Polycyclic Aromatic Hydrocarbons

Polycyclic Aromatic Hydrocarbons

CHAPTER SIX Polycyclic Aromatic Hydrocarbons: Part I. Exposure Okechukwu Clinton Ifegwu*, Chimezie Anyakora*,†,1 *The Centre for Applied Research on ...

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CHAPTER SIX

Polycyclic Aromatic Hydrocarbons: Part I. Exposure Okechukwu Clinton Ifegwu*, Chimezie Anyakora*,†,1 *The Centre for Applied Research on Separation Science, Lagos, Nigeria † Department of Pharmaceutical Chemistry, University of Lagos, Lagos, Nigeria 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. PAH Distribution and Exposure 3. The Concept of Biomarkers 3.1 Biomarkers of Exposure 3.2 Biomarkers of Effect 3.3 Biomarkers of Susceptibility 4. The Concept of Toxicokinetics 5. Toxicokinetics of PAH 5.1 Absorption 5.2 Distribution 5.3 Metabolism 5.4 Excretion References

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Abstract Polycyclic aromatic hydrocarbons (PAH) comprise the largest class of cancer-causing chemicals and are ranked ninth among chemical compounds threatening to humans. Although interest in PAH has been mainly due to their carcinogenic property, many of these compounds are genotoxic, mutagenic, teratogenic, and carcinogenic. They tend to bioaccumulate in the soft tissues of living organisms. Interestingly, many are not directly carcinogenic, but act like synergists. PAH carcinogenicity is related to their ability to bind DNA thereby causing a series of disruptive effects that can result in tumor initiation. Thus, any structural attribute or modification of a PAH molecule that enhances DNA cross linking can cause carcinogenicity. In part I, we review exposure to these dangerous chemicals across a spectrum of use in the community and industry.

Advances in Clinical Chemistry, Volume 72 ISSN 0065-2423 http://dx.doi.org/10.1016/bs.acc.2015.08.001

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2015 Elsevier Inc. All rights reserved.

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1. INTRODUCTION Polycyclic aromatic hydrocarbons (PAH) comprise the largest class of chemical compounds known to be cancer-causing agents and are included in the European Union (EU) and United States Environmental Protection Agency (USEPA) priority pollutant list due to their mutagenic and carcinogenic properties [1]. In 2001, PAH were ranked ninth most threatening chemical compounds to humans [2,3]. The interest in PAH has been mainly due to their carcinogenic properties [2,3]. Many of these compounds are genotoxic, mutagenic, teratogenic, and carcinogenic. They tend to bioaccumulate in the soft tissues of living organisms [4]. Many of these compounds are not directly carcinogenic act like synergists. The carcinogenicity of PAH is basically as a result of their ability to bind to DNA thereby causing a series of disruptive effects that often ends up in tumor initiation. Thus, any structural attribute or modification of a PAH molecule that enhances DNA complementary cross linking can cause carcinogenicity [5]. PAH have been implicated in different types of cancer. Gastric cancer risk was correlated to the consumption of a local wine sealed with a tar-like substance obtained through boiling and distilling fir and pinewood, that contains PAH [6]. Increased risk of colorectal adenomas was associated with benzo(a)pyrene intake in food [7]. Tobacco smoke which contains PAH has been implicated in lung cancer [8]. Increased risk of lung cancer was observed among subjects working on aluminum smelters [9], pavers, and roofers [10]. Tumors of the stomach, bladder, skin, and leukemia were also observed as a result of PAH exposure [5]. Apart from these established carcinogenicity, PAH have other numerous toxicological manifestations which include decreased body weight, enlarged liver with cellular edema, and congestion of the liver parenchyma, reproductive toxicity, intrauterine growth retardation, learning and IQ deficits, destruction of oocytes, and inflammation of kidney cells [11,12]. Developmental toxicity such as embryolethality, reduced fetal weight, and malformations have been reported in response to benz(a)anthracene, benzo(a)pyrene, dibenz(a,h)anthracene, and naphthalene [9]. Toxicology of PAH in humans has been widely studied and reported in several countries, such as Ukraine [13], the United States [14], Czech Republic [15], Denmark [16], United Kingdom [17], Poland [18], Germany [19], Sweden [20], and several other countries [21–25]. PAH are classified as persistent organic pollutants. They are found almost everywhere (air, water, food, soil, etc.), hence it is practically impossible for

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the human population to avoid the exposure to trace amounts of these toxicants in nature [26,27]. Given that several epidemiological studies have correlated PAH exposure to an increased risk of cancer [6–10], any exposure to PAH is assumed to pose a certain risk of cancer. Of a major concern is the fact that avoidable exposure to these deadly toxicants is still on the rise especially in low- and middle-income countries [1]. PAH are highly stable and have multiplicity of sources [28] which could be broadly classified as diagenetic in origin, pyrogenic in origin, or petrogenic in origin [28]. They are classified as diagenetic in origin when they occur as a transformation product of natural sources, such as volcanic eruption and microbial degradation of organic matter. When PAH occur as a result of incomplete combustion processes of organic matter for example combustion of wood, oil, vehicular emissions, industrial emission, forest fires, they are classified as pyrogenic. But when the contamination occurs from petroleum sources as a result of natural or anthropogenic causes such as oil spill, petroleum production, they are referred to as petrogenic in origin. Hundreds of PAH and related compounds have been detected and identified and these vary in the number of aromatic rings they contain. PAH do not occur as individual compounds but rather as a mixture of various PAH compounds. Among these, 16 are considered as priority by the USEPA because there is more information available on them and there is a greater possibility of people being exposed to them. These 16 are a small representativesubset of all PAH. They range in volatility from pure gas phase (2-ring) through phase distributed (3,4-ring) and essentially nonvolatile (5,6-ring) compounds. These PAH include acenaphthene, acenaphthylene, anthracene, benz(a)anthracene, benzo(a)pyrene, benzo(b)fluoranthene, benzo (ghi)perylene, benzo(k)fluoranthene, chrysene, dibenz(a,h)anthracene, fluoranthene, fluorene, indeno(1,2,3-cd)pyrene, naphthalene, phenanthrene, and pyrene. The chemical structures of these compounds are shown in Fig. 1. In order to determine the uptake of PAH in the body, various carcinogenic biomarkers have been employed including metabolites in urine, urinary thioethers, urinary mutagenicity, genetoxic end points in lymphocytes, hemoglobin adducts of benzo(a)pyrene, PAH–protein adducts, and PAH– DNA adducts [29]. Urinary mutagenicity, urinary thioethers, and genetoxic end points are nonspecific indicators of exposure to mutagenic agents. There is paucity of data on hemoglobin adducts of benzo(a)pyrene as its first results show limited usefulness [30]. DNA and protein adduct methods lack sensitivity in the case of occupational exposure to PAH and smoking is a very strong interfering confounder [30–33]. Besides the urinary metabolites, all

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Figure 1 Chemical structure of 16 priority PAH.

the other methods are not suitable for routine applications. Of a particular interest, urinary 1-hydroxypyrene (1-OHpy) has been established as the most relevant parameter (biomarker) for estimating an individual’s exposure to PAH and it has strongly been linked with an increased risk of cancer [34].

2. PAH DISTRIBUTION AND EXPOSURE PAH are toxic human mutagens, carcinogens and are potential developmental and reproductive toxicants [16,35,36]. They are acutely lethal in concentrations of a few ppm and chronically lethal in minute concentrations of a few ppb [37]. Aquatic toxicities of environmental PAH contamination have been widely demonstrated [38,39]. Their reproductive, neurotoxic, immunotoxic, and cytotoxic effects have been widely reported [40–44].

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The interest on PAH has been mainly due to their carcinogenic properties. Several epidemiological studies have shown increased mortality due to cancer associated with exposure to PAH-containing mixtures in humans exposed to emissions from coke-oven, roofing tar, petrogenic sources, cigarette, and others [45,46]. Their major sources are through natural (diagenic) and anthropogenic (pyrogenic and petrogenic) sources. While natural sources include volcanoes, natural fires, and thermal geological reactions [47,48] and anthropogenic sources include combustion of fossil fuels, including motor vehicle emission and power generation; wood burning and cooking; municipal and industrial waste incineration; coal tar, coke, asphalt, crude oil, creosote, asphalt roads, and roofing tar; discharges from industrial plants and waste water treatment plants; hazardous waste sites, coal-gasification sites, smoke houses, aluminum production plants, foundries, iron, and steel production; atmospheric contamination of leafy plants; cigarette smoke; petroleum refineries; and processed foods like charbroiled grilled, roasted, fried, and smoked meat [3,47–49]. Only a small number of PAH are produced commercially, including fluoranthene (Fig. 1), acenaphthene (Fig. 1), and fluorene (Fig. 1). Acridine (Fig. 2), a derivative of anthracene, is also produced commercially. These are employed as intermediates in the production of pharmaceuticals, fluorescent dyes, and perinon pigments, respectively [50,51]. A couple of drug formulations including phenanthrene-based antimalarials (halofantrine) (Fig. 3), phenanthrene-based antitumor drugs (phenanthrene-based tylophorine derivatives) (Fig. 4), naphthalene derivative beta blockers (propranolol) (Fig. 5), naphthalene derivative analgesics (Naproxen) (Fig. 6), naphthalene derivative anesthetics (3-{[(3-ethoxynaphthalen-2-yl)carbonyl]oxy}-N,N-diethylpropan-1-aminium chloride, or 2-ethoxy-3diethylaminopropylnaphthoate) (Fig. 7). These pharmaceutical compounds contain a core naphthalene or phenanthrene structure and can be synthesized efficiently in excellent yield as evidenced in Figs. 2–7. Some other medicinal alkaloids that also share in the PAH core structure are the phenanthroindolizidine and phenanthroquinolizidine alkaloids. Coupled to these, the fact that they have petrogenic sources make them

N

Figure 2 Chemical structure of acridine.

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Figure 3 Chemical structure of halofantrine.

OMe OMe

H R N

OMe

OMe

Figure 4 Chemical structure of tylophorine derivatives.

Figure 5 Chemical structure of propranolol.

Figure 6 Chemical structure of naproxen.

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N O O O HCl

Figure 7 Chemical structure of 3-{[(3-ethoxynaphthalen-2-yl)carbonyl]oxy}-N,Ndiethylpropan-1-aminium chloride.

prominent in personal skin care products like baby oil (mineral oil), vaseline, medicated skin cream, coal tar shampoos, coal tar topical ointment for psoriasis treatment, capsules, petrolatum, lipsticks, toothpaste, deodorant, hair cream, powder, and food processing. They are ubiquitous in the environment and low levels of these chemicals may be absorbed when a person uses any of the aforementioned personal care products containing PAH. Natural and synthetic wax sometimes serve as pharmaceutical excipient and thickener during a drug formulation. The ubiquitous nature of PAH compounds makes it practically inevitable for the human population to avoid exposure to trace amounts of these toxicants in nature [26,27]. The major routes of PAH uptake in human body include inhalation (air, smoking), ingestion (diet, drinking water), and dermal absorption (through medicinal drugs for the skin, children playing on and in dermal contact with contaminated soil). Most people are exposed to these toxicants environmentally or occupationally although it has been estimated that smoking and diet are the most important sources of PAH intake [52]. Environmental exposures include exposures from smoking, traffic pollution, generator exhaust fumes, pollution from industrial machines, use of coal and wood for cooking in nonindustrial region, and consumption of PAH-rich diet. It has equally been found that the concentration of airborne PAH is higher during winter than other seasons because motor vehicle emissions are higher with a corresponding lower yield of cold engine during winter [53]. Wood burning as a source of home heating during winter can contribute significantly to the level of PAH. Occupational exposures involve individuals that work in foundries, and petrochemical industries, those working with asphalt, fire fighters, traffic police, and soil remediation. In a comprehensive review by Hansen et al., of the 61 studies performed in various plants covering coal liquefaction, creosote facility, carbon black, iron foundries, fire-proof material producing plants, steel

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plants, aluminum plants, rubber vulcanizing plants, electrode manufacturing plant, etc., the urinary 1-hydroxypyrene concentrations measured among those workers were far higher than their corresponding controls. Some workers had urinary 1-hydroxypyrene levels as high as 1696 μmol/mol creatinine. Humans are exposed to complex mixture of PAH, which have been implicated in lung, stomach, skin, and breast cancer depending on the route of exposure or administration [53]. For example, oral, tracheal, and intratracheal applications resulted in gastric, skin, and lung tumors, respectively. This was evidenced in 1997 when Boffeta and colleagues observed an increase in lung and skin cancer following inhalation and dermal exposure in aluminum and coke production workers, iron and steel foundries workers, coal-gasification workers, tar distillation workers, roofing, carbon black, and carbon electron production workers while an increase in bladder cancer risk had been reported mainly in workers with PAH exposure from coal tars and pitches [54]. More worrisome is the fact that despite listing PAH in the EU and USEPA priority pollutant list and these compounds being rated ninth most threatening compounds, avoidable exposure to these deadly toxicants is still on the rise especially in low- and middle-income countries [55]. With limited healthcare facilities in these low-income countries, most deaths that occur as a result of certain occupational and environmental exposures to PAH may not be captured and this informs the need to determine the level of PAH exposure in order to extrapolate its carcinogenic and other health effects. This has necessitated the wide search for easier but reliable alternatives like biomarkers for PAH exposure and for predisposition to cancer in the assessment of tumor development stages, mechanism of carcinogenesis, and information pertinent to cancer risk. A biomarker is a measurable biochemical, physiological, behavioral, or other alteration within an organism that can be recognized and associated with an established or possible health impairment or disease. Researchers have advocated the use of biomarkers for predisposition to cancer as strong pointers to possible cancer initiation [53]. In order to determine the extent of exposure to PAH, various biomarkers have been employed.

3. THE CONCEPT OF BIOMARKERS Biological monitoring is the determination of a parent chemical or its metabolite in body fluids (blood or urine) or expired air. It is generally used as a measure of the individual internal dose [55] in an attempt to assess the

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OH

Figure 8 Chemical structure of 1-hydroxypyrene.

potential health risk the substance may induce. The unit being measured is termed a biological marker, or biomarker. Biomarkers are physiological, cellular, or molecular indicators used to evaluate xenobiotic exposures and potential population effects. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. When PAH enter the body, they are usually biotransformed to their metabolite so that they can be easily excreted. The urinary 1-hydroxypyrene (Fig. 8) (a specific metabolite of pyrene), for example, is a well validated and frequently used biomarker of human exposure to PAH and has been used as a biological monitoring indicator of exposure to PAH in several related occupational and environmental studies. The abundance of pyrene, a noncarcinogenic PAH, is relatively high in PAH mixtures [56–59] and since pyrene is always present in PAH mixtures, the biological indicator is not only an indicator of pyrene uptake, but also an indirect indicator of all PAH. Despite the fact that DNA and protein adducts give direct information on the extent of carcinogen reactions with DNA, urinary metabolites are usually preferable in that urine samples are easily accessed and obtained in quantity large enough that with the use of most modern analytical methods, reliable data can almost always be obtained. This is often not the case with measuring the former where many “not detected” values are obtained which is capable of frustrating the researcher and severely limits a study’s ultimate value. There are three major classifications of biomarkers, namely, biomarkers of exposure, biomarkers of effect, and biomarkers of susceptibility. These are briefly described below.

3.1 Biomarkers of Exposure Biomarkers of exposure refer to chemicals, their metabolites, or the products of interactions between chemicals and some target molecules or cells that are

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measured in the human body. There are different specific biomarkers of internal effective dose for exposure to PAH. They include urinary metabolites, leukocyte, or buccal cell PAH–DNA adducts (Fig. 9), protein (hemoglobin and albumin)–PAH adducts, circulating anti-DNA adduct antibodies [60]. Several methods for PAH–DNA adduct analysis have been developed as well and they include antibodies against specific PAH adducts (e.g., ELISA), fluorescence spectroscopy, mass spectrometry, and 32p postlabeling of modified nucleotide [61]. Several reports have also correlated elevated urinary 1-hydroxypyrene to occupationally exposed workers.

Figure 9 A typical PAH (benzo[a]pyrene in blue (black in the print version) at the middle)–DNA adduct (“Benzopyrene DNA adduct 1JDG” image by Zephyris at the English language Wikipedia).

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In 2012, Ifegwu et al. reported the presence of high concentrations of urinary 1-hydroxypyrene in mechanics, drivers, fuel attendants when compared to the control group [1].

3.2 Biomarkers of Effect Biomarkers of effect characterize the impact of exposure to chemicals or contaminants on a targeted system such as the blood. As a result, molecular, cellular, or even systemic effects can be observed before clinical symptoms manifest. A number of studies have considered DNA damage as an endpoint for the effects of air pollution, in particular “bulky” DNA adducts, which are related to exposure to aromatic compounds like the PAH. These biomarkers are often used during biomonitoring of exposed workers to evaluate the genotoxic and carcinogenic risk of PAH. For example, recovery of DNA adducts from blood or urine may reflect the risk of genotoxicity [62]. A number of these biomarkers of effect include standard cytogenic assays like micronuclei, chromosomal aberrations, sister chromatid exchanges, and high frequency of ras oncogene mutations, direct and oxidative DNA damage (e.g., DNA strand breaks).

3.3 Biomarkers of Susceptibility Biomarkers of susceptibility can potentially characterize how populations respond to exposures. In addition, biomarkers of susceptibility can identify potentially sensitive population subgroups. Not all individuals with a given biomarker of effect will develop the disease. Studies of genetic polymorphism can identify persons with enzyme types more likely to be affected by a chemical. This is to say that the genetic predisposition of an individual can affect this predisposition to carcinogen-induced cancer. Genetic susceptibility mainly results due to variation in genes for carcinogen metabolizing enzymes (e.g., cytochrome P-450, glutathione-S-transferases (GSTs)); variations in genes for repair of DNA adduct; polymorphism in enzymes involved in the activation of PAH to mutagens and subsequent detoxification (CYT 1A1, GSTS 1, GSTP 1, and NAT 2). For example, CYT P-450 (CYTP 1A1 and CYTP 1B1) are largely responsible for the carcinogenesis of PAH in different individuals. Susceptibility biomarkers have been individualized and used to evaluate the genotoxic and carcinogenic risk of PAH particularly in biomonitoring studies of exposed workers so that protective measures can be taken. They also play a crucial role in assessing the mechanism of toxicity [63].

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4. THE CONCEPT OF TOXICOKINETICS Toxicokinetics is the study of the kinetics of absorption, distribution, metabolism, and excretion of foreign chemicals and their toxic response in animals and man. It enables us to understand the chemical and biological basis for toxicological effects observed in the body and describes the behavior of a chemical in the body. Absorption is the process or processes by which an administered chemical enters the body [64]. Usually for a substance to reach the target organ of the body it must pass through a series of barriers, such as many membranes of the cells of the skin, the layer in the lungs, and gastrointestinal tract, the capillary cell, the cell of the organs that eliminate the chemicals, mainly the liver and the kidney [65]. The cell membranes consist of a bimolecular layer of lipid molecules coated on each side with a protein layer, branches of which penetrate the lipid bilayer or even extend right through it. At physiological temperatures, the lipids of the membranes have a quasifluid character, determined by the structure and relative proportion of unsaturated fatty acids. Most foreign chemicals cross the body membranes by simple diffusion whose rate and extent are influenced by morphology and dimension of the absorbing surface, perfusion of the absorbing area, chemical characteristics of the chemical substance, dose, and duration of exposure. Distribution is a process or processes by which an absorbed substance and/or its metabolites circulate and partition with the body [65]. The distribution of chemicals in the blood occurs rapidly and their distribution to the different tissues and organs is determined by the blood flow through the capillary walls and interstitial and cell barriers, by concentration gradient of the free unbound chemicals, and by affinity to binding sites in the tissues and organs. Chemicals are found in various tissues and organs in different concentrations according to its hydrophilicity and lipophilicity; hence, chemicals with high lipophilicity occur in much higher concentration in fats and are accumulated in the liver and kidney. Only the circulation system is a distinct closed compartment where chemicals are distributed rapidly. Distribution to the various tissues and organs (also termed peripheral compartments) is usually markedly delayed, and there is equilibrium of chemicals between the central circulatory system and peripheral compartment. As chemicals deplete from the circulatory system, by elimination, they are slowly released into circulation by the peripheral compartments. Depending on how perfused the organ or tissue is, it can be classified into different

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compartment models, such as one, two, or three compartmental models. For instance, many chemicals do not enter the central nervous system. Also in pregnancy there exists the placental barrier. Metabolism, which is also referred to as biotransformation, is a process or processes by which an administered xenobiotic is structurally altered in the body by either enzymatic or nonenzymatic reactions [65]. Metabolism basically converts poorly excretable lipophilic compounds to more polar entities that can be readily excreted in urine and/or bile. Compounds with high water/oil partition ratios or compounds that are highly hydrophilic are less likely to undergo metabolism because they can easily be excreted in the urine. Two or more sequential enzymatic reactions are routinely required to convert lipophilic xenobiotics to metabolites that are efficiently excreted and these can be classified into phase I and phase II reactions. The phase I reactions include oxidation, reduction, and hydrolysis, while phase II reactions are conjugation and synthesis. Usually, a phase II reaction is preceded by one or more phase I reactions. Chemicals are excreted from the body either unchanged or as watersoluble metabolites. The kidney is the organ for the excretion of watersoluble compounds, while liver and its biliary systems are for the excretion of specific compounds such as metals, high-molecular mass anions and cations, and most lipophilic substances. The lungs also excrete gasses such as carbon dioxide and volatile substances. The stomach and the intestine can also act as excretory organs for weak organic acids and bases [66,67]. Other less important routes of excretion include skin, hair, pancreas, saliva, and tears [68].

5. TOXICOKINETICS OF PAH In recent years, significant progress has been made in advancing the understanding of the biological action of PAH which can reach the systemic circulation through three main routes. They are absorbed through the lungs by transport across the mucus layer lining the bronchi [69]. They are absorbed through the gastrointestinal tract through uptake of fat soluble compounds [70]. Lastly, they are absorbed through the skin mostly by passive diffusion through the stratum comeum [71]. They are distributed to the tissues through the circulatory system of the body; hence, they reach the more perfused tissues rapidly and vice versa [72]. PAH cross the lungs through passive diffusion and partitioning into lipids and water layers of cells

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[73–75], while in the gastrointestinal tract, they are transported by lipoproteins to the blood through the thoracic duct lymph flow [70]. PAH are metabolized in the body in the presence of cytochrome P-450 and associated enzymes to several metabolites which include epoxide, dihydrodiols, phenols, quinones, and their various combinations. Cytochrome P-450 is found primarily in the liver but it is also present in the lungs, intestinal mucosa, and several other tissues [76]. The carcinogenicity of PAH is believed to be due to the formation via covalent bond of DNA–PAH metabolites as adducts. In the following sections, the absorption, distribution, metabolism, and excretion of PAH will be described in details.

5.1 Absorption There are three main routes of PAH absorption in humans. The routes are the lungs and respiratory tract following inhalation of aerosols or particulate containing PAH, dermal following skin contact, and gastrointestinal tract following ingestion in water and food. Several studies have provided evidence that PAH are absorbed following these routes [77–80]. The study of PAH absorption is usually separately conducted for inhalation, oral, and dermal exposure and most of these studies are limited to benzo(a)pyrene. Rapid absorption was recorded in rat exposed to benzo(a)pyrene inhalation [81,82]. Similar studies with guinea pigs and hamsters that had intratracheal exposure to benzo(a)pyrene produced similar results [83–85]. A study carried involving pregnant Wistar rats that were exposed to various concentrations of benzo(a)pyrene for 95 min showed that benzo(a)pyrene is well absorbed in the body [82]. PAH in air usually occur adsorbed to particles and their inhalation absorption may be affected by size of particles on which they are adsorbed. Several studies have supported this theory [86,87]. These studies showed that the smaller the particle size the faster the absorption. An in vitro study carried out by Gerde and Scholander corroborated these findings and proposed that the release rate of PAH from carrier particles is the rate determining step in the transport of these particles to the bronchial epithelium [88]. There is ample evidence suggesting that PAH are orally absorbed in humans [89,90]. Results of studies have shown that oils and fats in the gastrointestinal tract influence the absorption of PAH in laboratory animals such as rat [90–93]. Peak concentration was achieved in blood of the rat after 1–2 h postadministration [94]. Absorption from the gastrointestinal tract occurs rapidly. The two major determinants of gastrointestinal absorption

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are aqueous solubility and lipophilicity, since absorption requires compounds to go into solution in the lumen of the intestine, pass through the cell walls of the intestinal cells and be removed to the circulation. The absorption involves two main phases, uptake by the mucosa, followed by diffusion through the intestinal walls [95]. Therefore, the intestinal absorption of the individual PAH is highly dependent on their solubility, their lipophilicity, the presence of bile [96], and the lipid content of the various PAH-containing foods ingested. Whereas oils enhanced the absorption of PAH, water, and solid foods suppressed them [93]. A number of studies were conducted to demonstrate that PAH can be absorbed through the skin of humans [97–100]. The studies show low but significant differences in dermal PAH absorption between anatomical sites: shoulder > forehand, forearm, groin > ankle, hand (palmar site) [76]. In vitro study shows quite low permeation across viable human skin as Kao et al. reported an estimated 3% skin permeation after 24 h [101]. Dermal absorption of PAH may be influenced by the vehicle of administration [102,103]. In addition, dermal absorption is dose dependent as shown in a study carried out by Yang et al. with anthracene which demonstrated that skin permeation of anthracene significantly decreased over time [71].

5.2 Distribution For obvious reason, there is practically no study on distribution of PAH in humans but several studies have been conducted on laboratory animals [104–106]. In laboratory animals, PAH become widely distributed in the body following administration by any one of a variety of routes and are found in almost all internal organs, particularly those rich in lipid. A study by Bartosek et al. corroborated some of these results mentioned above [72]. They found out that benz(a)anthracene, chrysene, and pyrene were rapidly and widely distributed in rats [72]. Other PAH for which distribution in laboratory animals have been studied include dibenz(a,h)anthracene [107], dimethylbenz(a)anthracene, 3-methylcholanthrene [108], and a host of others [84,98]. Tissue distribution for benzo(a)pyrene following inhalation exposure exhibits similar trends in different species of laboratory animals [81–85,109]. According to a study conducted by Weaned and Bevan, the highest concentrations of intratracheally administered [3H]-benzo(a)pyrene to rat were distributed to the lungs, liver, kidney, and gastrointestinal tract. Maximum concentrations of benzo(a)pyrene were detected in the liver,

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esophagus, small intestine, and blood after 30 min of exposure by inhalation [105]. Oral exposure of benzo(a)pyrene to pregnant rat has shown that it crosses the placental barrier [109,110]. However, it does not cross the barrier readily and therefore the level in embryonic tissues did not reach the concentration detected in maternal tissues. Maximum concentrations of benzo(a)pyrene in perfused tissues (e.g., liver, blood, and brain) were achieved within 1–2 h after administration of high oral doses (76 and 152 mg/kg bw). In less perfused tissues (e.g., adipose and mammary tissue), maximum concentrations of this compound were achieved in 3–4 h [72].

5.3 Metabolism When PAH enters the body, they are usually biotransformed to their metabolites so that they can be easily excreted (Figs. 10 and 11). The metabolism of PAH is complex. PAH are activated by a pathway that involves both CYP enzymes and epoxide hydrolase (EH). After exposure, PAH molecules induce expression of phase I and II metabolizing enzymes [111] including aldo-ketone reductases, cytochrome P-450s (CYP 450), catechol-O-methyltransferase, EH, peroxidases, GSTs, acetyltransferases, sulfotransferases (SULTs), and other enzymes catalyzing conjugation reactions [112]. Phase I metabolism involves alteration of the structure of the compound to increase the polarity like in the conversion of pyrene to 1-hydroxypyrene by oxidation. This makes the compound more electrophilic, resulting in increased reactivity. Phase II normally involves the addition of polar groups, thereby increasing the bulkiness and aqueous solubility like further conjugation of 1-hydroxypyrene with glucuronide to form 1-hydroxypyrene glucuronide (Fig. 10). In general, the metabolic process involves the epoxidation of double bonds (Fig. 11), a reaction catalyzed by the cytochrome P-450-dependent monooxygenase, the rearrangement or hydration of such epoxides to yield phenols or diols (Figs. 11 and 12), respectively, and interconjugation of the hydroxylated derivatives. Reaction rates vary widely, and interindividual variations of up to 75-fold have been observed, for example, with human macrophages, mammary epithelial cells, and bronchial explants from different donors. While some PAH metabolism results in detoxification, others become activated to DNA-binding species, principally diolepoxides that can initiate tumors as depicted in Figure 10 [111–114]. Given that PAH are lipophilic, little data exist as to in vivo metabolism of PAH in human. It is hypothesized that phenols may be formed from the

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Pyrene Cytochrome P1A1/1B1

Su

lfot

ono

e hat

OH O

osp

OH

iph

ed

din

Uri

O H

HO H

H

H

H

O OH

ran

sfe

ras

e

1-Hydroxypyrene Uridine diphosphate glucuronosyl

cur

glu

syl

OH

Pyrene-1-glucuronide

O

O S O

OH

Pyrene-1-sulfate

OH O H

HO H

H

H O

H OH

OH

Pyrene-1-glucoside

Figure 10 Hydroxypyrene biotransformation.

parent compound in the liver by direct insertion of oxygen [115] or epoxide rearranged to phenols and further oxidized to quinine or undergo hydration to form trans-dihydrodiol catalyzed by EH [115]. These dihydrodiols can be converted into catechols (via dihydrodiol dehydrogenase) and further oxidized to ortho quinines (Fig. 12), which often undergo redox cycling to form reactive oxygen species (ROS) (e.g., superoxide anion, hydrogen peroxide, and hydroxyl radicals) that are capable of causing oxidative stress hence damaging cellular macromolecules and activating signaling pathway leading to cancer initiation. The orthoquinones can equally be converted by CYT P-450 (1A1, 1A2, 1B1, 3A4, and 2C) into diolepoxides (Fig. 13), which in turn forms an adduct with protein, RNA, or DNA or hydrolyzed via EH to tetraols. The bay-region diolepoxides (Fig. 13) of several PAH are considered as their promutagenic tumorigenic metabolite.

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Benzo[a]pyrene

Cytochrome P1A1/1B1 [O2]

(+)Benzo[a]pyrene-7,8-epoxide O

Epoxide hydrolase

(−)Benzo[a]pyrene-7,8-dihydrodiol OH OH

Cytochrome P1A1/1B1 [O2] O

OH OH

(+)Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide

Figure 11 Metabolism of benzo[a]pyrene yielding the carcinogenic benzo[a]pyrene7,8-dihydrodiol-9,10-epoxide (BPDE).

In phase I metabolism, the most common mechanism of metabolic activation of PAH, such as benzo[a]pyrene (B[a]P), is via the formation of bay-region dihydrodiol epoxides, e.g., benzo[a]pyrene-7,8-dihydrodiol9,10-epoxide (BPDE) (Fig. 13), via cytochrome (CYP)450 and EH. B[a] P has been used as a prototype carcinogenic PAH since its isolation from coal tar in the 1930s. One of its four enantiomeric diolepoxide, BPDE-2 is considered the ultimate carcinogen on the basis of binding to DNA,

295

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Cytochrome P450 Peroxidase

DNA C CH

Benzo[a]pyrene

Depurinating DNA adduct

+

Radical cation Radical cation pathway

Cytochrome P1A1/1B1 Epoxide hydrolase

O

DNA

Cytochrome P1A1/1B1

PAH-DNA adduct

OH

OH OH

OH

(+)Benzo[a]pyrene-7,8-dihydrodiol-9,10epoxide

Benzo[a]pyrene-7,8trans-dihydrodiol

Diolepoxide pathway Aldo-keto reductase(s) 1A1/1C1–1C4

Oxidative DNA damage O2 H2O2 Adduct formation with DNA, RNA, glutathione

Aldo-keto reductase(s) OH

NADP+

OH

Catechol

O

NADPH O

Benzo[a]-7,8-dione Ortho quinone pathway

Figure 12 Activation of PAH.

Figure 13 Chemical structure of benzo(a)pyrene diolepoxides.

mutagenesis, and extremely pulmonary carcinogenicity in newborn mice. Nevertheless, BPDE-1 has a similar binding to DNA and mutagenicity but they are not considered carcinogenic [113]. CYPs 1A1, 1A2, 1B1, 1B2, 3A4, and 3A5 are highly inducible by the exposure to PAH and these enzymes share the same mechanism with which PAH molecules interact with the aryl-hydrocarbon receptor (AhR). Usually after forming a complex with PAH (AhR-PAH), the heat shock protein 90 (Hsp90) is released from the AhR protein complex after which the new AhR-PAH complex

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translocates to the nucleus where it creates a heterodimer with an AhR nuclear translocator and thereafter binds to the DNA through the xenobiotic response element that is found in the promoter region of CYP1A and CYP1B genes [111]. Phase II metabolism involves conjugation of phase I metabolites with small molecules catalyzed by specific enzymes like SULTs, UDP-glucuronyl transferases, or GSTs to form bulkier polar conjugates that are aqueous soluble and readily excreted. Polymorphisms of phase II metabolism are associated with high risk of carcinogenesis and with DNA damage. Binkova and his coworkers established an important correlation between GSTM1 gene polymorphism and DNA adduct levels [116]. Polymorphisms of SULT1A1 have also been correlated with PAH–DNA adduct levels [117]. GSTs are equally crucial in quenching and detoxifying ROS and their derivatives [118]. It is worth noting that a good majority of the phase II metabolites are used as biomarkers of PAH exposure, e.g., 1-hydroxypyrene glucuronide [119].

5.4 Excretion PAH metabolites and their conjugates are predominantly excreted via the feces and to a lesser extent in the urine. Conjugates excreted in the bile can be hydrolyzed by enzymes in the gut flora and reabsorbed. It can be inferred from available data on total body burdens in humans that PAH do not persist for long periods of time in the body and that turnover is rapid. This excludes those PAH moieties that become covalently bound to tissue constituents, in particular to nucleic acids, and are not removed by repair. The excretion of urinary metabolites is a method used to access internal human exposure of PAH [120,121]. A number of researchers have reported the detection of PAH metabolites in human urine after exposure by inhalation [122,123]. Usually the metabolite used in urine analysis for the determination of concentration of excretion is 1-hydroxypyrene [76], 1- and 3-hydroxychrysene have also been used [124]. In several studies conducted with human subjects, some interesting conclusions were drawn. First, smokers had higher level of urinary 1-hydroxypyrene concentration than nonsmokers. Second, the level of urinary 1-hydroxypyrene in the electrode plant workers correlated inversely with age [76]. For studies performed on laboratory animals, it was discovered that the excretion of benzo(a)pyrene metabolites following low level of inhalation exposure is more rapid in rats [82–85] than in dogs and monkeys [125].

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In humans, elimination of 1-hydroxypyrene has been reported after some volunteers ingested food with high PAH content [89]. Similar results have also been reported for laboratory animals [124]. There are sufficient data to show that PAH are equally excreted following dermal exposure. A study on some patients with psoriasis that were treated with coal tar covering on their skin for 3 weeks show that 1-hydroxypyrene tremendously increased during the period but declined afterward perhaps as the skin healed and became less permeable [126]. However, in the study on automobile repair workers who used mineral oils and were exposed to high concentration of PAH showed that exposure to PAH through dermal contact with those who used engine oil is low since no significant difference was recorded in the 1-hydroxypyrene urinary level of the workers and those of control mineral oil [127]. For studies involving laboratory animals, elimination of PAH following dermal exposure was rather high in concentration [128,129].

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