Updated assessment of occupational safety and health hazards of climate change.

Workers, particularly outdoor workers, are among the populations most disproportionately affected by climate-related hazards. However, scientific research and control actions to comprehensively address these hazards are notably absent. To assess this absence, a seven-category framework was developed in 2009 to characterize the scientific literature published from 1988-2008. Using this framework, a second assessment examined the literature published through 2014, and the current one examines literature from 2014-2021. The objectives were to present literature that updates the framework and related topics and increases awareness of the role of climate change in occupational safety and health. In general, there is substantial literature on worker hazards related to ambient temperatures, biological hazards, and extreme weather but less on air pollution, ultraviolet radiation, industrial transitions, and the built environment. There is growing literature on mental health and health equity issues related to climate change, but much more research is needed. The socioeconomic impacts of climate change also require more research. This study illustrates that workers are experiencing increased morbidity and mortality related to climate change. In all areas of climate-related worker risk, including geoengineering, research is needed on the causality and prevalence of hazards, along with surveillance to identify, and interventions for hazard prevention and control.

Advancing the framework for considering the effects of climate change on worker safety and health.

In 2009, a preliminary framework for how climate change could affect worker safety and health was described. That framework was based on a literature search from 1988-2008 that supported seven categories of climate-related occupational hazards: (1) increased ambient temperature; (2) air pollution; (3) ultraviolet radiation exposure; (4) extreme weather; (5) vector-borne diseases and expanded habitats; (6) industrial transitions and emerging industries; and (7) changes in the built environment. This article reviews the published literature from 2008-2014 in each of the seven categories. Additionally, three new topics related to occupational safety and health are considered: mental health effects, economic burden, and potential worker safety and health impacts associated with the nascent field of climate intervention (geoengineering). Beyond updating the literature, this article also identifies key priorities for action to better characterize and understand how occupational safety and health may be associated with climate change events and ensure that worker health and safety issues are anticipated, recognized, evaluated, and mitigated. These key priorities include research, surveillance, risk assessment, risk management, and policy development. Strong evidence indicates that climate change will continue to present occupational safety and health hazards, and this framework may be a useful tool for preventing adverse effects to workers.

Polygenic inheritance of paclitaxel-induced sensory peripheral neuropathy driven by axon outgrowth gene sets in CALGB 40101 (Alliance).

Peripheral neuropathy is a common dose-limiting toxicity for patients treated with paclitaxel. For most individuals, there are no known risk factors that predispose patients to the adverse event, and pathogenesis for paclitaxel-induced peripheral neuropathy is unknown. Determining whether there is a heritable component to paclitaxel-induced peripheral neuropathy would be valuable in guiding clinical decisions and may provide insight into treatment of and mechanisms for the toxicity. Using genotype and patient information from the paclitaxel arm of CALGB 40101 (Alliance), a phase III clinical trial evaluating adjuvant therapies for breast cancer in women, we estimated the variance in maximum grade and dose at first instance of sensory peripheral neuropathy. Our results suggest that paclitaxel-induced neuropathy has a heritable component, driven in part by genes involved in axon outgrowth. Disruption of axon outgrowth may be one of the mechanisms by which paclitaxel treatment results in sensory peripheral neuropathy in susceptible patients.

The use of phenome-wide association studies (PheWAS) for exploration of novel genotype-phenotype relationships and pleiotropy discovery.

The field of phenomics has been investigating network structure among large arrays of phenotypes, and genome-wide association studies (GWAS) have been used to investigate the relationship between genetic variation and single diseases/outcomes. A novel approach has emerged combining both the exploration of phenotypic structure and genotypic variation, known as the phenome-wide association study (PheWAS). The Population Architecture using Genomics and Epidemiology (PAGE) network is a National Human Genome Research Institute (NHGRI)-supported collaboration of four groups accessing eight extensively characterized epidemiologic studies. The primary focus of PAGE is deep characterization of well-replicated GWAS variants and their relationships to various phenotypes and traits in diverse epidemiologic studies that include European Americans, African Americans, Mexican Americans/Hispanics, Asians/Pacific Islanders, and Native Americans. The rich phenotypic resources of PAGE studies provide a unique opportunity for PheWAS as each genotyped variant can be tested for an association with the wide array of phenotypic measurements available within the studies of PAGE, including prevalent and incident status for multiple common clinical conditions and risk factors, as well as clinical parameters and intermediate biomarkers. The results of PheWAS can be used to discover novel relationships between SNPs, phenotypes, and networks of interrelated phenotypes; identify pleiotropy; provide novel mechanistic insights; and foster hypothesis generation. The PAGE network has developed infrastructure to support and perform PheWAS in a high-throughput manner. As implementing the PheWAS approach has presented several challenges, the infrastructure and methodology, as well as insights gained in this project, are presented herein to benefit the larger scientific community.

Phenome-Wide Association Studies: Leveraging Comprehensive Phenotypic and Genotypic Data for Discovery.

With the large volume of clinical and epidemiological data being collected, increasingly linked to extensive genotypic data, coupled with expanding high-performance computational resources, there are considerable opportunities for comprehensively exploring the networks of connections that exist between the phenome and the genome. These networks can be identified through Phenome-Wide Association Studies (PheWAS) where the association between a collection of genetic variants, or in some cases a particular clinical lab variable, and a wide and diverse range of phenotypes, diagnoses, traits, and/or outcomes are evaluated. This is a departure from the more familiar genome-wide association study (GWAS) approach, which has been used to identify single nucleotide polymorphisms (SNPs) associated with one outcome or a very limited phenotypic domain. In addition to highlighting novel connections between multiple phenotypes and elucidating more of the phenotype-genotype landscape, PheWAS can generate new hypotheses for further exploration, and can also be used to narrow the search space for research using comprehensive data collections. The complex results of PheWAS also have the potential for uncovering new mechanistic insights. We review here how the PheWAS approach has been used with data from epidemiological studies, clinical trials, and de-identified electronic health record data. We also review methodologies for the analyses underlying PheWAS, and emerging methods developed for evaluating the comprehensive results of PheWAS including genotype-phenotype networks. This review also highlights PheWAS as an important tool for identifying new biomarkers, elucidating the genetic architecture of complex traits, and uncovering pleiotropy. There are many directions and new methodologies for the future of PheWAS analyses, from the phenotypic data to the genetic data, and herein we also discuss some of these important future PheWAS developments.

Effects of aryl substituents on the anti-HIV activity of the arylphosphoramidate derivatives of stavudine.

We compared the anti-HIV activity of 13 phenyl phosphate derivatives of stavudine (2',3'-didehydro-2',3'-dideoxythymidine/d4T) by examining their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells. Our results show that the introduction of electron-withdrawing substituents enhances the activity of these phosphoramidate derivatives. The rate of chemical hydrolysis under alkaline conditions (but not the lipophilicity) predicted the potency of the compounds.

N-[2-(4-methylphenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea as a potent inhibitor of NNRTI-resistant and multidrug-resistant human immunodeficiency virus type 1.

The composite non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket model was used to study a number of thiourea analogues with different substitutions at the 4-phenyl position including N-[2-(4-methylphenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (compound HI-244), which inhibited recombinant RT better than trovirdine or compound HI-275 with an unsubstituted phenyl ring. HI-244 effectively inhibited the replication of HIV-1 strain HTLV(IIIB) in human peripheral blood mononuclear cells with an IC50 value of 0.007 microM, which is equal to the IC50 value of trovirdine. Notably, HI-244 was 20 times more effective than trovirdine against the multidrug-resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V, 41L and 215Y) and seven times more potent than trovirdine against the NNRTI-resistant HIV-1 strain A17 with a Y181C mutation.

Multiple nuclear localization signals in XPG nuclease.

We report here evidence for the mechanism of nuclear localization of XPG nuclease in human cells. Several candidate nuclear localization signal (NLS) peptides have been proposed for XPG protein. We have identified XPG peptides containing functional NLS and a potential nuclear retention signal (NRS) using in situ immunofluorescene localization of transiently expressed beta-galactosidase fusion proteins. Two XPG regions with putative NLS [amino acid (AA) coordinates: NLS-B (AA 1057-1074) and NLS-C (AA 1171-1185)] were each shown to independently localize the beta-gal extensively (> 80%) to the nucleus of HeLa cells. The C-terminus peptide containing NLS-C, an NLS conserved evolutionarily between yeasts and humans, also directed sub-localization of beta-galactosidase to intranuclear foci reminiscent of native XPG protein, as well as to peri-nucleolar regions. Peptides in the putative XPG 'NLS domain' (AA approximately 1051-1185) apparently function in concert for nuclear localization and also for retention of XPG in nuclear matrix-associated foci. Evidence presented elsewhere (Park et al., 1995) indicates that the peptide containing NLS-C (AA 1146-1185) also regulates the dynamic localization of XPG in the nucleus following UV-irradiation.

A comparative study of the hydrolysis pathways of substituted aryl phosphoramidate versus aryl thiophosphoramidate derivatives of stavudine.

A comparative study of aryl phosphoramidate and aryl thiophosphoramidate derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) was performed. The study focused on the nature of the substituents and the influence of a thiophosphoramidate in the structure of these derivatives. The rate of alkaline hydrolysis of these two types of d4T derivatives indicated that replacement of oxygen with sulfur decreases the rate of hydrolysis by twofold. Additionally, the activation energy (E(a)) for the sulfur analogs is comparatively higher than that of the oxygen analogs. Notably, an intermediate was formed in the hydrolysis reaction of the sulfur analogs of d4T that was absent in the case of the oxygen analog, and the tentative structure of the intermediate was proposed based on LC/mass spectroscopy data. Using both HPLC and (31)P-NMR techniques, we identified the hydrolysis product of the phosphoramidate derivatives and were able to show in in vitro studies that porcine liver esterase can hydrolyze the methyl ester portion of the phosphoramidate derivatives. Aryl phosphoramidate derivatives of d4T were 1000-fold more active than the corresponding aryl thiophosphoramidate derivatives, indicating that the energy of activation of hydrolysis of these phosphoramidate derivatives plays a significant role in their biological potency.

Health status and satisfaction with health care: a longitudinal study among patients served by the Veterans Health Administration.

As the Veterans Health Administration (VHA) places high priority on becoming a performance-based organization, there is an increasing need to quantify and refine its outcome measurement system. Using panel data from VHA ambulatory care patients (1996-1998), we conducted cross-lagged correlations and ordinary least squares regression to examine the relationship between 2 VHA health care values: health status and satisfaction with care. The study results indicated that patients' health status was significantly associated with their satisfaction with care, indicating that patients with better health status were more likely to be satisfied with health care. Although satisfaction with care was both a consequence and a determinant of health status, the effects of health status on satisfaction seemed to be more important than the effects of satisfaction on health status. More research is needed for a better understanding of the dynamic relationship between health status and satisfaction with care.

An approach for estimating workplace exposure to o-toluidine, aniline, and nitrobenzene.

A comprehensive approach to estimating worker exposure to o-toluidine, aniline, and nitrobenzene using a combination of surface wipe, dermal badge, and air samples is described. Desorption of each sample was accomplished with ethanol followed by analyses using capillary gas chromatography with flame ionization detection. Analyte recovery was maximized when the gauze wipes and dermal badges were immediately desorbed in ethanol after sample collection. Sample collection of the airborne analytes was improved over previous solid sorbent samples by using a sampling train consisting of an acid-treated glass fiber filter in series with a large capacity silica gel tube (520/260 mg). The greatest recoveries of aniline and o-toluidine were from the acid-treated glass fiber filters and nitrobenzene from the large capacity silica gel sorbent tubes. The limit of detection for each analyte (1 micrograms) was approximately 10 times more sensitive than reported in previous National Institute for Occupational Safety and Health methods. Analyte recoveries for air samples were greatest under conditions of moderate relative humidity (53%), moderate sample volumes (< 50 L), and low flow rates (0.2 L/min). The overall relative standard deviation of the analytical method was 4.3%.

An alternative method for the analysis of phenol and o-, m-, and p-cresol by capillary GC/FID.

An alternative method for the sampling and simultaneous analysis of phenol, o-, m-, and p-cresol, employing XAD-7 as a sorbent for the collection of each analyte, is described. Desorption was achieved with methanol followed by analysis of all samples using gas chromatography with flame ionization detection. The separation of all analytes was achieved on a Stabilwax-DA capillary column. Sample collection and preparation was improved over current methods used at the National Institute for Occupational Safety and Health. The results obtained when a Stabilwax-DA capillary column was used in the analysis, as compared to those obtained using a Stabilwax capillary column, indicated achievement of baseline separation of the analytes. Peak resolution and overall peak shape were enhanced by the use of the Stabilwax-DA column. Lower limits of detection were achieved for each analyte. Desorption efficiency and storage stability results (30 days) were acceptable. Sample stability in solution and on solid sorbent tubes was examined. The relative standard deviation of the analytical portion of the method was found to be 0.045. This method provides a simplified, concise, simultaneous analysis of phenol, o-, m-, and p-cresol.

Determination of glycols in air: development of sampling and analytical methodology and application to theatrical smokes.

Glycol-based fluids are used in the production of theatrical smokes in theaters, concerts, and other stage productions. The fluids are heated and dispersed in aerosol form to create the effect of a smoke, mist, or fog. There have been reports of adverse health effects such as respiratory irritation, chest tightness, shortness of breath, asthma, and skin rashes. Previous attempts to collect and quantify the aerosolized glycols used in fogging agents have been plagued by inconsistent results, both in the efficiency of collection and in the chromatographic analysis of the glycol components. The development of improved sampling and analytical methodology for aerosolized glycols was required to assess workplace exposures more effectively. An Occupational Safety and Health Administration versatile sampler tube was selected for the collection of ethylene glycol, propylene glycol, 1,3-butylene glycol, diethylene glycol, triethylene glycol, and tetraethylene glycol aerosols. Analytical methodology for the separation, identification, and quantitation of the six glycols using gas chromatography/flame ionization detection is described. Limits of detection of the glycol analytes ranged from 7 to 16 micrograms/sample. Desorption efficiencies for all glycol compounds were determined over the range of study and averaged greater than 90%. Storage stability results were acceptable after 28 days for all analytes except ethylene glycol, which was stable at ambient temperature for 14 days. Based on the results of this study, the new glycol method was published in the NIOSH Manual of Analytical Methods.

Development of a versatile method for the detection of nicotine in air.

Nicotine, a rapid-acting poison, is present in environmental tobacco smoke and has been used as a greenhouse insecticide. Due to its toxicity, several health hazard evaluations (HHE) have resulted from potential nicotine exposures to casino workers, airline flight attendants, and greenhouse employees. Exposure to nicotine can occur by inhalation, skin adsorption, and ingestion, resulting in such adverse health effects as nausea, vomiting, headache, dizziness, tachycardia, hypertension, convulsions, and cardiac arrhythmia. The development of an improved sampling and analytical methodology for nicotine was required to accommodate the broad concentration of nicotine levels and varying sampling scenarios presented by the differing HHE requests. A XAD-4 sorbent tube was selected for the collection of airborne nicotine. Analytical methodology for the separation, identification, and quantitation of nicotine by both gas chromatography-flame ionization detection and gas chromatography-nitrogen/ phosphorous detection is described. The limit of detection for nicotine was 0.013 microg/sample. The desorption efficiency for nicotine was determined over the range of study and ranged from 90.9% (0.096 microg) to 93.7% (24.0 microg). Nicotine exhibited storage stability for 30 days at 5 degrees C and for 14 days at ambient temperature. Based on the results of this research study, the new method for nicotine was published in the NIOSH Manual of Analytical Methods (NMAM 2551).

N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea and N'-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1.

We have replaced the pyridyl ring of trovirdine with an alicyclic cyclohexenyl, adamantyl or cis-myrtanyl ring. Only the cyclohexenyl-containing thiourea compound N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]- thiourea (HI-346) (as well as its chlorine-substituted derivative N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]- thiourea/HI-445) showed RT inhibitory activity. HI-346 and HI-445 effectively inhibited recombinant RT with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cell-free RT inhibition assays was: HI-346 (IC50 = 0.4 microM) > HI-445 (IC50 = 0.5 microM) > trovirdine (IC50 = 0.8 microM) > MKC-442 (IC5 = 0.8 microM) = delavirdine (IC50 = 1.5 microM) > nevirapine (IC50 = 23 microM). In accord with this data, both compounds inhibited the replication of the drug-sensitive HIV-1 strain HTLV(IIIB) with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cellular HIV-1 inhibition assays was: HI-445 = HI-346 (IC50 = 3 nM) > MKC-442 (IC50 = 4 nM) = AZT (IC50 = 4 nM) > trovirdine (IC50 = 7 nM) > delavirdine (IC50 = 9 nM) > nevirapine (IC50 = 34 nM). Surprisingly, the lead compounds HI-346 and HI-445 were 3-times more effective against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V,41L, and 215Y) than they were against HTLV(IIIB) with wild-type RT. HI-346 and HI-445 were 20-times more potent than trovirdine, 200-times more potent than AZT, 300-times more potent than MKC-442, 400-times more potent than delavirdine, and 5000-times more potent than nevirapine against the multidrug resistant HIV-1 strain RT-MDR. HI-445 was also tested against the RT Y181C mutant A17 strain of HIV-1 and found to be >7-fold more effective than trovirdine and >1,400-fold more effective than nevirapine or delavirdine. Similarly, both HI-346 and HI-445 were more effective than trovirdine, nevirapine, and delavirdine against the problematic NNI-resistant HIV-1 strain A17-variant with both Y181C and K103N mutations in RT, although their activity was markedly reduced against this strain. Neither compound exhibited significant cytotoxicity at effective concentrations (CC50 >100 microM). These findings establish the lead compounds HI-346 and HI-445 as potent inhibitors of drug-sensitive as well as multidrug-resistant stains of HIV-1.

Lipase-mediated stereoselective hydrolysis of stampidine and other phosphoramidate derivatives of stavudine.

Enzymatic hydrolysis of stampidine and other aryl phosphate derivatives of stavudine were investigated using the Candida Antarctica Type B lipase. Modeling studies and comparison of the hydrolysis rate constants revealed a chiral preference of the lipase active site for the putative S-stereoisomer. The in vitro anti-HIV activity of these compounds correlated with their susceptibility to lipase- (but not esterase-) mediated hydrolysis. We propose that stampidine undergoes rapid enzymatic hydrolysis in the presence of lipase according to the following biochemical pathway: During the first step, hydrolysis of the ester group results in the formation of carboxylic acid. Subsequent step involves an intramolecular cyclization at the phosphorous center with simultaneous elimination of the phenoxy group to form a cyclic intermediate. In the presence of water, this intermediate is converted into the active metabolite Ala-d4T-MP. We postulate that the lipase hydrolyzes the methyl ester group of the l-alanine side chain to form the cyclic intermediate in a stereoselective fashion. This hypothesis was supported by experimental data showing that chloroethyl substituted derivatives of stampidine, which possess a chloroethyl linker unit instead of a methyl ester side chain, were resistant to lipase-mediated hydrolysis, which excludes the possibility of a direct hydrolysis of stampidine at the phosphorous center. Thus, our model implies that the lipase-mediated formation of the cyclic intermediate is a key step in metabolism of stampidine and relies on the initial configuration of the stereoisomers.

N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1.

The thiophene-ethyl thiourea (TET) compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (compound HI-443) was five times more potent than trovirdine, 1250 times more potent than nevirapine, 100 times more potent than delavirdine, 75 times more potent than MKC-442, and 50 times more potent than AZT against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation. HI-443 was almost as potent against the NNI-resistant HIV-1 strain A17 with a Y181C mutation as it was against HTLV(IIIB). The activity of HI-443 against A17 was ten times more potent than that of trovirdine, 2083 times more potent than that of nevirapine, and 1042 times more potent than that of delavirdine. HI-443 inhibited the replication of the NNI-resistant HIV-1 strain A17 variant with Y181C plus K103N mutations in RT with an IC50 value of 3.3 microM, whereas the IC50 values of trovirdine, nevirapine, and delavirdine were all >100 microM. These findings establish the novel thiophene containing thiourea compound HI-443 as a novel NNI with potent antiviral activity against NNI-sensitive, NNI-resistant and multidrug-resistant strains of HIV-1.

Microwave thermal imaging: initial in vivo experience with a single heating zone.

The deployment of hyperthermia as a routine adjuvant to radiation or chemotherapy is limited largely by the inability to devise treatment plans which can be monitored through temperature distribution feedback during therapy. A non-invasive microwave tomographic thermal imaging system is currently being developed which has previously exhibited excellent correlation between the recovered electrical conductivity of a heated zone and its actual temperature change during phantom studies. To extend the validation of this approach in vivo, the imaging system has been re-configured for small animal experiments to operate within the bore of a CT scanner for anatomical and thermometry registration. A series of 5-7 day old pigs have been imaged during hyperthermia with a monopole antenna array submerged in a saline tank where a small plastic tube surgically inserted the length of the abdomen has been used to create a zone of heated saline at pre-selected temperatures. Tomographic microwave data over the frequency range of 300-1000 MHz of the pig abdomen in the plane perpendicular to the torso is collected at regular intervals after the tube saline temperatures have settled to the desired settings. Images are reconstructed over a range of operating frequencies. The tube location is clearly visible and the recovered saline conductivity varies linearly with the controlled temperature values. Difference images utilizing the baseline state prior to heating reinforces the linear relationship between temperature and imaged saline conductivity. Demonstration of in vivo temperature recovery and correlation with an independent monitoring device is an important milestone prior to clinical integration of this non-invasive imaging system with a thermal therapy device.

Ultraviolet-induced movement of the human DNA repair protein, Xeroderma pigmentosum type G, in the nucleus.

Xeroderma pigmentosum type G (XPG) is a human genetic disease exhibiting extreme sensitivity to sunlight. XPG patients are defective XPG endonuclease, which is an enzyme essential for DNA repair of the major kinds of solar ultraviolet (UV)-induced DNA damages. Here we describe a novel dynamics of this protein within the cell nucleus after UV irradiation of human cells. Using confocal microscopy, we have localized the immunofluorescent, antigenic signal of XPG protein to foci throughout the cell nucleus. Our biochemical studies also established that XPG protein forms a tight association with nuclear structure(s). In human skin fibroblast cells, the number of XPG foci decreased within 2 h after UV irradiation, whereas total nuclear XPG fluorescence intensity remained constant, suggesting redistribution of XPG from a limited number of nuclear foci to the nucleus overall. Within 8 h after UV, most XPG antigenic signal was found as foci. Using beta-galactosidase-XPG fusion constructs (beta-gal-XPG) transfected into HeLa cells, we have identified a single region of XPG that is evidently responsible both for foci formation and for the UV dynamic response. The fusion protein carrying the C terminus of XPG (amino acids 1146-1185) localized beta-gal specific antigenic signal to foci and to the nucleolus regions. After UV irradiation, antigenic beta-gal translocated reversibly from the subnuclear structures to the whole nucleus with kinetics very similar to the movements of XPG protein. These findings lead us to propose a model in which distribution of XPG protein may regulate the rate of DNA repair within transcriptionally active and inactive compartments of the cell nucleus.