Environmental and behavioral factors and the risk of non-Hodgkin lymphoma.

Investigators around the world have reported that incidence and mortality rates for non-Hodgkin lymphoma (NHL) increased steadily and substantially over the last five decades of the 20th century. Identifying what changes in the environment or in behavior fueled this epidemic still presents a major challenge for cancer epidemiology. In April 2006, a symposium was held at the Annual Meeting of the InterLymph Consortium to discuss the role of environment in NHL risk. Papers from that meeting are presented in this issue and, in summary, show that several environmental and behavioral factors alter the risk of developing lymphoma and may have contributed to the long-term increase in rates. Our current understanding, although quite incomplete, represents real progress, much of it deriving from epidemiologic studies of the last decade and many represented in the InterLymph Consortium. Several infectious agents cause lymphomas, some by directly transforming normal lymphocytes, some by causing an immunodeficiency syndrome, and some through chronic immune stimulation (Engels). Some infectious agents seem to cause specific forms of lymphoma, such as EBV causing Burkitt or extranodal natural killer/T-cell lymphoma; human herpes virus 8 leading to primary effusion lymphoma; and human T-lymphotrophic virus type I causing adult T-cell leukemia/lymphoma. Chronic immune stimulation may have either highly specific effects (e.g., H. pylori and its association with mucosa-associated gastric lymphomas) or more general effects (e.g., hepatitis C virus). HIV is important in several forms of lymphoma, and successful treatment of the infection markedly reduces lymphoma risk. Current work focuses on understanding modes of action, surveillance for undiscovered agents, and evaluation of interactions with common variants in immune-related genes. Numerous occupations rather consistently appear more often among histories of lymphoma patients than among their peers (Boffetta and deVocht). Many studies show increased risks among farmers, teachers, printers, and wood workers and may represent occupational groups at risk of NHL, even without a known causal agent. It seems less certain, but likely, that meat workers, painters, electrical engineers, and health care workers also are at increased risk of developing NHL. Boffetta and deVoct advocate increased development and use of biomarkers and other measures to assess occupational exposures more sensitively and specifically. Although no single environmental chemical exposure has been convincingly established as a cause of NHL, several occupational and environmental chemical exposures have emerged as likely candidates, including benzene (Smith et al., Vineis et al.) and polychlorinated biphenyls (Engel et al.). These may be important to the etiology of NHL, but their relevance to the epidemic is less certain. Many workers encounter low levels of benzene (>0.1 ppm) in petroleum refineries, natural gas production, and fuel and solvent distribution. Studies of occupations with probable benzene exposure report varying relative risks of lymphoma, with typical values for more heavily exposed workers well above the null but lower than relative risks for leukemia (Smith et al.). Shortly after workers began accumulating substantial exposures to benzene, numerous observers reported a dramatic excess of leukemia and related diseases of the bone marrow. Many researchers hypothesized that lymphomawould increase as well, but studies showed that mature B cells were less susceptible than bone marrow to damage from benzene. A strikingly similar history of research occurred for ionizing radiation and lymphoma. Longer observation and more refined exposure assessments now show that both benzene and radiation probably cause lymphomas, but the risks at particular dose levels remain uncertain. Work by Vineis et al., reported in this issue, also suggests that a family history of autoimmune disease or malignant hematologic neoplasms predisposes to benzene-inducedNHL. Current research focuses on understanding whether benzene might act through toxicity to the immune system generally or through chromosomal translocations, deletions, or other damage (Vineis et al.). Both epidemiology and laboratory work will be required to move the field forward. Another family of environmental chemicals implicated in lymphoma are the polychlorinated biphenyls and related compounds (Engel, Lan, and Rothman). For polychlorinated biphenyls, dioxins, furans, and organochlorine pesticides, the most convincing evidence for an association with lymphoma comes from the biobank studies. Taken together, the published studies strongly support an association between lymphoma risk and blood levels in advance of diagnosis and, yet, the specific effects of individual compounds vary widely from study to study. The variability may reflect the correlation among exposures and some degree of inaccuracy of assessment, prompting a recommendation by these authors for more precise data on timing of exposure, more observations, and the exploitation of unusual opportunities to disentangle the effects of individual compounds. Yet another group of agents, solvents, especially chlorinated solvents, remain suspect and deserve scrutiny in both casecontrol and prospective cohorts (Vineis, Miligi, and Costantini). Although the iatrogenic lymphomas represent a minority of cases, they may serve as excellent model systems (Krishnan 367