Genotoxicity of complex chemical mixtures
Phillips, Tracie Denise
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Complex chemical mixtures are ubiquitous in the environment. Humans are frequently exposed to these mixtures; therefore, it is important to understand potential interactions of chemical mixtures. Mixture interactions may influence the absorption, distribution, metabolism or excretion of the components of a complex mixture. The research conducted for this dissertation has coupled chemical fractionation with in vitro and in vivo bioassays to assess the potential carcinogenic risk of complex mixtures. A non-aqueous phase liquid from a wood treatment plant was separated into acid (AF), base (BF) and neutral fractions (NF). The NF was further enriched using column chromatography to produce a polychlorinated dinbenzo-p-dioxin (PCDD) and a polycyclic aromatic hydrocarbon (PAH) fraction. The genotoxicity of these mixtures were assessed via analytical quantification, in vitro (Salmonella microsome and E. coli prophage induction) and in vivo (32P-postlabeling) bioassays. The NF was further tested to measure bulky DNA adducts and induction of tumor formation. The AF contained the highest level of pentachlorophenol and the highest concentration of total PAHs. Although the carcinogenic PAHs were highest in the PCDD fraction, the highest concentrations of benzo(a)pyrene (BAP), indeno(1,2,3-cd)pyrene and dibenz(a,h)anthracene were detected in the PAH fraction. A positive genotoxic response in Salmonella was induced by the crude extract, the PAH and BF, whereas the AF and BF induced a positive response in the E. coli assay. In vivo, the PAH fraction induced the highest DNA adduct frequencies in the lung. The NF, reconstituted mixture (RM) (which includes equivalent concentrations of seven carcinogenic PAHs in the NF), BAP and the NF amended with BAP (NF+BAP) were all tested in an infant mouse model. At the highest dose, after a 24 hr exposure, NF+BAP had the highest total DNA adducts measured in liver which was three to seven times higher than with other treatments. Adduct levels were comparable to the control after 280 days. The highest incidence of tumors was observed in the liver. At the high dose, NF+BAP elicited the highest incidence of tumors. The results of this research confirm previous studies and indicate that the carcinogenic potential of PAH mixtures may be greater than predicted by chemical analysis.