Exposure to Power-Frequency Magnetic Fields and the Risk of Infertility and Adverse Pregnancy Outcomes: Update on the Human Evidence and Recommendations for Future Study Designs.

Infertility and adverse pregnancy outcomes are significant public health concerns with global prevalence. Over the past 35 years, research has addressed whether exposure to power-frequency magnetic fields is one of the etiologic factors attributed to these conditions. However, no apparent authoritative reviews on this topic have been published in the peer-reviewed literature for nearly 15 years. This review provides an overview and critical analysis of human studies that were published in the peer-reviewed literature between 2002 and July 2015. Using PubMed, 13 epidemiology studies published during this time frame that concern exposure to magnetic fields and adverse prenatal (e.g., miscarriage), neonatal (e.g., preterm birth or birth defects), and male fertility (e.g., poor semen quality) outcomes were identified. Some of these studies reported associations whereas others did not, and study design limitations may explain these inconsistencies. Future investigations need to be designed with these limitations in mind to address existing research gaps. In particular, the following issues are discussed: (1) importance of selecting the appropriate study population, (2) need for addressing confounding due to unmeasured physical activity, (3) importance of minimizing information bias from exposure measurement error, (4) consideration of alternative magnetic field exposure metrics, and (5) implications and applications of personal exposure data that are correlated within female-male couples. Further epidemiologic research is needed, given the near ubiquitous exposures to power-frequency magnetic fields in the general population.

Exposure assessment approaches for engineered nanomaterials.

Products based on nanotechnology are rapidly emerging in the marketplace, sometimes with little notice to consumers of their nanotechnology pedigree. This wide variety of nanotechnology products will result (in some cases) in unintentional human exposure to purposely engineered nanoscale materials via the dermal, inhalation, ingestion, and ocular pathways. Occupational, consumer, and environmental exposure to the nanomaterials should be characterized during the entire product lifecycle-manufacture, use, and disposal. Monitoring the fate and transport of engineered nanomaterials is complicated by the lack of detection techniques and the lack of a defined set of standardized metrics to be consistently measured. New exposure metrics may be required for engineered nanomaterials, but progress is possible by building on existing tools. An exposure metric matrix could organize existing data by relating likely exposure pathways (dermal, inhalation, ocular, ingestion) with existing measurements of important characteristics of nanoscale materials (particle number, mass, size distribution, charge). Nanomaterial characteristics not commonly measured, but shown to initiate a biological response during toxicity testing, signal a need for further research, such as the pressing need to develop monitoring devices capable of measuring those aspects of engineered nanomaterials that result in biological responses in humans. Modeling the behavior of nanoparticles may require new types of exposure models that individually track particles through the environment while keeping track of the particle shape, surface area, and other surface characteristics as the nanoparticles are transformed or become reactive. Lifecycle analysis could also be used to develop conceptual models of exposure from engineered nanomaterials.

Nano risk analysis: advancing the science for nanomaterials risk management.

Scientists, activists, industry, and governments have raised concerns about health and environmental risks of nanoscale materials. The Society for Risk Analysis convened experts in September 2008 in Washington, DC to deliberate on issues relating to the unique attributes of nanoscale materials that raise novel concerns about health risks. This article reports on the overall themes and findings of the workshop, uncovering the underlying issues for each of these topics that become recurring themes. The attributes of nanoscale particles and other nanomaterials that present novel issues for risk analysis are evaluated in a risk analysis framework, identifying challenges and opportunities for risk analysts and others seeking to assess and manage the risks from emerging nanoscale materials and nanotechnologies. Workshop deliberations and recommendations for advancing the risk analysis and management of nanotechnologies are presented.

Relationships among particle number, surface area, and respirable mass concentrations in automotive engine manufacturing.

This study investigated the relationships between particle number, surface area, and respirable mass concentration measured simultaneously in a foundry and an automotive engine machining and assembly center. Aerosol concentrations were measured throughout each plant with a condensation particle counter for number concentration, a diffusion charger for active surface area concentration, and an optical particle counter for respirable mass concentration. At selected locations, particle size distributions were characterized with the optical particle counter and an electrical low pressure impactor. Statistical analyses showed that active surface area concentration was correlated with ultrafine particle number concentration and weakly correlated with respirable mass concentration. Correlation between number and active surface area concentration was stronger during winter (R2 = 0.6 for both plants) than in the summer (R2 = 0.38 and 0.36 for the foundry and engine plant respectively). The stronger correlation in winter was attributed to use of direct-fire gas fired heaters that produced substantial numbers of ultrafine particles with a modal diameter between 0.007 and 0.023 mu m. These correlations support findings obtained through theoretical analysis. Such analysis predicts that active surface area increasingly underestimates geometric surface area with increasing particle size, particularly for particles larger than 100 nm. Thus, a stronger correlation between particle number concentration and active surface area concentration is expected in the presence of high concentrations of ultrafine particles. In general, active surface area concentration may be a concentration metric that is distinct from particle number concentration and respirable mass concentration. For future health effects or toxicological studies involving nano-materials or ultrafine aerosols, this finding needs to be considered, as exposure metrics may influence data interpretation.

Meeting report: hazard assessment for nanoparticles--report from an interdisciplinary workshop.

In this report we present the findings from a nanotoxicology workshop held 6-7 April 2006 at the Woodrow Wilson International Center for Scholars in Washington, DC. Over 2 days, 26 scientists from government, academia, industry, and nonprofit organizations addressed two specific questions: what information is needed to understand the human health impact of engineered nanoparticles and how is this information best obtained? To assess hazards of nanoparticles in the near-term, most participants noted the need to use existing in vivo toxicologic tests because of their greater familiarity and interpretability. For all types of toxicology tests, the best measures of nanoparticle dose need to be determined. Most participants agreed that a standard set of nanoparticles should be validated by laboratories worldwide and made available for benchmarking tests of other newly created nanoparticles. The group concluded that a battery of tests should be developed to uncover particularly hazardous properties. Given the large number of diverse materials, most participants favored a tiered approach. Over the long term, research aimed at developing a mechanistic understanding of the numerous characteristics that influence nanoparticle toxicity was deemed essential. Predicting the potential toxicity of emerging nanoparticles will require hypothesis-driven research that elucidates how physicochemical parameters influence toxic effects on biological systems. Research needs should be determined in the context of the current availability of testing methods for nanoscale particles. Finally, the group identified general policy and strategic opportunities to accelerate the development and implementation of testing protocols and ensure that the information generated is translated effectively for all stakeholders.

Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles.

Nanoparticles are small-scale substances (<100 nm) with unique properties and, thus, complex exposure and health risk implications. This symposium review summarizes recent findings in exposure and toxicity of nanoparticles and their application for assessing human health risks. Characterization of airborne particles indicates that exposures will depend on particle behavior (e.g., disperse or aggregate) and that accurate, portable, and cost-effective measurement techniques are essential for understanding exposure. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods, and the effect of skin condition on penetration. Carbon nanotubes apparently have greater pulmonary toxicity (inflammation, granuloma) in mice than fine-scale carbon graphite, and their metal content may affect toxicity. Studies on TiO2 and quartz illustrate the complex relationship between toxicity and particle characteristics, including surface coatings, which make generalizations (e.g., smaller particles are always more toxic) incorrect for some substances. These recent toxicity and exposure data, combined with therapeutic and other related literature, are beginning to shape risk assessments that will be used to regulate the use of nanomaterials in consumer products.

In situ structure characterization of airborne carbon nanofibres by a tandem mobility-mass analysis.

Carbon nanofibres aerosolized by the agitation of as-produced commercial powder have been characterized in situ by using the differential mobility analyser-aerosol particle mass analyser (DMA-APM) method to determine their structural properties such as the effective density and fractal dimension for toxicology study. The effective density of the aerosolized carbon nanofibres decreased from 1.2 to 0.4 g cm(-3) as the mobility diameters increased from 100 to 700 nm, indicating that the carbon nanofibres had open structures with an overall void that increased with increasing diameter, due to increased agglomeration of the nanofibres. This was confirmed by transmission electron microscopy (TEM) observation, showing that 100 nm mobility diameter nanofibres were predominantly single fibres, while doubly or triply attached fibres were seen at mobility diameters of 200 and 400 nm. Effective densities calculated using Cox's theory were in reasonable agreement with experimental values. The mass fractal dimension of the carbon nanofibres was found to be 2.38 over the size range measured and higher than that of single-walled carbon nanotubes (SWCNTs), suggesting that the carbon nanofibres have more compact structure than SWCNTs.

Mitigating Risks to Pregnant Teens from Zika Virus.

Zika infection in pregnant women is associated with an elevated probability of giving birth to a child with microcephaly and multiple other disabilities. Public health messaging on Zika prevention has predominantly targeted women who know they are pregnant or intend to become pregnant, but not teenage females for whom unintended pregnancy is more likely. Vulnerabilities among this population to reproductive risks associated with Zika are further amplified by restrictive abortion laws in several Zika-impacted states. Key to prevention is enhanced, targeted public health messaging centered on teens nationally and particularly in certain high-risk regions.

Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome.

PERSONAL MEASURES OF POWER-FREQUENCY MAGNETIC FIELD EXPOSURE AMONG MEN FROM AN INFERTILITY CLINIC: DISTRIBUTION, TEMPORAL VARIABILITY AND CORRELATION WITH THEIR FEMALE PARTNERS' EXPOSURE.

Power-frequency magnetic field exposure science as it relates to men and couples have not been explored despite the advantage of this information in the design and interpretation of reproductive health epidemiology studies. This analysis examined the distribution and temporal variability of exposures in men, and the correlation of exposures within couples using data from a longitudinal study of 25 men and their female partners recruited from an infertility clinic. The average and 90th percentile demonstrated fair to good reproducibility, whereas the maximum showed poor reproducibility over repeated sampling days, each separated by a median of 4.6 weeks. Average magnetic field exposures were also strongly correlated within couples, suggesting that one partner's data could be used as a surrogate in the absence of data from the other for this metric. Environment was also an important effect modifier in these explored matters. These issues should be considered in future relevant epidemiology studies.

Protein Corona-Induced Modification of Silver Nanoparticle Aggregation in Simulated Gastric Fluid.

Due to their widespread incorporation into a range of biomedical and consumer products, the ingestion of silver nanoparticles (AgNPs) is of considerable concern to human health. However, the extent to which AgNPs will be modified within the gastric compartment of the gastrointestinal tract is still poorly understood. Studies have yet to fully evaluate the extent of physicochemical changes to AgNPs in the presence of biological macromolecules, such as pepsin, the most abundant protein in the stomach, or the influence of AgNPs on protein structure and activity. Herein, AgNPs of two different sizes and surface coatings (20 and 110 nm, citrate or polyvinylpyrrolidone) were added to simulated gastric fluid (SGF) with or without porcine pepsin at three pHs (2.0, 3.5, and 5.0), representing a range of values between preprandial (fasted) and postprandial (fed) conditions. Rapid increases in diameter were observed for all AgNPs, with a greater increase in diameter in the presence of pepsin, indicating that pepsin facilitated AgNPs aggregation. AgNPs interaction with pepsin only minimally reduced the protein's proteolytic functioning capability, with the greatest inhibitory effect caused by smaller (20 nm) particles of both coatings. No changes in pepsin secondary structural elements were observed for the different AgNPs, even at high particle concentrations. This research highlights the size-dependent kinetics of nanoparticle aggregation or dissolution from interaction with biological elements such as proteins in the gastrointestinal tract. Further, these results demonstrate that, in addition to mass, knowing the chemical form and aggregation state of nanoparticles is critical when evaluating toxicological effects from nanoparticle exposure in the body.

Effects of particle size and coating on toxicologic parameters, fecal elimination kinetics and tissue distribution of acutely ingested silver nanoparticles in a mouse model.

Consumer exposure to silver nanoparticles (AgNP) via ingestion can occur due to incorporation of AgNP into products such as food containers and dietary supplements. AgNP variations in size and coating may affect toxicity, elimination kinetics or tissue distribution. Here, we directly compared acute administration of AgNP of two differing coatings and sizes to mice, using doses of 0.1, 1 and 10 mg/kg body weight/day administered by oral gavage for 3 days. The maximal dose is equivalent to 2000× the EPA oral reference dose. Silver acetate at the same doses was used as ionic silver control. We found no toxicity and no significant tissue accumulation. Additionally, no toxicity was seen when AgNP were dosed concurrently with a broad-spectrum antibiotic. Between 70.5% and 98.6% of the administered silver dose was recovered in feces and particle size and coating differences did not significantly influence fecal silver. Peak fecal silver was detected between 6- and 9-h post-administration and <0.5% of the administered dose was cumulatively detected in liver, spleen, intestines or urine at 48 h. Although particle size and coating did not affect tissue accumulation, silver was detected in liver, spleen and kidney of mice administered ionic silver at marginally higher levels than those administered AgNP, suggesting that silver ion may be more bioavailable. Our results suggest that, irrespective of particle size and coating, acute oral exposure to AgNP at doses relevant to potential human exposure is associated with predominantly fecal elimination and is not associated with accumulation in tissue or toxicity.

Rapid Kinetics of Size and pH-Dependent Dissolution and Aggregation of Silver Nanoparticles in Simulated Gastric Fluid.

As silver nanoparticles (AgNPs) are used in a wide array of commercial products and can enter the human body through oral exposure, it is important to understand the fundamental physical and chemical processes leading to changes in nanoparticle size under the conditions of the gastrointestinal (GI) tract. Rapid AgNP growth was observed using nanoparticle tracking analysis with 30 s resolution over a period of 17 min in simulated gastric fluid (SGF) to explore rapid kinetics as a function of pH (SGF at pH 2, 3.5, 4.5 and 5), size (20 and 110 nm AgNPs), and nanoparticle coating (citrate and PVP). Growth was observed for 20 nm AgNP at each pH, decreasing in rate with increasing pH, with the kinetics shifting from second-order to first-order. The 110 nm AgNP showed growth at ≤3.5 pH, with no growth observed at higher pH. This behavior can be explained by the generation of Ag+ in acidic environments, which precipitates with Cl-, leading to particle growth and facilitating particle aggregation by decreasing their electrostatic repulsion in solution. These results highlight the need to further understand the importance of initial size, physicochemical properties, and kinetics of AgNPs after ingestion to assess potential toxicity.

Exposure to carbon nanotube material: aerosol release during the handling of unrefined single-walled carbon nanotube material.

Carbon nanotubes represent a relatively recently discovered allotrope of carbon that exhibits unique properties. While commercial interest in the material is leading to the development of mass production and handling facilities, little is known of the risk associated with exposure. In a two-part study, preliminary investigations have been carried out into the potential exposure routes and toxicity of single-walled carbon nanotube material (SWCNT)--a specific form of the allotrope. The material is characterized by bundles of fibrous carbon molecules that may be a few nanometers in diameter, but micrometers in length. The two production processes investigated use-transition metal catalysts, leading to the inclusion of nanometer-scale metallic particles within unrefined SWCNT material. A laboratory-based study was undertaken to evaluate the physical nature of the aerosol formed from SWCNT during mechanical agitation. This was complemented by a field study in which airborne and dermal exposure to SWCNT was investigated while handling unrefined material. Although laboratory studies indicated that with sufficient agitation, unrefined SWCNT material can release fine particles into the air, concentrations generated while handling material in the field were very low. Estimates of the airborne concentration of nanotube material generated during handling suggest that concentrations were lower than 53 microg/m(3) in all cases. Glove deposits of SWCNT during handling were estimated at between 0.2 mg and 6 mg per hand.

Recommendations for nanomedicine human subjects research oversight: an evolutionary approach for an emerging field.

The nanomedicine field is fast evolving toward complex, "active," and interactive formulations. Like many emerging technologies, nanomedicine raises questions of how human subjects research (HSR) should be conducted and the adequacy of current oversight, as well as how to integrate concerns over occupational, bystander, and environmental exposures. The history of oversight for HSR investigating emerging technologies is a patchwork quilt without systematic justification of when ordinary oversight for HSR is enough versus when added oversight is warranted. Nanomedicine HSR provides an occasion to think systematically about appropriate oversight, especially early in the evolution of a technology, when hazard and risk information may remain incomplete. This paper presents the consensus recommendations of a multidisciplinary, NIH-funded project group, to ensure a science-based and ethically informed approach to HSR issues in nanomedicine, and to integrate HSR analysis with analysis of occupational, bystander, and environmental concerns. We recommend creating two bodies, an interagency Human Subjects Research in Nanomedicine (HSR/N) Working Group and a Secretary's Advisory Committee on Nanomedicine (SAC/N). HSR/N and SAC/N should perform 3 primary functions: (1) analysis of the attributes and subsets of nanomedicine interventions that raise HSR challenges and current gaps in oversight; (2) providing advice to relevant agencies and institutional bodies on the HSR issues, as well as federal and federal-institutional coordination; and (3) gathering and analyzing information on HSR issues as they emerge in nanomedicine. HSR/N and SAC/N will create a home for HSR analysis and coordination in DHHS (the key agency for relevant HSR oversight), optimize federal and institutional approaches, and allow HSR review to evolve with greater knowledge about nanomedicine interventions and greater clarity about attributes of concern.