Recommended Reference Values for Risk Assessment of Oral Exposure to Copper.

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) database, the authoritative source of U.S. risk assessment toxicity factors, currently lacks an oral reference dose (RfD) for copper. In the absence of such a value, various health-based reference values for copper are available for use in risk assessment. We summarize the scientific bases and differences in assumptions among key reference values for ingested copper to guide selection of appropriate values for risk assessment. A comprehensive review of the scientific literature best supports the oral RfD of 0.04 mg/kg body weight/day derived by EPA from their Drinking Water Action Level. This value is based on acute gastrointestinal effects but is further supported by broader analysis of copper deficiency and toxicity.

Regulatory developments and their impacts to the nano-industry: A case study for nano-additives in 3D printing.

Nanotechnology has increasing applications in numerous markets, particularly in additive processing (3D printing) and manufacturing, which is important for consumer products, medical devices, construction, and general research and development across many other industries. Nanomaterials are desirable in many products due to their unique properties, but those same properties have made evaluating the risk and regulation of these materials challenging. For risk-based regulations, new applications and nanomaterials should be assessed for both human and environmental hazards and exposure to ensure protection. In general, many risk assessments to date have focused on the non-nano versions of chemicals. The lack of guidance on assessing the hazard and exposure of nanomaterials in 3D printing is apparent, and these areas of assessment are actively being evaluated. Industry in most cases will now need to provide specific additional information for assessing the risk of nanomaterials in 3D printing. This review paper focuses on the use of nanomaterials in 3D printing for industrial and manufacturing applications, summarizes the current literature on human health and safety related to 3D printing and inhalation exposure, and the regulations relating to 3D printing in the U.S., Canada, and Europe for this industry.

Critical Review of Exposure and Effects: Implications for Setting Regulatory Health Criteria for Ingested Copper.

Decades of study indicate that copper oral exposures are typically not a human health concern. Ingesting high levels of soluble copper salts can cause acute gastrointestinal symptoms and, in uncommon cases, liver toxicity in susceptible individuals with repeated exposure. This focused toxicological review evaluated the current literature since the last comprehensive reviews (2007-2010). Our review identified limitations in the existing United States and international guidance for determining an oral reference dose (RfD) for essential metals like copper. Instead, an alternative method using categorical regression analysis to develop an optimal dose that considers deficiency, toxicity, and integrates information from human and animal studies was reviewed for interpreting an oral RfD for copper. We also considered subchronic or chronic toxicity from genetic susceptibility to copper dysregulation leading to rare occurrences of liver and other organ toxicity with elevated copper exposure. Based on this approach, an oral RfD of 0.04 mg Cu/kg/day would be protective of acute or chronic toxicity in adults and children. This RfD is also protective for possible genetic susceptibility to elevated copper exposure and allows for background dietary exposures. This dose is not intended to be protective of patients with rare genetic disorders for copper sensitivity within typical nutritional intake ranges, nor is it protective for those with excessive supplement intake. Less soluble mineral forms of copper in soil have reduced bioavailability as compared with more soluble copper in water and diet, which should be considered in using this RfD for risk assessments of copper.

Degradation of 4-bromophenol by Ochrobactrum sp. HI1 isolated from desert soil: pathway and isotope effects.

Anthropogenic activities have introduced elevated levels of brominated phenols to the environment. These compounds are associated with toxic and endocrine effects, and their environmental fate is of interest. An aerobic strain Ochrobactrum sp. HI1 was isolated from soils in the vicinity of a bromophenol production plant and tested for its ability to degrade 4-bromophenol (4-BP). A ring hydroxylation pathway of degradation was proposed, using the evidence from degradation intermediates analysis and multi-element (C, Br, H) compound-specific isotope analysis. Benzenetriol and 4-bromocatechol were detected during degradation of 4-bromophenol. Degradation resulted in a normal carbon isotope effect (εC = -1.11 ± 0.09‰), and in insignificant bromine and hydrogen isotope fractionation. The dual C-Br isotope trend for ring hydroxylation obtained in the present study differs from the trends expected for reductive debromination or photolysis. Thus, the isotope data reported herein can be applied in future field studies to delineate aerobic biodegradation processes and differentiate them from other natural attenuation processes.

The influences of arbuscular mycorrhizal fungus on phytostabilization of lead/zinc tailings using four plant species.

A greenhouse experiment was conducted to investigate the effects of the arbuscular mycorrhizal fungus Funneliformis mosseae on three parameters: Pb, Zn, Cu and Cd accumulation, translocation and plant growth in perennial ryegrass (Lolium perenne), tall fescue (Festuca arundinacea), showy stonecrop (Hylotelephium spectabile) and Purple Heart (Tradescantia pallida). The purpose of this work is to enhance site-specific phytostabilization of lead/zinc mine tailings using native plant species. The results showed that mycorrhizal fungi inoculation significantly increased plant biomass of F. arundinacea, H. spectabile and T. pallida. The Pb, Zn, Cu and Cd concentrations in roots were higher than those in shoots both with and without mycorrhizae, with the exception of the Zn concentration in H. spectabile. Mycorrhizae generally increased metal concentrations in roots and decreased metal concentrations in shoots of L. perenne and F. arundinacea. In addition, it was found that the majority of the bioconcentration and translocation factors were lower than 1 and mycorrhizal fungi inoculation further reduced these values. These results suggest that appropriate plant species inoculated with mycorrhiza might be a potential approach to revegetating mine tailing sites and that H. spectabile is an appropriate plant for phytostabilization of Pb/Zn tailings in northern China due to its higher biomass production and lower metal accumulation in shoots.

D-amino acids inhibit initial bacterial adhesion: thermodynamic evidence.

Bacterial biofilms are structured communities of cells enclosed in a self-produced hydrated polymeric matrix that can adhere to inert or living surfaces. D-Amino acids were previously identified as self-produced compounds that mediate biofilm disassembly by causing the release of the protein component of the polymeric matrix. However, whether exogenous D-amino acids could inhibit initial bacterial adhesion is still unknown. Here, the effect of the exogenous amino acid D-tyrosine on initial bacterial adhesion was determined by combined use of chemical analysis, force spectroscopic measurement, and theoretical predictions. The surface thermodynamic theory demonstrated that the total interaction energy increased with more D-tyrosine, and the contribution of Lewis acid-base interactions relative to the change in the total interaction energy was much greater than the overall nonspecific interactions. Finally, atomic force microscopy analysis implied that the hydrogen bond numbers and adhesion forces decreased with the increase in D-tyrosine concentrations. D-Tyrosine contributed to the repulsive nature of the cell and ultimately led to the inhibition of bacterial adhesion. This study provides a new way to regulate biofilm formation by manipulating the contents of D-amino acids in natural or engineered systems.

Carbon and clay nanoparticles induce minimal stress responses in gram negative bacteria and eukaryotic fish cells.

We investigated in vitro the potential mutagenic and toxic effects of two clay-based nanoparticles, Cloisite® Na(+) (Cloisite) and halloysite; and multi-walled carbon nanotubes (MWCNT), commonly used in the polymer composite industry. Using the Ames test, the three nanoparticles did not have a true mutagenic effect, although growth of Salmonella enterica var. Typhimurium (S.typhimurium) was diminished at higher nanoparticle concentrations. We investigated the impact of nanoparticles on Escherichia coli and S. typhimurium including oxyR and rpoS mutants, which are susceptible to oxidative stress. The oxyR mutants were inhibited in the presence of nanoparticles, when grown aerobically with light. Toxicity was not observed in the absence of light or during anaerobic growth. E. coli rpoS mutants exhibited some toxicity when cultured with Cloisite and MWCNT only when grown aerobically with light. There was no effect with other nanoparticles, or with S. typhimurium rpoS mutants. MWCNT exhibited a slight toxic effect against Epithelioma papulosum cyprini (EPC) cells only at the highest concentration tested. There was no discernable toxicity to EPC cells caused by the clay nanoparticles. We conclude that clay-based nanoparticles and MWCNT do not exert a mutagenic effect and do not have a general toxic effect across all bacterial species or between prokaryotic and eukaryotic cells. Modest toxicity was only observed in eukaryotic EPC cells against MWCNT at the highest concentration tested. Limited species-specific toxicity to clay based and MWCNT nanoparticles was seen in bacterial strains primarily due to culture conditions and mutations that exacerbate oxidative stress.

N-halamine surface coating for mitigation of biofilm and microbial contamination in water systems for space travel.

A copolymer termed HASL produced from monomeric units of 2-acrylamido-2-methyl-1-(5-methylhydantoinyl)propane (HA) and of 3-(trimethoxysilyl)propyl methacrylate (SL) has been coated onto stainless steel and Inconel™ substrates, which upon halogenation with either aqueous oxidative chlorine or bromine, became antimicrobial. It has been demonstrated that the halogenated stainless steel and Inconel™ substrates were effective in producing 6 to 7 log inactivations of Staphylococcus aureus and Escherichia coli O157:H7 within about 10 min, and in prevention of Pseudomonas aeruginosa biofilm formation over a period of at least 72 h on the stainless steel substrates. Upon loss of halogen, the HASL coating could be re-charged with aqueous halogen. The HASL coating was easily applied to the substrates via a simple dip-coating method and was reasonably stable to contact with water. Both chlorinated substrates could be loaded with at least 6 × 1016 oxidative Cl atoms per cm2 and maintained a loading of greater than 1 × 1016 chlorine atoms per cm2 for a period of 3-7 days while agitated in aqueous solution. After loss of chlorine to a level below 1 × 1016 atoms per cm2, the substrates could be recharged to the 6 × 1016 Cl atoms per cm2 level for at least 5 times over a 28 day period. The new antimicrobial coating technology has potential for use in a variety of important applications, particularly for water treatment and storage on spacecraft.

Abundance, fate, and effects of pharmaceuticals and personal care products in aquatic environments.

Pharmaceuticals and personal care products (PPCPs) are found in wastewater, and thus, the environment. In this study, current knowledge about the occurrence and fate of PPCPs in aquatic systems-including wastewater treatment plants (WWTPs) and natural waters around the world-is critically reviewed to inform the state of the science and highlight existing knowledge gaps. Excretion by humans is the primary route of PPCPs entry into municipal wastewater systems, but significant contributions also occur through emissions from hospitals, PPCPs manufacturers, and agriculture. Abundance of PPCPs in raw wastewater is influenced by several factors, including the population density and demography served by WWTPs, presence of hospitals and drugs manufacturers in the sewershed, disease burden of the population served, local regulations, and climatic conditions. Based on the data obtained from WWTPs, analgesics, antibiotics, and stimulants (e.g., caffeine) are the most abundant PPCPs in raw wastewater. In conventional WWTPs, most removal of PPCPs occurs during secondary treatment, and overall removal exceeds 90% for treatable PPCPs. Regardless, the total PPCP mass discharged with effluent by an average WWTP into receiving waters (7.35-20,160 g/day) is still considerable, because potential adverse effects of some PPCPs (such as ibuprofen) on aquatic organisms occur within measured concentrations found in surface waters.

Infant feeding mode predicts the costs of healthcare services in one region of Canada: a data linkage pilot study.

OBJECTIVE: The aim is to perform a pilot study evaluating the differences in healthcare service use and its associated costs by infant feeding mode in an infant's first year of life. Data from a prospective cohort study and administrative databases were linked to examine healthcare use in healthy full term infants (N = 160). Exposure was categorized as exclusively breastfed, mixed fed and exclusively formula fed. Outcomes included hospitalizations, emergency room and physician visits. Descriptive statistics and generalized linear modelling were performed. RESULTS: Overall $315,235 was spent on healthcare service use for the sample of infants during their first year of life. When compared to exclusive breastfeeding, mixed feeding and exclusive formula feeding were found to be significant predictors of total healthcare service use costs (p < 0.05), driven by costs of hospital admissions. Due to the human and economic burden associated with not breastfeeding, policies and programs that support and encourage breastfeeding should be priority.

The conserved microRNA miR-34 regulates synaptogenesis via coordination of distinct mechanisms in presynaptic and postsynaptic cells.

Micro(mi)RNA-based post-transcriptional regulatory mechanisms have been broadly implicated in the assembly and modulation of synaptic connections required to shape neural circuits, however, relatively few specific miRNAs have been identified that control synapse formation. Using a conditional transgenic toolkit for competitive inhibition of miRNA function in Drosophila, we performed an unbiased screen for novel regulators of synapse morphogenesis at the larval neuromuscular junction (NMJ). From a set of ten new validated regulators of NMJ growth, we discovered that miR-34 mutants display synaptic phenotypes and cell type-specific functions suggesting distinct downstream mechanisms in the presynaptic and postsynaptic compartments. A search for conserved downstream targets for miR-34 identified the junctional receptor CNTNAP4/Neurexin-IV (Nrx-IV) and the membrane cytoskeletal effector Adducin/Hu-li tai shao (Hts) as proteins whose synaptic expression is restricted by miR-34. Manipulation of miR-34, Nrx-IV or Hts-M function in motor neurons or muscle supports a model where presynaptic miR-34 inhibits Nrx-IV to influence active zone formation, whereas, postsynaptic miR-34 inhibits Hts to regulate the initiation of bouton formation from presynaptic terminals.

Drosophila enabled promotes synapse morphogenesis and regulates active zone form and function.

BACKGROUND: Recent studies of synapse form and function highlight the importance of the actin cytoskeleton in regulating multiple aspects of morphogenesis, neurotransmission, and neural plasticity. The conserved actin-associated protein Enabled (Ena) is known to regulate development of the Drosophila larval neuromuscular junction through a postsynaptic mechanism. However, the functions and regulation of Ena within the presynaptic terminal has not been determined. METHODS: Here, we use a conditional genetic approach to address a presynaptic role for Ena on presynaptic morphology and ultrastructure, and also examine the pathway in which Ena functions through epistasis experiments. RESULTS: We find that Ena is required to promote the morphogenesis of presynaptic boutons and branches, in contrast to its inhibitory role in muscle. Moreover, while postsynaptic Ena is regulated by microRNA-mediated mechanisms, presynaptic Ena relays the output of the highly conserved receptor protein tyrosine phosphatase Dlar and associated proteins including the heparan sulfate proteoglycan Syndecan, and the non-receptor Abelson tyrosine kinase to regulate addition of presynaptic varicosities. Interestingly, Ena also influences active zones, where it restricts active zone size, regulates the recruitment of synaptic vesicles, and controls the amplitude and frequency of spontaneous glutamate release. CONCLUSION: We thus show that Ena, under control of the Dlar pathway, is required for presynaptic terminal morphogenesis and bouton addition and that Ena has active zone and neurotransmission phenotypes. Notably, in contrast to Dlar, Ena appears to integrate multiple pathways that regulate synapse form and function.

Human Milk Expression After Domperidone Treatment in Postpartum Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Insufficient milk production is among the most cited reasons by mothers for discontinuing breastfeeding. Medications that can increase milk production, such as domperidone, an off-label galactagogue, are often prescribed. Domperidone is controversial as it is not approved for any purpose in the United States and is approved only for gastrokinetic purposes in Canada and other countries. RESEARCH AIM: The aim was to update the existing literature on the efficacy of domperidone as a galactagogue compared to placebo when given to mothers with insufficient human milk production. The primary outcome is the change in expressed human milk volume per day from baseline. METHODS: The authors independently searched the literature from inception to May 2018. The search included any randomized controlled trials examining the efficacy of domperidone increasing mothers' expressed human milk, measured via a human milk pump. Both authors independently assessed quality and risk of bias and extracted relevant data. Meta-analysis on expressed human milk volume per day was performed. RESULTS: Seven studies met the inclusion criteria for review; two were excluded from the meta-analysis due to quality grading and insufficient reporting of the outcome of interest. Five studies (N = 239) were combined in the meta-analysis. The effect size showed an increase in the mean difference of expressed human milk volume in mothers given domperidone, 93.97 mL per day (95% CI [71.12, 116.83 mL]; random effect, T2 0.00, I2 0%). CONCLUSION: This meta-analysis reports a significant improvement in expressed human milk volume per day with the use of domperidone in mothers experiencing insufficient human milk production.

Removal of boron from wastewater: Evaluation of seven poplar clones for B accumulation and tolerance.

Boron (B) contamination of wastewater is a serious environmental and health problem, which has proved difficult to remediate. One potential approach is phytoremediation, i.e., the use of plants to extract B into the shoot systems, which can then be harvested and removed. The purpose of this study was to investigate the ability of seven hybrid poplar clones to accumulate and tolerate B at different levels of B and salinity. The clones were grown in quarter strength Hoagland's nutrient solution and exposed to four B treatments: 0.25, 25, 75 and 125 mg B L-1 in factorial combination with three salinity treatments: 0, 0.5 and 5 g L-1. Measurements were made of biomass (dry weight) and B concentrations (analyzed by inductively coupled plasma-optical emission spectroscopy) of plant tissues. The results showed that, with increasing level of B supply, the B concentrations in the shoot tissue of the poplar clones increased, while shoot biomass decreased. Comparison of the seven different poplar clones revealed that the clone designated 195-529 exhibited the greatest ability for B accumulation and tolerance. Generally, the 0.5 g L-1 level of salinity was beneficial for poplar growth and B removal, while the high salinity level of 5 g L-1 significantly inhibited poplar growth and B translocation from roots to shoots. Based on the results obtained with this hydroponic system, the clone 195-529 (P. trichocarpa × P. deltoides) is likely to be the most useful for the removal of B from B contaminated wastewater.

Validation of the Standardized Touchscreen Assessment of Cognition with neurotypical adults.

BACKGROUND: Portable electronic devices are increasingly being used for clinical assessment of individuals with cognitive deficits. Prior to implementation of tablet-based assessments, comparison with other standard measures is needed. OBJECTIVE: The study purpose was to compare an iPad administered cognitive assessment known as the Standardized Touchscreen Assessment of Cognition (STAC) to the Cognitive Linguistic Quick Test (CLQT) and the Cognitive Assessment of Minnesota (CAM). METHODS: Eighty-eight neurotypical participants completed the STAC, CAM, and CLQT in a randomized order. The researchers compared the participants' responses across similar subtests. Performance across iPad comfort levels was also explored. RESULTS: Findings revealed moderate correlations in some areas of assessment: generative naming and immediate visual memory. The correlations varied across age groups within each area of assessment with no consistent pattern. Additionally, people with comfort using an iPad performed significantly better on three areas of STAC assessment (generative naming category and first letter, and auditory working memory) compared to people who reported no iPad comfort. CONCLUSIONS: Initial testing of the STAC in a neurotypical population identified moderate correlations with standard measures in some subtests; however, additional testing of the STAC is needed to determine the clinical utility and validity of assessing populations with cognitive impairments.

Effects of copper particles on a model septic system's function and microbial community.

There is concern surrounding the addition of nanoparticles into consumer products due to toxicity potential and the increased risk of human and environmental exposures to these particles. Copper nanoparticles are found in many common consumer goods; therefore, the disposal and subsequent interactions between potentially toxic Cu-based nanoparticles and microbial communities may have detrimental impacts on wastewater treatment processes. This study investigates the effects of three copper particles (micron- and nano-scale Cu particles, and a nano-scale Cu(OH)2-based fungicide) on the function and operation of a model septic tank. Septic system analyses included water quality evaluations and microbial community characterizations to detect changes in and relationships between the septic tank function and microbial community phenotype/genotype. As would be expected for optimal wastewater treatment, biological oxygen demand (BOD5) was reduced by at least 63% during nano-scale Cu exposure, indicating normal function. pH was reduced to below the optimum anaerobic fermentation range during the micro Cu exposure, suggesting incomplete degradation of organic waste may have occurred. The copper fungicide, Cu(OH)2, caused a 57% increase in total organic carbon (TOC), which is well above the typical range for septic systems and also corresponded to increased BOD5 during the majority of the Cu(OH)2 exposure. The changes in TOC and BOD5 demonstrate that the system was improperly treating waste. Overall, results imply individual exposures to the three Cu particles caused distinct disruptions in septic tank function. However, it was observed that the system was able to recover to typical operating conditions after three weeks post-exposure. These results imply that during periods of Cu introduction, there are likely pulses of improper removal of total organic carbon and significant changes in pH not in the optimal range for the system.

Understanding the transformation, speciation, and hazard potential of copper particles in a model septic tank system using zebrafish to monitor the effluent.

Although copper-containing nanoparticles are used in commercial products such as fungicides and bactericides, we presently do not understand the environmental impact on other organisms that may be inadvertently exposed. In this study, we used the zebrafish embryo as a screening tool to study the potential impact of two nano Cu-based materials, CuPRO and Kocide, in comparison to nanosized and micron-sized Cu and CuO particles in their pristine form (0-10 ppm) as well as following their transformation in an experimental wastewater treatment system. This was accomplished by construction of a modeled domestic septic tank system from which effluents could be retrieved at different stages following particle introduction (10 ppm). The Cu speciation in the effluent was identified as nondissolvable inorganic Cu(H2PO2)2 and nondiffusible organic Cu by X-ray diffraction, inductively coupled plasma mass spectrometry (ICP-MS), diffusive gradients in thin-films (DGT), and Visual MINTEQ software. While the nanoscale materials, including the commercial particles, were clearly more potent (showing 50% hatching interference above 0.5 ppm) than the micron-scale particulates with no effect on hatching up to 10 ppm, the Cu released from the particles in the septic tank underwent transformation into nonbioavailable species that failed to interfere with the function of the zebrafish embryo hatching enzyme. Moreover, we demonstrate that the addition of humic acid, as an organic carbon component, could lead to a dose-dependent decrease in Cu toxicity in our high content zebrafish embryo screening assay. Thus, the use of zebrafish embryo screening, in combination with the effluents obtained from a modeled exposure environment, enables a bioassay approach to follow the change in the speciation and hazard potential of Cu particles instead of difficult-to-perform direct particle tracking.

Deposition and disinfection of Escherichia coli O157:H7 on naturally occurring photoactive materials in a parallel plate chamber.

Dissolved organic matter in combination with iron oxides has been shown to facilitate photochemical disinfection through the production of reactive oxygen species (ROS) under UV and visible light. However, due to the extremely short lifetime of these radicals, the disinfection efficiency is limited by the successful transport of ROS to bacterial surfaces. This study was designed to quantitatively investigate three collector surfaces with various potentials to produce ROS [bare quartz, hematite (α-Fe2O3) coated quartz, and Suwannee River humic acid (SRHA)] and the effects of extracellular polymeric substance (EPS) (full or partial coating) and solution chemistry (ionic strength, IS) on the interactions between bacteria and the ROS-producing substrates. With few exceptions, bacterial deposition studies in a parallel plate (PP) flow chamber have revealed increasing cell adhesion with IS. Furthermore, interactions between collector surfaces and cells can be explained by electrostatic forces, with negatively charged SRHA reducing and positively charged α-Fe2O3 enhancing bacterial deposition significantly. Increased deposition was also observed with full EPS content, indicating the ability of EPS to facilitate interaction between cells and surfaces in the aquatic environment. In complementary disinfection studies conducted with simulated light, viability loss was observed for cells fully coated with EPS when attached to α-Fe2O3 under all IS conditions. Based upon our prior study in which EPS was found to not inhibit hydroxyl radical activity toward bacteria, we proposed that EPS might therefore promote disinfection by facilitating cell attachment to ROS-producing surfaces where higher concentrations of ROS are expected at closer proximities to reactive substrates (e.g., SRHA and α-Fe2O3). Our findings on the mechanism and controlling factors of cell interactions with photoactive substrates provide insight as to the role of ionic strength in photochemical disinfection processes.

Novel 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones as IMPDH inhibitors.

The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).