January 2016 - Issue 4
Welcome to Battelle’s Life Sciences Research CRO+ Today Newsletter. The Battelle Life Sciences Research team provides fast, accurate answers for discovery, safety and efficacy with our integrated scientific and technological capabilities, world-class facilities and ability to meet technical, development and regulatory needs. Battelle Life Sciences CRO+ Today will keep you up-to-date on cutting-edge life sciences research.
Nanomaterials are revolutionizing materials science—but what are they doing to our health? Since it is early in the development of these materials and their applications, there is limited information on which to make protective recommendations. Scientists at Battelle are conducting a series of inhalation toxicology studies to find out whether these innovative materials have unintended side effects.
The modern nanomaterial era began in the 1980s with the discovery of Buckminsterfullerene(C60), more commonly known as the “buckyball”: a soccer-ball shaped carbon nanostructure with exceptional hardness. Over the last two decades, materials science research has focused on development and commercialization of carbon nanotubes. These tiny cylindrical carbon structures can have diameters as small as one ten thousandths of a human hair.
Carbon nanotubes have unique properties of strength, stiffness, tenacity, and thermal and electrical conductivity that make them highly valuable for many different applications. Carbon nanotubes have been used to make very strong, lightweight materials for aviation, armor, medical devices and prosthetics, sporting goods, and a wide range of other consumer and industrial products. While carbon-based materials are the most commonly used today, nanomaterials made out of silica or other materials are also in development.
However, while nanomaterials are becoming more ubiquitous, very little research has been done on their potential health impacts. Because these particles are microscopic and easily inhaled, inhalation toxicity is a particular concern. While consumers of finished products are unlikely to have much exposure, workers who handle nanomaterials during manufacturing may be exposed to large quantities of aerosolized nanotubes as they grind, sand, cut or drill the materials.
Because these materials are so new, regulations have not kept pace with their development. Until recently, since there was no Occupational Safety and Health Administration (OSHA) recommended permissible exposure limit for carbon nanotubes; the permissible exposure limits for graphite (5,000 micrograms per cubic meter (ug/m3)) or carbon black (3,500 ug/m3) were being inappropriately applied as a guide to control worker exposures to carbon nanotubes. In 2013, limits for carbon nanotube exposure were dramatically reduced to 1.0 (μg/m3) as an 8-hour time-weighted average. However, significant gaps exist in the knowledge base needed to set safe exposure limits for different kinds of nanoparticles.
Because nanoparticles are orders of magnitude smaller than ordinary particulates, their impact on the body can be very different. Nanoparticles may be able to penetrate skin, for example. When inhaled, they may be deposited in the lungs in a different pattern than is typical for larger particles, and may more easily enter the bloodstream and be transported to different parts of the body. Some nanoparticles may even be able to cross the blood-brain barrier. And because of their near-atomic size, they are able to interact with molecules in the body in different ways. These differences mean that nanoparticles may have much greater toxic effects than a similar quantity of the same material with a larger particle size.
In order to set safe exposure limits, manufacturers and regulators need to have a better understanding of these differences and how nanoparticle properties impact toxicity. There can be many variations of the same nanomaterial, leading to varying levels of toxicity. For example, there is a wide variation among carbon nanotubes depending on how they are generated. Carbon nanotubes can be single-walled or multi-walled and come in a variety of lengths and diameters. They may also contain tiny amounts of the metal catalyst used during generation (usually nickel, iron, molybdenum or cobalt). All of these variations in size, structure and composition can impact the way the particles interact with the body. The same issues apply to non-carbon based nanomaterials.
In order to get a better understanding of these factors, Battelle is conducting inhalation toxicology studies of carbon nanoparticles. In 2009, toxicologists conducted extensive research on buckyballs as part of the National Toxicology Program (NTP) for the National Institute of Environmental Health Sciences (NIEHS), an interagency program overseen by the U.S. Department of Health and Human Services. In 2011, Battelle researchers developed an aerosol exposure system that was capable of generating reproducible aerosols of a multi-walled carbon nanotube in a whole-body exposure chamber. This exposure system was tested by Battelle to generate and characterize an inhalation exposure atmosphere using five different varieties of multi-walled carbon nanotubes. They are also getting ready to start a two-year chronic exposure study with multi-walled carbon nanotubes.
Conducting inhalation toxicology studies with nanomaterials required researchers to first develop new methods to aerosolize, characterize and measure dosages for nanoparticles. Working with nanoparticles presents a number of challenges for inhalation research. Most inhalation studies express doses in terms of mg/m3. However, with the tiny size of nanoparticles it is not clear whether this is even the right measure to express dosage. Nanoparticles have a very high surface area-to-mass ratio; a given quantity by mass will have many more nanoparticles in the same volume than a sample with the same mass of micro-particles. Before conducting the studies, researchers needed to have a better understanding of how to accurately measure nanoparticle samples for precise dosing.
Nanoparticles tend to quickly agglomerate together due to the high surface attraction forces at this size range. Once they have agglomerated, they are no longer of nanometer size, changing their properties and potential for toxicity. Researchers had to develop a novel generation system that would allow them to control the aerosol particle size at the desired concentrations in order to make sure particles remained at the right size at the time of dosing.
In earlier studies, Battelle researchers characterized nanoparticles that are released during sanding of nanoparticle-impregnated composite materials and observed their particle size and concentration in near real-time using a scanning mobility particle sizer. Since the nanoparticle size and properties may change with time, it is necessary to complement the traditional techniques of aerosol characterization with real-time or near real-time characterization. These observations have helped to inform the generation of agglomerated samples that more closely resemble the characteristics of particles that workers might inhale during manufacturing.
This precise characterization is necessary in order to untangle the variables that may impact the toxicity of nanoparticles. These studies are an important first step in enabling manufacturers and regulatory bodies to set informed exposure limits. Future studies will be needed to examine the heath effects of other types of nanoparticles.
Battelle offers a complete package of inhalation toxicology services for safety pharmacology, drug development and environmental toxicology.
Phosgene is used as a chemical intermediate in the production of pesticides, plastics, dyes, polyurethanes and pharmaceuticals. Nearly a million metric tons of phosgene are produced and used annually in the United States with a potential exposure of approximately 10,000 workers. Due to phosgene’s wide availability and use in both the chemical and pharmaceutical industries, it is a health concern from both accidental and deliberate releases.
Site Clinical Veterinarian Dr. Sara Roshwalb is helping to keep the Battelle Biomedical Research Center (BBRC) at the forefront of good laboratory practice. Her work ensures that all laboratory animals are kept in accordance with the current health and safety standards and that pre-clinical trials are conducted using the latest standards and practices.
Jen Plahovinsak is the face of the Battelle Life Sciences Research Group for many of our clients. As a Principal Research Scientist and Study Director, she works with clients to understand their needs, evaluates study designs to ensure that those needs are being met, and communicates study results. Her leadership keeps toxicology projects on track and on target.
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