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Background: After the Chernobyl accident in 1986, children of the contaminated Narodichesky region of Ukraine were obliged to participate in a yearly medical screening. They have been exposed to 137cesium (137Cs; half-life = 30 years) in contaminated soils, air, and food. Objective: Using a 'natural experiment' approach and a longitudinal prospective cohort study design, we investigated the association of soil 137Cs and spirometry measures for 415 children using 1,888 repeated measurements from 1993 to 1998. Methods: Mean baseline village soil 137Cs measurements, which varied from 29.0 to 879 kBq/m2, were used as exposure indicators. A standardized spirometry protocol and prediction equations specific to Ukrainian children were used by the same pulmonologist in all screenings. Results: Children living in villages with the highest quintile of soil 137Cs were 2.60 times more likely to have forced vital capacity (FVC) < 80% of predicted [95% confidence interval (CI), 1.07-6.34] and 5.08 times more likely to have a ratio of forced expiratory volume in 1 sec (FEV1) to FVC% < 80% (95% CI, 1.02-25.19). We found statistically significant evidence of both airway obstruction (FEV1/FVC%, peak expiratory flow, and maximum expiratory flow at 25%, 50%, and 75% of FVC) and restriction (FVC) with increasing soil 137Cs. Conclusions: These findings are unique and suggest significant airway obstruction and restriction consequences for children chronically exposed to low-dose radioactive contaminants such as those found downwind of the Chernobyl Nuclear Power Plant. [ABSTRACT FROM AUTHOR]

Objective: Higher levels of insulin-like growth factor-I (IGF-I) and lower levels of IGF binding protein-3 (IGFBP-3) have been associated with an increased risk of prostate cancer. Nutrition is known to partially regulate IGF levels and it is possible that nutritional factors mediate the impact of IGF levels on prostate cancer risk.Design: A cross-sectional analysis of the impact of nutritional factors measured by a dietary questionnaire on plasma levels of IGF-I, IGFBP-3 and their molar ratio. Multiple linear regression analysis was used to test for effects of nutrients on IGF levels.Setting: Prostate cancer screening at the Hollings Cancer Center in Charleston, South Carolina.Subjects: Ninety-five African American and 138 white males aged 33-83 years attending the screening.Results: In whites, intakes of total, saturated and monounsaturated fats were positively associated with an increase in the molar ratio, while there was no association in African Americans. In African Americans, we found that increasing intake of calcium and dairy servings was positively associated with IGF-I levels. Increased vegetable intake was positively associated with IGFBP-3 in African Americans, while there was no effect in whites. A higher percentage of alcohol in the total diet was significantly associated with a decrease in the molar ratio and an increase in IGFBP-3 in both groups.Conclusions: Our results confirm previous findings of nutritional determinants of IGF levels. Additionally, we found the impact of several nutrients on IGF levels to be different in whites and African Americans, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Trichloroethylene (TCE) is a suspected human carcinogen and a common groundwater contaminant. Chloral hydrate (CH) is the major metabolite of TCE formed in the liver by cytochrome P450 2E1. CH is metabolized to the hepatocarcinogen trichloroacetate (TCA) by aldehyde dehydrogenase (ALDH) and to the noncarcinogenic metabolite trichloroethanol (TCOH) by alcohol dehydrogenase (ADH) . ALDH and ADH are polymorphic in humans, and these polymorphisms are known to affect the elimination of ethanol. It is therefore possible that polymorphisms in CH metabolism will yield subpopulations with greater than expected TCA formation with associated enhanced risk of liver tumors after TCE exposure. Methods: The present studies were undertaken to determine the feasibility of using commercially available, cryogenically preserved human hepatocytes to determine simultaneously the kinetics of CH metabolism and ALDH/ADH genotype. Thirteen human hepatocyte samples were examined. Linear reciprocal plots were obtained for 11 ADH and 12 ALDH determinations. Results: There was large interindividual variation in the V(subscript)max(/subscript) values for both TCOH and TCA formation. Within this limited sample size, no correlation with ADH/ALDH genotype was apparent. Despite the large variation in V(subscript)max(/subscript) values among individuals, disposition of CH into the two competing pathways was relatively constant. Conclusions: These data support the use of cryopreserved human hepatocytes as an experimental system to generate metabolic and genomic information for incorporation into TCE cancer risk assessment models. The data are discussed with regard to cellular factors, other than genotype, that may contribute to the observed variability in metabolism of CH in human liver. [ABSTRACT FROM AUTHOR]

Objective: Trends in cancer mortality, cardiovascular mortality, and cancer incidence are assessed among US whites to determine whether aging of the population and smoking patterns completely account for increased cancer rates from 1973 through 1987.Design: For mortality, percentage changes in age-specific rates were calculated. For cancer incidence, trends in age-specific rates across time periods and birth cohorts were assessed for several sites.Main Outcome Measures: National US cardiovascular and cancer mortality rates and incidence rates for smoking-related cancer, breast cancer, and all other types of cancer in 10% of the US population covered by the National Cancer Institute's Surveillance, Epidemiology, and End Results Program were analyzed.Results: From 1973 through 1987, cardiovascular mortality decreased 42% in the age group 0 to 54 years and decreased 33% in the age group 55 to 84 years; concurrently, cancer mortality decreased 17% in the younger group but increased 12% in the older group. By 1987, even though proportionally fewer people in the older age groups died, relatively more of them died of cancer. Men born in the 1940s had twice as much cancer as those born in 1888 through 1897 and more than twice as much cancer not linked to smoking; women born during this period had 50% and 30% more of these same cancers, respectively. Rates of smoking-related cancers in recent cohorts of women were five to six times greater than in those born in 1888 through 1897, while rates in men declined. Recent cohorts of women also had more than twice as much breast cancer as those born in 1888 through 1897.Conclusions: In recent US birth cohorts, our model found that increases in cancer have occurred that are not solely linked to aging of the population and smoking patterns. In light of these results and similar findings in Sweden, changes in carcinogenic hazards in addition to smoking are likely to have occurred and need to be studied further. [ABSTRACT FROM AUTHOR]

This article aims to alert the medical community and public health authorities to accumulating evidence on health benefits from sun exposure, which suggests that insufficient sun exposure is a significant public health problem. Studies in the past decade indicate that insufficient sun exposure may be responsible for 340,000 deaths in the United States and 480,000 deaths in Europe per year, and an increased incidence of breast cancer, colorectal cancer, hypertension, cardiovascular disease, metabolic syndrome, multiple sclerosis, Alzheimer's disease, autism, asthma, type 1 diabetes and myopia. Vitamin D has long been considered the principal mediator of beneficial effects of sun exposure. However, oral vitamin D supplementation has not been convincingly shown to prevent the above conditions; thus, serum 25(OH)D as an indicator of vitamin D status may be a proxy for and not a mediator of beneficial effects of sun exposure. New candidate mechanisms include the release of nitric oxide from the skin and direct effects of ultraviolet radiation (UVR) on peripheral blood cells. Collectively, this evidence indicates it would be wise for people living outside the tropics to ensure they expose their skin sufficiently to the sun. To minimize the harms of excessive sun exposure, great care must be taken to avoid sunburn, and sun exposure during high ambient UVR seasons should be obtained incrementally at not more than 5-30 min a day (depending on skin type and UV index), in season-appropriate clothing and with eyes closed or protected by sunglasses that filter UVR.

The use of low doses of radium-224 (224Ra) chloride for the treatment of ankylosing spondylitis was stopped following the discovery that patients treated with it had a higher than control incidence of leukaemia and other cancers. This was so even though the treatment resulted in decreased pain and increased mobility-both of which are associated with decreased mortality. It was decided to re-analyze the epidemiological data looking at all causes of death. The risk of leukaemia, solid cancer, death from non-cancer causes and from all causes in a study populations of men that received either the typical dose of 5.6 to 11.1 MBq of 224Ra, any dose of 224Ra or no radium were compared using the Cox proportional hazard model. For patients that received the typical dose of 224Ra agreed with the excess cancer was similar to that reported in previous studies. In contrast, these patients were less likely to die from non-cancer diseases and from all causes of death than the control patients. No excess mortality was also found in the population of all males that received the radionuclide. It is concluded that 224Ra treatment administered at low doses to patients with ankylosing spondylitis did not impact mortality from all causes. The study demonstrates the need to consider all causes of death and longevity when assessing health impacts following irradiation., Competing Interests: The authors have declared that no competing interests exist.

There have been many public health recommendations for avoiding UV radiation exposures. This is primarily due to concerns about skin cancer and especially melanoma, the most serious type of skin cancer. However, UV radiation is also known as the primary source of vitamin D and other compounds needed for good health. This brief commentary lists several of the many important recent studies of adverse health effects associated with low sun exposure, including some specific cancers, multiple sclerosis, diabetes, cardiovascular disease, autism, Alzheimer's disease, and age-related macular degeneration. Our conclusion is that non-burning UV exposure is a health benefit and-in moderation-should be recommended as such.

Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Estimating cancer risks for continuous radiation exposures based upon data from acute exposures has been an important public health problem. A dose and dose rate effectiveness factor (DDREF) is typically used to estimate cancer risks for chronic exposures based upon risk estimates from acute exposures. A value of 2 for a DDREF has most often been used as proposed by the ICRP in ICRP60; however, an influential analysis of several cohorts concluded that there is no risk difference between acute and chronic exposures. It is the purpose of this article to analyze the recent nuclear worker studies and estimate the dose rate effectiveness factor, DREF, for solid cancers., Materials and Methods: Twelve mortality studies were identified each with at least 100 cancer deaths and a meta-analysis was then carried out using their individual ratio of low dose rate cancer effect (LDR) to the corresponding high dose rate effect from the A-bomb cohort (LSS). The ratio is denoted by Q and its reciprocal is then an estimate of the DREF., Results: The result was Q= 0.36 (95% CI = 0.11, 0.60) and DREF = 2.63 (95% confidence interval [CI] = 1.61, 7.14). Clearly, this estimate is more consistent with a DREF of 2 than with a DREF of 1. The difficulty with the estimate Q = 0.36 is that it is driven by only two large and dissimilar worker studies, the INWORKS study (q 1  = 1.14) and the Mayak worker cohort (q 3  = 0.30). The higher exposures for these nuclear workers were often in the early years (e.g. before 1960) with exposures from neutrons and internal emitters that are not included in the risk analyses resulting in likely overestimation of cancer effects per dose which would increase the estimate of the DREF. The Mayak study did, however, adjust for plutonium exposures. Finally, consideration is given to other cohort studies where DREF values may possibly be determined, such as the environmental exposures to the Techa River area residents and the Chernobyl cleanup workers as well as medical X-ray workers. Although dissimilar an overall meta-analysis yielded a Q = 0.45 (95% CI = 0.24, 0.66)., Conclusions: It is concluded that the best estimate of a DREF is still about 2. However, because of the various problems with the epidemiology studies, especially their dosimetry, it is concluded that a DREF of about 2 should be accepted with considerable caution since it is driven solely by the Mayak study.

In this study, the B6CF 1 mice from the JANUS program at the Argonne National Laboratory were analyzed for increased cardiovascular disease (CVD) mortality from 60 Co γ ray or fission neutron exposures administered in either a single dose or protracted weekly doses. The data used for this study represent the last studies conducted at Argonne and have been archived for at least 15 years. CVD mortality increased in a dose-dependent manner from γ rays as well as from neutron exposures. The relative biological effectiveness (RBE) for neutrons is about 4 or 5. CVD mortality appeared to be enhanced when the dose was protracted, with a DDREF (dose and dose rate effectiveness factor) in the range of 0.4-0.45 for neutron and gamma ray exposure, respectively.

There have been many case-control studies of melanoma and the use of indoor tanning equipment. A recent meta analysis of 8 credible studies in North America estimated an overall significant odds ratio of 1.23. Three of these 8 studies also reported separately on commercial use and home use of indoor tanning equipment. For home use the overall odds ratio was a significant 1.53 while for commercial use there was a non significant 1.05.

Public health authorities in the United States are recommending that men, women and children reduce their exposure to sunlight, based on concerns that this exposure will promote skin cancer. On the other hand, data show that increasing numbers of Americans suffer from vitamin D deficiencies and serious health problems caused by insufficient sun exposure. The body of science concerning the benefits of moderate sun exposure is growing rapidly, and is causing a different perception of sun/UV as it relates to human health. Melanoma and its relationship to sun exposure and sunburn is not adequately addressed in most of the scientific literature. Reports of favorable health outcomes related to adequate serum 25(OH)D concentration or vitamin D supplementation have been inappropriately merged, so that benefits of sun exposure other than production of vitamin D are not adequately described. This review of recent studies and their analyses consider the risks and benefits of sun exposure which indicate that insufficient sun exposure is an emerging public health problem. This review considers the studies that have shown a wide range health benefits from sun/UV exposure. These benefits include among others various types of cancer, cardiovascular disease, Alzheimer disease/dementia, myopia and macular degeneration, diabetes and multiple sclerosis. The message of sun avoidance must be changed to acceptance of non-burning sun exposure sufficient to achieve serum 25(OH)D concentration of 30 ng/mL or higher in the sunny season and the general benefits of UV exposure beyond those of vitamin D.

Purpose: This review evaluates the role of dose rate on cell and molecular responses. It focuses on the influence of dose rate on key events in critical pathways in the development of cancer. This approach is similar to that used by the U.S. EPA and others to evaluate risk from chemicals. It provides a mechanistic method to account for the influence of the dose rate from low-LET radiation, especially in the low-dose region on cancer risk assessment. Molecular, cellular, and tissues changes are observed in many key events and change as a function of dose rate. The magnitude and direction of change can be used to help establish an appropriate dose rate effectiveness factor (DREF)., Conclusions: Extensive data on key events suggest that exposure to low dose-rates are less effective in producing changes than high dose rates. Most of these data at the molecular and cellular level support a large (2-30) DREF. In addition, some evidence suggests that doses delivered at a low dose rate decrease damage to levels below that observed in the controls. However, there are some data human and mechanistic data that support a dose-rate effectiveness factor of 1. In summary, a review of the available molecular, cellular and tissue data indicates that not only is dose rate an important variable in understanding radiation risk but it also supports the selection of a DREF greater than one as currently recommended by ICRP ( 2007 ) and BEIR VII (NRC/NAS 2006 ).

Background: Experimental rodent bioassays performed up to now have failed to provide conclusive confirmation of the carcinogenicity of extremely low frequency magnetic fields (ELFMF)., Objectives: To evaluate the potential synergistic carcinogenic effects of concurrent exposure to ELFMF and formaldehyde in four groups of male and female Sprague-Dawley rats., Methods: One group was exposed from prenatal life until natural death to S-50 Hz MF and to formaldehyde in drinking water from 6 weeks of age for 104 weeks, two groups were treated only with formaldehyde or only with MF and one group served as untreated control., Results: Compared to untreated controls, exposure to MF and formaldehyde causes in males a statistically significant increased incidence of malignant tumors (P ≤ 0.01), thyroid C-cell carcinomas (P ≤ 0.01), and hemolymphoreticular neoplasias (P ≤ 0.05). No statistically significant differences were observed among female groups., Conclusions: Life-span exposure to MF and formaldehyde induces statistically significant carcinogenic effects in male rats. Am. J. Ind. Med. 59:509-521, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background In 2002 the International Agency for Research on Cancer classified extremely low frequency magnetic fields (ELFMF) as a possible carcinogen on the basis of epidemiological evidence. Experimental bioassays on rats and mice performed up to now on ELFMF alone or in association with known carcinogens have failed to provide conclusive confirmation. Objectives To study the carcinogenic effects of combined exposure to sinusoidal-50 Hz (S-50 Hz) magnetic fields and acute γ radiation in Sprague-Dawley rats. Methods We studied groups of male and female Sprague-Dawley rats exposed from prenatal life until natural death to 20 or 1000 μT S-50 Hz MF and also to 0.1 Gy γ radiation delivered as a single acute exposure at 6 weeks of age. Results The results of the study showed significant carcinogenic effects for the mammary gland in males and females and a significant increased incidence of malignant schwannomas of the heart as well as increased incidence of lymphomas/leukemias in males. Conclusions These results call for a re-evaluation of the safety of non-ionizing radiation.

Radiation cancer risk estimates have been based primarily on the atomic bomb survivor cohorts, which involve an acute exposure. To adjust for lower dose and continuous exposures, a dose and dose rate effectiveness factor (DDREF) is applied to the acute risk estimates. The commonly accepted value for the DDREF at 1 Gy by the ICRP and the NCRP has been 2. BEIR VII changed this by estimating the value to be 1.5 including an uncertainty distribution. The BEIR VII committee used the atomic bomb solid cancer incidence data to make this estimation, and they chose to truncate the data at 1.5 Gy. The Committee also used the Oak Ridge mouse studies and estimated a DDREF based on these data. Finally they used the animal data-derived DDREF distribution as a Bayesian prior distribution for the atomic bomb survivor DDREF distribution and used the posterior distribution as their DDREF result. The resulting distribution had a maximum likelihood estimate of 1.4, and the Committee chose 1.5 as their best estimate. The purpose of this paper is to reexamine the BEIR VII analysis of both the atomic bomb survivor data and the mouse data. Based upon this analysis, the author concludes that changing the DDREF from 2 to 1.5 is not justified.

U.S. Environmental Protection Agency (EPA) recently conducted a risk assessment for exposure to Libby amphibole asbestos that is precedent-setting for two reasons. First, the Agency has not previously conducted a risk assessment for a specific type of asbestos fiber. Second, the risk assessment includes not only an inhalation unit risk (IUR) for the cancer endpoints, but also a reference concentration (RfC) for nonmalignant disease. In this paper, we review the procedures used by the Agency for both cancer and nonmalignant disease and discuss the strengths and limitations of these procedures. The estimate of the RfC uses the benchmark dose method applied to pleural plaques in a small subcohort of vermiculite workers in Marysville, Ohio. We show that these data are too sparse to inform the exposure-response relationship in the low-exposure region critical for estimation of an RfC, and that different models with very different exposure-response shapes fit the data equally well. Furthermore, pleural plaques do not represent a disease condition and do not appear to meet the EPA's definition of an adverse condition. The estimation of the IUR for cancer is based on a subcohort of Libby miners, discarding the vast majority of lung cancers and mesotheliomas in the entire cohort and ignoring important time-related factors in exposure and risk, including effect modification by age. We propose that an IUR based on an endpoint that combines lung cancer, mesothelioma, and nonmalignant respiratory disease (NMRD) in this cohort would protect against both malignant and nonmalignant disease. However, the IUR should be based on the entire cohort of Libby miners, and the analysis should properly account for temporal factors. We illustrate our discussion with our own independent analyses of the data used by the Agency.

While radiation health risks at low doses have traditionally been estimated from high-dose studies, we have reviewed recent literature and concluded that the mechanisms of action for many biological endpoints may be different at low doses from those observed at high doses; that acute doses <100 mSv may be too small to allow epidemiological detection of excess cancers given the background of naturally occurring cancers; that low-dose radiation research should use holistic approaches such as systems-based methods to develop models that define the shape of the dose-response relationship; and that these results should be combined with the latest epidemiology to produce a comprehensive understanding of radiation effects that addresses both damage, likely with a linear effect, and response, possibly with non-linear consequences. Continued research is needed to understand how radiobiology and epidemiology advances should be used to effectively model radiation worker risks.

Purpose: To determine the relative toxicity of alpha- and beta-radiations under conditions of controlled temporal and spatial dose distribution., Methods: Fused aluminosilicate particles were radiolabelled with either (45)Ca (a beta-emitter) or (242)Cm (an alpha-emitter). These were injected into CBA/Ca mice to give lifespan, whole-body doses of approximately 0.5, 1.0 or 1.5 Gy. Most animals were entered into a lifespan toxicity study, but some were killed for radiochemical analysis and autoradiography., Results: Twenty-seven tumour types were identified. The most common malignant tumours were: Mammary carcinoma; liver carcinoma; malignant lymphoma; uterine histiocytic sarcoma. Excess relative risk (strictly hazard ratio) was higher for radiation-induced carcinomas than for sarcomas. The carcinomas, but not sarcomas showed a reduction in relative risk at the highest radiation dose employed. This reduction was most easily attributed to a systemic effect. The highest relative toxicity measured was for liver carcinoma (5.9, 95% confidence intervals [CI] 2.4, 14) and the lowest for uterine carcinoma (0.6, CI 0.03, 9.7). Overall, the excess relative risk ratio for SURVIVAL WAS 1.9 (CI 1.1, 3.2), FOR ALL CARCINOMA WAS 2.3 (CI 1.7, 3.0) AND FOR ALL SARCOMA WAS 2.7 (CI 0.72, 10)., Conclusions: The 10-fold variability in the observed toxicity ratio for different tumour endpoints shows that tissue sensitivity is a more important determinant of relative toxicity than radiation quality. The use of single radiation-weighting (w(R)) factors for radiation risk prediction and for radiological protection dosimetry is inconsistent with scientific observation.

The Mayak Production Association (MPA) worker registry has shown evidence of plutonium-induced health effects. Workers were potentially exposed to plutonium nitrate [(239)Pu(NO(3))(4)] and plutonium dioxide ((239)PuO(2)). Studies of plutonium-induced health effects in animal models can complement human studies by providing more specific data than is possible in human observational studies. Lung, liver, and bone cancer mortality rate ratios in the MPA worker cohort were compared to those seen in beagle dogs, and models of the excess relative risk of lung, liver, and bone cancer mortality from the MPA worker cohort were applied to data from life-span studies of beagle dogs. The lung cancer mortality rate ratios in beagle dogs are similar to those seen in the MPA worker cohort. At cumulative doses less than 3 Gy, the liver cancer mortality rate ratios in the MPA worker cohort are statistically similar to those in beagle dogs. Bone cancer mortality only occurred in MPA workers with doses over 10 Gy. In dogs given (239)Pu, the adjusted excess relative risk of lung cancer mortality per Gy was 1.32 (95% CI 0.56-3.22). The liver cancer mortality adjusted excess relative risk per Gy was 55.3 (95% CI 23.0-133.1). The adjusted excess relative risk of bone cancer mortality per Gy(2) was 1,482 (95% CI 566.0-5686). Models of lung cancer mortality based on MPA worker data with additional covariates adequately described the beagle dog data, while the liver and bone cancer models were less successful.

Determination of radiation protection guidelines for persons working with plutonium has been complicated by limited human data on the biological behavior and subsequent health effects from internally deposited plutonium. One solution has been the use of animal models to predict likely health effects in humans. To compare the relationships between plutonium inhalation and lung fibrosis and lung cancer, data from life-span studies of beagle dogs given a single exposure to either plutonium-238 dioxide (238PuO2) or plutonium-239 dioxide (239PuO2) were analyzed. Estimates of the cumulative hazard of lung fibrosis and lung cancer after exposure to either were generated. The hazard of lung fibrosis was not consistent with a linear no-threshold model, although the magnitude of the threshold differed by radionuclide. In dogs given 239PuO2, the best model of lung fibrosis incorporated a linear dose-response function; a linear-quadratic dose-response function fit the data better in dogs given 238PuO2. At any given cumulative dose, the lung fibrosis hazard was greater for dogs given 238PuO2. In dogs given 238PuO2, with or without covariates, a quadratic dose-response function for lung cancer hazard fit better than a linear no-threshold model. In dogs given 239PuO2, models of lung cancer with the dose-response function as the sole predictor variable were consistent with a linear no-threshold model; however, a quadratic dose-response function with a cell-killing term fit better. These findings have implications for radiation protection because, while lung cancer hazard was dependent on cumulative dose, regardless of isotope, the lung fibrosis hazard depended on both cumulative dose and isotope.

Background: Laboratory studies often involve analyses of highly skewed data for which means are not an adequate measure of central tendency because they are sensitive to outliers. Attempts to transform skewed data to symmetry are not always successful, and medians are better measures of central tendency for such skewed distributions. When medians are compared across groups, confounding can be an issue, so there is a need for adjusted medians., Methods: We illustrate the use of quantile regression to obtain adjusted medians. The method is illustrated by use of skewed nutrient data obtained from black and white men attending a prostate cancer screening. For 3 nutrients, saturated fats, caffeine, and vitamin K, we obtained medians adjusted by age, body mass index, and calories for men in each race group., Results: Quantile regression, linear regression, and log-normal regression produced substantially different adjusted estimates of central tendency for saturated fats, caffeine, and vitamin K., Conclusions: Our method was useful for analysis of skewed and other nonnormally distributed continuous outcome data and for calculation of adjusted medians.

Trichloroethylene (TCE) is a widespread environmental contaminant that is carcinogenic when given in high, chronic doses to certain strains of mice and rats. The capacity of TCE to cause cancer in humans is less clear. The current maximum contaminant level (MCL) of 5 ppb (microg/L) is based on an US Environment Protection Agency (USEPA) policy decision rather than the underlying science. In view of major advances in understanding the etiology and mechanisms of chemically induced cancer, USEPA began in the late 1990s to revise its guidelines for cancer risk assessment. TCE was chosen as the pilot chemical. The USEPA (2005) final guidelines emphasized a "weight-of-evidence" approach with consideration of dose-response relationships, modes of action, and metabolic/toxicokinetic processes. Where adequate data are available to support reversible binding of the carcinogenic moiety to biological receptors as the initiating event (i.e., a threshold exists), a nonlinear approach is to be used. Otherwise, the default assumption of a linear (i.e., nonthreshold) dose-response is utilized. When validated physiologically based pharmacokinetic (PBPK) models are available, they are to be used to predict internal dosimetry as the basis for species and dose extrapolations. The present article reviews pertinent literature and discusses areas where research may resolve some outstanding issues and facilitate the reassessment process. Key research needs are proposed, including role of dichloroacetic acid (DCA) in TCE-induced liver tumorigenesis in humans; extension of current PBPK models to predict target organ deposition of trichloroacetic acid (TCA) and DCA in humans ingesting TCE in drinking water; use of human hepatocytes to ascertain metabolic rate constants for use in PBPK models that incorporate variability in metabolism of TCE by potentially sensitive subpopulations; measurement of the efficiency of first-pass elimination of trace levels of TCE in drinking water; and assessment of exogenous factors' (e.g., alcohol, drugs) ability to alter metabolic activation and risks at such low-level exposure.

Generalized relative and absolute risk models are fitted to the latest Japanese atomic bomb survivor solid cancer and leukemia mortality data (through 2000), with the latest (DS02) dosimetry, by classical (regression calibration) and Bayesian techniques, taking account of errors in dose estimates and other uncertainties. Linear-quadratic and linear-quadratic-exponential models are fitted and used to assess risks for contemporary populations of China, Japan, Puerto Rico, the U.S. and the UK. Many of these models are the same as or very similar to models used in the UNSCEAR 2006 report. For a test dose of 0.1 Sv, the solid cancer mortality for a UK population using the generalized linear-quadratic relative risk model is estimated as 5.4% Sv(-1) [90% Bayesian credible interval (BCI) 3.1, 8.0]. At 0.1 Sv, leukemia mortality for a UK population using the generalized linear-quadratic relative risk model is estimated as 0.50% Sv(-1) (90% BCI 0.11, 0.97). Risk estimates varied little between populations; at 0.1 Sv the central estimates ranged from 3.7 to 5.4% Sv(-1) for solid cancers and from 0.4 to 0.6% Sv(-1) for leukemia. Analyses using regression calibration techniques yield central estimates of risk very similar to those for the Bayesian approach. The central estimates of population risk were similar for the generalized absolute risk model and the relative risk model. Linear-quadratic-exponential models predict lower risks (at least at low test doses) and appear to fit as well, although for other (theoretical) reasons we favor the simpler linear-quadratic models.

We conducted an ecological analysis of childhood acute lymphoblastic leukaemia-incidence data from children or=$5000 as potential predictors. Incidence was lower among black boys (rate ratio (RR)=0.5) and black girls (RR=0.4) than among other children of the same sex; no other significant racial differences were detected. Incidence was elevated among males (but not females) residing in counties where >or=50% of the population relocated (RR=1.5) and among females (but not males) residing in counties where <6% of the households had incomes <$5000 (RR=1.5). These sex differences in risk factors were unexpected.

The meta-analysis combined and statistically analysed studies of childhood leukaemia and nuclear facilities. Focus was on studies that calculated standardized rates for individual facilities. Due to variability between study designs, eight separate analyses were performed stratified by age and zone. One hundred and thirty-six sites were used in at least one analysis. Unadjusted, fixed effects and random effects models were used. Meta-rates greater than one were found in all models at all stratification levels often achieving statistical significance. Caution must be used when interpreting these results. The meta-analysis was able to show an increase in childhood leukaemia near nuclear facilities, but does not support a hypothesis to explain the excess. Each type of model utilized has limitations. Fixed effects models give greater weight to larger studies; however, population density may be a risk factor. Random effects models give greater weight to smaller studies that may be more likely to be affected by publication bias. A limitation of the overall study design is that standardized rates must be available for individual sites which led to exclusion of studies that only calculated rates for multiple sites and those that presented other statistical methods. Further, dose-response studies do not support excess rates found near nuclear facilities. However, it cannot be ignored that the majority of studies have found elevated rates, although not usually statistically significant.

Approximately 1800 female CBA/Ca mice were exposed by inhalation at three dose levels to beta particles from (45)Ca-labeled fused aluminosilicate particles (FAP), to alpha particles from (242)Cm-labeled FAP, or to carrier control FAP. Another group of mice inhaled no FAP and were designated as untreated cage controls. The FAP in combination with these radionuclides was used to achieve the same spatial and temporal distribution of alpha- and beta-particle dose within the irradiated mice. Some mice were killed to determine the clearance of radiolabeled FAP from their lungs, and the remainder were allocated to a life-span study. All animals were subjected to a detailed necropsy. To facilitate the identification of small tumors, the lungs were rendered transparent in methyl salicylate and examined under back illumination for the presence of lesions. Lung nodules and other microscopic lesions were excised for histological examination. The median survival of mice in all groups was approximately 910 days. The control animals lived longer than those that were irradiated, but it was difficult to determine a dose-response relationship for survival among the exposed mice. Benign adenomas and, less frequently, malignant adenocarcinomas were identified in all animal groups. The prevalence of these tumors was approximately 28.8% in the control mice, which is consistent with the results of other studies using the same strain of mouse. After exposure to radionuclide-labeled FAP, there was a significant dose-related increase in the prevalence of lung tumors in (242)Cm- (peak prevalence 55%) and (45)Ca-exposed (peak prevalence 48.6%) mice. The prevalence of tumors in the mice that received (242)Cm-labeled FAP was approximately twice that in the mice that inhaled (45)Ca-labeled FAP within the range of doses employed (0.55-4.69 Gy). Using the ratio of the slope of the linear component of the dose-response curves, the toxicity of the alpha particles relative to the beta particles was 1.5 (90% CI: 0.7, 9.0) for all adenomas and 9.4 (90% CI: 5.0, 23.0) for the less frequent adenocarcinomas. The relative toxicity for adenocarcinomas was found to decrease with increasing dose.

For more than 15 years the A-bomb survivor studies have shown increased noncancer mortality due to radiation exposures. The most prominent cause of this increase is circulatory disease mortality. Although the estimated relative risk is less than for solid cancers (1.2 versus 1.6 per Sv), there are measurable increases in cardiovascular disease mortality at doses greater than 0.5 Sv. The evidence for circulatory diseases in mortality studies of occupational cohorts exposed to external radiation is less compelling. It is generally accepted that atherosclerosis is an inflammatory disease of the arteries and a risk factor for myocardial infarction. Immunological markers for inflammatory disease have been shown to be dose related in A-bomb survivors. Evidence from animal studies reveals increased cardiovascular mortality and arterial endothelial damage from both neutron and, to a lesser extent, gamma exposures.

Background: A program of medical evaluation for former Savannah River Site (SRS) workers at health effects due to exposures to hazardous or radioactive agents was conducted., Methods: This study includes data from 1,368 participants aged 45 years or older who were assessed regarding work-history and exposures to industrial agents. According to the standard industrial classification (SIC), participants were employed in five of the SIC divisions. Based on the International Labour Office Classification of Radiographs, two categories of pleural and parenchymal abnormalities were evaluated by a single radiologist. The SRS results were compared with the second national health and nutrition examination survey (NHANES II) results., Results: The odds ratio of the SRS male aged 45-75 compared to NHANES was 2.4 for pleura abnormalities and 0.8 for parenchymal abnormalities. Using logistic regression, the highest-risk worker division was construction (OR = 2.76); asbestos exposure was clearly associated with pleural abnormality (OR = 2.15)., Conclusions: Pulmonary abnormalities were higher in former SRS workers than that in general population. Asbestos and possibly other exposures were related to pulmonary disease in this population.

The large United States county-based study () in which an inverse relationship has been suggested between residential low-dose radon levels and lung cancer mortality has been reviewed. While this study has been used to evaluate the validity of the linear nonthreshold theory, the grouped nature of its data limits the usefulness of this application. Our assessment of the study's approach, including a reanalysis of its data, also indicates that the likelihood of strong, undetected confounding effects by cigarette smoking, coupled with approximations of data values and uncertainties in accuracy of data sources regarding levels of radon exposure and intensity of smoking, compromises the study's analytic power. The most clear data for estimating lung cancer risk from low levels of radon exposure continue to rest with higher-dose studies of miner populations in which projections to zero dose are consistent with estimates arising from most case-control studies regarding residential exposure.

Cancer incidence and mortality data from the cohort of Japanese atomic bomb survivors in Hiroshima have been adjusted for the uncertainty that exists in the dose estimates, the systematic error in the neutron dose estimates, and a dose-dependent relative biological effectiveness. Once the adjustments were incorporated in the dose estimates, the data were modeled with a threshold term to allow for the possibility of a threshold dose response. The dose response models that were fit to the data were otherwise the same models used in the original papers. The threshold term was included in the model allowing for possible threshold values ranging from 0 to 0.35 Sv. These analyses suggest that the fit of the A-bomb solid tumor and leukemia incidence data are significantly improved by the addition of a threshold term in comparison with the purely linear or linear quadratic model. The results from the mortality data suggest that the leukemia data agree more with the threshold model than the linear quadratic model although the linear quadratic model is statistically equivalent, while the solid tumor data does not suggest any improvement with a threshold.

Introduction: The purpose of this study was to determine the frequency of translocations and insertions in the blood of long-term pilots in relation to estimated cumulative radiation dose received while flying, and to compare that to the frequency in a group of similarly aged men without a history of frequent airline travel., Methods: Healthy, non-smoking male pilots aged 40-60 yr were recruited from a single airline. Non-pilot controls were recruited from healthy, non-smoking professional males in the same age range and without a history of frequent flying. Eligibility was determined based on screening surveys. Career pilot radiation doses were calculated individually using airline flight profiles, personal flight history, and the CARI computer program. Translocation frequency was determined using fluorescence in situ hybridization., Results: Blood samples for chromosome analysis were provided by 19 individuals. The mean number of metaphases counted per subject was 2802 in the pilots and 3000 in the controls. The mean number of translocations per cell (genome equivalent) was significantly higher among the pilots (mean +/- SE; 0.0031 +/- 0.0008) than among the controls (0.0010 +/- 0.0003) (p = 0.03, Mann-Whitney U test). However, within the 26 to 72 millisievert range encountered in this study, observed values among the pilots did not follow the dose-response pattern expected based on available models for chronic low dose radiation exposure., Conclusions: There was a statistically significant higher number of translocations per cell among pilots than among controls, although the expected dose-response relationship for radiation was not observed among the pilots.

Purpose: To determine the proportion of women who underwent clinical breast examination (CBE) within 12 months before undergoing screening mammography and to examine which factors, if any, were associated with having undergone CBE within 12 months before screening mammography., Materials and Methods: A cross-sectional study of 1,135 women presenting for screening mammography was conducted with a self-administered questionnaire. Data were collected regarding sociodemographic information, health care provider information, breast self-examination practices, and CBE history. Data were analyzed with the chi(2) test of independence., Results: One hundred forty (38.5%) of 364 nonwhite women and 366 (57.4%) of 638 white women reported having undergone CBE 12 months before screening mammography. This association between race and CBE was statistically significant before (P <.001) and after adjusting for education, age, and type of referring physician (P <.001). There was a statistically significant association between undergoing CBE within 12 months and age (P <.001), type of referring physician (P <.001), and education level (P <.001). Health insurance status was associated with having undergone CBE within the past 12 months, but it was not a statistically significant association after controlling for race., Conclusion: The proportion of women who undergo comprehensive breast cancer screening differs by race, education level, and type of referring physician., (Copyright RSNA, 2002)

This study evaluated individual and population dose variability during screening mammography, among 570 white and black women in South Carolina, USA. Aspects of dosimetry that were considered include compressed breast thickness (CBT), number of films per screening session, and dose in previous or subsequent sessions. Breast dose was log-normally distributed in the population, with a geometric mean of 6.6 mGy per session. Doses were significantly higher for black women, for women with high CBT or who receive more than two views per breast, and for the mediolateral oblique, compared to the craniocaudal, view. No relationship was observed between age and dose. Total dose per breast varied by a factor of 20 across the study population, but the individual's dose varied little among repeat screening sessions, especially after adjusting for the number of films received per session. These results may inform assessments of the projected risks of inducing breast cancer from screening mammography.

Mammography dose increases with compressed breast thickness (CBT), but few studies have examined other correlates of dose. The purpose of this study was to evaluate the relation between factors such as race, age, body mass index (BMI), CBT, and menopausal status and mammography screening dose, measured for 509 women in a US population. A multiple linear regression model was developed for dose, based on consideration of these factors as well as examination characteristics. BMI and number of films during examination were positively related to dose. After adjusting for these factors, high CBT also leads to higher dose. Whites receive lower doses than black women but differences are slight after controlling for the effects of CBT and BMI, which were significantly higher among black women. Pre-menopausal women receive higher doses, after adjusting for all other factors, than post-menopausal women. Jointly, these factors account for approximately 75% to 80% of the variability in dose among this study population. Because rates of overweight are increasing in the US, average doses from mammography may be increasing as well.

Background: The airline pilot works within a complex exposure environment that may present physiological challenges to long-term health., Methods: This study investigated self-reported disease outcomes among a large group of active and retired commercial airline pilots in the United States and Canada. A survey methodology was used, including the collection of historical information., Results: Of 10,678 surveys mailed, 6609 were returned (6533 men, 63 women). Given the limitations of survey methodology, increased disease rates among pilots were suggested for melanoma, motor neuron disease, and cataracts. However, rates for other diseases were in general lower than those for the U.S. population., Conclusions: Further study has been initiated to verify and follow reported cases, to expand the study to a larger group, and to collect more in-depth information on flight histories, occupational exposures, and lifestyle factors.

Background: Airline pilots are exposed to magnetic fields generated by the aircraft's electrical system. The objectives of this study were (1) to directly measure flight deck magnetic fields in terms of personal exposure to the pilots when flying on different aircraft types over a 75-hour flight-duty month, and (2) to compare magnetic field exposures across flight deck types and job titles., Methods: Measurements were taken using personal dosimeters carried by either the Captain or the First Officer on Boeing 737/200, Boeing 747/400, Boeing 767/300ER, and Airbus 320 aircraft., Results: Approximately 1,008 block hours were recorded at a sampling frequency of 3 seconds. Total block time exposure to the pilots ranged from a harmonic geometric mean of 6.7 milliGauss (mG) for the Boeing 767/300ER to 12.7 mG for the Boeing 737/200., Conclusions: Measured flight deck magnetic field levels were substantially above the 0.8-1 mG level typically found in the home or office and suggest the need for further study to evaluate potential health effects of long-term exposure., (Copyright 2000 Wiley-Liss, Inc.)

Radiation cancer risks are typically determined by the use of simple statistical descriptions of epidemiological data. It is important in risk assessment in general, however, to attempt to incorporate as much biological information into the risk models as possible. We illustrate this by presenting a biologically-based linear-quadratic-exponential (LQE) incidence rate model for radiation-induced chronic myeloid leukemia (CML). The model consists of a linear-quadratic dose-response for the induction of BCR-ABL, a waiting time distribution between BCR-ABL formation and detection of CML, and an exponential cell-killing term that multiplies both the background and induced incidence rates. Using data exclusive of the A-bomb survivor cohort, Bayesian priors are defined for each of the nine parameters in this LQE model. The priors are based on chromosomal translocations in lymphocytes, hematopoietic stem cell survival experiments, CML waiting times in women irradiated for benign disease, the background CML incidence rate in the U.S. population, and genomic DNA target sizes of BCR and ABL. Fixing three of the LQE model parameters to the means of their priors, maximum likelihood estimates of the remaining six parameters were obtained using A-bomb survivor incidence data for Hiroshima males. The likelihood estimates and the corresponding six prior distributions, both approximated as multivariate normal, were then used to form Bayesian posteriors for the six parameters not fixed. With these posteriors the LQE model yields Qgamma*=0.0042 Gy(-1) where Qgamma* is the upper 95% confidence bound of the lifetime CML risk per person-gray in the limit of low doses of gamma-rays. This value is slightly less than Qgamma*=0.0049 Gy(-1) obtained from likelihood estimates of the LQE parameters, and substantially less than Qgamma*=0.0158 Gy(-1) obtained for a simple statistical model linear in dose for kermas less than 4 Gy.

Formation of the BCR-ABL chromosomal translocation t(9;22)(q34;q11) is essential to the genesis of chronic myeloid leukemia (CML). An interest in the dose-response of radiation induced CML therefore leads naturally to an interest in the dose-response of BCR-ABL formation. To predict the BCR-ABL dose-response to low-linear energy transfer (LET) ionizing radiation, three models valid over three different dose ranges are examined: the first for doses greater than 80 Gy, the second for doses less than 5 Gy and the third for doses greater than 2 Gy. The first of the models, due to Holley and Chatterjee, ignores the accidental binary eurejoining of DNA double-strand break (DSB) free ends ('eurejoining' refers to the accidental restitution of DSB free ends with their own proper mates). As a result, the model is valid only in the limit of high doses. The second model is derived directly from cytogenetic data. This model has the attractive feature that it implicitly accounts for single-track effects at low doses. The third model, based on the Sax-Markov binary eurejoining/misrejoining (SMBE) algorithm, does not account for single-track effects and is therefore limited to moderate doses greater than approximately 2 Gy. Comparing the second model to lifetime excess CML risks expected after 1 Gy, estimates of the number of hematopoietic stem cells capable of causing CML were obtained for male and female atomic bomb survivors in Hiroshima and Nagasaki. The stem cell number estimates lie in the range of 5 x 10(7)-3 x 10(8) cells.

To search for unexplained patterns in cancer incidence, we analyzed data from 1975 to 1994 that represent approximately 10% of the population of the United States. Our analysis focused on long-term time trends in incidence and on deviations from those trends attributable to birth cohorts or to calendar periods. On average, cancer incidence rose 0.8% annually in white women and 1.8% in white men. After removing several cancers related to smoking and increased screening, average annual increases fell to 0.1% in white women but persisted at 1.7% in white men. In particular, yearly increases in non-Hodgkin's lymphoma averaged 2.4% in white women and 4.7% in white men. Among men, incidence changes attributable to cohorts grew progressively larger from one cohort to the next. Cancer incidence patterns among black men and women were similar to those among whites despite smaller population sizes. Unexplained patterns of cancer incidence may signal changes in underlying risk factors and highlight the continuing need for research on cancer etiology and prevention.

Background: Flight crews are exposed to elevated levels of cosmic radiation and to magnetic fields generated by the aircraft's electrical system. The purpose of this study was to quantify these two occupational exposures., Methods: Magnetic fields were measured during 37 flights (23 in the cockpit and 14 in the cabin) using an Emdex Lite personal dosimeter. All cockpit measurements were taken on the B737/200. Cabin measurements were taken in several aircraft types, including the B737, B757, DC9, and L1011. Cosmic radiation was computer estimated for 206 flights using the Federal Aviation Administration's program CARI-3C., Results: Magnetic field levels in the cockpit had a mean value of approximately 17 milliGauss (mG), while cabin measurements were lower (mean values of approximately 3 or less in economy, 6 in first class, 8 in front serving areas). Cosmic radiation equivalent dose rates to bone marrow and skeletal tissue ranged from 0.3 to 5.7 microsieverts per hour., Conclusions: Elevated magnetic field levels in front serving areas and the cockpit suggest the need for further study to evaluate long-term exposure to flight crew members who work in these areas. Cosmic radiation levels are well below occupational limits for adults, but may require some pregnant flight crew members to adjust their flying time or routes.

The airline industry may be an occupational setting with specific health risks. Two environmental agents to which flight crews are known to be exposed are cosmic radiation and magnetic fields generated by the aircraft's electrical system. Other factors to be considered are circadian disruption and conditions specific to air travel, such as noise, vibration, mild hypoxia, reduced atmospheric pressure, low humidity, and air quality. This study investigated mortality among US commercial pilots and navigators, using proportional mortality ratios for cancer and noncancer end points. Proportional cancer mortality ratios and mortality odds ratios were also calculated for comparison to the proportional mortality ratios for cancer causes of death. Results indicated that US pilots and navigators have experienced significantly increased mortality due to cancer of the kidney and renal pelvis, motor neuron disease, and external causes. In addition, increased mortality due to prostate cancer, brain cancer, colon cancer, and cancer of the lip, buccal cavity, and pharynx was suggested. Mortality was significantly decreased for 11 causes. To determine if these health outcomes are related to occupational exposures, it will be necessary to quantify each exposure separately, to study the potential synergy of effects, and to couple this information with disease data on an individual basis.