Biography

Dr. Rothman received an A.B. in biochemistry and molecular biology at Harvard College and an M.D. at Northwestern University. At The Johns Hopkins University, he received training in internal medicine, occupational and environmental medicine, and epidemiology. Dr. Rothman joined the NCI in 1990. His research focuses on using biologic markers of exposure, early biologic effect, and genetic susceptibility in epidemiologic studies of occupational and environmental causes of cancer. Dr. Rothman received the PHS Achievement Medal for research on cancer biomarkers and the Commendation Medal for studies of benzene. He is the author of more than 90 publications.

Research Interests

Molecular Epidemiology Studies of Occupational and Environmental Causes of Cancer

We are using biomarkers of exposure, early biologic effect, and genetic susceptibility to investigate the carcinogenic potential and mechanism of action of proven or suspected occupational and environmental compounds; to evaluate the influence of inter-individual variation in metabolism on the formation of important early biologic markers, such as DNA adducts and cytogenetic aberrations; and to assess the risk of premalignant conditions and cancer associated with exposure to occupational and environmental agents.

Benzene

Benzene is an established human leukemogen, and it may also cause non Hodgkin's lymphoma and other cancers. However, its mechanism of action is uncertain, and its ability to cause cancer at low levels of exposure is unknown. We carried out a study of healthy workers exposed to high levels of benzene in China to identify mechanistically based biomarkers that reflect early biologic effects of benzene. We observed an increased frequency of cytogenetic and genetic alterations in peripheral white blood cells (e.g., t8;21, del(5q), del(7q), 5 ,7 , AML 1/ETO fused transcript). These markers are relevant for leukemia and support the hypothesis that benzene's mechanism of action is mediated through chromosomal damage. An important unanswered question concerns the biologic effect of low exposure levels in the occupational setting and from environmental sources experienced by the general population. In a new investigation, we will be applying the most sensitive and specific biomarkers for benzene exposure to determine if the cytogenetic and molecular events observed in our previous study also occur among workers exposed to relatively low levels of benzene.

Aromatic Amines

We found that among workers in India exposed to the aromatic diamine benzidine, N acetylated benzidine was the predominant DNA adduct in exfoliated urothelial cells. This finding documented that acetylation activates rather than detoxifies benzidine in humans, in contrast to the deactivation role of acetylation for aromatic monoamines, such as 4 aminobiphenyl. We also showed that urine pH, which is influenced primarily by the diet, had a profound influence on DNA adducts levels. This finding is consistent with previous in vitro results that acidic urine hydrolyzes glucuronidated aromatic amines, which enables free compounds to bind DNA. This research indicates that gene environment interactions can be highly exposure specific, and that nongenetic sources of susceptibility may interact with xenobiotic exposures and play an important role in determining an individual's cancer risk. We are pursuing these findings in a large case control study of bladder cancer in Spain, which will for the first time combine state of the art industrial hygiene exposure assessment techniques with biomarkers of genetic susceptibility. The effort will provide the opportunity to evaluate interactions between aromatic amine exposure from occupational and environmental sources, polymorphisms in relevant activating and detoxifying genes (e.g., NAT1, NAT2, GSTM1), and urine pH.

Organochlorines

The reasons for the steady increase in the incidence of non Hodgkin's lymphoma since the late 1940s remain mostly unknown. To evaluate exposure to organochlorines, which are ubiquitous environmental contaminants and suspected human carcinogens, on the risk of non Hodgkin's lymphoma, we conducted a nested case control study within a cohort of 25,802 healthy subjects who provided blood samples in 1974. We found that serum PCB levels were strongly associated with subsequent risk of non Hodgkin's lymphoma, and that the effect was potentiated by seropositivity for the Epstein Barr virus early antigen. We are following up these observations in similarly designed prospective studies.

Polycyclic Aromatic Hydrocarbons

Polycyclic aromatic hydrocarbons (PAH) may play a role in the etiology of gastrointestinal tract cancers. These compounds may act directly as carcinogens or indirectly through the induction of enzymes that activate other potential carcinogens, such as heterocyclic aromatic amines. It has been difficult to assess PAH exposure using standard epidemiologic methods, because humans are exposed from many different sources, including occupational, environmental, dietary, and tobacco. We demonstrated that various PAH metabolites and macromolecular adducts can be used to integrate major sources of recent exposure. We are applying these findings to a newly completed case control study of colon adenomas to evaluate the relation between risk and PAH metabolites and adducts in urine and peripheral white blood cells. We will also use a database developed with the U.S. Department of Agriculture on dietary sources of PAH, as well as occupational and environmental exposure assessment methods, to estimate long term PAH exposure and its influence on adenoma risk. We plan to apply these methods in case control studies recently completed in Poland, the United States, and China to evaluate PAH exposure on risk of stomach and esophageal cancer, and to assess the interaction between PAH exposure and polymorphic genes (e.g., CYP1A1, GSTM1, and NQO1) that activate or detoxify these compounds.

Keywords

aromatic amines, benzene, benzidine, genetic susceptibility, molecular epidemiology, occupational cancer, organochlorines, polycyclic aromatic hydrocarbons (PAH), polymorphic genes

Selected Publications

• Langholz B, et al. "Cohort studies for characterizing measured genes." J Natl Cancer Inst Monograph 1999; 26:39-42.
• Rothman N, et al. Chapter 9. "The impact of misclassification in case-control studies of gene-environment interactions." IARC Sci Publ 1999; 148:89-96.
• Marcus PM, et al. "The interactive effect of NAT2 acetylation status and cigarette smoking on bladder cancer risk: a case-series meta-analysis." Cancer Epidemiol Biomarkers Prev 2000; 9:461-467.
• Rothman N, et al. "The use of common polymorphisms to enhance the epidemiologic study of environmental carcinogens." Biochim Biophys Acta 2000; 87:1-10.

Collaborators

DCEG Collaborators

• Michael Alavanja, Dr.P.H.; Dalsu Baris, M.D., Ph.D.; Aaron Blair, Ph.D.; Kenneth Cantor, Ph.D.; Neil Caporaso, M.D.; Wong Ho Chow, Ph.D.; Mustafa Dosemeci, Ph.D.; Montserrat Garcia-Closas, M.D., Dr.P.H..; Richard Hayes, D.D.S., Ph.D.; Robert Hoover, M.D., Sc.D.; Qing Lan, M.D.; Martha Linet, M.D.; Charles Rabkin, M.D.; Rashmi Sinha, Ph.D.; Patricia Stewart, Ph.D.; Sholom Wacholder, Ph.D.; Mary Ward, Ph.D.; Shelia H. Zahm, Sc.D.

Other NCI Collaborators

• Curt Harris, M.D ; Miriam Poirier, Ph.D.; Mark Roth, M.D.; Wyndham Wilson, M.D., Ph.D.

Other NIH Collaborators

• Douglas Bell, Ph.D., National Institute of Environmental Health Sciences

Other Scientific Collaborators

• Stefano Bonassi, M.D., University of Genoa, Italy
• Larry Figgs, Ph.D.; Terry Zenser, Ph.D., University of Louisville, Louisville, KY
• David Hein Ph.D., University of Louisville, Louisville, KY
• Kathy Helzlsouer, M.D.; Paul Strickland, Ph.D., The Johns Hopkins University, Baltimore, MD
• David Hunter, M.B.B.S., Sc.D., Harvard University, Boston, MA
• S.K. Kashyap, M.D., Ph.D., National Institute of Occupational Health, India
• Nicholas Lang, M.D., University of Arkansas, Little Rock, AR
• Loic Le Marchand, M.D., University of Hawaii, Honolulu, HI
• Larry Needham, Ph.D., Centers for Disease Control and Prevention, Atlanta, GA
• Stephen Rappaport, Ph.D., University of North Carolina, Chapel Hill, NC
• Paul Schulte, Ph.D.; Ainsley Weston, Ph.D., National Institute for Occupational Safety and Health, Cincinnati, OH
• Peter Shields, M.D., Georgetown University, Washington, D.C.
• Martyn Smith, Ph.D., University of California, Berkeley, CA
• Yin Songnian, M.D.; S Yin, M.D., Chinese Academy of Preventive Medicine, Beijing, China
• Susan Sturgeon, Ph.D., University of Massachusetts, Amherst, MA
• Glenn Talaska, Ph.D., University of Cincinnati, Cincinnati, OH
• Wei Zhang, M.D., Ph.D., Vanderbilt University, Nashville, TN