Polychlorinated biphenyls (PCBs) are ubiquitious environmental pollutants that cause a number of diverse toxicities. The chemical stability of PCBs is responsible for their persistence in the environment, while their lipid solubility and resistance to biotransformation results in their accumulation in a number of animal species. The rate of PCB elimination is dependent on the ability of each animal species to metabolize a particular PCB congener. The goal of this project was to determine if in vitro liver microsomal metabolism studies could predict in vivo metabolism and to examine the reasons for the species variation in PCB metabolism. Kinetic constants were developed from in vitro metabolism studies using 4,4'-dichlorobiphenyl (4-DCB), 2,2',3,3',6,6'-hexachlorobiphenyl (236-HCB) and 2,2',4,4',5,5'-hexachlorobiphenyl (245-HCB) and liver microsomes from the human, dog, monkey and rat. An excellent correlation between the in vitro Vmax values and the in vivo hepatic clearance values was obtained. Human microsomal PCB metabolism was most similar to the rat. The in vitro human results were consistent with available in vivo data. All species produced the same major metabolites. The major metabolite of 4-DCB was 4,4'-dichloro-3-biphenylol and the two major metabolites of 236-HCB were 2,2',3,3',6,6'-hexachloro-4-biphenylol and 2,2',3,3',6,6'-hexachloro-5-biphenylol. The dog was the only species found to metabolize 245-HCB in vitro. Metabolites of 245-HCB were not identified. Studies of metabolism, covalent binding of PCB-equivalents to microsomal protein and metabolites demonstrated that the dog can metabolize PCBs more readily than other species because the dog has an alternate pathway of PCB metabolism. This pathway is either not found in other species or only found to a limited extent. Furthermore, an arene oxide does not seem to be involved in this alternative pathway. In summary, for certain classes of compounds in vitro to in vivo extrapolation is possible and may prove to be very useful in predicting the appropriate animal model for humans. Secondly, the dog appears to be quite different in its metabolism of PCBs in that it may have an alternate route of metabolism not involving an arene oxide.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / abstract / Biochemistry / Doctoral / Doctor of Philosophy

Typescript (photocopy) / v, 94 leaves, [49] leaves of ill. : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1982

Typescript (photocopy) / v, 94 leaves, [49] leaves of ill. : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physiology, 1982

Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on February 29, 2008) Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2007. / Also available in print.

Thesis (M.Eng. (Mechanical and Aeronautical Engineering)) -- University of Pretoria, 2006. / Includes bibliographical references.

Thesis (Ph. D.)--Rutgers University, 2010. / "Graduate Program in Chemical and Biochemical Engineering." Includes bibliographical references (p. 154-164).

Thesis (M. Med. Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 28-34).