Synergism between sinusoidal-50 Hz magnetic field and formaldehyde in triggering carcinogenic effects in male Sprague-Dawley rats.

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.

A review and critique of U.S. EPA's risk assessments for asbestos.

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.

Administration of lower doses of radium-224 to ankylosing spondylitis patients results in no evidence of significant overall detriment.

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.

Insufficient Sun Exposure Has Become a Real Public Health Problem.

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.

Using median regression to obtain adjusted estimates of central tendency for skewed laboratory and epidemiologic data.

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 risk assessment: a review and commentary.

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.

Nuclear epidemiologic studies and the estimation of DREF.

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 (q1 = 1.14) and the Mayak worker cohort (q3 = 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.

Sun Exposure Public Health Directives.

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.

Commercial tanning salons and melanoma risk.

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.

Cardiovascular effects of fission neutron or 60Co γ exposure in the B6CF1 mouse.

In this study, the B6CF1 mice from the JANUS program at the Argonne National Laboratory were analyzed for increased cardiovascular disease (CVD) mortality from 60Co 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.

Application of cryopreserved human hepatocytes in trichloroethylene risk assessment: relative disposition of chloral hydrate to trichloroacetate and trichloroethanol.

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 Vmax 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 Vmax 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.

Ionizing radiation and cardiovascular disease.

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.

The role of dose rate in radiation cancer risk: evaluating the effect of dose rate at the molecular, cellular and tissue levels using key events in critical pathways following exposure to low LET radiation.

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 ).

The risks and benefits of sun exposure 2016.

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.

Life-span exposure to sinusoidal-50 Hz magnetic field and acute low-dose γ radiation induce carcinogenic effects in Sprague-Dawley rats.

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.

Comments on the DDREF estimate of the BEIR VII Committee.

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.

Corrections in the atomic bomb data to examine low dose risk.

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.

Relative toxicity of (45)Ca beta-particles and (242)Cm alpha-particles following their intravenous injection into mice as radiolabelled FAP.

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.

Review and evaluation of updated research on the health effects associated with low-dose ionising radiation.

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.