Graduation Year


Document Type




Degree Granting Department

Environmental and Occupational Health

Major Professor

Raymond Harbison, Ph.D.

Committee Member

Steven Morris, M.D.

Committee Member

Steven Mylnarek, Ph.D.

Committee Member

Foday Jaward, Ph.D.


Threshold, Causation, Hill Criteria, Cancer, Lymphoproliferative, Leukemia


Significant benzene exposure has historically been associated with the development of a host of hematological disorders in humans and animals. In particular, benzene is known to cause disturbances of the peripheral blood, aplastic anemia and cancer of the lymphohematopoietic system. In 1928, the first modern report of an association between cancer and benzene exposure was published. This case report was followed by additional reports from around the world. In most instances, ailments resulted from long term, high level exposure to benzene found in glues, and through accidental industrial spills. Throughout the 1960's and 1970's, case reports accumulated linking benzene exposure to hematological cancers, particularly among leather workers in Turkey and Italy. At the time, only qualitative measures of benzene exposure were often available and most exposure information was based upon short term grab samples and subjective symptoms. However, this situation changed drastically in the mid-1970s, when the first report was published on a little known industry that manufactured rubber hydrochloride, also known as Pliofilm. This clear film product was made from natural rubber latex and processing utilized benzene in multiple stages. It appeared from the outset that there were an unusually large number of acute leukemia cases in this cohort of workers. Since that time, multiple follow-up evaluations of the same cohort have attempted to refine the benzene exposure of these workers. Benzene has subsequently been classified as a human carcinogen by several regulatory bodies and the allowable 8 hour time-weighted average has been lowered to 1 ppm. In pursuing the goal of protecting workers, regulatory bodies utilize a linear extrapolation, or no threshold dose, approach to cancer causation. This methodology assumes that every exposure brings an incremental rise in risk. In this work, the linear extrapolation methodology is tested utilizing the criteria proposed by Sir Bradford Hill. The Hill Criteria are used to critically evaluate the weight of evidence for a threshold dose that can cause hematological cancer in humans following benzene exposure. This evaluation revealed that there is sufficient evidence for a threshold dose and that linear extrapolation is designed to protect, not predict disease.