D. Michal Freedman

Body-mass index and mortality among 1.46 million white adults.

BACKGROUND A high body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) is associated with increased mortality from cardiovascular disease and certain cancers, but the precise relationship between BMI and all-cause mortality remains uncertain. METHODS We used Cox regression to estimate hazard ratios and 95% confidence intervals for an association between BMI and all-cause mortality, adjusting for age, study, physical activity, alcohol consumption, education, and marital status in pooled data from 19 prospective studies encompassing 1.46 million white adults, 19 to 84 years of age (median, 58). RESULTS The median baseline BMI was 26.2. During a median follow-up period of 10 years (range, 5 to 28), 160,087 deaths were identified. Among healthy participants who never smoked, there was a J-shaped relationship between BMI and all-cause mortality. With a BMI of 22.5 to 24.9 as the reference category, hazard ratios among women were 1.47 (95 percent confidence interval [CI], 1.33 to 1.62) for a BMI of 15.0 to 18.4; 1.14 (95% CI, 1.07 to 1.22) for a BMI of 18.5 to 19.9; 1.00 (95% CI, 0.96 to 1.04) for a BMI of 20.0 to 22.4; 1.13 (95% CI, 1.09 to 1.17) for a BMI of 25.0 to 29.9; 1.44 (95% CI, 1.38 to 1.50) for a BMI of 30.0 to 34.9; 1.88 (95% CI, 1.77 to 2.00) for a BMI of 35.0 to 39.9; and 2.51 (95% CI, 2.30 to 2.73) for a BMI of 40.0 to 49.9. In general, the hazard ratios for the men were similar. Hazard ratios for a BMI below 20.0 were attenuated with longer-term follow-up. CONCLUSIONS In white adults, overweight and obesity (and possibly underweight) are associated with increased all-cause mortality. All-cause mortality is generally lowest with a BMI of 20.0 to 24.9.

Risk of cataract after exposure to low doses of ionizing radiation: a 20-year prospective cohort study among US radiologic technologists.

The study aim was to determine the risk of cataract among radiologic technologists with respect to occupational and nonoccupational exposures to ionizing radiation and to personal characteristics. A prospective cohort of 35,705 cataract-free US radiologic technologists aged 24-44 years was followed for nearly 20 years (1983-2004) by using two follow-up questionnaires. During the study period, 2,382 cataracts and 647 cataract extractions were reported. Cigarette smoking for >or=5 pack-years; body mass index of >or=25 kg/m(2); and history of diabetes, hypertension, hypercholesterolemia, or arthritis at baseline were significantly (p <or= 0.05) associated with increased risk of cataract. In multivariate models, self-report of >or=3 x-rays to the face/neck was associated with a hazard ratio of cataract of 1.25 (95% confidence interval: 1.06, 1.47). For workers in the highest category (mean, 60 mGy) versus lowest category (mean, 5 mGy) of occupational dose to the lens of the eye, the adjusted hazard ratio of cataract was 1.18 (95% confidence interval: 0.99, 1.40). Findings challenge the National Council on Radiation Protection and International Commission on Radiological Protection assumptions that the lowest cumulative ionizing radiation dose to the lens of the eye that can produce a progressive cataract is approximately 2 Gy, and they support the hypothesis that the lowest cataractogenic dose in humans is substantially less than previously thought.

Mortality from multiple sclerosis and exposure to residential and occupational solar radiation: a case-control study based on death certificates

OBJECTIVES To explore whether mortality from multiple sclerosis is negatively associated with exposure to sunlight. METHODS Two case-control studies based on death certificates were conducted for mortality from multiple sclerosis and non-melanoma skin cancer (as a positive control) to examine associations with residential and occupational exposure to sunlight. Cases were all deaths from multiple sclerosis between 1984 and 1995 in 24 states of the United States. Controls, which were age frequency matched to a series of cases, excluded cancer and certain neurological deaths. The effects of occupational exposure to sunlight were assessed among subjects with usual occupations requiring substantial activity, so as to exclude those whose indoor jobs resulted from disabilities subsequent to the onset of the disease. Multiple logistic regression analyses were applied, with adjustment for age, sex, race, and socioeconomic status. RESULTS Unlike mortality from skin cancer, mortality from multiple sclerosis was negatively associated with residential exposure to sunlight (odds ratio (OR)=0.53 (multiple sclerosis) and OR=1.24 (skin cancer)). Odds ratios for the highest occupational exposure to sunlight were 0.74 (95% confidence interval (95% CI) 0.61 to 0.89) for mortality from multiple sclerosis, compared with 1.21 (1.09 to 1.34) for mortality from non-melanoma skin cancer. The OR was 0.24 for the combined effect of the highest levels of residential and occupational exposure to sunlight on multiple sclerosis, compared with an OR of 1.38 for skin cancer. CONCLUSIONS In this exploratory study, mortality from multiple sclerosis, unlike mortality from skin cancer, was negatively associated with both residential and occupational exposure to sunlight.

Increased Risk of Second Primary Cancers After a Diagnosis of Melanoma

OBJECTIVE To quantify the risk of subsequent primary cancers among patients with primary cutaneous malignant melanoma. DESIGN Population-based registry study. SETTING We evaluated data from 9 cancer registries of the Surveillance, Epidemiology, and End Results program from 1973-2006. PARTICIPANTS We included 89 515 patients who survived at least 2 months after their initial melanoma diagnosis. RESULTS Of the patients with melanoma, 10 857 (12.1%) developed 1 or more subsequent primary cancers. The overall risk of a subsequent primary cancer increased by 28% (observed to expected [O:E] ratio = 1.28). One quarter of the cancers were subsequent primary melanomas (O:E = 8.61). Women with head and neck melanoma and patients younger than 30 had markedly increased risks (O:E = 13.22 and 13.40, respectively) of developing a subsequent melanoma. Second melanomas were more likely to be thin than were the first of multiple primary melanomas (thickness at diagnosis <1.00 mm, 77.9% vs 70.3%, respectively; P < .001). Melanoma survivors had increased risk of developing several cancers; the most common cancers with elevated risks were breast, prostate, and non-Hodgkin lymphoma (O:E = 1.10, 1.15, and 1.25, respectively). CONCLUSIONS Melanoma survivors have an approximately 9-fold increased risk of developing subsequent melanoma compared with the general population. The risk remains elevated more than 20 years after the initial melanoma diagnosis. This increased risk may be owing to behavioral factors, genetic susceptibility, or medical surveillance. Although the percentage of subsequent primary melanomas thicker than 1 mm is lower than for the first of multiple primary melanomas, it is still substantial. Melanoma survivors should remain under surveillance not only for recurrence but also for future primary melanomas and other cancers.

Correlates of circulating 25-hydroxyvitamin D: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Low vitamin D status is common globally and is associated with multiple disease outcomes. Understanding the correlates of vitamin D status will help guide clinical practice, research, and interpretation of studies. Correlates of circulating 25-hydroxyvitamin D (25(OH)D) concentrations measured in a single laboratory were examined in 4,723 cancer-free men and women from 10 cohorts participating in the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, which covers a worldwide geographic area. Demographic and lifestyle characteristics were examined in relation to 25(OH)D using stepwise linear regression and polytomous logistic regression. The prevalence of 25(OH)D concentrations less than 25 nmol/L ranged from 3% to 36% across cohorts, and the prevalence of 25(OH)D concentrations less than 50 nmol/L ranged from 29% to 82%. Seasonal differences in circulating 25(OH)D were most marked among whites from northern latitudes. Statistically significant positive correlates of 25(OH)D included male sex, summer blood draw, vigorous physical activity, vitamin D intake, fish intake, multivitamin use, and calcium supplement use. Significant inverse correlates were body mass index, winter and spring blood draw, history of diabetes, sedentary behavior, smoking, and black race/ethnicity. Correlates varied somewhat within season, race/ethnicity, and sex. These findings help identify persons at risk for low vitamin D status for both clinical and research purposes.

Risk of melanoma in relation to smoking, alcohol intake, and other factors in a large occupational cohort.

Objective: To investigate whether smoking, alcohol intake, female hormonal or anthropometric factors affect melanoma risk. Methods: Using Cox proportional hazards regression analyses, we analyzed 68,588 white subjects (79% female) from the US Radiologic Technologists (USRT) Study who were cancer-free (other than non-melanoma skin cancer) as of the first of two self-administered questionnaires. Follow-up covered 698,028 person-years, with 207 cases of melanoma. Results: We found that melanoma risk was not associated with height, weight or BMI, nor with age at menarche, menopausal status, use of hormone replacement therapy, parity, age at first birth or oral contraceptive use. Melanoma risk was elevated with increasing alcohol use (RR: 2.1; 95% CI: 0.9–4.8, for >14 drinks/week compared to never drinking; (p(trend) = 0.08)). Smoking for long durations compared to never smoking was inversely related to melanoma risk (RR: 0.6; 0.3–1.3; ≥30 years; p(trend) = 0.03), though risk was not associated with number of packs smoked per day. Conclusions: None of the anthropometric or female reproductive/hormonal factors evaluated were related to melanoma risk. It is unclear whether the positive association with alcohol intake and inverse association with smoking for long duration are causal. The alcohol and smoking findings warrant detailed assessment in studies with substantial statistical power where potential biases can be more fully evaluated.

Nonradiation Risk Factors for Thyroid Cancer in the US Radiologic Technologists Study

The incidence of thyroid cancer has been rapidly increasing in the United States, but few risk factors have been established. The authors prospectively examined the associations of self-reported medical history, anthropometric factors, and behavioral factors with thyroid cancer risk among 90,713 US radiologic technologists (69,506 women and 21,207 men) followed from 1983 through 2006. Incident thyroid cancers in 242 women and 40 men were reported. Elevated risks were observed for women with benign thyroid conditions (hazard ratio (HR) = 2.35, 95% confidence interval (CI): 1.73, 3.20), benign breast disease (HR = 1.56, 95% CI: 1.08, 2.26), asthma (HR = 1.68, 95% CI: 1.00, 2.83), and body mass index > or =35.0 versus 18.5-24.9 kg/m(2) (HR = 1.74, 95% CI: 1.03, 2.94; P-trend = 0.04). Current smoking was inversely associated with thyroid cancer risk (HR = 0.54). No clear associations emerged for reproductive factors, other medical conditions, alcohol intake, or physical activity. Despite few thyroid cancers in men, men with benign thyroid conditions had a significantly increased risk of thyroid cancer (HR = 4.65, 95% CI: 1.62, 13.34), and results for other risk factors were similar to those for women. Consistent with prior studies, obesity and benign thyroid conditions increased and current smoking decreased the risk of thyroid cancer. The novel findings for benign breast disease and asthma warrant further investigation.

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

IntroductionSeveral common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.MethodsWe evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.ResultsThese analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.ConclusionsThe relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.

Cancer and other causes of mortality among radiologic technologists in the United States.

Data are limited on the role of chronic exposure to low‐dose ionizing radiation in the etiology of cancer. In a nationwide cohort of 146,022 U.S. radiologic technologists (73% female), we evaluated mortality risks in relation to work characteristics. Standardized mortality ratios (SMRs) were computed to compare mortality in the total cohort vs. the general population of the United States. Mortality risks were low for all causes (SMR = 0.76) and for all cancers (SMR = 0.82) among the radiologic technologists. We also calculated relative risks (RR) for the 90,305 technologists who responded to a baseline mailed questionnaire, using Poisson regression models, adjusted for known risk factors. Risks were higher for all cancers (RR = 1.28, 95% confidence interval [CI] = 0.93–1.69) and breast cancer (RR = 2.92, 95% CI = 1.22–7.00) among radiologic technologists first employed prior to 1940 compared to those first employed in 1960 or later, and risks declined with more recent calendar year of first employment (p‐trend = 0.04 and 0.002, respectively), irrespective of employment duration. Risk for the combined category of acute lymphocytic, acute myeloid and chronic myeloid leukemias was increased among those first employed prior to 1950 (RR = 1.64, 95% CI = 0.42–6.31) compared to those first employed in 1950 or later. Risks rose for breast cancer (p‐trend = 0.018) and for acute lymphocytic, acute myeloid and chronic myeloid leukemias (p‐trend = 0.05) with increasing duration of employment as a radiologic technologist prior to 1950. The elevated mortality risks for breast cancer and for the combined group of acute lymphocytic, acute myeloid and chronic myeloid leukemias are consistent with a radiation etiology given greater occupational exposures to ionizing radiation prior to 1950 than in more recent times.

Prospective study of ultraviolet radiation exposure and risk of cancer in the United States

Ecologic studies have reported that solar ultraviolet radiation (UVR) exposure is associated with cancer; however, little evidence is available from prospective studies. We aimed to assess the association between an objective measure of ambient UVR exposure and risk of total and site‐specific cancer in a large, regionally diverse cohort [450,934 white, non‐Hispanic subjects (50–71 years) in the prospective National Institutes of Health (NIH)‐AARP Diet and Health Study] after accounting for individual‐level confounding risk factors. Estimated erythemal UVR exposure from satellite Total Ozone Mapping Spectrometer (TOMS) data from NASA was linked to the US Census Bureau 2000 census tract (centroid) of baseline residence for each subject. We used Cox proportional hazards models adjusted for multiple potential confounders to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for quartiles of UVR exposure. Restricted cubic splines examined nonlinear relationships. Over 9 years of follow‐up, UVR exposure was inversely associated with total cancer risk (N = 75,917; highest versus lowest quartile; HR = 0.97, 95% CI = 0.95–0.99; p‐trend < 0.001). In site‐specific cancer analyses, UVR exposure was associated with increased melanoma risk (highest versus lowest quartile; HR = 1.22, 95% CI = 1.13–1.32; p‐trend < 0.001) and decreased risk of non‐Hodgkins lymphoma (HR = 0.82, 95% CI = 0.74–0.92) and colon (HR = 0.88, 95% CI = 0.82–0.96), squamous cell lung (HR = 0.86, 95% CI = 0.75–0.98), pleural (HR = 0.57, 95% CI = 0.38–0.84), prostate (HR = 0.91, 95% CI = 0.88–0.95), kidney (HR = 0.83, 95% CI = 0.73–0.94) and bladder (HR = 0.88, 95% CI = 0.81–0.96) cancers (all p‐trend < 0.05). We also found nonlinear associations for some cancer sites, including the thyroid and pancreas. Our results add to mounting evidence for the influential role of UVR exposure on cancer.