Characterizing occupational radon exposure greater than 100 Bq/m3 in a highly exposed country.

Radon is an established lung carcinogen concentrating in indoor environments with importance for many workers worldwide. However, a systematic assessment of radon levels faced by all workers, not just those with direct uranium or radon exposure, has not previously been completed. The objective of this study was to estimate the prevalence of workers exposed to radon, and the level of exposure (> 100-200 Bq/m3, 200-400 Bq/m3, 400-800 Bq/m3, and > 800 Bq/m3) in a highly exposed country (Canada). Exposures among underground workers were assessed using the CAREX Canada approach. Radon concentrations in indoor workplaces, obtained from two Canadian surveys, were modelled using lognormal distributions. Distributions were then applied to the susceptible indoor worker population to yield the number of exposed workers, by occupation, industry, province, and sex. In total, an estimated 603,000 out of Canada's 18,268,120 workers are exposed to radon in Canada. An estimated52% of exposed workers are women, even though they comprise only 48% of the labour force. The majority (68%) are exposed at a level of > 100-200 Bq/m3. Workers are primarily exposed in educational services, professional, scientific and technical services, and health care and social assistance, but workers in mining, quarrying, and oil and gas extraction have the largest number of exposed workers at high levels (> 800 Bq/m3). Overall, a significant number of workers are exposed to radon, many of whom are not adequately protected by existing guidelines. Radon surveys across multiple industries and occupations are needed to better characterize occupational exposure. These results can be used to identify exposed workers, and to support lung cancer prevention programs within these groups.

Estimating the burden of lung cancer in Canada attributed to occupational radon exposure using a novel exposure assessment method.

OBJECTIVE: Exposure to radon causes lung cancer. The scope and impact of exposure among Canadian workers have not been assessed. Our study estimated occupational radon exposure in Canada and its associated lung cancer burden. METHODS: Exposed workers were identified among the working population during the risk exposure period (1961-2001) using data from the Canadian Census and Labour Force Survey. Exposure levels were assigned based on 12,865 workplace radon measurements for indoor workers and assumed to be 1800 mg/m3 for underground workers. Lung cancer risks were calculated using the Biological Effects of Ionizing Radiation (BEIR) VI exposure-age-concentration model. Population attributable fractions were calculated with Levin's equation and applied to 2011 Canadian lung cancer statistics. RESULTS: Approximately 15.5 million Canadian workers were exposed to radon during the risk exposure period. 79% of exposed workers were exposed to radon levels < 50 Bq/m3 and 4.8% were exposed to levels > 150 Bq/m3. We estimated that 0.8% of lung cancers in Canada were attributable to occupational radon exposure, corresponding to approximately 188 incident lung cancers in 2011. CONCLUSIONS: The lung cancer burden associated with occupational radon exposure in Canada is small, with the greatest burden occurring among those exposed to low levels of radon.

Early changes in respiratory health in trades' apprentices and physician visits for respiratory illnesses later in life.

OBJECTIVES: An inception cohort of trades' apprentices had rapid declines in lung function (forced expiratory volume in 1 s (FEV(1))) and rapid increases in bronchial responsiveness ( upward arrowBR) over the first 2 years of employment. We used physician visit data to assess respiratory health over the following 13 years. METHODS: Construction painter, electrician, insulator and machinist apprentices beginning at a British Columbia trade school in 1988 were invited to participate and were followed up 2 years later. Subjects were linked to provincial medical databases to examine physician visits for asthma and other respiratory illnesses for the 13 years following. Multivariable models with rapid decline in FEV(1) and rapid increase in BR from years 1 to 3 were constructed. Respiratory symptoms were also examined as predictors of visit rates and meeting a case definition (for asthma or other respiratory illness). RESULTS: The cohort included 281 apprentices (97% are men). Sixteen subjects met the asthma case definition (>or=2 visits coded as asthma in 1 year) and 20 met the other respiratory illness case definition (>or=3 visits for bronchitis, emphysema, respiratory symptoms in 1 year). In models controlling for demographic factors and smoking, subjects with bronchitis symptoms at baseline were more likely to develop other respiratory illness during follow-up (RR 4.4, 95% CI 1.6 to 11.9). Apprentices who developed asthma symptoms over the first 2 years were approximately six times more likely to become asthma cases (95% CI 1.9 to 18.8). Those with a rapid increase in BR were at increased risk of becoming asthma cases (RR 5.5, 95% CI 1.9 to 16.1), as well as having higher asthma visit rates (RR 6.5). Subjects with rapid decline in FEV(1) were 3.2 times more likely to become asthma cases (95% CI 0.8 to 12.1). CONCLUSIONS: Changes in respiratory health early in adulthood, especially increased BR, are associated with respiratory physician visits. These findings are important for workplace screening and prevention and also suggest that physician visit databases are promising research tools in respiratory epidemiology.

Anesthetic concentrations of propofol protect against oxidative stress in primary astrocyte cultures: comparison with hypothermia.

BACKGROUND: The extracellular concentration of glutamate in the brain increases after oxidative damage. This increase may be caused, in part, by changes in glutamate transport by astrocytes. The authors hypothesized that propofol and hypothermia mitigate the effects on astrocytes of oxidative stress. METHODS: Primary cultures of rat cerebral astrocytes were subjected to oxidative stress by incubation with tert-butyl hydroperoxide for 30 min, followed by a 30-90-min washout period. The effects of prophylactic (simultaneous with tert-butyl hydroperoxide application) and delayed (administered 30 min after the oxidant) propofol or hypothermia were determined by measuring the uptake of glutamate as well as the release of preloaded d-aspartate (a nonmetabolizable analog of glutamate) and endogenous lactate dehydrogenase (a cytosolic marker). RESULTS: Delayed administration of an anesthetic concentration of propofol (1-3 microm) prevented the inhibition of high-affinity glutamate uptake, stimulation of d-aspartate release, and increase in lactate dehydrogenase release caused by tert-butyl hydroperoxide (1 mm, 37 degrees C). The protective effect of propofol (EC50 = 2 microm) on glutamate uptake was 20-fold more potent than that of alpha-tocopherol (EC50 = 40 microm). Prophylactic hypothermia (28 and 33 degrees C) also protected astrocytes from tert-butyl hydroperoxide. Delayed hypothermia was not protective but did not compromise rescue by propofol. CONCLUSIONS: Clinical levels of propofol and hypothermia mitigate the effects of oxidative stress on astrocytic uptake and retention of glutamate, with propofol having a relatively larger therapeutic window. The ability of these treatments to normalize cell transport systems may attenuate the pathologic increase in extracellular glutamate at synapses and thus prevent excitotoxic neuronal death.

Glutamate stimulates ascorbate transport by astrocytes.

The concentrations of glutamate and ascorbate in brain extracellular fluid increase following seizure activity, trauma and ischemia. Extracellular ascorbate concentration also rises following intracerebral glutamate injection. We hypothesized that glutamate triggers the release of ascorbate from astrocytes. We observed in primary cultures of rat cerebral astrocytes that glutamate increased ascorbate efflux significantly within 30 min. The half-maximal effective concentration of glutamate was 180+/-30 microM. Glutamate-stimulated efflux of ascorbate was attenuated by hypertonic media. 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid inhibited both Na(+)-dependent glutamate uptake and ascorbate efflux. Two other inhibitors of volume-sensitive organic anion channels (1, 9-dideoxyforskolin and 5-nitro-2-(3-phenylpropylamino) benzoic acid) did not slow glutamate uptake but prevented stimulation of ascorbate efflux. Glutamate also stimulated the uptake of ascorbate by ascorbate-depleted astrocytes. In contrast, glutamate uptake was not affected by intracellular ascorbate, thus ruling out a putative glutamate-ascorbate heteroexchange mechanism. These results are consistent with activation by glutamate of ascorbate-permeant channels in astrocytes.

Estrogen replacement in ovariectomized rats results in physiologically significant levels of circulating progesterone, and co-administration of progesterone markedly reduces the circulating estrogen.

Estrogen and progesterone replacement in ovariectomized rats in an often-used experimental system for determination of the specific effects of these hormones. In this study, two different delivery systems and two different dosage levels of estrogen, progesterone or a combination of the two have been used. Estrogen and progesterone in the circulation have been measured in response to each treatment. It is reported that estrogen treatment (237.2 +/- 49.2 pg/mL) results in physiologically significant levels of circulating progesterone (11.1 +/- 1.3 ng/mL). Also, co-administration of progesterone (23.7 +/- 2.0 ng/mL) with estrogen decreases the level of estrogen over that seen with estrogen alone (96.7 +/- 19.2 pg/mL with progesterone vs 237.2 +/- 49.2 pg/mL without progesterone). Thus, contrary to expectations, estrogen replacement therapy is not specific to estrogen and some of the antagonistic effects of progesterone are the result of a decrease in circulating estrogen, and not a specific effect on a target tissue. Whereas the mechanism of these effects has not been determined, obvious artifactitous phenomena have been excluded as being their cause. These results could have a major impact on the interpretation of past and future experiments of this kind.

Nicotinamide reduces tumour interstitial fluid pressure in a dose- and time-dependent manner.

Nicotinamide radiosensitizes a number of experimental tumours, and increases blood flow and mean pO2 in some tumours. It has been suggested that nicotinamide reduces tumour interstitial fluid pressure (IFP), thereby reducing transient vessel non-perfusion and acute hypoxia, and radiosensitizing tumours. To test this hypothesis, tumour IFP, transient vessel non-perfusion, and radiosensitivity after nicotinamide administration were examined in the murine carcinoma NT. Nicotinamide at doses of 500 and 1000 mg kg-1 significantly reduced tumour IFP within 20 min of administration, with recovery to control values by 60-80 min; 100 mg kg-1 had no effect. The percentage of previously non-perfused vessels that became perfused 20 min after administering 1000 mg kg-1 of nicotinamide significantly exceeded the percentage that became perfused within 20 min in the absence of nicotinamide. By 90 min after nicotinamide administration, this differential effect was abolished. The correlation in the time courses of reduced IFP and increased vessel perfusion after nicotinamide administration suggest that decreased IFP may accompany vessel reperfusion. However, 1000 mg kg-1 of nicotinamide radiosensitized the NT carcinoma 80 min after administration, whilst no radiosensitization was seen within 10 min. Thus it is unlikely that increased vessel perfusion is the sole mechanism of nicotinamide-induced radiosensitization in this tumour.

Effects of estrogen on thermoregulatory evaporation in rats exposed to heat.

The purpose of this study was to determine the effects of estrogen (E2) replacement on thermoregulation in ovariectomized rats exposed to heat. Female Sprague-Dawley rats were ovariectomized and splenectomized and implanted with a temperature-sensitive transmitter. Each rat was studied when E2 treated (after an E2 pellet implant) and untreated. Animals were divided into two groups with opposite order of treatment and were studied over a 9-wk period. Measurements of body core temperature (Tc) and evaporative water loss (EWL) were made on unrestrained animals resting at 38 degrees C air temperature. E2-treated animals increased EWL at all levels of Tc, reduced the threshold Tc for onset of saliva spreading, and regulated Tc at a lower level during heat exposure. E2 treatment elevated plasma E2 and reduced hematocrit but did not affect plasma osmolality. These effects of E2 on evaporative cooling and Tc in heat-stressed rats are similar to those that have been reported in human females. The mechanisms of the thermoregulatory effects of E2 remain to be studied.

Blood flow modification in the SCCVII tumor: effects of 5-hydroxytryptamine, hydralazine, and propranolol.

The effects of hydralazine, 5-hydroxytryptamine (5-HT), and propranolol on blood flow in the SCCVII tumor were assessed using laser Doppler flowmetry. Both hydralazine and 5-HT, at doses of 1 and 5 mg/kg, reduced blood flow, as did propranolol at 10 mg/kg. Hydralazine and 5-HT at doses of 0.25 mg/kg slightly increased tumor blood flow, and a 10-20% increase in blood flow was also observed after 1 mg/kg of propranolol. However, propranolol at 1 mg/kg enhanced the blood flow reduction observed with 1 mg/kg of hydralazine. The concomitant administration of hydralazine and propranolol at these doses also translated into increased potentiation of the tumor cytotoxicity of the hypoxic cell cytotoxin RSU-1069.

Drug induced perturbations in tumor blood flow: therapeutic potential and possible limitations.

Chemical modulation of tumor blood flow has until recently received relatively little attention as a therapeutic tool. Developments in the last few years, both in technology and in drug development, have changed this perspective. Fluorescence activated cell sorting techniques have provided evidence for the existence of acutely hypoxic cells resulting from transient fluctuations in microregional tumor blood flow in experimental tumor systems. We have used such techniques to assess the effects of three systemically administered agents, nicotinamide, flunarazine and Flusol-DA, on the amount of acute hypoxia in the SCCVII tumor. The most effective agent identified in this study is the benzamide analog nicotinamide. We suggest that compounds which modulate such hypoxia could well have a role in radiation therapy, particularly when combined with techniques which increase the oxygen carrying capacity of the blood. The potential of tumor blood flow reduction to improve the effectiveness of bioreductive agents administered alone or in combination with radiation and/or hyperthermia, is well established in experimental systems. Further data are presented, which show that combining hydralazine and the beta-blocker propranolol can provide greater reduction in tumor blood flow than observed with hydralazine alone. Potential limitations of drug induced reduction in tumor blood flow are discussed including the possibility of inducing hypoxia in normal tissues.

Disruption of pattern formation in palatal rugae in fetal mice heterozygous for First arch (Far).

The purpose of this study was to document the extent of disruption in the pattern of palatal rugae caused by the presence of one copy of the First arch mutation. The palatal ruga pattern was found to be disrupted in 86% of 15- to 17-day mouse fetuses that were heterozygous for the First arch mutation in the ICR/Bc strain, compared with 9% in ICR/Bc fetuses of normal (+/+) genotype. This new observation in First arch heterozygotes, together with the previously reported dominant effects of the First arch mutation, particularly the bifurcation of the maxillary nerve (100% in both BALB/cGaBc and ICR/Bc strains), the disruption of maxillary vibrissa pattern (80% in ICR/Bc), and the hemifacial deficiency (38% in ICR/Bc), has led us to redefine the First arch mutation as a semidominant, Far. Like the other defects caused by Far, the rugal defects are in tissue derived from the embryonic maxillary prominence. The rugal defects observed in +/Far palates were always asymmetrical and most often involved fragmentation and misalignment of two or more of rugae 4-7. The relatively large degree of variation in ruga pattern observed in fetuses of normal genotype suggests that it is a less well canalized trait than the normal pattern of maxillary vibrissae which varies only in a few very specific and minor ways. The First arch mutation, which in heterozygotes disrupts pattern formation in both palatal rugae and maxillary vibrissae, can be used to study genetic control of pattern formation in mammalian embryos.