Bioaccessibility of PAH from Danish soils.

A test method for the determination of PAH relative bioaccessibility from contaminated soils was implemented and validated for use in risk assessment of soils from contaminated sites meeting performance requirement set for evaluation against regulatory limits. Relative bioaccessibilities of soil benzo(a)pyrene obtained with the test were linearly correlated to relative bioavailability data obtained previously in in vivo investigations with experimental animals, but the relative bioaccessibilities were lower than the relative bioavailabilities. Tests of soil samples from 4 Danish sites contaminated with benzo(a)pyrene and dibenz(a,h)anthracene from different sources and with different ages demonstrated that using the bioaccessible concentrations in risk assessment instead of total concentrations would have produced lower risk classifications of the sites. An urgent requirement is demonstrated for an accepted and valid method for investigating the bioavailability of organic soil contaminants such as PAH and also for soil samples with accepted relative bioavailability data.

Bioavailability and risk assessment of orally ingested polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAHs) are a family of toxicants that are ubiquitous in the environment. These contaminants generate considerable interest, because some of them are highly carcinogenic in laboratory animals and have been implicated in breast, lung, and colon cancers in humans. These chemicals commonly enter the human body through inhalation of cigarette smoke or consumption of contaminated food. Of these two pathways, dietary intake of PAHs constitutes a major source of exposure in humans. Although many reviews and books on PAHs have been published, factors affecting the accumulation of PAHs in the diet, their absorption following ingestion, and strategies to assess risk from exposure to these hydrocarbons following ingestion have received much less attention. This review, therefore, focuses on concentrations of PAHs in widely consumed dietary ingredients along with gastrointestinal absorption rates in humans. Metabolism and bioavailability of PAHs in animal models and the processes, which influence the disposition of these chemicals, are discussed. The utilitarian value of structure and metabolism in predicting PAH toxicity and carcinogenesis is also emphasized. Finally, based on intake, disposition, and tumorigenesis data, the exposure risk to PAHs from diet, and contaminated soil is presented. This information is expected to provide a framework for refinements in risk assessment of PAHs from a multimedia exposure perspective.

Synthesis of suspected carcinogenic metabolites of 7H-benzo[c]fluorene, a coal tar component implicated in causation of lung tumors.

High incidences of lung tumors were observed in mice fed coal tar in their diet. The principal component of tar that gives rise to DNA-bound adducts in mouse lung was identified as 7H-benzo[c]fluorene (BcF). We now report the synthesis of suspected active metabolites of BcF, specifically the trans-3,4-dihydrodiol of BcF (2), its likely proximate carcinogenic metabolite, and the corresponding anti- and syn-diol epoxides of BcF (3 and 4) in which the epoxide ring resides in the pseudobay region. The diol epoxide derivatives (3 and 4) are postulated to be ultimate carcinogenic metabolites of BcF that bind to DNA in mouse lung.

Characterization of a major aromatic DNA adduct detected in human breast tissues.

A bulky DNA adduct (Spot 1) was previously detected in normal adjacent breast tissues of 41% (36/87) of women with breast cancer and in none (0/29) of the noncancer controls by (32)P-postlabeling. To characterize this adduct, it was chromatographically compared with DNA adduct profiles generated in several in vitro and in vivo experimental systems. First, MCF-7 cells were exposed to a number of chemical carcinogens, that is, benzo[a]pyrene (B[a]P), 4-OH-B[a]P, 9-OH-B[a]P, 11-OH-B[a]P, B[a]P-trans-4,5-dihydrodiol, 1-nitropyrene, 6-nitrochrysene, dibenzo[a,l]pyrene, benzo[c]phenanthrene, dibenzo[a,h]anthracene, 3-methylcholanthrene, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Spot 1 was detected as a minor adduct in cells treated with B[a]P but not other compounds. Second, to determine whether Spot 1 is derived from lipid peroxidation products or estrogen metabolites, it was compared with adduct profiles of cells or DNAs exposed to 17beta-estradiol, 4-hydroxy estradiol, 4-hydroxynonenal, or oxidized oat oil. Spot 1 was not detectable in these samples. In addition, Spot 1 did not comigrate with the 1,N(2)-ethenodeoxyguanosine adduct standard. Third, to explore the mechanism of Spot 1 formation, it was compared with adduct profiles detected in DNA or mononucleotides reacted with BPDE, 1-OH-7,8-dihydrodiol of B[a]P, and 3-OH-7,8-dihydrodiol of B[a]P as well as in rats orally treated with B[a]P. Spot 1 comigrated with a minor adduct in BPDE-treated DNA during anion exchange rechromatography but these two adducts were separated by partition chromatography. Spot 1 also behaved in a manner that was very similar to that of the polar B[a]P adducts detected in rat liver, but the two adducts were separated by HPLC. Fourth, Spot 1 was compared with CD1 mice exposed to 7H-benzo[c]fluorene (B[c]F). Spot 1 from some patients comigrated with a major adduct induced by B[c]F. Finally, we found that the presence of Spot 1 in human breast tissues was not related to smoking status but, rather, with CYP1A1 MspI polymorphism. The CYP1A1 mutant carriers had a significantly higher frequency of this adduct than did the wild-type genotypes. Furthermore, individuals with Spot 1 had a significantly higher staining intensity for BPDE-PAH adducts in their tissue sections than those without it. These results demonstrate that this major bulky DNA adduct detected in human breast tissues is related to PAH exposure.

Induction of CYP1A1 and CYP1A2 expressions by prototypic and atypical inducers in the human lung.

The inducibility of cytochrome P4501A1 gene (CYP1A1) expression was examined in human lung samples from 27 subjects, using an explant culture system and semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. CYP1A1 transcripts were present in all of the lung specimens and were induced by the prototypic inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (B[a]P), and by the atypical inducers pyridine, nicotine, and omeprazole. 2-Hydroxypyridine was a better inducer than pyridine, implicating metabolites in CYP1A1 induction by the parent compound. The prototypical inducers were the most effective inducers in many samples but were ineffective in some samples in which the atypical compounds were effective inducers. Cytochrome P4501A2 (CYP1A2) transcripts were also detected in most of the lung specimens and were inducible in some specimens. The results show the suitability of the explant culture system for examining the inducibility of human pulmonary CYP1A1 and CYP1A2, indicate the heterogeneity in individual sensitivity to the induction, and underscore the need to include atypical inducers in studies of CYP1A inducibility in humans.