Polycyclic Aromatic Hydrocarbons

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Polycyclic aromatic hydrocarbons (PAHs) are a group of unsaturated cyclic hydrocarbons containing two or more rings, derived from the incomplete burning of organic materials. They are common environmental contaminants produced by diverse industrial (Ball and Dawson 1969; Ball et al. 1966; Gricuite 1979) and domestic (Huhti 1981; Aggarwal et al. 1982; Grimmer and Pott 1983) processes. Contamination and exposure to PAHs can occur in industrial, rural, and urban settings, as PAHs can be found in plastics, dyes, medicines, charbroiled meat, tobacco, pesticides, and industrial materials such as asphalt, petroleum, and coal tar products, creosote, and roofing tar. Environmental PAH contamination occurs mainly by release into the air from residential wood burning and automobile exhaust (Autrup et al. 1995). Occupational exposure occurs most prominently in industries utilizing petroleum products, while exposure in the home occurs mainly from cigarette smoke and charbroiled foods.

Naturally produced PAHs are generally found as a mixture of a variety of PAH compounds; thus, exposure to only one specific PAH is rare and only occurs in the laboratory. There are over 100 described natural and synthetic PAHs, but benzo(a)pyrene (B(a)P), 3-methylcholanthrene, 7,12-dimethyl-benz(a)anthracene, benzo(b)fluoranthene, chrysene, and phenanthrene are some of the more common and better characterized forms. B(a)P is the most studied PAH compound and is found in combustion pollutants including car exhaust and tobacco smoke; thus, it is often used as a model for other PAH exposure.

When present in the environment, PAHs are found in the air as vapors or adhered to small particulate matter. Some PAHs have limited solubility in water but most remain adhered to particulate matter and settle into soils or the bottoms of lakes and rivers. Human and animal exposure can then occur from inhalation, dermal contact, or ingestion. Once in the body, the lipophilic nature of PAHs causes them to preferentially partition to tissues with a high adipose content, such as the liver kidneys and fat stores. PAHs are metabolized rapidly by members of the cytochrome

P450 family and glutathione-S-transferase into compounds that may be more or less harmful than the original PAH. The metabolized compounds are more water-soluble, however, and are eliminated more rapidly than the original PAH. Elimination rates of PAHs and their resulting metabolites appear to be species-specific, e.g., transformation and elimination of B(a)P is rapid in the rat but slower in dogs and monkeys (U.S. DHHS 1995).

Placental transfer of PAHs occurs, but at a reduced rate compared to distribution throughout the body of the mother (Salhab et al. 1987; Autrup et al. 1995; U.S. DHHS 1995). Autrup et al. (1995) investigated the transplacental transfer of PAHs from cigarette smoke or ambient air by comparing the PAH-albumin adducts present in maternal and fetal umbilical cord blood. A positive association was observed between adduct levels in the maternal blood and umbilical cord blood, indicating that fetal exposure will parallel maternal exposure; however, the levels of adducts in the cord blood were lower than in the maternal blood in all cases. Pregnant women may be exposed to B(a)P levels as high as 150 mg/day in highly polluted areas and up to 3 mg/day due to heavy cigarette smoking (Rodriguez et al. 1999).

Exposure to these PAHs can cause cancer, and B(a)P is generally recognized as the most potent carcinogenic PAH (Urso and Gengozian 1984). In addition to being carcinogenic, PAHs can also induce immune suppression in humans and laboratory animals (Luster and Blank 1987). In coke oven workers, inhalation exposure to a mixture of PAHs lowered immunoglobulin levels, particularly IgG and IgA (Szc-zeklik et al. 1994). Suppression of cellular and humoral immune function has been demonstrated in adult mice. Adult female B6C3F1 mice were exposed to 10 different PAHs at subchronic exposures and immune response measured by antibody production to sheep red blood cells (White et al. 1985). Anthracene, chrysene, benzo(e)pyrene and perylene did not significantly suppress antibody production; however, benz(a)anthracene, benzo(a)pyrene, dibenz(a,c)anthracene and dibenz(a,h)anthracene suppressed the antibody forming cell response by 55 to 91%. In another study, B6C3F1 mice demonstrated reduced antibody production to both T-dependent and T-independent antigens after exposure to B(a)P (Dean et al. 1983).

PAH exposure during gestation can cause developmental abnormalities in animals, including stillbirths, reabsorbed fetuses, decreased birth weight, birth defects, and infertility or sterility of the offspring (U.S. DHHS 1995). PAHs are also toxic to the developing fetal immune system. Exposure of experimental animals to B(a)P during immune system ontogenesis appears to result in persistent alterations in immune function. Mouse progeny of dams exposed to B(a)P during mid-pregnancy had abnormalities in their cell mediated and humoral immune response. For example, offspring of pregnant mice receiving 150 mg/kg B(a)P from days 11 to 17 of gestation showed suppression in plaque-forming cells, graft-vs.-host, and mixed lymphocyte responses. Suppression of immune responses was detected during gestation, one week after birth, and still demonstrable at 18 months of age (Urso and Gengozian 1984). These animals further exhibited an 8 to 10 fold higher tumor incidence than vehicle-exposed controls. Other studies have also demonstrated an increase in tumor rate associated with suppression of cell and humoral immune function after in utero PAH exposure (Urso and Gengozian, 1980 1982). The authors concluded that in utero exposure to B(a)P alters development of immunity, and that such exposure during development can lead to severe and sustained postnatal immunosuppression (Urso and Gengozian 1984).

The toxicity of B(a)P is in large part due to production of a highly reactive epoxide metabolite by microsomal mixed-function oxidase enzymes such as cytochrome P450 isozymes, or prostaglandin H synthase and lipooxygenase (Rodriguez et al. 2002). Cytochrome P450 isozymes are generally considered to be the main enzymes responsible for B(a)P metabolism. As summarized by Rodriguez et al. (2002), maternal tissues contain high concentrations of the P4501A1 and P4501A2 isozymes to convert B(a)P, although concentrations of these isozymes are low in placental and fetal tissues. Fetal tissues metabolize B(a)P mainly with the fetal isozyme P4503A7; however, prostaglandin H synthase and lipooxygenase are present in the fetus also. The main placental isozyme is P4501A1, and while it is found in low concentrations in nonsmokers, it is highly inducible in women who smoke (Rodriguez et al. 2002). B(a)P is metabolized to B(a)P-7,8-diol-9,10-epoxide (BPDE) which covalently binds DNA and other nucleophilic intracellular macro-molecules. Thus, rapidly proliferating cells, such as those composing the immune system, are targeted (Holbrook 1980). Interestingly, a study evaluating the covalent binding of B(a)P in fetal mouse tissues found liver hematopoietic cells to be the most active (Salhab et al. 1987). Further, the extent of transplacental enzyme induction compared to control was greatest in hematopoietic cells (18-fold), followed closely by whole fetal liver (16-fold) (Salhab et al. 1987; Urso and Johnson 1987). Such results indicate that fetal liver, the primary hematopoietic organ in the fetus, and its hematopoietic cells are specific targets of B(a)P, and may explain, at least in part, the significant toxicity to the developing immune system resulting from exposure to this compound.

The exact mechanisms of PAH immunotoxicity in the developing fetus are not known but it is clear that B(a)P disrupts T cell differentiation (Holladay and Smith 1994; Lummus and Henningsen 1995; Rodriguez et al. 1999). In utero exposure to B(a)P was found to alter expression of murine thymocyte and liver fetal cell-surface markers (Holladay and Smith 1994). Pregnant mice were treated orally with 0, 50, 100, or 150 mg B(a)P/kg/d on GDs 13 to 17, and offspring were examined on GD 18. Severe thymic atrophy and cellular depletion were found in B(a)P exposed fetal mice. Flow cytometric analysis indicated that the B(a)P treatment resulted in a significant decrease in the percentage of CD4+8+ fetal thymocytes, as well as significantly increased CD4-8- and CD4-8+ thymocytes (Table 8.3). The B(a)P treatment was also found to decrease total fetal liver cellularity, including numbers of cells within resident hematopoietic subpopulations. In particular, prolymphocytic cells, identified by CD45R antigen expression and by presence of nuclear terminal deoxynucleotidyl transferase, were significantly decreased in animals gestationally exposed to B(a)P (Table 8.4). In another study, a single injection of 150 mg/kg of B(a)P to pregnant mice at mid-gestation significantly reduced the number of T cells present in the thymus of newborn and in the spleens of 1-week-old progeny (Rodriguez et al. 1999). The percentage of newborn CD4+CD8+, CD4+CD8+Vg2+TCR+, and of CD4+CD8+Vb8+TCR+ thymocytes was significantly reduced following in utero exposure to B(a)P. Normal expression of the cell surface TCR molecules Vg2and Vp8 is necessary for routine T cell function (Rod-

Table 8.3 Effect of Gestational Exposure of Mice to B(a)P on GD 18 Thymocyte, Populations Defined by CD4 and CD8 Antigens

Population

Control

50 mg/kg

100 mg/kg

CD4+8-

2.8 ± 0.1

3.2 ± 0.1

2.8 ± 0.2

CD4+8+

78.0 ± 4.9

57.6 ± 1.0a

33.4 ± 5.3a

CD4-8-

18.1 ± 2.3

37.2 ± 1.2a

62.0 ± 5.3a

CD4-8+

1.1 ± 0.1

2.0 ± 0.2a

3.6 ± 0.2a

Note: Numbers are percentages (means ± SE) of cells within each phenotype, N = 5.

Note: Numbers are percentages (means ± SE) of cells within each phenotype, N = 5.

a Significantly different from control, p < 0.05.

Table 8.4 Prolymphoid Cell Populations Present in GD 18 Fetal Liver from Vehicle- and B(a)P-Exposed Mice

Marker Expression

Cell Number

(% positive)

(x 10-6)

Treatment

CD45R

TdT

CD45R

TdT

Vehicle

14.5 + 2.2

8.4 + 1.8

1.7 + 0.3

1.0 + 0.2

100 mg/kg B(a)P

19.7 + 1.6

ND

0.8 + 0.3

ND

150 mg/kg B(a)P

20.8 ± 4.9

10.5 ± 2.0

0.8 ± 0.2a

0.4 ± 0.2a

Note: Fetal liver antigen expression in GD 18 fetal mice after maternal exposure to 100 or 150 mg/kg/day B(a)P from GD 13 to 17. Numbers are means + SE, N = 3. ND = not determined. a Significantly different from control, p < 0.05. Source: Modified from Holladay and Smith 1994.

riguez et al. 1999). In a third study, lymphocytes of B(a)P-exposed GD 19 fetuses showed decreased subpopulation frequencies in fetal liver of total T cells (from 56% to 16%), Ly1+ expressing cells (from 33% to 9%), and Ly2+ expressing cells (from 56% to 1%) compared with untreated controls (Lummus and Henningsen 1995). These data clearly show that B(a)P, in addition to producing fetal thymic hypocel-lularity, inhibits normal fetal thymocyte maturation.

An additional possible mechanism for the PAH-induced immunosuppression is increased immune cell apoptosis. B(a)P is metabolized to BPDE; once formed, BPDE can bind to the DNA of developing T cells. BPDE-DNA adducts have been detected in mouse fetal and maternal tissues at high levels (Lu and Wang 1990). Rodriguez et al. (2002) found BPDE-DNA adducts after a single injection of B(a)P in mouse maternal and placental tissues and in fetal splenocytes and CD4+ and CD8+ thymocytes. DNA adducts were present at day 19 of gestation, at birth, and 1 week after birth (Rodriguez et al. 2002). B(a)P and BPDE induce apoptosis of T lymphocytes in vitro and may be responsible for inducing apoptosis in the immune system, affecting positive and negative selection of T cells in the developing fetus (Rodriguez et al. 2002). The developing thymus is comprised of approximately 95% CD4+CD8+ T cells, which may present a large susceptible population for BPDE-DNA adduct formation. Apoptosis of T cells can be blocked by a-naphthoflavone, a metabolic inhibition of the conversion of B(a)P to BPDE, indicating that conversion to BPDE may be necessary to induce T cell apoptosis (Davila et al. 1996; Rodriguez et al. 1999). It is possible that BPDE-DNA adduct formation induces apoptosis in the fetal thymus to selectively reduce CD4+CD8+, CD4+CD8+ Vg2+ TCR+, and CD4+CD8+ Vß8 TCR+ cells with the net result of secondary lymphoid tissue reduction in the spleen.

Mechanisms involving DNA adduct formation cannot alone fully explain PAH immunosuppression. PAHs also appear to affect T cell function via binding to the Ah receptor, similar to TCCD, which can directly affect T cell function through altered regulation of gene expression (Davila et al. 1996). An additional interesting finding demonstrating the complexity of B(a)P induced immunosuppression is that maternal immune capability influenced the immunotoxicity of B(a)P in offspring (Wolisi et al. 2001). In this study, adult female mice were thymectomized at 6 weeks, mated and injected with 150 |mg B(a)P)/g body weight at GD 12. Maternal thymec-tomy and B(a)P exposure reduced average litter size by 40%. Progeny from thymec-tomized mothers exposed to B(a)P showed enhanced cell mediated immunity (CMI) compared to progeny of both the control mothers and nonthymectomized B(a)P-treated mothers. CMI in progeny from nonthymectomized B(a)P treated dams was significantly reduced compared to progeny form controls. Humoral immunity as measured by PFC assay was suppressed equally in offspring from B(a)P-treated thymectomized and nonthymectomized mothers. Thus, thymectomy of the mother prevents CMI immunosuppression by B(a)P, while humoral immune suppression is unaffected by maternal thymectomy. These results indicate that the maternal thymus is somehow necessary for incurring the effect of B(a)P on progeny CMI (Wolisi et al. 2001).

The above collective data taken together indicate that postnatal immune suppression following in utero exposure to B(a)P may result from several intracellular mechanisms targeting immune cells at different hematopoietic levels. Possible mechanisms for immune suppression include increased apoptosis in developing hemato-poietic tissues, production of various toxic metabolites of B(a)P, alterations to cell signaling and activation pathways, as well as Ah receptor involvement. Regardless of the mechanism involved, the end result of in utero B(a)P exposure is a reduction in developing T cells, which results in immunosuppression.

Surprisingly, along with causing immunosuppression, in utero exposure to PAHs may also induce an increased hypersensitivity response in the offspring. Recent work has correlated the mother's exposure to PAHs via cigarette smoke and vehicle exhaust with increased inhalant allergies and asthma in children. The bulk of the work has examined the effects of pre- and postnatal exposure to cigarette smoke on pulmonary function and bronchial hyperreactivity. The results of these studies are inconclusive regarding inhalant allergies and asthma with numerous data demonstrating either positive or no association of cigarette smoke and allergies or asthma in children (Oliveti et al. 1996; Schäfer et al. 1997; Kulig et al. 1999). The conflicting results could easily be due to examining immune status in different ages of children, or to the inability to delineate the contributions of pre- and postnatal exposure to altered immune function. Further work will be necessary to resolve this particular question.

In addition to possibly increasing inhalant allergies and asthma in children, evidence indicates that exposure to cigarette smoke (and thus PAHs) may cause other immune hypersensitivity reactions as well. In a study by Kulig et al. (1999), children three years of age who were pre- and postnatally exposed to tobacco smoke had a statistically higher risk of sensitization to food allergens than unexposed children. Children who were only exposed postnatally also had a higher risk of sensitization than unexposed children. The allergens investigated were cow's milk, hen's egg, soybean, and wheat. No significant effect of tobacco smoke was seen on the inhalant allergens, birch, grass pollen, mite or cat. Exposure to environmental tobacco smoke reaches its peak at 1 year of age (due to increased physical contact of a small infant with its parent), which is the same time a child is first exposed to food allergens. The authors suggest it may be the simultaneous exposure to the tobacco smoke and food allergens at 1 year of age that interferes with development of normal tolerance, thus facilitating sensitization to food (Kulig et al. 1999). Schäfer et al. (1997) reported that neonates of mothers who smoked during pregnancy showed elevated levels of IgE, IgA, and IgG3, and that maternal smoking in pregnancy and lactation was found to be associated with an increased risk for atopic eczema, but not respiratory atopy later in life.

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A Disquistion On The Evils Of Using Tobacco

A Disquistion On The Evils Of Using Tobacco

Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.

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