Serum microRNA profiles among dioxin exposed veterans with monoclonal gammopathy of undetermined significance.

Previously an increased risk for monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma (MM), was reported among Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Dysregulated expression of certain microRNAs (miRNAs) was demonstrated in MGUS and MM. Given the important role of miRNAs in cellular homeostasis, the aim of this study was to determine if there was an association between serum levels of selected miRNAs and TCDD in 47 MGUS cases identified in our previous investigation using serum specimens and exposure data archived by the Air Force Health Study (AFHS). A total of 13 miRNA levels (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335, and miR-361) was measured in serum stored during the 2002 AFHS follow-up and the relationship to lipid-adjusted serum TCDD levels in 1987 was determined. miR-34a showed the strongest relationship with TCDD; after age-adjustment, this positive association was more pronounced. In contrast, the other 12 miRNAs displayed absolute values of age adjusted coefficient estimates below 1.16 and non-significant p-values. The observed strong positive association between high body burdens of TCDD and miR-34a, a tumor suppressor regulated by p53, in this MGUS population warrants clarification of the TCDD-miR-34a relationship and its role in the pathogenesis of MGUS and risk for MM.

Prevalence and associated demographic characteristics of exposure to multiple metals and their species in human populations: The United States NHANES, 2007-2012.

Lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As) are among the top 10 pollutants of global health concern. Studies have shown that exposures to these metals produce severe adverse effects. However, the mechanisms underlying these effects, particularly joint toxicities, are poorly understood in humans. The objective of this investigation was to identify and characterize prevalent combinations of these metals and their species in the U.S. NHANES population to provide background data for future studies of potential metal interactions. Exposure was defined as urine or blood levels ≥ medians of the NHANES 2007-2012 participants ≥6 years (n = 7408). Adjusted-odds ratios (adj-OR) and 95% confidence intervals were determined for covariates (age, gender, and race/ethnicity, cotinine and body mass index). Species-specific analysis was also conducted for As and Hg including iAs (urinary arsenous acid and/or arsenic acid), met-iAs (urinary monomethylarsonic acid and/or dimethylarsinic acid), and oHg (blood methyl-mercury and/or ethyl-mercury). For combinations of As and Hg species, age- and gender-specific prevalence was determined among NHANES 2011-2012 participants (n = 2342). Data showed that approximately 49.3% of the population contained a combination of three or more metals. The most prevalent unique specific combinations were Pb/Cd/Hg/As, Pb/Cd/Hg, and Pb/Cd. Age was consistently associated with these combinations: adj-ORs ranged from 10.9 (Pb/Cd) to 11.2 (Pb/Cd/Hg/As). Race/ethnicity was significant for Pb/Cd/Hg/As. Among women of reproductive age, frequency of oHg/iAs/met-iAS and oHg/met-iAs was 22.9 and 40.3%, respectively. These findings may help prioritize efforts to assess joint toxicities and their impact on public health.

Monoclonal B-cell lymphocytosis in healthy blood donors: an unexpectedly common finding.

Circulating monoclonal B cells may be detected in healthy adults, a condition called monoclonal B-cell lymphocytosis (MBL). MBL has also been identified in donated blood, but no systematic study of blood donors has been reported. Using sensitive and specific laboratory methods, we detected MBL in 149 (7.1%; 95% confidence interval, 6.0% to 8.3%) of 2098 unique donors ages 45 years or older in a Midwestern US regional blood center between 2010 and 2011. Most of the 149 donors had low-count MBL, including 99 chronic lymphocytic leukemia-like (66.4%), 22 atypical (14.8%), and 19 CD5(-) (12.8%) immunophenotypes. However, 5 donors (3.4%) had B-cell clonal counts above 500 cells per µL, including 3 with 1693 to 2887 cells per µL; the clone accounted for nearly all their circulating B cells. Four donors (2.7%) had 2 distinct MBL clones. Of 51 MBL samples in which immunoglobulin heavy chain (IGH)V-D-J genotypes could be determined, 71% and 29% used IGHV3- and IGHV4-family genes, respectively. Sequencing revealed 82% with somatic hypermutation, whereas 18% had >98% germ-line identity, including 5 with entirely germ-line sequences. In conclusion, MBL prevalence is much higher in blood donors than previously reported, and although uncommon, the presence of high-count MBL warrants further investigations to define the biological fate of the transfused cells in recipients.

Respiratory protective equipment, mask use, and respiratory outcomes among World Trade Center rescue and recovery workers.

BACKGROUND: Serious respiratory illnesses have been reported among rescue/recovery workers (RRW) following the World Trade Center (WTC) attacks. METHODS: We studied RRW enrolled in the WTC Health Registry to assess the effects of different respiratory protection equipment (RPE) types on respiratory outcomes, such as recurrent respiratory symptoms and diseases possibly associated with 9/11 exposures. We performed descriptive and multivariate analyses adjusting for demographics and exposure variables. RESULTS: A total of 9,296 RRW met inclusion criteria. The strongest predictors of using adequate RPE were being affiliated with construction, utilities or environmental remediation organizations and having received RPE training. Workers who used respirators were less likely to report adverse respiratory outcomes compared to those who reported no/lower levels of respiratory protection. CONCLUSIONS: Level of respiratory protection was associated with the odds of reporting respiratory symptoms and diseases. Training, selection, fit testing, and consistent use of RPE should be emphasized among emergency responders.

9/11 Residential Exposures: The Impact of World Trade Center Dust on Respiratory Outcomes of Lower Manhattan Residents.

Thousands of lower Manhattan residents sustained damage to their homes following the collapse of the Twin Towers on 11 September 2001. Respiratory outcomes have been reported in this population. We sought to describe patterns of home damage and cleaning practices in lower Manhattan and their impacts on respiratory outcomes among World Trade Center Health Registry (WTCHR) respondents. Data were derived from WTCHR Wave 1 (W1) (9/2003⁻11/2004) and Wave 2 (W2) (11/2006⁻12/2007) surveys. Outcomes of interest were respiratory symptoms (shortness of breath (SoB), wheezing, persistent chronic cough, upper respiratory symptoms (URS)) first occurring or worsening after 9/11 W1 and still present at W2 and respiratory diseases (asthma and chronic obstructive pulmonary disease (COPD)) first diagnosed after 9/11 W1 and present at W2. We performed descriptive statistics, multivariate logistic regression and geospatial analyses, controlling for demographics and other exposure variables. A total of 6447 residents were included. Mean age on 9/11 was 45.1 years (±15.1 years), 42% were male, 45% had ever smoked cigarettes, and 44% reported some or intense dust cloud exposure on 9/11. The presence of debris was associated with chronic cough (adjusted OR (aOR) = 1.56, CI: 1.12⁻2.17), and upper respiratory symptoms (aOR = 1.56, CI: 1.24⁻1.95). A heavy coating of dust was associated with increased shortness of breath (aOR = 1.65, CI: 1.24⁻2.18), wheezing (aOR = 1.43, CI: 1.03⁻1.97), and chronic cough (aOR = 1.59, CI: 1.09⁻2.28). Dusting or sweeping without water was the cleaning behavior associated with the largest number of respiratory outcomes, such as shortness of breath, wheezing, and URS. Lower Manhattan residents who suffered home damage following the 9/11 attacks were more likely to report respiratory symptoms and diseases compared to those who did not report home damage.

B cells behaving badly.

The pathogenesis of B-cell lymphoproliferative disorders in general and B-cell chronic lymphocytic leukaemia in particular appears to involve dysfunctional regulation of humoral and cellular immunity with the subsequent development of genetic aberrations in B cells. In theory, either component may arise de novo or may be influenced by environmental exposures including infectious agents, antigens, genotoxic chemicals, or radiation. As an intermediary within the exposure-disease continuum, monoclonal B-cell lymphocytosis may be a helpful biomarker for teasing out these various contributions to risk. This article introduces a series of papers that resulted from an International Workshop held in May 2007 entitled 'Monoclonal B-cell Lymphocytosis and Chronic Lymphocytic Leukemia: Environmental and Genetic Risk Factors'. Research efforts, such as those described in this issue, should lead to improved interventions, more predictive biomarkers, more effective treatments, and a greater appreciation of how the immune system functions over the entire human lifespan.

Monoclonal B-cell lymphocytosis as a biomarker in environmental health studies.

The first studies of monoclonal B-cell lymphocytosis (MBL) in the general population were conducted as part of environmental health investigations that began in 1991. MBL was observed as an unexpected finding when blood samples were immunophenotyped by two-colour flow cytometric methods in common use at that time. The initial observations led to a workshop in 1995, at which case definitions were considered and medical follow-up investigations were recommended. Medical follow-ups were conducted in 1997 and 2003. A total of eight cases of confirmed MBL and three cases of presumptive MBL were identified. This review summarizes the findings from those investigations and discusses the issues related to using MBL as a biomarker in environmental health research and population-based studies.

Overview of monoclonal B-cell lymphocytosis.

Monoclonal B-cell lymphocytosis (MBL) has been the subject of more intensive investigation for the last 10 years. The increased presence of MBL in unaffected, first-degree relatives with familial chronic lymphocytic leukaemia (CLL) suggest that it is surrogate marker for early disease. In normal population studies, MBL is found to be increased in ageing subjects. Consensus criteria for the diagnosis of MBL have been proposed. The differential diagnosis has been further clarified and the prevalence of MBL is most prominent in the elderly. The aetiology of MBL is unknown but probably involves immune mechanism of senescence or altered response. Environmental health studies suggest that exposure to certain toxins may lead to MBL but further work is needed. MBL is a precursor to CLL but may also regress, remain stable or progress to clinical CLL.

Prevalence and natural history of monoclonal and polyclonal B-cell lymphocytosis in a residential adult population.

BACKGROUND: Monoclonal B-cells can be detected in the peripheral blood of some adults without B-cell malignancies, a condition recently termed monoclonal B-cell lymphocytosis (MBL). The risk of individuals with MBL progressing to a B-cell malignancy is unknown. Polyclonal B-cell lymphocytosis (PCBL) has not been systematically studied in the general population. METHODS: We obtained lymphocyte subset counts on 1,926 residential adults aged 40-76 years in a series of environmental health studies between 1991 and 1994. We then conducted two follow-ups in 1997 and 2003 on consenting participants with B-cell lymphocytosis, which included nine participants with MBL. To ascertain the clinical implications of MBL, we reviewed medical records and death certificates. RESULTS: The overall prevalence of MBL was 0.57% (11/1,926): nine cases at baseline and two additional cases identified at follow-up. Two (19%) MBL cases subsequently developed a B-cell malignancy; MBL persisted in the remaining nine cases (81%). All PCBL cases where no clone emerged regressed to normal B-cell counts over the follow-up period. MBL was significantly more frequent in residents near a hazardous waste site than in the control populations (age-adjusted OR 6.2; 95%CI 1.1-36.2). CONCLUSION: MBL confers an elevated risk for developing a B-cell malignancy, although it occurs only in a minority of cases. PCBL is most often a transient state, but a monoclonal population can emerge and persist. Prospective studies are needed to distinguish stable from progressive forms of B-cell lymphocytosis and to clarify the etiologic role of environmental exposures.

Potential residential exposure to toxics release inventory chemicals during pregnancy and childhood brain cancer.

BACKGROUND: Although the susceptibility of the developing fetus to various chemical exposures is well documented, the role of environmental chemicals in childhood brain cancer etiology is not well understood. OBJECTIVES: We aimed to evaluate whether mothers of childhood brain cancer cases had greater potential residential exposure to Toxics Release Inventory (TRI) chemicals than control mothers during pregnancy. METHODS: We included 382 brain cancer cases diagnosed at < 10 years of age from 1993 through 1997 who were identified from four statewide cancer registries. One-to-one matched controls were selected by random-digit dialing. Computer-assisted telephone interviews were conducted. Using residential history of mothers during pregnancy, we measured proximity to TRI facilities and exposure index, including mass and chemicals released. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression to estimate brain cancer risk associated with TRI chemicals. RESULTS: Increased risk was observed for mothers living within 1 mi of a TRI facility (OR = 1.66 ; 95% CI, 1.11-2.48) and living within 1 mi of a facility releasing carcinogens (OR = 1.72 ; 95% CI, 1.05-2.82) for having children diagnosed with brain cancer before 5 years of age, compared to living > 1 mi from a facility. Taking into account the mass and toxicity of chemical releases, we found a nonsignificant increase in risk (OR = 1.25 ; 95% CI, 0.67-2.34) comparing those with the lowest versus highest exposure index. CONCLUSIONS: Risk of childhood brain cancers may be associated with living near a TRI facility ; however, this is an exploratory study and further studies are needed.

Exposures to air pollutants during pregnancy and preterm delivery.

The association between preterm delivery (PTD) and exposure to air pollutants has recently become a major concern. We investigated this relationship in Incheon, Republic of Korea, using spatial and temporal modeling to better infer individual exposures. The birth cohort consisted of 52,113 singleton births in 2001-2002, and data included residential address, gestational age, sex, birth date and order, and parental age and education. We used a geographic information system and kriging methods to construct spatial and temporal exposure models. Associations between exposure and PTD were evaluated using univariate and multivariate log-binomial regressions. Given the gestational age, birth date, and the mother's residential address, we estimated each mother's potential exposure to air pollutants during critical periods of the pregnancy. The adjusted risk ratios for PTD in the highest quartiles of the first trimester exposure were 1.26 [95% confidence interval (CI), 1.11-1.44] for carbon monoxide, 1.27 (95% CI, 1.04-1.56) for particulate matter with aerodynamic diameter < or = 10 microm, 1.24 (95% CI, 1.09-1.41) for nitrogen dioxide, and 1.21 (95% CI, 1.04-1.42) for sulfur dioxide. The relationships between PTD and exposures to CO, NO2, and SO2 were dose dependent (p < 0.001, p < 0.02, p < 0.02, respectively) . In addition, the results of our study indicated a significant association between air pollution and PTD during the third trimester of pregnancy. In conclusion, our study showed that relatively low concentrations of air pollution under current air quality standards during pregnancy may contribute to an increased risk of PTD. A biologic mechanism through increased prostaglandin levels that are triggered by inflammatory mediators during exposure periods is discussed.

Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study.

IMPORTANCE: Multiple myeloma has been classified as exhibiting "limited or suggestive evidence" of an association with exposure to herbicides in Vietnam War veterans. Occupational studies have shown that other pesticides (ie, insecticides, herbicides, fungicides) are associated with excess risk of multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance (MGUS); however, to our knowledge, no studies have uncovered such an association in Vietnam War veterans. OBJECTIVE: To examine the relationship between MGUS and exposure to Agent Orange, including its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in Vietnam War veterans. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study conducted in 2013 to 2014, testing for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study (AFHS). The relevant exposure data collected by the AFHS was also used. We tested all specimens in 2013 without knowledge of the exposure status. The AFHS included former US Air Force personnel who participated in Operation Ranch Hand (Ranch Hand veterans) and other US Air Force personnel who had similar duties in Southeast Asia during the same time period (1962 to 1971) but were not involved in herbicide spray missions (comparison veterans). Agent Orange was used by the US Air Force personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in Vietnam from 1962 to 1971. We included 479 Ranch Hand veterans and 479 comparison veterans who participated in the 2002 follow-up examination of AFHS. EXPOSURES: Agent Orange and TCDD. Serum TCDD levels were measured in 1987, 1992, 1997, and 2002. MAIN OUTCOMES AND MEASURES: Risk of MGUS measured by prevalence, odds ratios (ORs), and 95% CIs. RESULTS: The 479 Ranch Hand veterans and 479 comparison veterans had similar demographic and lifestyle characteristics and medical histories. The crude prevalence of overall MGUS was 7.1% (34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans. This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P=.007). CONCLUSIONS AND RELEVANCE: Operation Ranch Hand veterans have a significantly increased risk of MGUS, supporting an association between Agent Orange exposure and multiple myeloma.

Long-term follow-up of monoclonal B-cell lymphocytosis detected in environmental health studies.

BACKGROUND: Four individuals in whom Monoclonal B cell Lymphocytosis (MBL) had been previously detected were evaluated for the fourth time after 15-18 years since initial testing. All four were environmental health study participants without hematologic malignancies who had elevated absolute B cell counts at initial testing. METHODS: The current laboratory evaluation included complete blood counts, lymphocyte immunophenotypes, immunoglobulin heavy-chain variable (IGHV) gene mutation status, and serum tests for monoclonal immunoglobulins and free light chains. Results from this evaluation were compared with those from the three previous evaluations. Clinical status was assessed by reviewing medical records. RESULTS: B-cell clones with phenotypic characteristics of the original MBL clone were detected in three of the four individuals. Since the last evaluation in 2003, one participant who had a clinical diagnosis of Waldenstrom's Macroglobulinemia had developed a diffuse large cell lymphoma and was treated. Another participant continued to show a decline in lymphocyte and B cell counts, reaching clinical lymphocytopenia and B cell lymphopenia. The MBL clone was still detectable. The remaining two participants had stable blood counts and MBL phenotypes. Neither had been diagnosed with a hematologic malignancy. However, molecular analysis revealed clonal changes in both: one showed a marked decline in the percentage of somatically-mutated B cells, and the other showed a clonal transition from IGHV3-13 to IGHV4-34. CONCLUSIONS: A diversity of clonal evolution was observed in these MBL cases. These observations suggest that long-term follow-up studies using standardized MBL subcategories are essential to understanding B-cell pathobiology and optimizing clinical management.

Prevalence of monoclonal B-cell lymphocytosis: a systematic review.

BACKGROUND: Individuals with monoclonal B-cell lymphocytosis (MBL) have been identified in clinic outpatients, in unaffected relatives of patients with chronic lymphocytic leukemia (CLL), and in general populations. MBL and its relationship with CLL have been actively investigated over the last decade. This report systematically reviews the prevalence of MBL in the context of the populations studied and the evolution of laboratory methods used to define MBL. METHODS: To identify published studies that have assessed the prevalence of MBL, we systematically searched the MEDLINE databases and consulted with members of the International MBL Study Group. We reviewed the 10 articles that were identified by this process. We abstracted information on study populations, laboratory tests, criteria for designating MBL, and the reported frequencies. RESULTS: Three of the ten studies were published in 2009, three between 2007 and 2008, and four between 2002 and 2004. Reported prevalences varied widely, ranging from 0.12 to 18.2%. This variability was clearly associated with both the laboratory methods and the populations studied. MBL was more common among older individuals and kindred of persons with CLL. The most common MBL subtype was CLL-like MBL. CONCLUSIONS: Large population-based studies of MBL that employ standardized laboratory methods with a consensus case definition are needed to assess prevalence and establish risk factors. These studies should include prospective follow-up of MBL cases to determine the relationship between MBL and CLL. Data from original studies should be reported in sufficient detail to allow future synthesis of information from multiple studies, such as meta-analysis.

Commentary: Comparison of current flow cytometry methods for monoclonal B cell lymphocytosis detection.

Monoclonal B cell lymphocytosis (MBL) is now recognized as the B-lymphocyte analogue of a monoclonal gammopathy of unknown significance. MBL can be the precursor of chronic lymphocytic leukemia or associated with non-Hodgkin's lymphoma. It may be associated with an autoimmune abnormality or be related to aging (immunosenescence). The combination of available new fluorochrome-conjugated monoclonal antibody reagents, multilaser instrumentation, and improved software tools have led to a new level of multicolor analysis of MBL. Presently, several centers, including the University of Salamanca (Spain), Duke University (Durham, NC), Mayo Clinic (Rochester, MN), and the National Cancer Institute (Bethesda, MD) in conjunction with the Genetics and Epidemiology of Familial chronic lymphocytic leukemia Consortium, the Food and Drug Administration (Bethesda, MD), and the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (Atlanta, GA) in collaboration with Saint Luke's Hospital (Kansas City, MO), the Università Vita-Salute San Raffaele in Milan (Italy), and Leeds Teaching Hospital (UK) are all actively conducting studies on MBL. This commentary is an updated summary of the current methods used in these centers. It is important to note the diversity of use in reagents, instruments, and methods of analysis. Despite this diversity, there is a consensus in what constitutes the diagnosis of MBL and its subtypes. There is also an emerging consensus on what the next investigative steps should be.

Parental exposure to pesticides and childhood brain cancer: U.S. Atlantic coast childhood brain cancer study.

BACKGROUND: The etiology of childhood brain cancer remains largely unknown. However, previous studies have yielded suggestive associations with parental pesticide use. OBJECTIVES: We aimed to evaluate parental exposure to pesticides at home and on the job in relation to the occurrence of brain cancer in children. METHODS: We included 526 one-to-one-matched case-control pairs. Brain cancer cases were diagnosed at < 10 years of age, and were identified from statewide cancer registries of four U.S. Atlantic Coast states. We selected controls by random digit dialing. We conducted computer-assisted telephone interviews with mothers. Using information on residential pesticide use and jobs held by fathers during the 2-year period before the child's birth, we assessed potential exposure to insecticides, herbicides, and fungicides. For each job, two raters independently classified the probability and intensity of exposure; 421 pairs were available for final analysis. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, after adjustment for maternal education. RESULTS: A significant risk of astrocytoma was associated with exposures to herbicides from residential use (OR = 1.9; 95% CI, 1.2-3.0). Combining parental exposures to herbicides from both residential and occupational sources, the elevated risk remained significant (OR = 1.8; 95% CI, 1.1-3.1). We observed little association with primitive neuroectodermal tumors (PNET) for any of the pesticide classes or exposure sources considered. CONCLUSIONS: Our observation is consistent with a previous literature reporting suggestive associations between parental exposure to pesticides and risk of astrocytoma in offspring but not PNET. However, these findings should be viewed in light of limitations in exposure assessment and effective sample size.