Occupation and Risk of Non-Hodgkin Lymphoma and Its Subtypes: A Pooled Analysis from the InterLymph Consortium.

BACKGROUND: Various occupations have been associated with an elevated risk of non-Hodgkin lymphoma (NHL), but results have been inconsistent across studies. OBJECTIVES: We investigated occupational risk of NHL and of four common NHL subtypes with particular focus on occupations of a priori interest. METHODS: We conducted a pooled analysis of 10,046 cases and 12,025 controls from 10 NHL studies participating in the InterLymph Consortium. We harmonized the occupational coding using the 1968 International Standard Classification of Occupations (ISCO-1968) and grouped occupations previously associated with NHL into 25 a priori groups. Odds ratios (ORs) adjusted for center, age, and sex were determined for NHL overall and for the following four subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and peripheral T-cell lymphoma (PTCL). RESULTS: We confirmed previously reported positive associations between NHL and farming occupations [field crop/vegetable farm workers OR = 1.26; 95% confidence interval (CI): 1.05, 1.51; general farm workers OR = 1.19; 95% CI: 1.03, 1.37]; we also confirmed associations of NHL with specific occupations such as women's hairdressers (OR = 1.34; 95% CI: 1.02, 1.74), charworkers/cleaners (OR = 1.17; 95% CI: 1.01, 1.36), spray-painters (OR = 2.07; 95% CI: 1.30, 3.29), electrical wiremen (OR = 1.24; 95% CI: 1.00, 1.54), and carpenters (OR = 1.42; 95% CI: 1.04, 1.93). We observed subtype-specific associations for DLBCL and CLL/SLL in women's hairdressers and for DLBCL and PTCL in textile workers. CONCLUSIONS: Our pooled analysis of 10 international studies adds to evidence suggesting that farming, hairdressing, and textile industry-related exposures may contribute to NHL risk. Associations with women's hairdresser and textile occupations may be specific for certain NHL subtypes. CITATION: 't Mannetje A, De Roos AJ, Boffetta P, Vermeulen R, Benke G, Fritschi L, Brennan P, Foretova L, Maynadié M, Becker N, Nieters A, Staines A, Campagna M, Chiu B, Clavel J, de Sanjose S, Hartge P, Holly EA, Bracci P, Linet MS, Monnereau A, Orsi L, Purdue MP, Rothman N, Lan Q, Kane E, Seniori Costantini A, Miligi L, Spinelli JJ, Zheng T, Cocco P, Kricker A. 2016. Occupation and risk of non-Hodgkin lymphoma and its subtypes: a pooled analysis from the InterLymph Consortium. Environ Health Perspect 124:396-405; http://dx.doi.org/10.1289/ehp.1409294.

A pooled analysis of cigarette smoking and risk of multiple myeloma from the international multiple myeloma consortium.

BACKGROUND: Past investigations of cigarette smoking and multiple myeloma have been underpowered to detect moderate associations, particularly within subgroups. To clarify this association, we conducted a pooled analysis of nine case-control studies in the International Multiple Myeloma Consortium, with individual-level questionnaire data on cigarette smoking history and other covariates. METHODS: Using a pooled population of 2,670 cases and 11,913 controls, we computed odds ratios (OR) and 95% confidence intervals (CI) relating smoking to multiple myeloma risk using unconditional logistic regression adjusting for gender, age group, race, education, body mass index, alcohol consumption, and study center. RESULTS: Neither ever smokers (OR, 0.95; 95% CI, 0.87-1.05), current smokers (OR, 0.82; 95% CI, 0.73-0.93), nor former smokers (OR, 1.03; 95% CI, 0.92-1.14) had increased risks of multiple myeloma compared with never smokers. Analyses of smoking frequency, pack-years, and duration did not reveal significant or consistent patterns, and there was no significant effect modification by subgroups. CONCLUSION: Findings from this large pooled analysis do not support the hypothesis of cigarette smoking as a causal factor for multiple myeloma. IMPACT: Cigarette smoking is one of the most important risk factors for cancer, but the association with multiple myeloma was inconclusive. This study had excellent power to detect modest associations, and had individual-level data to evaluate confounding and effect modification by potentially important factors that were not evaluated in previous studies. Our findings confirm that smoking is not a risk factor for multiple myeloma. Cancer Epidemiol Biomarkers Prev; 24(3); 631-4. ©2014 AACR.

Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. METHODS: We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control. RESULTS: The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes. CONCLUSIONS: The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.

Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are two subtypes of non-Hodgkin lymphoma. A number of studies have evaluated associations between risk factors and CLL/SLL risk. However, these associations remain inconsistent or lacked confirmation. This may be due, in part, to the inadequate sample size of CLL/SLL cases. METHODS: We performed a pooled analysis of 2440 CLL/SLL cases and 15186 controls from 13 case-control studies from Europe, North America, and Australia. We evaluated associations of medical history, family history, lifestyle, and occupational risk factors with CLL/SLL risk. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We confirmed prior inverse associations with any atopic condition and recreational sun exposure. We also confirmed prior elevated associations with usual adult height, hepatitis C virus seropositivity, living or working on a farm, and family history of any hematological malignancy. Novel associations were identified with hairdresser occupation (OR = 1.77, 95% CI = 1.05 to 2.98) and blood transfusion history (OR = 0.79, 95% CI = 0.66 to 0.94). We also found smoking to have modest protective effect (OR = 0.9, 95% CI = 0.81 to 0.99). All exposures showed evidence of independent effects. CONCLUSIONS: We have identified or confirmed several independent risk factors for CLL/SLL supporting a role for genetics (through family history), immune function (through allergy and sun), infection (through hepatitis C virus), and height, and other pathways of immune response. Given that CLL/SLL has more than 30 susceptibility loci identified to date, studies evaluating the interaction among genetic and nongenetic factors are warranted.

Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes. METHODS: We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE). RESULTS: Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. CONCLUSIONS: Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

A pooled analysis of alcohol consumption and risk of multiple myeloma in the international multiple myeloma consortium.

BACKGROUND: Recent findings suggest that alcohol consumption may reduce risk of multiple myeloma. METHODS: To better understand this relationship, we conducted an analysis of six case-control studies participating in the International Multiple Myeloma Consortium (1,567 cases, 7,296 controls). Summary ORs and 95% confidence intervals (CI) relating different measures of alcohol consumption and multiple myeloma risk were computed by unconditional logistic regression with adjustment for age, race, and study center. RESULTS: Cases were significantly less likely than controls to report ever drinking alcohol (men: OR = 0.72; 95% CI, 0.59-0.89; women: OR = 0.81; 95% CI, 0.68-0.95). The inverse association with multiple myeloma was stronger when comparing current to never drinkers (men: OR = 0.57; 95% CI, 0.45-0.72; women: OR = 0.55; 95% CI, 0.45-0.68), but null among former drinkers. We did not observe an exposure-response relationship with increasing alcohol frequency, duration, or cumulative lifetime consumption. Additional adjustment for body mass index, education, or smoking did not affect our results; and the patterns of association were similar for each type of alcohol beverage examined. CONCLUSIONS: Our study is, to our knowledge, the largest of its kind to date, and our findings suggest that alcohol consumption may be associated with reduced risk of multiple myeloma. IMPACT: Prospective studies, especially those conducted as pooled analyses with large sample sizes, are needed to confirm our findings and further explore whether alcohol consumption provides true biologic protection against this rare, highly fatal malignancy.

Childhood infectious diseases and risk of leukaemia in an adult population.

Our study is aimed at investigating the association between common childhood infectious diseases (measles, chickenpox, rubella, mumps and pertussis) and the risk of developing leukaemia in an adult population. A reanalysis of a large population-based case-control study was carried out. Original data included 1,771 controls and 649 leukaemia cases from 11 Italian areas. To contain recall bias, the analysis was restricted to subjects directly interviewed and with a good quality interview (1,165 controls and 312 cases). Odds ratios (ORs) and their related 95% confidence intervals (95% CIs) were estimated by unconditional polychotomous logistic regression model adjusting for age, gender and occupational and lifestyle exposures. A protective effect of at least one infection (OR = 0.66, 95% CI: 0.45-0.97), measles (OR = 0.57, 95% CI: 0.39-0.82) and pertussis (OR = 0.66, 95% CI: 0.45-0.98) was observed for chronic lymphoid leukaemia (CLL). The number of infections was strongly inversely associated with the risk of CLL (p = 0.002, test for trend). With regard to the other types of leukaemia, only a protective effect of pertussis was observed for AML (OR = 0.52, 95% CI: 0.32-0.87). Our results pointed out a protective role of childhood infectious diseases on the risk of CLL in adults. Although a specific antioncogenic effect of some infectious disease, especially measles, cannot be ruled out, the observed decrease of risk with increasing number of infections suggests that a more general "hygiene hypothesis" could be the most likely explanation of the detected association. The protective role of pertussis remains to be elucidated.

Self-reported history of infections and the risk of non-Hodgkin lymphoma: an InterLymph pooled analysis.

We performed a pooled analysis of data on self-reported history of infections in relation to the risk of non-Hodgkin lymphoma (NHL) from 17 case-control studies that included 12,585 cases and 15,416 controls aged 16-96 years at recruitment. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were estimated in two-stage random-effect or joint fixed-effect models, adjusting for age, sex and study centre. Data from the 2 years before diagnosis (or date of interview for controls) were excluded. A self-reported history of infectious mononucleosis was associated with an excess risk of NHL (OR = 1.26, 95% CI = 1.01-1.57 based on data from 16 studies); study-specific results indicate significant (I(2) = 51%, p = 0.01) heterogeneity. A self-reported history of measles or whooping cough was associated with an approximate 15% reduction in risk. History of other infection was not associated with NHL. We find little clear evidence of an association between NHL risk and infection although the limitations of data based on self-reported medical history (particularly of childhood illness reported by older people) are well recognized.

Lung cancer risk and residence in the neighborhood of a sewage plant in Italy. A case-control study.

AIMS AND BACKGROUND: Environmental pollution originating in sewage and industrial plants can be associated with lung cancer risk, as ecological and case-control studies have indicated. In the present study, the association between lung cancer occurrence and residence near a sewage plant in Prato (Italy) was investigated. A previous geographic study in the same area had shown an increasing trend of lung cancer mortality and incidence with propinquity to the plant. METHODS: A case-control study was carried out in the male population of Prato. Incident cases in the period 1987-1997 were identified from the Tuscan Cancer Registry (no. 918). Controls were randomly extracted from the Registry Office of the Municipality of Prato (no. 1852). For all subjects, the residential history was reconstructed. A weighted average distance from the plant was computed and used as a proxy variable of exposure. Two analyses were performed: on the whole data set and on a subset of subjects for whom information on tobacco exposure and education was obtained through a postal questionnaire (response rate, 41.1%). Logistic regression models were applied to estimate odds ratios and 95% CI. RESULTS: Both analyses showed a significantly elevated lung cancer risk for subjects living within 1.5 km (ORwhole= 1.56, 1.06-2.28; ORsubset= 2.28, 1.06-4.86) and suggested a risk increase with a decrease of weighted average distance from the plant. CONCLUSIONS: The findings highlight a possible role, in lung cancer occurrence, for environmental pollution spread from the plant. Due to drawbacks of the study, further analyses are needed to evidence a noncontroversial etiological conclusion. When environmental data are not available, results of epidemiological studies using residential histories may be useful in preventive policies regarding point source emissions.

Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients.

PURPOSE: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion). METHODS AND MATERIALS: Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose. RESULTS: Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR=53.36; 95% confidence intervals [95% CI], 3.56-798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR=38.26; 95% CI, 1.19-1232.52). CONCLUSIONS: To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings.

Birth order and risk of non-hodgkin lymphoma--true association or bias?

There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983-2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.

InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions.

After publication of the updated World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues in 2008, the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph) now presents an update of the hierarchical classification of lymphoid neoplasms for epidemiologic research based on the 2001 WHO classification, which we published in 2007. The updated hierarchical classification incorporates all of the major and provisional entities in the 2008 WHO classification, including newly defined entities based on age, site, certain infections, and molecular characteristics, as well as borderline categories, early and "in situ" lesions, disorders with limited capacity for clinical progression, lesions without current International Classification of Diseases for Oncology, 3rd Edition codes, and immunodeficiency-associated lymphoproliferative disorders. WHO subtypes are defined in hierarchical groupings, with newly defined groups for small B-cell lymphomas with plasmacytic differentiation and for primary cutaneous T-cell lymphomas. We suggest approaches for applying the hierarchical classification in various epidemiologic settings, including strategies for dealing with multiple coexisting lymphoma subtypes in one patient, and cases with incomplete pathologic information. The pathology materials useful for state-of-the-art epidemiology studies are also discussed. We encourage epidemiologists to adopt the updated InterLymph hierarchical classification, which incorporates the most recent WHO entities while demonstrating their relationship to older classifications.

Lung cancer mortality trend by birth cohort in men, Tuscany, 1971-2006.

AIMS AND BACKGROUND: In Tuscany, lung cancer mortality in men has shown a decreasing geographical trend over the last 3 decades from the most industrialized north-western coastal areas (Massa-Carrara, Viareggio) to the south-eastern areas (Arezzo, Siena), following the path of the development of industrial activities. The aim of the study was to evaluate lung cancer mortality in males by birth cohort in order to verify whether there was also a decreasing birth cohort trend in male lung cancer mortality rates between north-western and south-eastern Tuscan areas. METHODS: Lung cancer deaths that occurred in men resident in Tuscany, 1971-2006, were analyzed by birth cohort, age group and local health authority area. RESULTS: Rates in men >65 years were significantly higher in Viareggio and Massa-Carrara than in the south-eastern areas for all generations, in particular for men born in 1896-1926. Rates for men aged 55-64 years were higher in Massa-Carrara and Viareggio than in south-eastern areas for men born before 1926, whereas for younger generations the rates leveled off. For men aged 45-54 years, rates were similar in all areas only for younger generations (men born around 1951 and 1956), whereas for men aged 35-44 years, rates were similar in all areas for all generations considered. CONCLUSIONS: The higher lung cancer mortality rates in men aged >65 years and born in 1896-1926 in the north-western areas than in those born in the south-eastern areas may indicate that the tobacco epidemic spread earlier in the north-western areas of Tuscany, following the path of industrialization. However, the higher mortality rates in north-western than in south-eastern areas are at least in part attributable to the high occupational risks for lung cancer experienced by workers in these areas during the first half of 20th century.

Atopic disease and risk of non-Hodgkin lymphoma: an InterLymph pooled analysis.

We performed a pooled analysis of data on atopic disease and risk of non-Hodgkin lymphoma (NHL) from 13 case-control studies, including 13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed 2 years or more before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were computed in two-stage random-effects or joint fixed-effects models, and adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, specific allergy (excluding hay fever, asthma, and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with a history of allergy (OR, 0.80; 95% CI, 0.68-0.94) and reduced B-cell NHL risk was associated with history of hay fever (OR, 0.85; 95% CI, 0.77-0.95) and allergy (OR, 0.84; 95% CI, 0.76-0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic-those with hay fever, allergy, or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study shows evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy.

Exposure to benzene and risk of breast cancer among shoe factory workers in Italy.

AIMS AND BACKGROUND: Evidence of the association between leukemia and benzene exposure has been provided by several epidemiological studies. An increased risk of breast cancer among women exposed to benzene has also been suggested. The aim of this study was to analyze breast cancer risk in a cohort of 1,002 women exposed to benzene in a shoe factory in Florence, Italy, where an excess of leukemia in men was reported. METHODS: The cohort of women at work on January 1st, 1950, was followed from 1950 to 2003 for mortality and from 1985 to 2000 for incidence of breast cancer. For a sub-cohort of 797 women, cumulative exposure to benzene was available. RESULTS: Standardized mortality ratios were obtained for the 797 women for whom information on cumulative exposure was available. For those with < 30 years of latency the standardized mortality ratio was 58.5 (95% CI, 18.9-181.2, based on 3 deaths) and 151.1 (95% CI, 78.6-290.3, based on 9 deaths) for > or = 30 years of latency. In the > 40 ppm-year and > or = 30 year latency period category, the standardized mortality ratio was 166.0 (95% CI, 62.3-442.2, based on 4 deaths). The standardized incidence ratio for women with a latency period < 30 years was 140.9 (95% CI, 75.8-261.9, based on 10 cases) and 108.2 (95% CI, 64.1-182.7) for a latency period > or = 30 years. For cumulative exposure > 40 ppm-years and a latency period < 30 years, the standardized incidence ratio was 211.9 (95% CI, 29.9-1504.1, based on 1 case). CONCLUSIONS: The study moderately supports the hypothesis that benzene represents a risk factor for breast cancer.

Epidemiology, public health, and the rhetoric of false positives.

BACKGROUND: As an observational science, epidemiology is regarded by some researchers as inherently flawed and open to false results. In a recent paper, Boffetta et al. [Boffetta P, McLaughlin JK, LaVecchia C, Tarone RE, Lipworth L, Blot WJ. False-positive results in cancer epidemiology: a plea for epistemological modesty. J Natl Cancer Inst 100:988-995 (2008)] argued that "epidemiology is particularly prone to the generation of false-positive results." They also said "the tendency to emphasize and over-interpret what appear to be new findings is commonplace, perhaps in part because of a belief that the findings provide information that may ultimately improve public health" and that "this tendency to hype new findings increases the likelihood of downplaying inconsistencies within the data or any lack of concordance with other sources of evidence." The authors supported these serious charges against epidemiology and epidemiologists with few examples. Although we acknowledge that false positives do occur, we view the position of Boffetta and colleagues on false positives as unbalanced and potentially harmful to public health. OBJECTIVE: We aim to provide a more balanced evaluation of epidemiology and its contribution to public health discourse. DISCUSSION: Boffetta and colleagues ignore the fact that false negatives may arise from the very processes that they tout as generating false-positive results. We further disagree with their proposition that false-positive results from a single study will lead to faulty decision making in matters of public health importance. In practice, such public health evaluations are based on all the data available from all relevant disciplines and never to our knowledge on a single study. CONCLUSIONS: The lack of balance by Boffetta and colleagues in their evaluation of the impact of false-positive findings on epidemiology, the charge that "methodological vigilance is often absent" in epidemiologists' interpretation of their own results, and the false characterization of how epidemiologic findings are used in societal decision making all undermine a major source of information regarding disease risks. We reaffirm the importance of epidemiologic evidence as a critical component of the foundation of public health protection.

Colorectal cancer mortality in two areas of Tuscany with different screening exposures.

Several randomized trials have demonstrated the efficacy of colorectal cancer screening by the fecal occult blood test in reducing colorectal cancer mortality, but an evaluation of population-based screening programs is still lacking. We compared the colorectal cancer mortality rates (both adjusted rates and 3-year moving average rates) during 1985-2006 for two geographic areas in the provinces of Florence and Prato in the Tuscany region of Italy that began active population-based screening for colorectal cancer at different times: the Empolese-Mugello district, in the early 1980s, and the rest of the Florence and Prato provinces, in early 2000. A log-linear Poisson model was used to estimate the annual percent change in mortality and to examine whether geographic area modified the effect of calendar year on it. The Empolese-Mugello district had a greater decrease in colorectal cancer mortality than the rest of the Florence and Prato provinces (estimated annual percent change in age-adjusted colorectal cancer mortality rate, 2.7% decrease per year [95% confidence interval {CI} = 1.7% to 3.7%] vs 1.3% decrease per year [95% CI = 0.8% to 1.7%], respectively). The interaction between calendar period and area was statistically significant (P < .001). Our results support the hypothesis that the implementation of colorectal cancer screening in the early 1980s in the Empolese-Mugello district, where approximately 17 500 people were tested each year with the fecal occult blood test, was associated with a larger reduction in colorectal cancer mortality than that observed in the rest of Florence and Prato provinces, where screening started 15-20 years later and where approximately 38 000 people were screened each year beginning in 2000.

Risk of leukemia and multiple myeloma associated with exposure to benzene and other organic solvents: evidence from the Italian Multicenter Case-control study.

BACKGROUND: While there is a general consensus about the ability of benzene to induce acute myeloid leukemia (AML), its effects on chronic lymphoid leukemia and multiple myeloma (MM) are still under debate. We conducted a population-based case-control study to evaluate the association between exposure to organic solvents and risk of myeloid and lymphoid leukemia and MM. METHODS: Five hundred eighty-six cases of leukemia (and 1,278 population controls), 263 cases of MM (and 1,100 population controls) were collected. Experts assessed exposure at individual level to a range of chemicals. RESULTS: We found no association between exposure to any solvent and AML. There were elevated point estimates for the associations between medium/high benzene exposure and chronic lymphatic leukemia (OR = 1.8, 95% CI = 0.9-3.9) and MM (OR = 1.9, 95% CI = 0.9-3.9). Risks of chronic lymphatic leukemia were somewhat elevated, albeit with wide confidence intervals, from medium/high exposure to xylene and toluene as well. CONCLUSIONS: We did not confirm the known association between benzene and AML, though this is likely explained by the strict regulation of benzene in Italy nearly three decades prior to study initiation. Our results support the association between benzene, xylene, and toluene and chronic lymphatic leukemia and between benzene and MM with longer latencies than have been observed for AML in other studies.

Benzene exposure in a sample of population residing in a district of Florence, Italy.

OBJECTIVE: Personal exposure to airborne benzene is influenced by various outdoor and indoor sources. The first aim of this study was to assess the benzene exposure of a sample of urban inhabitants living in an inner-city neighborhood of Florence, Italy, excluding exposure from active smoking. The secondary objective was to differentiate the personal exposures according to personal usage patterns of the vehicles. METHODS: A sample of 67 healthy non-smokers was monitored by passive samplers during two 4-weekday campaigns in winter and late spring. Simultaneously, benzene measurements were also taken for a subset of participants, inside and outside their houses. A 4-day time microenvironment activity diary was completed by each subject during each sampling period. Other relevant exposure data were collected by a questionnaire before the sampling. Additional data on urban ambient air benzene levels were also available from the public air quality network. The passive samplers, after automated thermal desorption, were analyzed by GC-FID. RESULTS: Benzene personal exposure levels averaged 6.9 (SD=2.1) and 2.3 (SD=0.7) microg/m(3) in winter and spring, respectively. Outdoor and indoor levels showed high correlation in winter and poor in spring. In winter the highest benzene personal exposure levels were for people traveling by more public transport, followed by users of only car and by users of only bus respectively. CONCLUSIONS: The time spent in-transport for work or leisure makes a major contribution to benzene exposure among Florentine non-smoking citizens. Indoor pollution and transportation means contribute significantly to individual exposure levels especially in winter season.

Gastric cancer mortality trends in Tuscany, Italy, 1971-2004.

UNLABELLED: AIMS, BACKGROUND, AND METHODS: In Tuscany, Italy, gastric cancer mortality has been decreasing since 1950, although with relevant geographical variability across the region. In Eastern Tuscan areas close to the mountains (high risk areas), gastric cancer mortality has been and is still significantly higher than that recorded in Western coastal areas and in the city of Florence (low risk areas). High-risk areas also showed higher Helicobacter pylori seroprevalence. Aim of this paper is to study gastric cancer mortality trends in high and low-risk areas, during the period 1971-2004, using age-period-cohort models. RESULTS: In high-risk areas, gastric cancer mortality rates declined from 61.4 per 100,000 in 1971-74 to 19.8 in 2000-2004 and in low-risk areas from 34.9 to 9.8. Mortality decline in high-risk areas was mainly attributable to a birth cohort effect, whereas in low-risk areas it was due either to a birth cohort effect or a period effect. In low- and high-risk areas, birth-cohort risks of dying decreased over subsequent generations, except for the birth cohorts born around the second world war. CONCLUSIONS: Gastric cancer mortality in areas with higher H. pylori seroprevalence in Tuscany (high-risk areas) showed a predominant decline by birth cohort, in particular for younger generations, possibly due to the decrease of the infection for improvement of living conditions.