Comparative assessing for radiological, chemical, and physical exposures at the French uranium conversion plant: Is uranium the only stressor?

This study presents the pattern of exposure to uranium and other occupational pollutants known to be potentially carcinogenic, mutagenic or toxic and used at the main uranium conversion plant in France. For different uranium compounds specified according to their solubility and purity, and 16 other categories of pollutants: chemicals, fibres, vapours, dust, and heat a time- and plant-specific job exposure matrix (JEM) was created covering the period 1960-2006. For 73 jobs and for each pollutant the amount and frequency of exposure were assessed on a four-level scale by different time periods. The JEM shows 73% sensitivity and 83% specificity. Although exposure assessment was semi-quantitative, the JEM allows computing of individual cumulative exposure score for each pollutant across time. Despite the predominant natural uranium compounds exposure, the amount of exposure to other pollutants such as TCE and other chlorinated products, asbestos, and fibres, is important at the plant. Numerous correlations detected between uranium compounds exposure and exposure to chemicals warrants improving biological monitoring of exposed workers and accounting for associated exposures in epidemiological studies. Results of this study will be used for further investigation of association between exposure and mortality among uranium conversion workers cohort.     

Enhancement of fotemustine (Muphoran) cytotoxicity by amifostine in malignant melanoma cell lines

Fotemustine (Muphoran, S10036), a nitrosourea derivative active in the treatment of malignant melanoma and primary brain tumors, was evaluated in combination with the free radicals cytoprotective agent amifostine (Ethyol, WR-2721) and its alkaline phosphatase (AP)-generated active metabolite WR-1065 in four human melanoma (RPMI-7950, SK-MEL2, SK-MEL5 and WM-115) and lung fibroblast (MRC-5) cell lines. No difference in AP activity was found among the melanoma cell lines, but AP was found to be significantly higher in MRC-5. For combination experiments, cell lines were first exposed to amifostine or WR-1065 for 15 min and then exposed to fotemustine for two cell doubling times. Non-cytotoxic amifostine and WR-1065 concentrations used (0.2 and 0.6 and 0.1 and 0.3 mmol/l, respectively) were deduced from clinically achieved plasma values. Interactions were analyzed from the variations in IC(50) of fotemustine induced by pre-exposure of the cells to amifostine or WR-1065. In all melanoma cell lines, amifostine enhanced the cytotoxic activity of fotemustine as a significant decrease in IC(50) was observed. No significant difference was found between synergistic effects achieved with amifostine and WR-1065 given at half concentrations. No differential effect was found in the MRC-5 cell line as compared with the melanoma cell lines. Expression variation of O(6)-methylguanine methyltransferase was not found to be implicated in the interaction. The present results demonstrating that amifostine or its main active metabolite do not impair the cytotoxicity of fotemustine justify an extensive clinical evaluation of this combination in metastatic melanoma.     

Effectiveness of incidence thresholds for detection and control of meningococcal meningitis epidemics in northern Togo

BACKGROUND: Early outbreak detection is necessary for control of meningococcal meningitis epidemics. A weekly incidence of 15 cases per 100 000 inhabitants averaged over 2 consecutive weeks is recommended by the World Health Organization (WHO) for detection of meningitis epidemics in Africa. This and other thresholds are tested for ability to predict outbreaks and timeliness for control measures. METHODS: Meningitis cases recorded for 1990-1997 in health centres of northern Togo were reviewed. Weekly and annual incidences were determined for each district. Ability of different weekly incidence thresholds to detect outbreaks was assessed according to sensitivity, specificity, and positive and negative predictive values. The number of cases potentially prevented by reactive vaccination in 1997 was calculated for each threshold. RESULTS: Outbreaks occurred in 1995-1996 and in 1996-1997. The WHO-recommended threshold had good specificity but low sensitivity. Thresholds of 10 and 7 cases per 100,000 inhabitants in one week had sensitivity and specificity of 100% and increased the time available for intervention by more than one or two weeks, respectively. A maximum of 65% of cases could have been prevented during the 1997 epidemic, with up to 8% fewer cases prevented for each week of delay in achieving vaccine coverage. CONCLUSIONS: In northern Togo, thresholds of 7 or 10 cases per 100,000 inhabitants per week were excellent predictors of meningitis epidemics and allowed more time for a reactive vaccination strategy than current recommendations.     

Enhancement of antineoplastic action of 5-aza-2'-deoxycytidine by zebularine on L1210 leukemia

Tumor suppressor genes that have been silenced by aberrant DNA methylation are potential targets for reactivation by novel chemotherapeutic agents. The potent inhibitor of DNA methylation and antileukemic agent, 5-aza-2'-deoxycytidine (5-AZA-CdR, Decitabine), can reactivate silent tumor suppressor genes. One hindrance to the curative potential of 5-AZA-CdR is its rapid in vivo inactivation by cytidine deaminase (CD). An approach to overcome this obstacle is to use 5-AZA-CdR in combination with zebularine (Zeb), a potent inhibitor of CD. Zeb also possesses independent antineoplastic activity due to its inhibition of DNA methylation. We tested the capacity of 5-AZA-CdR and Zeb alone and in combination to inhibit growth and colony formation of different leukemic cell lines. 5-AZA-CdR and Zeb in combination produced a greater inhibition of growth against murine L1210 lymphoid leukemic cells, and a greater reduction in colony formation by L1210 and human HL-60 myeloid leukemic cells, than either agent alone. The ability of these agents to reactivate the tumor suppressor gene, p57KIP2, was also tested using RT-PCR. The combination produced a synergistic reactivation of p57KIP2 in HL-60 leukemic cells. A methylation-specific PCR assay showed that this combination also induced a significantly greater demethylation level of the p57KIP2 promoter than either drug alone. The in vivo antineoplastic activity of the agents was evaluated in mice with L1210 leukemia. A greater increase in survival time of mice with L1210 leukemia was observed with the combination than with either agent alone using three different dose schedules. The enhanced activity observed with 5-AZA-CdR plus Zeb in both murine and human leukemic cells lines provides a rationale for the clinical investigation of these drugs in patients with advanced leukemia. The probable mechanism of this drug interaction involves inhibition of CD by Zeb and the complementary inhibition of DNA methylation by both agents.     

Polychlorinated Biphenyl Exposures and Cognition in Older U.S. Adults: NHANES (1999–2002)

Background: Polychlorinated biphenyls (PCBs) are ubiquitously present in humans because of their resistance to degradation and accumulation in fatty tissues. Data on neurotoxic effects in older adults are limited.Objective: We examined the cross-sectional association between serum PCB concentrations and cognitive function in older adults from the general U.S. population.Methods: We analyzed data from 708 respondents, 60–84 years of age, participating in the National Health and Nutrition Examination Survey (1999–2002). We used the summed concentrations of 12 lipid-standardized PCB congeners as the measure of exposure and assessed cognitive function with the Digit-Symbol Coding test. We adjusted analyses for age, education, race/ethnicity, and poverty/income ratio.Results: The median concentration of lipid-standardized PCBs in serum was 271 ng/g (interquartile range, 193–399 ng/g). We found a significant interaction between dioxin-like PCB concentration and age in association with cognitive score (p = 0.04). Among older individuals (70–84 years of age), a 100-ng/g increase in serum concentrations of dioxin-like PCBs was associated with a significantly lower cognitive score (–2.7 points; 95% CI: –5.1, –0.2; p = 0.04); however, in younger individuals (60–69 years of age), there was a nonsignificant positive association (2.9 points; 95% CI: –1.8, 7.7; p = 0.32). Among the older participants, the negative association was more pronounced in women than in men.Conclusion: Our findings support the hypothesis that PCB exposure has adverse cognitive effects even at levels generally considered to pose low or no risk, perhaps affecting mainly those of advanced age.Citation: Bouchard MF, Oulhote Y, Sagiv SK, Saint-Amour D, Weuve J. 2014. Polychlorinated biphenyl exposures and cognition in older U.S. adults: NHANES (1999–2002). Environ Health Perspect 122:73–78; http://dx.doi.org/10.1289/ehp.1306532     

Incorporation and distribution of uranium in rats after a contamination on intact or wounded skin

Uranium uptake can occur accidentally by inhalation, ingestion, injection, or absorption through intact or wounded skin. Intact or wounded skin routes of absorption of uranium have received little attention. The aims of our work were (1) to evaluate the influence of the type of wound contamination on the short term distribution and excretion of uranium in rats and (2) to generate data to assess the time available to treat contamination of intact or wounded skin before significant uptake of uranium occurs. Biokinetic data presented in the present paper are based on an in vivo rat model. This study shows that a significant uptake of a uranyl nitrate solution through intact skin can occur within the first 6 h of exposure. Absorption of a uranyl nitrate solution through excoriated skin is significant after only 30 min of exposure. After a 24-h exposure, uranium uptake through intact skin and excoriated skin represents about 0.4% and 38% of the initial deposit of uranium, respectively. Contaminated serious chemical skin burns induced by HNO3 or NaOH are paradoxically less important in terms of uranium uptake risk because 99% of the incorporated uranium remains trapped at the wound site and its incorporation is delayed for at least 6 h after the beginning of contamination. These results confirm that the biokinetics of a given physicochemical form of uranium incorporated after wound contamination depend largely on the physiological evolution of the considered wound. Each type of wound, with its corresponding biokinetics of a uranium species, is a particular case.     

Chronic contamination with 137Cesium affects Vitamin D3 metabolism in rats

Twenty years after Chernobyl disaster, many people are still chronically exposed to low dose of (137)Cs, mainly through the food consumption. A large variety of diseases have been described in highly exposed people with (137)Cs, which include bone disorders. The aim of this work was to investigate the biological effects of a chronic exposure to (137)Cs on Vitamin D(3) metabolism, a hormone essential in bone homeostasis. Rats were exposed to (137)Cs in their drinking water for 3 months at a dose of 6500 Bq/l (approximately 150 Bq/rat/day), a similar concentration ingested by the population living in contaminated territories in the former USSR countries. Cytochromes P450 enzymes involved in Vitamin D(3) metabolism, related nuclear receptors and Vitamin D(3) target genes were assessed by real time PCR in liver, kidney and brain. Vitamin D, PTH, calcium and phosphate levels were measured in plasma. An increase in the expression level of cyp2r1 (40%, p<0.05) was observed in the liver of (137)Cs-exposed rats. However a significant decrease of Vitamin D (1,25(OH)D(3)) plasma level (53%, p=0.02) was observed. In brain, cyp2r1 mRNA level was decreased by 20% (p<0.05), while the expression level of cyp27b1 is increased (35%, p<0.05) after (137)Cs contamination. In conclusion, this study showed for the first time that chronic exposure with post-accidental doses of (137)Cs affects Vitamin D(3) active form level and induces molecular modifications of CYPs enzymes involved its metabolism in liver and brain, without leading to mineral homeostasis disorders.     

Effects of depleted uranium after short-term exposure on vitamin D metabolism in rat

Uranium is a natural radioactive heavy metal. Its toxicity has been demonstrated for different organs, including bone, kidney, liver and brain. Effects of an acute contamination by depleted uranium (DU) were investigated in vivo on vitamin D₃ biosynthetic pathway. Rats received an intragastric administration of DU (204 mg/kg) and various parameters were studied either on day 1 or day 3 after contamination. Cytochrome P450 (CYP27A1, CYP2R1, CYP27B1, CYP24A1) enzymes involved in vitamin D metabolism and two vitamin D₃-target genes (ECaC1, CaBP-D9K) were assessed by real time RT-PCR in liver and kidneys. CYP27A1 activity was measured in liver and vitamin D and parathyroid hormone (PTH) level were measured in plasma. In acute treated-rats, vitamin D level was increased by 62% and decreased by 68% in plasma, respectively at day 1 and at day 3, which paralleled with a concomitant decrease of PTH level (90%) at day 3. In liver, cyp2r1 mRNA level was increased at day 3. Cyp27a1 activity decreased at day 1 and increased markedly at day 3. In kidney, cyp27b1 mRNA was increased at days 1 and 3 (11- and 4-fold respectively). Moreover, ecac1 and cabp-d9k mRNA levels were increased at day 1 and decreased at day 3. This work shows for the first time that DU acute contamination modulates both activity and expression of CYP enzymes involved in vitamin D metabolism in liver and kidney, and consequently affects vitamin D target genes levels.     

Dose-effect relationships between manganese exposure and neurological, neuropsychological and pulmonary function in confined space bridge welders

Background

Although adverse neuropsychological and neurological health effects are well known among workers with high manganese (Mn) exposures in mining, ore‐processing and ferroalloy production, the risks among welders with lower exposures are less well understood.

Methods

Confined space welding in construction of a new span of the San Francisco–Oakland Bay Bridge without adequate protection was studied using a multidisciplinary method to identify the dose–effect relationship between adverse health effects and Mn in air or whole blood. Bridge welders (n = 43) with little or no personal protection equipment and exposed to a welding fume containing Mn, were administered neurological, neuropsychological, neurophysiological and pulmonary tests. Outcome variables were analysed in relation to whole blood Mn (MnB) and a Cumulative Exposure Index (CEI) based on Mn‐air, duration and type of welding. Welders performed a mean of 16.5 months of welding on the bridge, were on average 43.8 years of age and had on average 12.6 years of education.

Results

The mean time weighted average of Mn‐air ranged from 0.11–0.46 mg/m³ (55% >0.20 mg/m³). MnB >10 µg/l was found in 43% of the workers, but the concentrations of Mn in urine, lead in blood and copper and iron in plasma were normal. Forced expiratory volume at 1s: forced vital capacity ratios (FEV₁/FVC) were found to be abnormal in 33.3% of the welders after about 1.5 years of welding at the bridge. Mean scores of bradykinesia and Unified Parkinson Disease Rating Scale exceeded 4 and 6, respectively. Computer assisted tremor analysis system hand tremor and body sway tests, and University of Pennsylvania Smell Identification Test showed impairment in 38.5/61.5, 51.4 and 88% of the welders, respectively. Significant inverse dose–effect relationships with CEI and/or MnB were found for IQ (p⩽0.05), executive function (p⩽0.03), sustaining concentration and sequencing (p⩽0.04), verbal learning (p⩽0.01), working (p⩽0.04) and immediate memory (p⩽0.02), even when adjusted for demographics and years of welding before Bay Bridge. Symptoms reported by the welders while working were: tremors (41.9%); numbness (60.5%); excessive fatigue (65.1%); sleep disturbance (79.1%); sexual dysfunction (58.1%); toxic hallucinations (18.6%); depression (53.5%); and anxiety (39.5%). Dose–effect associations between CEI and sexual function (p<0.05), fatigue (p<0.05), depression (p<0.01) and headache (p<0.05) were statistically significant.

Conclusions

Confined space welding was shown to be associated with neurological, neuropsychological and pulmonary adverse health effects. A careful enquiry of occupational histories is recommended for all welders presenting with neurological or pulmonary complaints, and a more stringent prevention strategy should be considered for Mn exposure due to inhalation of welding fume.Manganese (Mn) exposure through welding fume has been reported to cause parkinsonian syndrome, sometimes described as welding fume‐related parkinsonism and often misdiagnosed as Parkinson''s disease because of similarities in neurological features including tremor, masked facies and generalised bradykinesia.¹ However, important differences in movement disturbance between Mn‐induced parkinsonism (also called manganism) and idiopathic Parkinson''s disease (IPD) include an awkward high‐stepping dystonic gait in manganism, which is in stark contrast with the typical shuffling gait in patients with IPD, and the tendency to lose balance by falling backward in IPD and forward in manganism. Additionally, tremor characteristics are different, usually resting tremor in IPD and postural intention tremor in manganism.¹ Magnetic resonance imaging (MRI) may be used to differentiate IPD from Mn‐induced parkinsonism if a patient has had excess Mn exposure within the previous 6 months.² Positive MRIs can show cerebral Mn²⁺ deposition in both animals and humans, especially in the globus pallidus (possibly in the striatum), by exhibiting a T₁‐weighted signal hyperintensity.³ IPD, however, is associated with lesions in the substantia nigra pars compacta, and does not exhibit MRI abnormality in the globus pallidus. Two other key features differentiating between Mn‐induced parkinsonism and IPD are: (1) a younger age of onset for Mn‐exposed workers and (2) little or no response to l‐dopa among Mn‐induced parkinsonism cases.^4,5 Case reports of neurological findings in career welders exposed to Mn have shown dystonia bilaterally in the shoulders and four distal limbs, as well as other parkinsonian features—for example, tremor and postural instability.^5,6Welders have been reported to be exposed to “a wide variety of potential respiratory hazards”,^7,8 although earlier studies did not show increases in chronic bronchitis.⁹ However, shipyard welders have been reported to have a higher standardised mortality ratio for lung cancer, a finding which was also supported by the California Occupational Mortality Survey, after adjustment for smoking and asbestos exposure. Sjögren presented evidence of a causal relationship between exposure to stainless steel welding and lung cancer.¹⁰Diagnosis of Mn intoxication in workers actively exposed to excessive Mn in welding fumes can be further supported by biomarkers of exposure indicating increased internal Mn concentrations—for example, in whole blood and to a lesser extent in plasma/serum or urine. Sjögren et al¹¹ reported a mean concentration of 8.4 μg/l for whole blood Mn (MnB) in welders, whereas in other industrial settings the mean MnB ranged from 8.1 to 25.3 µg/l. No clear cutoff value of MnB is currently agreed upon, but HAR postulates that any values >10 µg/l is of concern.Mn air levels (Mn‐air) as reported in a few welder studies indicate that aerosols in welding operations (external exposure) usually contain <0.5 mg Mn/m³ (total dust), but sometimes they are >1 mg Mn/m³. A paramount feature of welding fume is that most of the airborne particles are in the respirable fraction (particle size <10 µm).¹² It is astonishing that reliable levels of respirable Mn particulate have rarely been reported, given the importance of the pulmonary uptake of Mn via the alveoli and its significance for Mn distribution to and effects on the central nervous system.¹³ It should be pointed out that inhalation exposure to Mn is for most of the jurisdictions regulated on the basis of total (or inhalable) dust: however, in the particular case of welding, a permissible exposure level established on the respirable fraction would enhance health prevention strategies.Neuropsychological testing methods used over the past two decades have successfully differentiated Mn‐exposed welders from unexposed controls.^4,6,11 There have been 13 reports on welders showing deficits for motor, tremor, memory and neurocognitive domains, as well as for sleep, sexual function and vision. Although not all reports dealt with all of these domains, 11 studies indicated slowing of motor speed/efficiency^{4,6,11,14,15,16,17,18,19,20,21} and tremor^{3,4,6,14,15,16,17,19,20,21,22}; eight found loss of neurocognitive functioning^{4,6,11,14,16,18,19,21}; and six reported diminished memory function.^{4,6,11,14,18,21} Six studies reported sleep disturbances^{4,6,11,14,15,17} and three sexual problems.^4,6,14 Vision was assessed in only two studies, and both found loss of colour vision associated with Mn exposure.^6,14Welders exposed to Mn‐containing welding fumes and dust have rarely been investigated by clinical neuropsychologists using an epidemiological study design in which actual measurements of internal and external exposure to Mn are studied in relation to outcome variables of a comprehensive test battery (including measures of IQ). Therefore, in the latter part of 2004, we decided to evaluate a welder group with health complaints, identified as employees on the reconstruction project of the San Francisco–Oakland Bay Bridge, which was damaged during the 1989 earthquake. The work on a vulnerable portion of the East span of the bridge began in 2003, requiring confined space welding of 28 anchoring foundations or piers, consisting of steel piles and footing boxes. The welding operations took place below the Bay''s surface in unpressurised cofferdams. During the first 1.5 years of welding on the support piers for the new bridge, welders began to express concerns of ill health feared to be the result of exposure to fumes due to confined space welding. During this period the welders were not required to wear personal protective equipment, and ventilation was minimal or ineffective. After receiving health complaints from almost 90% of the welders employed on the project, workers'' compensation evaluations were enacted, which supported their report of adverse health effects. A multidisciplinary study group took advantage of this “natural experiment” for undertaking additional clinical evaluations (1) to assess the extent of neurological, neuropsychological, neurophysiological and pulmonary effects, (2) to explore whether these effects were associated with internal and/or external measures of Mn exposure and (3) to define a tentative permissible exposure level for Mn in welding fume.