not many studies have measured protein adducts, and the data on PAH-protein adducts in humans are inconclusive owing to lack of sensibility in the assays used (Ka¨fferlein et al., 2010). Hemoglobin adduct concentrations of benzo(a)pyrene diol epoxide (BPDE) were reported to be high in newspaper vendors exposed to traffic exhaust (Pastorelli et al., 1996), compared with nonsmokers. On the other hand, BaP-albumin adducts did not show any significant difference between iron foundry workers and nonsmokers when serum samples were evaluated as an exposure measure (Omland et al., 1994). Similar results were reported from coke oven plant workers and nonoccupationally exposed individuals in an industrial area in Poland (Kure et al., 1997). The techniques employed for detection and quantitation of

TABLE 29.2

PAH-protein (albumin and/or globin) adducts for biomonitoring purposes are summarized in Table 29.2.

OTHER BIOMARKERS OF EXPOSURE Aside from hydroxylated metabolites and PAH-DNA adducts, serum levels of liver enzymes such as alanine aminotransferase, aspartate aminotransferase, and superoxide dismutase, which are associated with liver function, have been used as indicators of PAH exposure in workers from occupational settings such as coke oven plants (Wu et al., 1997), brick kilns (Kamal et al., 2014), and petrochemical industry (Min et al., 2015). Additionally, in some instances markers of inflammation such as C-reactive protein and activated leukocyte cell adhesion molecule showed a positive correlation with hydroxylated metabolites of PAHs in coke oven workers (Yang et al., 2016). On the other hand, some studies do not provide conclusive evidence to establish a relationship between PAH exposure and some of these biomarkers (Clark et al., 2012; Alhamdow et al., 2017)). There are other caveats that limit the utilitarian value of the above-mentioned markers, which include the exposure dose, duration (time spent on assigned task), and other confounding factors such as smoking, diet, and BMI status. Therefore, the lack of robustness associated with these markers discourages their use for routine monitoring purposes.

BIOMARKERS OF EFFECT Genetic Alterations Some of the cytogenetic biomarkers that are currently being used as biomarkers of effect include chromosome

Sample Matrices and Methods Employed for Biomonitoring of PAH-Protein Adducts in Susceptible Populations

Exposure Route

Biological Matrix

Population

Analytical Method

References

Dermal (coal tar)

White blood cells

Psoriasis patients

ELISA

Santella et al. (1995)

Inhalation (occupational)

Globin

Auto mechanics

Gas chromatography-mass spectrometry (GC-MS)

Nielsen et al. (1996)

Inhalation (occupational)

Serum albumin

Coke oven plant workers

ELISA

Kure et al. (1997)

Inhalation (occupational)

Serum albumin

Bus drivers, mail delivery workersELISA

Autrup et al. (1999)

Inhalation (occupational)

Globin

Auto mechanics

GC-MS

Melikian et al. (1999)

Inhalation (occupational)

Serum albumin

Traffic police officers

ELISA

Ruchirawat et al. (2002)

Inhalation (occupational)

Peripheral blood lymphocytes

Coke oven plant workers

HPLC

Wang et al. (2007)

Inhalation (occupational)

Peripheral blood lymphocytes

Coke oven plant workers

HPLC

Huang et al. (2012)

Healthy subjects

GC-MS

Scherer et al. (2000)

Diet and inhalation (smoking) Globin and albumin

BIOMARKERS OF SUSCEPTIBILITY

aberrations (CAs), SCEs, and micronuclei (MN). The CAs are characterized by structural alterations and rearrangements in chromosomes. Gu et al. (2008) observed BPDE (a carcinogenic metabolite of BaP)einduced chromosome 9p21 aberrations in bladder cancer cases. These studies suggest 9p21 as a marker for PAH-induced bladder cancers. The above-mentioned BaP metabolite has also been implicated in chromosome 3p deletions, which serves as a marker of an individual’s susceptibility to renal cell carcinoma (Zhu et al., 2008). MN are formed after mitosis from lagging chromatids. Cells bearing MN if enter mitosis produce daughter cells without MN. The formation of MN is linked to genetic damage. Increased frequencies of MN were found in coal-tar workers, who may have been exposed to PAHs in tar (Giri et al., 2012). In addition to occupational exposures, MN levels were monitored in mothers and newborns from a region in Czech Republic impacted by severe air pollution, whose BaP levels were found to be elevated in air samples (Rossnerova et al., 2011). SCEs are exchanges of DNA segments between sister chromatids of a duplicated metaphase chromosome. Asphalt workers exposed to bitumen fumes registered a significant increase in SCEs (Karaman and Pirim, 2009). In addition, results of a metaanalysis study revealed statistically significant SCE frequencies in peripheral blood lymphocytes and peoples occupational exposure to PAHs (Wang et al., 2012a,b). Glycophorin A (GPA) assay, which detects and quantifies erythrocytes with variant phenotypes at the autosomal locus, is a marker for population exposure to genotoxicants. A slight increase in GPA mutations was noticed in iron foundry workers exposed to PAHs (Perera et al., 1993). Additionally, a strong association between urinary PAH metabolites and GPA mutation frequencies was seen in incineration workers (Lee et al., 2002a,b). The hypoxanthine-guanine phosphoribosyltransferase (HPRT) is used to denote transgene expression in T lymphocytes. Smoking (rich source of PAHs)e associated mutations at the HPRT locus was deleted in T lymphocytes of lung cancer patients (Hackman et al., 2000). Results of a metaanalysis study also revealed that children who are exposed to mothers’ smoke registered a higher frequency of HPRT mutations as well (Neri et al., 2006). In addition to chromosomal alterations, oncogenes and tumor suppressor genes have been used as markers of PAH exposure. Alguacil et al. (2003) used k-ras mutations to find out whether occupational exposure to PAHs had any effect on exocrine pancreatic cancer in factory workers. A weak association was noticed which cannot provide a definitive link between exposure and disease etiology. It could be possible that some k-ras mutations are present at relatively high frequencies in some human

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tissues, but the methods applied may not have been able to detect those. Using an allele-specific competitive blocker polymerase chain reaction assay, Parsons et al. (2010) found k-ras mutations in normal human colon mucosa samples at high frequencies. A dose response for k-ras mutations caused by BaP has already been reported (Meng et al., 2010). Given the fact that dietary intake of PAHs contributes to colon cancers, oncomutations could be used as potential biomarkers for measuring PAH exposures in humans from occupational, environmental, and dietary settings. The tumor suppressor gene p53 has also been used as a biomarker of PAH exposure. This gene regulates cell proliferation, differentiation, apoptosis, and DNA repair (Levine, 1997). Mordukhovich et al. (2010) reported an association between PAH exposure and p53 mutations subgroups in participants from the Long Island Breast Cancer Study Project. Other studies also have found positive association between PAH sources and p53 mutations in colon and lung cancers (Diergaarde et al., 2003; Harty et al., 1996). Rossner et al. (2013b) studied the biomarkers of effect in Czech population exposed to PAHs through inhalation of polluted air in a highly contaminated region (Ostrava) and clean region (Prague). Samples collected from exposed humans were analyzed for oxidative stress markers (8-oxo-7,8-dihydro-20 -deoxyguanosine [8-oxodG], 15-F(2t)-isoprostane [15-F2t-ISOP]) and cytogenetic parameters (stable and unstable chromosomal aberrations). Lipid peroxidation measured by isoprostanes was elevated in subjects from Ostrava region compared with inhabitants of Prague. Other markers such as urinary excretion of 8-oxodG and unstable chromosomal aberrations were mostly comparable in both locations.

BIOMARKERS OF SUSCEPTIBILITY Polymorphisms in PAH-metabolizing enzymes serve as markers of susceptibility. The PAH bioactivation enzyme, cytochrome P4501A1 (CYP1A1) gene polymorphism, was recorded in coal-tar workers (Giri et al., 2012). Gene polymorphisms in another CYP isozyme CYP1B1 and the antioxidant enzyme, catalase, were linked to BaP-DNA adduct levels in human lymphocytes (Schults et al., 2013). A strong association between PAH exposure during pregnancy and CYP1B1 polymorphisms leads to deficits in cognitive development of African American, Dominican, and Caucasian children (Wang et al., 2010). Also of interest was the finding that children living in the surrounding of a petrochemical factory in Mexico showed CYP1A1 and glutathione-S-transferase M1 (GSTM1) polymorphisms, increased DNA damage, and 1-OHP concentrations

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making them vulnerable to PAH exposure (SanchezGuerra et al., 2012). Polymorphisms in CYP genes from 500 patients with colon cancer showed CYP1A2, CYP2E1, and microsomal epoxide hydrolase (mEH) (Kiss et al., 2007), indicating the susceptibility of individuals with CYP and mEH polymorphisms to colon cancer as these genes control PAH metabolism. Another study reported polymorphisms in CYP1A2, CYP2E1, CYP1B1, and CYP2C9 genes, which showed a strong association with red or processed meat consumption, a rich source of PAHs (Ku¨ry et al., 2007). PAHs adsorbed onto particles in polluted air have been implicated in cardiovascular diseases and lung cancers in exposed populations. Binkova et al. (2007) found a strong association between PAH-DNA adducts levels and polymorphisms of DNA repair gene xeroderma pigmentosum group D (XPD) and the detoxification enzyme GSTM1 in population exposed to polluted air in Prague. This enzyme has also been suggested as a marker to monitor metabolic activation of PAHs in smokers (Wang et al., 2012b). Polymorphisms of another isozyme of GST family, the GSTP1, have been implicated in reduced fetal growth. These studies suggest the potential use of GSTP1 as a marker to detect risks arising from exposure to PAHs by mothers from susceptible populations (Duarte-Salles et al., 2012). Additionally, polymorphisms in genes coding for other detoxification enzymes such as GSTM1 and GSTT1 detected in smokers also showed a strong association with colorectal adenomas (Moore et al., 2005). Another PAH detoxification enzyme, the UDPglucuronosyltransferase (UGT) polymorphisms, has been associated with a reduced elimination of PAHs from the body. An increased risk of colon cancer was predicted in a population-based study whose subjects had UGT1A1 polymorphisms (Girard et al., 2008). Because intake of PAHs through diet has been involved in colon cancer causation (reviewed in Diggs et al., 2011), functional polymorphisms in other PAH detoxification genes hold lot of promise as markers not only for colon but also for other gastrointestinal tract cancers. In addition to drug metabolizing enzymes, polymorphisms in aryl hydrocarbon receptor (AhR) gene is another biomarker, worthy of consideration. Gu et al. (2011) reported AhR polymorphisms in idiopathic infertile male subjects. These polymorphisms were found to be associated with reduced sperm concentration, increase in sperm DNA fragmentation, and BPDE-DNA adduct levels in spermatozoa. Not only are polymorphisms in PAH activation and detoxification enzymes but also polymorphisms in DNA repair genes serve as useful biomarkers. In addition to DNA repair gene XPD (Binkova et al., 2007), polymorphisms exist in other DNA repair enzymes as well.

An association among polymorphisms in DNA repair gene, the DNA methyltransferase 1 and 3B and DNA strand breaks were reported by Leng et al. (2008). These findings suggest that variants in haplotypes of these genes could be used as markers to predict cancer susceptibility. Polymorphisms in ataxia telangiectasia (ATM) lead to impairment in repair of chromosomal damage and cell cycle control in people exposed to toxicants. Wang et al. (2011) found that in workers occupationally exposed to PAHs, the ATM polymorphisms were associated with susceptibility to DNA repair capacity.

CONCLUDING REMARKS AND FUTURE DIRECTIONS One of the caveats in using biomarkers is categorizing the exposure scenarios. Sometimes exposure misclassification cannot be avoided. This situation may lead to employing an incorrect biomarker that may not be able to capture the functional relationship between exposure and effect. In such situations, ex vivo studies are useful to control exposure settings so that geneegene interactions could be studied well and help validating the biomarkers. Thus far, several biomarkers that denote exposure, effect, and susceptibility have been proposed and studies involving these for most part yielded definitive information. At the same time, some studies were inconclusive because of the lack of correlation between biomarkers. In some studies, the PAH-DNA adducts concentrations failed to show either a correlation with urinary metabolites of PAHs or with DNA repair enzymes. To fully exploit the potential of biomarkers in PAH-induced disease diagnosis and intervention strategies, correlation among biomarkers of exposure and effect and effect and susceptibility needs to be investigated. This approach could be integrated into the exposome concept to address environmental and human health issues arising from PAH exposures. Additionally, bioinformatics and systems biology resources could be exploited to advance the field further. Proteomic and genomic approaches could be used to identify additional biomarkers of PAH exposure, effect, or susceptibility. Data from these studies could facilitate the discovery and validation of new biomarkers for PAH-induced cardiovascular, neurological, reproductive, and developmental disorders and cancer.

Acknowledgments The authors gratefully acknowledge the research funding from the National Institutes of Health through grant numbers 1RO1CA142845-04 (Ramesh), U54RR026140 (Archibong), 5G12RR03032 (Archibong and Ramesh), R56ES017448, U54NS041071 (Hood), S11ES014156 (Hood,

III. CHEMICAL AGENTS, SOLVENTS AND GASES TOXICITY BIOMARKERS

REFERENCES

Ramesh and Archibong), 5T32HL007735-20 (Banks), 1F31ESO2407901 (Kelly Harris), Southern Regional Education Board, Atlanta (Kelly Harris), 5R25GM059994-13 (Kenneth Harris), and Title III grant from the US Department of Education (Mantey).

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