The Agency for Toxic Substances and Disease Registry (ATSDR) conducts health studies in communities located near hazardous waste sites. For several of these studies since 1991, the laboratory at the Centers for Disease Control and Prevention (CDC) has conducted tests to evaluate the status of the immune system. These laboratory tests included enumeration of lymphocytes, and of their major subsets, T-cells and B-cells. By 1994, immune test results from about 6000 individuals had been obtained. In 11 of these individuals, test results showed increased numbers of B-cells and changes in the patterns of certain B-cell surface receptors. These findings are associated with early stages of B-cell chronic lymphocytic leukemia (B-CLL), the most common type of leukemia in the United States. Therefore, the findings in these 11
individuals were termed “B-CLL-like phenotypes.”

    Confirmation of the diagnosis of B-CLL requires demonstration of “monoclonality”, ie, that all malignant B-cells originate from a single precursor cell.  The Food and Drug Administration conducted a detailed analysis on 3 of the 11 B-CLL-like samples and confirmed the presence of monoclonal B-cells in all three. In addition, another of the 11 people with B-CLL-like findings was retrospectively discovered to have already been diagnosed with B-CLL. After reviewing this evidence, CDC, FDA, and ATSDR concluded that the remaining 7 individuals were also probably at risk for B-CLL or other B-cell malignancies.  Therefore, CDC, FDA and ATSDR invited experts in epidemiology, hematology, oncology, and immunology to review the B-CLL-like findings in a workshop held June 12-13, 1995.

    These experts found that the laboratory results require follow-up using a case definition of “B-cell monoclonal lymphocytosis” (BCML) based on stringent criteria from repeated laboratory testing. They emphasized that the natural history and relationship of B-CLL-like phenotypes, BCML and B-CLL must be ascertained by long-term studies of individuals with these findings. Other epidemiologic approaches were also recommended, such as case-control studies
using data sets already in existence. Some of these recommendations have been initiated in protocols currently in progress or submitted for institutional review and approval.

    The public health concern over these findings is related to the recognition of an emerging epidemic of B-cell non-Hodgkin's lymphoma (NHL), which is another B-cell malignancy closely related to B-CLL. The frequency of B-CLL-like phenotypes found in the ATSDR studies suggests that early B-CLL and perhaps NHL (particularly low-grade) may be much more common than is clinically apparent or suspected. The workshop participants emphasized that
the prevalence and natural history of BCML in an adult reference population must be determined in order to establish the full public health implications of BCML.

    Although the cases identified at CDC were almost twice as common in study subjects living near hazardous waste sites as among people in comparison groups, the workshop participants agreed that the findings in these ATSDR studies neither support nor rule out environmental exposures as risk factors for BCML. Further studies in well-defined exposure cohorts and reference populations are required to resolve this question.

    Other studies from occupational epidemiology suggest that certain pesticides and organic solvents are risk factors for B-CLL and NHL. The participants emphasized that multiple contributing factors are likely to be associated with risk for these diseases, so that any single risk factor may have only a modest contribution. This contribution of multiple risk factors is consistent with our increased understanding of cancer as a multi-step process. An environmentally-induced mutation in a B-cell could have several consequences, since B-cells may be more able to tolerate mutations than other cells. Detection of BCML could serve to indicate previous exposure to a mutagenic agent, which might increase risk for any of a variety of cancers. The concept of B-cells as sentinels for environmental mutagen exposure would be somewhat analogous to coal miners traditional use of canaries in the cage to detect the presence of harmful gasses in their dangerous environment. These properties of B-cells could make them sensitive sentinels of environmental exposure to mutagenic agents.

    In summary, participants at this conference presented findings and discussed the implications of BCML, a newly-recognized entity that may be associated with an emerging epidemic of B-cell lymphoproliferative disorders.  They recommended stringent laboratory criteria to define BCML using flow cytometry and molecular biology. Finally, they encouraged cross-sectional and
longitudinal studies applying these advanced techniques to study the causes and consequences of BCML.