Radionuclides in cigarettes may lead to carcinogenesis via p16 inactivation

It is widely accepted that tobacco smoke is responsible for the vast majority of lung cancers worldwide. There are many known and suspected carcinogens present in cigarette smoke, including α-emitting radioisotopes. Epidemiologic studies have shown that increased lung cancer risk is associated with exposure to ionizing radiation, and it is estimated that the majority of smoking-induced lung cancers may be at least partly attributable to the inhaled and deposited radiation dose from radioisotopes in the cigarette smoke itself. Recent research shows that silencing of the tumor suppressor gene p16^INK4a (p16) by promoter methylation plays a role in smoking-related lung cancer. Inactivation of p16 has also been associated with lung cancer incidence in radiation-exposed workers, suggesting that radionuclides in cigarette smoke may be acting with other compounds to cause smoking-induced lung cancer. We evaluated the mechanism of ionizing radiation as an accepted cause of lung cancer in terms of its dose from tobacco smoke and silencing of p16. Because both radiation and cigarette smoking are associated with inactivation of p16, and p16 inactivation has been shown to play a major role in carcinogenesis, ionizing radiation from cigarette smoke likely plays a role in lung cancer risk. How large a role it plays, relative to chemical carcinogens and other modes of action, remains to be elucidated.     

Determination of causes of death in animal survival experiments

Life-span studies, using the laboratory mouse, are an efficient means for determining potential chronic toxicity of various materials. However, difficulties that affect the analysis of the data include (1) incomplete and missing observations due to canabilism or autolysis, (b) possible differences in overall mortality rate between treated and control populations that preclude assessments based upon observed final incidence, and (c) potential interaction between specific pathological states. Being aware of these difficulties does not eliminate their consequence, but careful attention to ascertaining the presence or absence of a disease state coupled with an assessment of its significance for each individual can allow greater confidence to be placed in data obtained from survival studies. The question of possible interaction between disease states is better approached experimentally by judicious use of serial killing to define age-specific disease prevalence.Many diseases are difficult to identify in animals as small as the mouse. At the other extreme, too much importance may be attributed to some disease states, not because of their lethality, but because of their ease of detection. One way to minimize the uncertainties introduced by conscious and unconscious observational bias is to adhere to a highly systematic tissue examination of every animal, regardless of condition of apparent cause of death. Through application of well-defined and stable diagnostic criteria a better appreciation can be obtained of the full spectrum of lethal and incidental pathologies observed in animals dying throughout the survival study.     

Stochastic mortality theory and the mortality potential: A biophysical model for certain competing risks

The theory of competing risks cannot be based entirely on the analysis of postmortem pathology data. It is necessary also to know the prevalence and residence times of the diseases in question, separately and jointly, in the living population at risk. It is also necessary to have a conceptual model of the transition process from health to disease, or from one disease state to another, within the organism, so that the formal transition probabilities estimated from epidemiological data can be interpreted in biophysical terms as arising from changes in the physico-chemical state of the organism. This paper offers such a model for transition processes arising from fluctuations of physiological state (for example, lapse into diabetic coma or insulin shock as a result of extreme high or low excursions of the blood sugar level). A Gaussian fluctuation process is postulated, and the transition probability, or incidence rate, is calculated as the frequency with which the state variable fluctuates beyond a specified distance, Λ, from the mean state. An explicit solution is given for the limiting, but biologically reasonable, case that such an excursion is a rare event. In this case, the transition probability varies exponentially for linear displacement of Λ or of the dispersion of fluctuations, σ. If Λ decreases, and/or σ increases, as a linear function of age, this model yields an exponential (Gompertzian) relation of disease incidence to age. Generalization to more than one variable is accomplished by introducing the concept of a mortality potential surface, in which the disease transitions are geometrized as saddle points, or “passes”, on the surface.     

Mutagenic and carcinogenic potency of extracts of diesel and related environmental emissions: Two-stage carcinogenesis in skin tumor sensitive mice (SENCAR)

Skin tumors can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase), followed by repetitive treatment with a noncarcinogenic tumor promoter. There is a very good dose-response relationship between the induction of the number of papillomas per mouse at early times (10 to 20 weeks) by either tumor initiators and promoters and the final carcinoma incidence after a longer latency (20 to 50 weeks) in SENCAR mice. This system not only can be used to determine the tumor initiating and promoting activities of a compound but if the agent is given repeatedly by itself one can also determine if it is a complete carcinogen, i.e., if it has both tumor initiating and promoting activity. In addition, if the agent is given concurrently with a known complete carcinogen or a tumor initiator one can also determine if the agent has cocarcinogenic or cotumor initiating activity or even possibly anticarcinogenic activity. Likewise, if the agent is given concurrently with a known tumor promoter one can determine if the agent has copromoting or antipromoting activity. Using the SENCAR skin carcinogenesis system we have undertaken the determination of the skin carcinogenic, cocarcinogenic, tumor initiating and promoting activities of various diesel emission particle extracts as well as for comparative purposes, standards such as benzo(a)pyrene and 12-0-tetradecanoylphorbol-13-acetate and extracts of emissions from a gasoline engine, roofing tar, coke oven and cigarette smoke condensate. Most of the studies are still in progress but some preliminary data is available on the comparative tumor initiating activities of the various samples at 14 weeks. Caterpillar diesel and cigarette smoke condensate were essentially without activity, whereas the Mustang gasoline catalyst and Olds diesel gave extremely low values although they were slightly above background. Roofing tar, coke oven and Nissan Diesel all gave moderate activity at high doses (1 to 10 mg) but when compared to benzo(a)pyrene were relatively low values.     

Trends in lung cancer in London in relation to exposure to diesel fumes

Mortality from lung cancer among males in England and Wales is now beginning to decline, and the urban excess that has persisted for many years is also becoming smaller. There is nothing in these national trends to suggest that pollution from diesel vehicles, which has been increasing in recent decades, would be involved. Some preliminary results are presented from a long-term study of the incidence of lung cancer among London Transport staff, including men who work in bus garages where there are high concentrations of smoke from diesel buses. Over the 25 year period from 1950–1974 the numbers of cases reported in each of the several job categories have been below those expected on the basis of Greater London rates. The absence of data on smoking habits makes it difficult to determine whether the small differences in rates between job categories are of any importance, but the standardised mortality ratios are all well within the range of those found in national studies of lung cancer mortality and smoking in relation to occupation.     

Housing interventions and health: Quantifying the impact of indoor particles on mortality and morbidity with disease recovery

Housing interventions for energy efficiency and greenhouse gas emission reduction have the potential to reduce exposure to indoor air pollution if they are implemented correctly. This work assessed the health impacts of home energy efficiency measures in England and Wales resulting in a reduction in average indoor PM_2.5 exposures of 3 μg m^− 3. The assessment was performed using a new multistate life table model which allows transition into and between multiple morbid states, including recovery to disease-free status and relapse, with transition rates informed by age- and cause-specific disease prevalence, incidence and mortality data. Such models have not previously included disease recovery. The results demonstrate that incorporation of recovery in the model is necessary for conditions such as asthma which have high incidence in early life but likelihood of recovery in adulthood. The impact assessment of the home energy efficiency intervention showed that the reduction in PM_2.5 exposure would be associated with substantial benefits for mortality and morbidity from asthma, coronary heart disease and lung cancer. The overall impact would be an increase in life expectancy of two to three months and approximately 13 million QALYs gained over the 90 year follow-up period. Substantial quality-of-life benefits were also observed, with a decrease in asthma over all age groups and larger benefits due to reduced coronary heart disease and lung cancer, particularly in older age groups. The multistate model with recovery provides important additional information for assessing the impact on health of environmental policies and interventions compared with mortality-only life tables, allowing more realistic representation of diseases with substantial non-mortality burdens.     

The impact of warming on the appearance of furunculosis in fish of the James Bay region,Quebec, Canada

A regional climate change impact assessment was conducted which investigated the timing of the first appearance of furunculosis caused by the bacterium, Aeromonas salmonicida, in fish of the Ouje-Bougoumou region of northern Quebec, Canada. Historical data were used to assess whether there was a temporal relationship between increased temperatures (observed climate data) and the appearance of furunculosis (traditional environmental knowledge was used to provide context). To project future impacts of climate change, climate models and lake models were used. Regression analysis revealed a significant, positive temporal trend in mean air temperature. The temperature range conducive to A. salmoncida survival coincided with the first appearance of furunculosis. In addition, it is predicted that lake temperatures will remain suitable for the presence of A. salmonicida into the future; it is likely that the disease will persist throughout the twenty-first century. Climate change appears to be a factor explaining the onset of furunculosis; however, other factors/stressors cannot be discounted, such as, the effects past mining activities near the lakes of the Ouje-Bougoumou region have had on the body burden of contaminants in the fish (and the potential effects on the fish immune system).     

Terrestrial isopods congregate under a low-level beta-emitter source

Ionizing radiation is ubiquitous, but very few experiments have investigated the biological effects of the natural background radiation at very low doses (>10 mGy/yr). We examined whether the background radiation, or radiation of a slightly higher level, has a role in evoking changes in behaviors of terrestrial isopods (woodlice). Upon exposure to a source giving 15 times the background level placed at one end of a box, a significant increase in the number of woodlice gathering under the beta-source was observed with time, as compared with the sham control. Terrestrial isopods have chemoreceptors (the olfactory system) on the terminal segment of their antennae. An additional experiment confirmed the involvement of these antennae in the radiation effect on behavior. After the excision of the antennae, no beta-taxis response was observed. The behavior of the group exposed to the source giving 30 times the background tended to decrease gradually in the area of the source, and the individuals aggregated in the area away from the source. Thus, the olfactory sensor in the antennae may be an important organ involved in the prompt response to radiation exposure, and the discrimination of the radiation field strengths of radioisotopes.     

The additivity of multiple doses of a liver carcinogen in rats

The temporal pattern and dose-rate dependence of liver cancer in rats fed 2-fluorenylacetamide (2-FAA) was compared to analytical formulas derived from a specific model. The model was based on the idea that carcinogens have two distinct actions on cells: (1) transformation and (2) acceleration of progression. Transformed cells are by definition progressing toward cancer, but their rate of progression may depend on several factors, specifically, the amount of carcinogen. In the experiments the carcinogen was removed from the diet after various times and the rate of tumor progression was estimated from the time of tumor occurrence. The results were consistent with the idea that 2-FAA accelerated the progression of the cancers. The model provides a simple explanation of Druckrey's law in that the temporal occurrence of tumors induced by a carcinogen represents the acceleration of a naturally occurring disease progression.     

Detecting environmental impacts on metapopulations of mound spring invertebrates: assessing an incidence function model.

We use a stochastic patch occupancy model of invertebrates in the Mound Springs ecosystem of South Australia to assess the ability of incidence function models to detect environmental impacts on metapopulations. We assume that the probability of colonisation decreases with increasing isolation and the probability of extinction is constant across spring vents. We run the models to quasi-equilibrium, and then impose an impact by increasing the local extinction probability. We sample the output at various times pre- and postimpact, and examine the probability of detecting a significant change in population parameters. The incidence function model approach turns out to have little power to detect environmental impacts on metapopulations with small numbers of patches.     

Brain cancer associated with environmental lead exposure: Evidence from implementation of a National Petrol-Lead Phase-Out Program (PLPOP) in Taiwan between 1979 and 2007

Background and objectiveIn 1981, a Petrol-Lead Phase-Out Program (PLPOP) was launched in Taiwan for the abatement of environmental lead emissions. The present study was intended to examine whether the high Petrol-Lead Emission Areas (PLEA) would result in an increase in the incidence rate of brain cancer based on a national data bank.MethodsThe national brain cancer incidence data was obtained from the Taiwan National Cancer Registry. Age standardized incidence rates were calculated based on the 2000 WHO world standard population, and gasoline consumption data was obtained from the Bureau of Energy. The differences in the trend tests for age-standardized incidence rates of brain cancer between high, median, low, and small PLEA were analyzed.ResultsA significant increase was found from small to high PLEA in age-standardized incidence rates of brain cancer. By taking six possible confounders into account, the age-standardized incidence rates for brain cancer were highly correlated with the median and high PLEA by reference to the small PLEA.ConclusionAfter being adjusted for a number of relevant confounders, it could be concluded that high PLEA might result in an increase in the incidence rate of brain cancer resulting from high lead exposures.     

Soil radioactivity and incidence of cancer in Nigeria

The significance of exposure from natural radioactivity in soil and the potential risk for causing health detriment have not received adequate attention in Nigeria. Cancer has become a major cause of mortality in the recent times and now the public interest in the long-term effects of radiation on humans has assumed great prominence following the establishment of a nuclear regulatory body in Nigeria. This study is an effort to investigate a possible relationship between reported cancer incidence and external terrestrial radiation dose level across the six geo-political zones of the country. Data from the national cancer registries across the zones were compared with expected cancer incidences due to soil radioactivity based on the linear no-threshold model (LNT). A regression equation that best describe the reported cancer incidence and the expected cancer incidence was developed. It was observed that cancer cases attributable to radiation exposure due to soil radioactivity is low, constituting only between 1.3% and 9.2% of the total reported cases.     

Carcinogenicity of diesel exhaust as tested in strain a mice

Groups of strain A mice were exposed to diesel exhaust by inhalation and diesel particulate by intraperitoneal injection. The animals were exposed from seven to eight weeks and then sacrificed 26–30 weeks postexposure. Other animals were exposed for up to seven months by the inhalation route. Some animals were promoted using urethane at a dose below which tumors would occur. There was no increase in incidence of pulmonary adenomas in the animals exposed to either diesel exhaust or diesel particulate over the control animals. In the animals which were promoted using urethane at a low dose, there was a significant increase in pulmonary adenomas. Diesel particulate was found in the lungs and bronchial lymph nodes of animals exposed to diesel exhaust 26–30 weeks after cessation of exposure.     

Radiation effects in wild terrestrial vertebrates - the EPIC collection

The paper presents data on radiation effects in populations of wild vertebrate animals inhabiting contaminated terrestrial ecosystems. The data were extracted from the database "Radiation effects on biota", compiled within the framework of the EC Project EPIC (2000-2003). The data collection, based on publications in Russian, demonstrates radiation effects in the areas characterized with high levels of radionuclides (Kyshtym radioactive trace; "spots" of enhanced natural radioactivity in the Komi region of Russia; territories contaminated from the Chernobyl fallout). The data covers a wide range of exposures from acute accidental irradiation to lifetime exposures at relatively low dose rates. Radiation effects include mortality, changes in reproduction, decrease of health, ecological effects, cytogenetic effects, adaptation to radiation, and others. Peculiarities of radiation effects caused by different radionuclides are described, also the severity of effects as they appear in different organisms (e.g. mice, frogs, birds, etc.).     

Indoor air exposure to coal and wood combustion emissions associated with a high lung cancer rate in Xuan Wei, China

Residents of Xuan Wei County in China have unusually high lung cancer mortality that cannot be attributed to tobacco use or occupational exposure. They are exposed to smoke from unvented, open pit coal or wood fires (often used for cooking and heating). The variation in lung cancer rates among communes within the county suggests that indoor combustion of smoky coal may be the prime determinant of lung cancer. To characterize the air in Xuan Wei homes, samples of air particles and semivolatile organic compounds were collected from homes located in two communes; one commune has a high rate of lung cancer, and the other has a low rate. Samples collected in the commune where the lung cancer rate is high and where smoky coal is the predominant fuel contained high concentrations of small particles with high organic content; organic extracts of these samples were mutagenic. Samples from homes in the wood-burning commune, which has a low rate of lung cancer, consisted mostly of larger particles of lower organic content and mutagenicity. The smoky coal sample was a mouse skin carcinogen and was a more potent initiator of skin tumors in comparison to the wood or smokeless coal sample.     

Genotoxicity of syrian hamster lung cells treated in vivo with diesel exhaust particulates

Polycyclic aromatic hydrocarbons extracted and concentrated from diesel exhaust particulates have been shown to be mutagenic and carcinogenic, but attempts to induce pulmonary tumors through chronic inhalation of diesel exhaust by experimental animals have failed. We have attempted to resolve this incongruity by measuring chromosomal damage in lung tissue of chronically exposed hamsters, using the highly sensitive test for genotoxic chemical agents, sister chromatid exchange (SCE) analysis. To determine the degree of responsiveness of the test system to both diesel exhaust particulates and benzo(a)pyrene (BaP), these agents were instilled intratracheally into anesthetized hamsters as suspensions in 0.25 ml volumes of Hank's balanced salt solution (HBSS). Lung tissues from these animals were subsequently cultured in vitro and chromosomes from the resulting cell divisions were scored for exchanges of chromatin between sister chromatids. Control animals, treated weekly with 0.25 ml of BSS for 10 weeks, showed an average value of 12 SCE's per cell, while animals treated weekly with 200 ng BaP over a 10-week period showed an average of 17 SCE's per cell. HBSS, given as a single treatment, also produced an average of 12 SCE's per cell in control animals, but animals treated with a single instillation of 12.5 μg BaP showed an average SCE value of 19. These data confirmed that the procarcinogen BaP can be metabolically activated by lung cells in vivo and also demonstrated the efficacy of using this technical approach to study the effect of chemical mutagens that enter the lungs. Diesel exhaust particulates, administered in a range from 0 to 20 mg per hamster over a 24 h exposure period, produced a linear SCE dose-response ranging from 12 to 26 SCE's per metaphase. This curve suggested that a concentration of 3 mg of diesel particulates per hamster would not produce a statistically significant increase in SCE's above control values. One group of 8 hamsters, chronically exposed to diesel exhaust particulates for 3 months showed an average of 12 SCE's per cell. This was equivalent to a set of 5 control animals which also showed an average of 12 SCE's per cell. Although the scope of this study was limited, the data demonstrated that diesel exhaust particulates can induce genotoxic damage but a 3-month exposure to 6 mg/m³ of diesel exhaust particulates was insufficient to produce measurable mutagenic changes in lung cells. This negative response is consistent with the results from other studies in which similar exposures failed to produce pulmonary tumors.     

南水北调中线工程水源区蒸散发计算方法比较及影响因素分析

以南水北调中线工程水源区为研究区域,采用1961~2007年9个气象站点气象观测数据和黄家港水文站实测径流资料,以FAO彭曼蒙特斯公式和水文模拟法为标准分别对多种潜在蒸散发计算方法和实际蒸散发计算方法进行比较研究,并分析了陆面蒸散发的影响因素。研究表明：南水北调中线工程水源区存在“蒸发悖论”现象,Priestley Taylor公式计算结果偏大,但与FAO 彭曼蒙特斯公式存在良好的相关关系,在气象资料较少时可以考虑建立相关方程进行推求。傅抱璞公式与水文模拟法计算结果较为接近,相关关系最优。潜在蒸散发与平均温度、气温日较差、实际水汽压、降雨量、风速、净太阳辐射、日照时数呈正相关,而实际蒸散发与平均温度、气温日较差、实际水汽压、降雨量、净太阳辐射、日照时数呈正相关,与风速呈负相关。净太阳辐射是影响陆面蒸散发的核心因素     

Long-term investigation of anthropogenic and naturally occurring radionuclides at reference sites in western Sweden

In case of an accidental release of radioactive substances into the environment, it is important to quickly and reliably estimate the radiation dose received by people in the affected area, and to determine the extent of the contamination. Measurements of the extent of the release and the subsequent contamination can be facilitated if there are predetermined reference sampling sites with known background radiation and inventory of radionuclides. Since 1996, 34 reference sites for soil sampling, field gamma, and intensimeter measurements have been established in western Sweden. Time series data for dose rates and radioisotope inventory have been collected at these sites, allowing for the investigation of changes in these parameters over time. The mass activity densities for the uranium and thorium series elements varied approximately between 10 and 50 Bq/kg and between 10 and 40 Bq/kg, respectively. The mass activity density of ⁴⁰K was approximately in the range 300–800 Bq/kg. The radiation exposure due to ¹³⁷Cs was rather small in this area. The dose rates calculated from in situ measurement data showed that the contribution to the total dose rate was almost entirely due to naturally occurring radionuclides. The measured dose rate was about twice as high as the calculated rate, even after subtracting the contribution from cosmic radiation. This may be explained by the fact that intensimeters generally are calibrated to measure the quantity ambient dose equivalent, which should not underestimate the effective dose.     

Preliminary indoor radon risk assessment at the Poços de Caldas Plateau,MG-Brazil

This paper aims to present an assessment of the environmental radiological exposure at a Brazilian area of high natural radiation and discusses the indoor radon exposure risk. A survey of inhabitant exposures arising from the inhalation of radon progeny and external gamma exposure was conducted in urban and rural areas of the Po?os de Caldas Plateau, which is recognized worldwide as a high natural radiation region. The results of this survey indicated that highest radiation exposure was restricted to the rural area of Po?os de Caldas. The radiation exposure in urban locations was quite similar to the values observed in normal background areas in some Brazilian counties. By the application of a constant relative risk model, an additional 20% in the lifetime risk of lung cancer mortality due to the exposure to radon progeny was estimated at Po?os de Caldas. It was also estimated that 16% of all lung cancer deaths at Po?os de Caldas county could be attributable to radon exposure.     

Benzo[a]pyrene metabolism in mice exposed to diesel exhaust: I. Uptake and distribution

In this study we examined the effect of diesel exhaust (DE) exposure on the disposition of a typical polycyclic aromatic hydrocarbon. DE-exposed and nonexposed A/Jax mice were divided into three groups and each mouse instilled intratracheally with benzo[a]pyrene (BaP). One group (A) received ¹⁴C-BaP, and at intervals of 2, 24, and 168 h, three mice from the group were killed and quick frozen for whole body autoradiography. Sagittal sections were cut at 0.5 mm intervals and autoradiograms prepared. Adjacent sections were studied so that radioactive areas were matched to specific organs. The second group (B) received ³H-BaP and at 2, 24, and 168 h these mice were killed. Livers, lungs, and testes were weighed and frozen. From these tissues metabolites were analyzed; these data are reported in the next paper. Histofluorescent examination of tissues from mice instilled with nonradioactive BaP (group C) confirmed that BaP was present in the lung. The autoradiography data are the basis for elucidating the BaP distribution in the mouse. Within 2 h after instillation radioactivity was detected in the entire animal, with most in lungs, liver, and GI tract. By 24 h after instillation considerable radioactivity had redistributed to the GI tract. At 168 h after instillation only a trace of label was found in the GI mucosa.