Mass Casualty Decontamination in a Chemical or Radiological/Nuclear Incident with External Contamination: Guiding Principles and Research Needs.

Hazardous chemical, radiological, and nuclear materials threaten public health in scenarios of accidental or intentional release which can lead to external contamination of people.  Without intervention, the contamination could cause severe adverse health effects, through systemic absorption by the contaminated casualties as well as spread of contamination to other people, medical equipment, and facilities.  Timely decontamination can prevent or interrupt absorption into the body and minimize opportunities for spread of the contamination, thereby mitigating the health impact of the incident.  Although the specific physicochemical characteristics of the hazardous material(s) will determine the nature of an incident and its risks, some decontamination and medical challenges and recommended response strategies are common among chemical and radioactive material incidents.  Furthermore, the identity of the hazardous material released may not be known early in an incident.  Therefore, it may be beneficial to compare the evidence and harmonize approaches between chemical and radioactive contamination incidents.  Experts from the Global Health Security Initiative's Chemical and Radiological/Nuclear Working Groups present here a succinct summary of guiding principles for planning and response based on current best practices, as well as research needs, to address the challenges of managing contaminated casualties in a chemical or radiological/nuclear incident.

Association of radiation-induced genes with noncancer chronic diseases in Mayak workers occupationally exposed to prolonged radiation.

We examined the association of gene expression with noncancer chronic disease outcomes in Mayak nuclear weapons plant workers who were exposed to radiation due to their occupation. We conducted a cross-sectional study with selection based on radiation exposure status of Mayak plant workers living in Ozyorsk who were alive in 2011 and either exposed to: combined incorporated Plutonium-239 ((239)Pu) and external gamma-ray exposure (n = 82); external gamma-ray exposure alone (n = 18); or were unexposed (n = 50) of Ozyorsk residents who provided community-based professional support for plant personnel and who were alive in 2011. Peripheral blood was taken and RNA was isolated and then converted into cDNA and stored at -20°C. In a previous analysis we screened the whole genome for radiation-associated candidate genes, and validated 15 mRNAs and 15 microRNAs using qRT-PCR. In the current analysis we examined the association of these genes with 15 different chronic diseases on 92 samples (47 males, 45 females). We examined the radiation-to-gene and gene-to-disease associations in statistical models stratified by gender and separately for each disease and exposure. We modeled radiation exposure as gamma or (239)Pu on both the continuous and categorical scales. Unconditional logistic regression was used to calculate odds ratios (OR), 95% confidence intervals (CI), and the concordance for genes that were significantly associated with radiation exposure and a specific disease outcome were identified. Altogether 12 mRNAs and 9 microRNAs appeared to be significantly associated with 6 diseases, including thyroid diseases (3 genes, OR: 1.2-5.1, concordance: 71-78%), atherosclerotic diseases (4 genes, OR: 2.5-10, concordance: 70-75%), kidney diseases (6 genes, OR: 1.3-8.6, concordance: 69-85%), cholelithiasis (3 genes, OR: 0.2-0.3, concordance: 74-75%), benign tumors [1 gene (AGAP4), OR: 3.7, concordance: 81%] and chronic radiation syndrome (4 genes, OR: 2.5-4.3, concordance: 70-99%). Further associations were found for systolic blood pressure (6 genes, OR: 3.7-10.6, concordance: 81-88%) and body mass index [1 gene (miR-484), OR: 3.7, concordance: 81%]. All associations were gender and exposure dependent. These findings suggest that gene expression changes observed after occupational prolonged radiation exposures may increase the risk for certain noncancer chronic diseases.

Independent validation of candidate genes identified after a whole genome screening on Mayak workers exposed to prolonged occupational radiation.

We evaluated gene expression in the peripheral blood of Mayak workers in relationship to occupational chronic exposure to identify permanent post-exposure signatures. The Mayak workers had experienced either a combined exposure to incorporated (239)Pu and external gamma rays (n = 82) or exposure to external gamma rays (n = 18). Fifty unexposed individuals served as controls. Peripheral blood was collected and then the RNA was isolated, converting it into cDNA and stored at -20°C. In a previous study at stage I, we screened the mRNA and microRNA transcriptome using 40 of the 150 samples and identified 95 mRNAs and 45 microRNAs. In stage II of this study, we now validated our 140 candidate genes using the qRT-PCR technique for the remaining 92 blood samples (18 samples were lost due to methodological reasons). We analyzed associations of normalized gene expression values in linear models separately for both exposure types (continuous and categorical scales) and adjusted for exposure age as well as stratified by gender. After further adjustment for confounders such as chronic non-cancer diseases or age at biosampling, mostly binary (on/off) dose-to-gene relationships were found for 15 mRNAs and 15 microRNAs, of which 8 mRNAs and 6 microRNAs remained significant after Bonferroni correction. Almost all of them were associated with plutonium incorporation and gender. Our study provides mRNA and microRNA gene expression changes dependent on the exposure type and gender, which occur and seem to persist after chronic radiation exposures supporting the concept of permanent post-exposure signatures.

Gene expression analysis in Mayak workers with prolonged occupational radiation exposure.

The authors evaluated gene expression in the peripheral blood in relation to occupational exposure in Mayak workers to find out about the existence of a permanent post exposure signature. Workers were exposed to combined incorporated ²³9Pu and external gamma rays (n = 82) or to external gamma rays only (n = 18), and 50 unexposed individuals served as controls. Peripheral blood was taken from workers older than 70 y. RNA was isolated, converted into cDNA, and stored at -20°C. A two-stage study design was performed focusing on examinations on the transcriptional (mRNA) and post-transcriptional level (microRNA). In the first stage, 40 samples were identified for screening purposes and selection of candidate genes. For examinations on the transcriptional level, whole genome microarrays and qRT-PCR were employed on the post-transcriptional level (667 microRNAs). Candidate genes were assessed by (1) introducing a twofold difference in gene expression over the reference group and (2) showing a significant p-value using the Kruskal-Wallis test. From 42,545 transcripts of the whole genome microarray, 376 candidate genes (80 up-regulated and 296 down-regulated relative to the reference group) were selected. Expression of almost all of these genes (70-98%) appeared significantly associated with internal ²³9Pu and to a lesser extent were associated with external gamma-ray exposure (2-30%). Associations in the same direction were found for 45 microRNAs. Although both exposures led to modulations of different gene sets in different directions, the authors could detect no differences in gene set enrichment analysis.

Sulfur mustard research--strategies for the development of improved medical therapy.

OBJECTIVE: Sulfur mustard (SM) is a bifunctional alkylating substance being used as chemical warfare agent (vesicant). It is still regarded as a significant threat in chemical warfare and terrorism. Exposure to SM produces cutaneous blisters, respiratory and gastrointestinal tract injury, eye lesions, and bone marrow depression. Victims of World War I as well as those of the Iran-Iraq war have suffered from devastating chronic health impairment. Even decades after exposure, severe long-term effects like chronic obstructive lung disease, lung fibrosis, recurrent corneal ulcer disease, chronic conjunctivitis, abnormal pigmentation of the skin, and different forms of cancer have been diagnosed. METHODS: This review briefly summarizes the scientific literature and own results concerning detection, organ toxicity of SM, its proposed toxicodynamic actions, and strategies for the development of improved medical therapy. RESULTS: Despite extensive research efforts during the last century, efficient antidotes against SM have not yet been generated because its mechanism of action is not fully understood. However, deeper insights into these mechanisms gained in the last decade and promising developments of new drugs now offer new chances to minimize SM-induced organ damage and late effects. CONCLUSION: Polymerase inhibitors, anti-inflammatory drugs, antioxidants, matrix metalloproteinase inhibitors, and probably regulators of DNA damage repair are identified as promising approaches to improve treatment.

Cytotoxicity of the dental composite component TEGDMA and selected metabolic by-products in human pulmonary cells.

OBJECTIVES: The comonomer triethyleneglycoldimethacrylate (TEGDMA) is a commonly used constituent of resin-based dental materials. Upon placement, light-cured dental polymers may release a wide spectrum of residual compounds due to incomplete monomer-conversion during polymerization. Apart from liberating unreacted monomers, additional compound release might occur due to mechanical wear and enzymatic degradation on the salivary surface of resin fillings. Following delivery into the local bio phase, leached compounds may encounter a variety of different enzymes, which might be present in their oral or systemic environment. Metabolic by-products formerly associated with TEGDMA-degradation include triethylene glycol (TEG), methacrylic acid (MA), 2,3-epoxymethacrylic acid (2,3-EMA), and formaldehyde. METHODS: Cytotoxicitiy of TEGDMA-derived intermediates was measured as mitochondrial dehydrogenase activity assessed by colorimetric measurement of formazan formation as a cleavage-product from the tetrazolium salt XTT by metabolically active A549 cells. EC(50)-values were calculated by using curve fitting software (GraphPad Prism). RESULTS: The following EC(50)-values (mmol/L) (95% confidence interval) were obtained: 2,3-EMA 1.65 (1.28-2.13), TEGDMA 1.83 (1.46-2.30), MA 4.91 (4.22-5.71), and paraformaldehyde (PFA) 5.48 (4.56-6.58). For TEG no cytotoxic effects up to a concentration of 10mM could be found. SIGNIFICANCE: The epoxy compound 2,3-EMA induced comparable toxic effects as the raw comonomer TEGDMA. It is therefore concluded that the formation of toxic intermediates might significantly contribute to TEGDMA-induced cytotoxicity in human pulmonary cells.

Assessment of alterations in barrier functionality and induction of proinflammatory and cytotoxic effects after sulfur mustard exposure of an in vitro coculture model of the human alveolo-capillary barrier.

Acute lung injury after sulfur mustard (SM) inhalation is characterized by massive, localized hemorrhage and alveolar edema, which implies severe disruption of the vascular and distal airway barrier. In this study, we tested a recently established in vitro coculture model of the alveolo-capillary barrier for its applicability to investigate acute toxic effects of SM at the human respiratory unit. The epithelial compartment of cocultures was exposed to varying concentrations of SM (0-1000 microM; t = 30 min). Following exposure, functional and structural barrier integrity of cocultures was monitored over a period of 24 h. A 50% reduction of transbilayer electrical resistance (TER) within 12-24 h after exposure to 300 microM SM and within 8 h after 1000 microM SM revealed a time- and concentration-dependent impairment of barrier functionality, which was associated with structural loss of both cell layers. Subsequent quantification of interleukin (IL)-6 and IL-8 in cell culture supernatants of exposed cocultures showed enhanced liberation of proinflammatory markers. Highest mediator levels were detected after 300 microM SM, with pronounced stimulation in the endothelial compartment. SM-related cytotoxicity was determined by assessing adenylate kinase (AK) release and by quantifying the fraction of DNA-fragmented nuclei using terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling (TUNEL) and nuclear Hoechst staining. Both methods exposed a concentration-dependent increase of SM-mediated cytotoxic effects with high effects on endothelial cells. We conclude that the described in vitro model reflects important characteristics of SM-mediated acute lung injury in vivo and thus can be used to explore involved pathophysiological pathways.