Nanotechnology and Nanotoxicology

Toxicol Rev 2006; 25 (4): 245-260REVIEW ARTICLE 1176-2551/06/0004-0245/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Nanotechnology and NanotoxicologyA Primer for Clinicians

John Curtis,1 Michael Greenberg,1 Janet Kester,2 Scott Phillips3 and Gary Krieger4

1 Division of Medical Toxicology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA2 Newfields, LLC, St Louis, Missouri, USA3 Division of Clinical Pharmacology and Toxicology, University of Colorado Health Sciences Center, Rocky Mountain

Poison and Drug Center, Denver, Colorado, USA4 Department of Pharmaceutical Sciences, Molecular Toxicology Section, School of Pharmacy, University of Colorado

Health Sciences Center, Denver, Colorado, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2451. Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2462. Primary Products of Nanotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

2.1 Fullerenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2472.2 Carbon Nanotubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2472.3 Quantum Dots . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

3. Commercial Uses and Economic Importance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2483.1 Medical Uses of Nanotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

3.1.1 Drug Delivery and Biomedical Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2493.1.2 Biosensing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250

4. Toxicity of Nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2504.1 Inhalational and Pulmonary Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2504.2 Toxicity Following Dermal Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2524.3 Toxicity Following Ingestion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2534.4 Toxicity Due to Crossing of Biological Barriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2534.5 Health Effects Due to Chemical Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2534.6 Antigenicity of Carbon Nanomaterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2544.7 Genotoxicity and Effects on Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

5. Environmental and Regulatory Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2545.1 Potential Environmental Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2545.2 US Regulatory Statutes and Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255

6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

Nanotechnology is the manipulation of matter in dimensions <100nm. At this size, matter can take onAbstractdifferent chemical and physical properties, giving the products characteristics useful to industry, medicine andtechnology. Government funding and private investors provide billions of research dollars for the developmentof new materials and applications. The potential utility of these technologies is such that they are expected be atrillion-dollar industry within the next 10 years.

However, the novel properties of nanoengineered materials lead to the potential for different toxicitycompared with the bulk material. The field of nanotoxicology is still in its infancy, however, with very limitedliterature regarding potential health effects. Inhalational toxicity is to be expected, given the known effects ofinhaled fine particulate matter. However, the degree to which most nanoparticles will aerosolise remains to bedetermined. It has been proposed that dermal exposure will be the most relevant route of exposure, but there is

246 Curtis et al.

considerably less literature regarding dermal effects and absorption. Less defined still are the potential effects ofnanoproducts on fetal development and the environment.

The prefix ‘nano-’ is derived from the Greek word for dwarf, manufacture and use of these important technologies. This articleand mathematically indicates one one-billionth. Nanotechnology reviews some of the more important areas of research in theseis the science and technology that deals with the study and con- fields, with a focus on products that are or might be produced on atrolled manufacture of particles that are <100 nanometres (nm) in large scale, particularly those with potential consumer or medicallength. This minuteness can be appreciated by considering the fact uses that would be expected to lead to significant human orthat a nanometre is one-billionth (10–9) of a metre, roughly the environmental exposures. The results of early cytotoxicity andwidth of ten hydrogen atoms or one hundred thousandth the width biocompatibility studies will be reviewed by route of exposure andof an average human hair. Thus, most nanoparticles are substan- mechanism, and finally the implications of this early research ontially smaller than eukaryotic or prokaryotic cells, and are compa- environmental and occupational regulation will be discussed.rable to the size of an antibody or virus.[1]

Nanotechnology finds or will find uses in most sectors of 1. Historical Perspectiveindustry. For example, in the energy sector, its use in solar cells,fuel additives and batteries is being explored. In medicine, it will

Nanotechnology is, broadly defined, the fields of science thatfind use in biometric sensors for medical screening and in applica-

encompass the understanding and control of matter at extremelytions for the sequencing of DNA. The industrial materials sector

minute sizes ranging from approximately 1 to 100nm, whereuses or will use nanotechnology in catalysts, coatings, alloys,

unique phenomena enable novel applications. Encompassing na-abrasives, glues, electrical circuits and other applications.

noscale science, engineering and technology, nanotechnology in-Nanotechnology is a varied, multidisciplinary science, with the

volves imaging, measuring, modelling and manipulating matter inonly unifying theme being the minuscule dimensions involved.

the nanometre range. At the nanoscale, the physical, chemical andThe substances themselves and the processes used to create them

biological properties of materials differ in fundamental ways frommay differ dramatically from case to case. Thus, it is impossible to

the properties of individual atoms, molecules or conglomerationsascribe uniform physical and chemical characteristics to the mater-

thereof. Research and development in nanotechnology is directedials encompassed by the umbrella term ‘nanotechnology’. The

toward understanding and creating improved materials, devices,great differences between products make it exceedingly difficult to

and systems that exploit these new properties.accurately generalise the potential toxicological effects of these

The rudiments of the science of nanotechnology evolved frommaterials on the occupationally exposed worker or the productresearch in a variety of endeavours. In 1959, the renowned physi-consumer.cist Richard Feynman suggested that machines could be made on aAt ‘nano’ sizes, the usual chemical properties of a substancescale small enough to produce objects with precision at the atomicmay be substantially altered. This effect is partly due to the factlevel. In addition, Feynman predicted that information could bethat compared with larger particles, the relative surface area isstored with unprecedented density. Feynman first promulgated hismuch larger per unit mass, and atoms on the surface of a moleculeideas in a presentation entitled There’s Plenty of Room at thebecome potentially available to participate in chemical reactions.Bottom. This presentation is considered to be the foundation ofFurthermore, the quantum effects that are more prominent overnanotechnology.such minute distances can change the fundamental ways in which

a given substance behaves. Thus, nanomaterials may have differ- In the 1970s, Eric Drexler realised that ‘molecular machines’ent chemical, optical, magnetic and structural properties, and could control the chemical manufacture of complex products. Hisconsequently different toxicities, than are normally attributed to ideas formed the basis for what would eventually become molecu-the bulk material. While nanomaterials may have an enhanced lar manufacturing. The term ‘nanotechnology’ was first intro-commercial value, these differences in fundamental properties duced into the scientific parlance by Taniguchi in the 1970s.make it necessary to specifically examine their biological effects. However, it was Drexler in 1986 who popularised the term in a

book entitled Engines of Creation describing both this approach toWith nanomaterials becoming an integral part of the economymanufacturing as well as potential adverse consequences. In anand a more frequent component of consumer products, many haveattempt to raise awareness of the implications of this ‘new’ tech-recognised the importance of prospectively identifying the poten-nology, Drexler founded the Foresight Institute.tial human health and environmental risks associated with the

© 2006 Adis Data Information BV. All rights reserved. Toxicol Rev 2006; 25 (4)

Nanotechnology and Nanotoxicology 247

In the early 1990s, Drexler published an outline of the manufac- 2.1 Fullerenesture of very high-performance machines made from molecular

Fullerenes are the ‘buckyballs’ already familiar to some of thecarbon lattices termed ‘diamondoid’. The term ‘nanotechnology’

general public. In 1996, Curl, Kroto and Smalley were awarded arapidly became popular, and almost immediately its meaning

Nobel prize for the discovery of this other allotropic form ofbegan to shift. By 1992, Drexler referred to ‘molecular na-

carbon in 1985. Fullerenes were first created by vaporising carbonnotechnology’ or ‘molecular manufacturing’ to distinguish his

and allowing it to condense in an atmosphere of inert gas. Themanufacturing ideas from the less complex product-focused re-

resulting carbon was found to be arranged in clusters of differentsearch. This research, producing shorter-term results, came to

numbers of atoms, with the most prevalent configuration being adefine the field for many observers, and has continued to claim the

60-carbon structure. C60 was found to have 32 sides, 20 with 6term ‘nanotechnology’.

angles and 12 with 5 angles. This arrangement, the same as that ofFederal funding for nanotechnology research began under Pres-

a soccer ball, is also found in a famous geodesic dome designed byident Clinton with the formation of the National Nanotechnology

the architect R. Buckminster Fuller, which resulted in the use ofInitiative (NNI), a federal research and development programme

the term buckminsterfullerene for the 60-carbon structure, andestablished in 1996 to coordinate governmental multi-agency ef-

hence ‘buckyballs’.forts in nanoscale science, engineering and technology. The NNIfunds nanoscale technology, defined as anything with a size be- 2.2 Carbon Nanotubestween 1 and 100nm with novel properties. This includes cutting-

Carbon nanotubes (CNTs) were discovered by Sumio Iijima inedge semiconductor research, several developing fields of chemis-1991 while experimenting with previously described methods oftry and advances in materials. Noted computer scientist Bill Joysynthesizing C60.[3] While similar to the carbon arrangements inauthored an article entitled Why the Future Doesn’t Need Usgraphite, rather than being arrayed in sheets, carbon atoms inpublished in Wired, which first publicised concerns regarding thenanotubes are arranged helically, curling into cylindrical struc-safety of this new technology.[2] These claims gained force sincetures that resemble elongated fullerenes. CNTs display axial sym-molecular manufacturing research was (and remains) highly tech-metry and high aspect (length to width) ratios, and are oftennical, interdisciplinary, theoretical and mostly undemonstrated.capped on one or both ends. They are produced from a variety ofThree general areas of current government-funded researchcarbon sources using a variety of methods.impact nanoscale materials. These include: (i) basic research to

CNTs are themselves a diverse set, both chemically and struc-expand knowledge and understanding of how nanomaterials be-turally. They can be single-walled (SWCNT) or multi-walledhave, both in the environment and in the human body; (ii) research(MWCNT), and vary in width from 0.4nm for SWCNTs to hun-to develop instrumentation and methods for measuring, character-dreds of nanometres for MWCNTs.[4] Furthermore, rather thanising and testing nanomaterials as well as for monitoring exposure;simply representing slender tubes, there are a variety of configura-and (iii) research toward assessing safety of chemicals, food, drugstions of the composite carbon atoms; they have armchair, zigzag orand medical devices, among other items. The concept of riskchiral substructures.[4] The substructures become even more com-involves two factors – hazard and exposure. Today, researchersplicated for MWCNTs, and it is impossible to characterise nano-must be cognizant of potential hazards when working with newtubes and nanofilaments as a homogeneous chemical group basedmaterials having unknown properties, but there is generally nosolely on their shapes. They may be hydrophilic or hydrophobic,exposure to the public or environment from these activities andwith or without metal catalysts (including iron, nickel and yttri-thus, little risk. In its recent review of the NNI, the Nationalum),[5] and may have electrical properties similar to metals or toNanotechnology Advisory Panel (NNAP) noted that the greatestsemiconductors. It is this potential to manipulate electrical andlikelihood of exposure to nanomaterials is during manufacture.mechanical properties that make CNTs so attractive and versatile.

2. Primary Products of Nanotechnology2.3 Quantum Dots

While there are many different products that qualify as na- Quantum dots (Qdots, QDs) or nanocrystals are luminescentnotechnology, there are several that deserve special attention for particles with dimensions smaller than the Exciton Bohr Radiustheir historical importance and potential usefulness. Since research (the natural physical separation in a crystal between an electron inand production of these specific technologies is already maturing, the conduction band and the hole it leaves behind in the valencethe potential for exposure and health effects needs to be consid- band). For bulk materials, the energy difference between theered. conduction band and the valence band (the bandgap) is fixed,


248 Curtis et al.

resulting in a release of energy of a fixed wavelength. Because of ment of Labor (including the Occupational Safety and Healthquantum confinement, decreasing the size of the crystal below Administration [OSHA]), the US Food and Drug Administrationabout 10nm increases the size of the bandgap – resulting in higher (FDA), the Environmental Protection Agency (EPA), and theenergy (blue-shifted) energy emissions. This is the basis of the National Institute for Occupational Safety and Health (NIOSH).size-dependant ‘tunability’ of Qdots. The NNI has coordinated over $US3.2 billion in grant money for

nanotechnology research from the period of 2000–04.[12]Qdots are composed of several layers: a nanocrystalline coreusually composed of atoms from groups II–VI or III–V of the International spending on nanotechnology initiatives is also onperiodic table, and a surrounding protective shell, often made of the rise, with China, India, South Africa as well as East Asian andzinc sulphide. This shell can then be coated with functional groups Central and South American governments planning to spend mil-that increase solubility or specifically bind to targets. Qdots are lions of dollars in the next few years.[13,14] Japan is also on the‘tunable’ to various emission frequencies by changing their physi- forefront of nanotechnology research, not only in governmentalcal dimensions.[6] At a core diameter of 6nm they emit a red light, funding, but also in its well developed private sector.[15] It is hopedbut decreasing sizes yield shorter wavelengths, and a 3nm core that nanotechnology will improve large segments of the develop-will produce green fluorescence. Further decreasing their size ing world through advancements in energy storage and transmis-results in Qdots that are also able to emit light outside of the visible sion, agricultural productivity and water treatment.[13]

spectrum. Governmental spending is not the only source of funding forA potential problem limiting the in vivo use of Qdots has been nanotechnology, and research laboratories are not the only sources

the fact that they tend to clump together and lose their fluorescence for production of nanotechnologies. The private sector has longin the intracellular environment.[7] A strategy to overcome this since realised the potential of nanomaterials to revolutionise theirlimitation is to add biocompatible surface modifications to the businesses and create profits. In fact, the current nanotechnologynanocrystals, or to complex them with proteins such as albumin.[8] market is measured in hundreds of millions of dollars annually,

By attaching biotargeting peptides, it is possible to generate and is expected by the NSF and others to reach approximatelywater-soluble luminescent markers that can be directed to tissue- $US1 trillion dollars by 2015.[16]

specific sites both in vitro and in vivo, including human breast Merril-Lynch compares the economic impact of nanotechnolo-cancer cells, lung and brain endothelium.[9] gy to that of information technology and the Internet in the recent

Qdots of various emission frequencies and intensities can be past, and in 2004 introduced a nanotechnology index, which isimplanted uniformly and reproducibly into microbeads to give an updated by the American Stock Exchange every 15 seconds.[17] Aenormous number of identifiable bead ‘identities’. These beads recent review found 212 consumer products that currently usecan be targeted with DNA sequences and used to identify millions nanotechnology, with the cosmetics industry leading the list.[18]

of unique sequences.[10] As the commercial impact of nanotechnology becomes moreevident, companies and universities are rushing to patent theirinventions. This is an unusual situation for nascent industries,3. Commercial Uses and Economic Importanceespecially since the multidisciplinary nature of nanotechnologycould allow such patents to stretch across many industries.[19]From its early stages, nanotechnology has been recognised asThese patents have not stemmed the influx of nanotechnology-having the potential for revolutionising many areas of our lives,inspired products into the consumer market, however.from our understanding of matter on a small scale, to creating

products that will greatly affect our day-to-day lives. This promise A recent article summarised the current uses of nanotechnologywas recognised not only by the private sector, but also by the in the UK: “catalysts, lubricants and fuel additives, paints, pig-scientific and regulatory communities. ments and coatings, conductive inks and printing materials, cos-

President Clinton nearly doubled the government’s funding for metics and personal care products (e.g. sunscreens), drug delivery/nanotechnology when he began the NNI in 2000. Involved in this bionanotechnology, functional coatings (e.g. on glass, textiles),new endeavour were the agencies that represented some of the hydrogen storage and fuel cell applications, nanoelectronics andareas in which nanotechnology was expected to have the most sensor devices, optics and optic devices, security and authentica-influence, including the National Science Foundation (NSF), the tion applications, structural (composite) materials, therapeutics,Department of Defense (DOD), the Department of Energy (DOE), medical and dental and UV light absorbers and free-radical scav-National Institutes of Health (NIH), National Aeronautics and engers.”[16] This list is certainly incomplete and destined to expandSpace Administration (NASA), and National Institute of Stan- rapidly in the coming decades. While not traditionally considereddards and Technology (NIST).[11] Also involved are the Depart- ‘nanotechnology’, the metal tracings on semiconductor chips are



currently under the 100nm ‘cutoff’ for nanoscale technologies.[20] glycol (PEG), which has been shown to increase the time particlesAs the pressure to condense computational power onto smaller and spend in circulation.[21]

smaller surface areas increased, the physical limits of the current Nanoparticles can leave the circulation through a variety ofmaterials will be stressed or exceeded, leading to the search for routes. Paracellular egress is limited by endothelial tight junctions,new, and quite possibly carbon-based semiconducting materials, which at <2nm are typically too small to allow even nanoparticlesalready an active area for nanotechnology research. Perhaps one of to slip between cells.[22] Interestingly, in some cancers, the endo-the most promising areas of use is one in which the biocompatibili- thelium becomes more porous, potentially allowing a de factoty of nanomaterials will be most important: medicine. targeting of these sites.[23] Transcellular egress is effected through

receptor-mediated endocytosis or nonspecific processes such as3.1 Medical Uses of Nanotechnology pinocytosis. Tissue targeting by entering or binding to specific cell

populations has been attempted by various means, but usuallyMedical uses for these technologies are emerging daily, and involves the use of specific coatings and chemical modifications.

some of these products are hoped to bring the capabilities of These techniques have shown the potential to localise drugs,molecular genetics, such as customised, genotype-specific thera- contrast agents or biomarkers to a variety tissues, including bonepies, into broader clinical use. However, use of nanotechnology in marrow,[24] lymph [25] and brain.[26] Another potential use of na-the medical setting, especially for therapeutic uses or in vivo notechnology is the intracellular delivery of drugs, peptides, DNAdiagnosis means that the biocompatibility of these materials will or proteins. Modified CNTs have been shown to enter human cellhave to be more completely defined. Some of the early areas of lines. This has allowed their use to deliver peptides and otheractive research are reviewed below. molecules intracellularly and, depending on the specific molecules

used, localise the transported molecules either to the cytoplasm or3.1.1 Drug Delivery and Biomedical Imagingto the nucleus of cells.[27]

The topics of targeted drug delivery and biomedical imagingBy targeting a drug to a specific site and encasing it in a carrierwill be considered together, since in essence they are they same

molecule, it is hoped that systemic toxicity could be dramaticallytechnology with the difference being the delivery of either alessened. A similar rationale could be used to develop safertherapeutic or diagnostic agent.contrast agents. For example, some nuclear medicine contrastOne of the principal early areas of interest for nanotechnologyagents rely on the chelation of potentially toxic metals to preventin the medical setting was delivering chemicals to particular areastissue toxicity. The chelating agents prevent interaction of theof the body. A discussion of the principles that make this possiblemetals with tissue proteins. However, tissue toxicity may resultis useful, since it serves to review current knowledge concerningfrom the in vivo dissociation of the metal-chelator complex, andthe distribution and pharmacokinetics of many nanoparticles inmore stable chelators are constantly being sought. Fullerenes, withvivo.their stable, 3-dimensional cage-like structure could possibly pro-When considering the fate of nanoparticulates in the body,vide useful vehicles for imaging and even therapeutic agents.several factors must be taken into account. Hydrophobic particles,

There are already techniques in place by which lymphotrophicsuch as unmodified carbon nanostructures, frequently becomemagnetic nanoparticles have been shown to be able to detectcoated by serum proteins in a process called opsonification. Thisdifferences in normal versus malignant lymph nodes, offering theleads to clearance by specialised cells of the reticuloendothelialpossibility of accurate, non-invasive tumour staging. One study ofsystem (RES), which are located primarily in the spleen, liver andthis technique in staging prostate cancer correctly identified alllymphatic system. Left to these processes, some nanomedicinespatients with metastases and improved per-lymph-node accuracywill be automatically ‘targeted’ to these sites. An example of thisfrom 35% for conventional MRI to >90%.[28] However, the use ofprocess would be the RES-specific contrasts for magneticnanotechnology for imaging agents is not limited to magneticresonance imaging. These are typically colloidal solutions ofmaterials. As noted in section 2.3, several of the photoelectricsuperparamagnetic nanoparticles (attracted to a magnetic field butproperties of nanomaterials make them attractive as fluorescentretaining no residual magnetism after the field is removed) thatbiological stains and markers.[29]utilise phagocytosis by the reticuloendothelial system to localise

contrast to the liver and spleen. These contrast agents allow better Another area of potential for nanoparticles and nano-baseddetection of gastrointestinal tumours in these areas. Opsonification drug delivery systems is in the delivery of diagnostic or therapeu-and uptake by the RES are obviously not always desirable, and this tic agents to the brain, a prospect normally severely limited by theprocess can be attenuated by coating hydrophobic particles with blood brain barrier (BBB). The BBB is a continuous layer ofcompounds that increase hydrophilicity, especially polyethylene tightly joined epithelial cells that, in effect, function as a single cell


250 Curtis et al.

membrane, severely limiting the diffusion of hydrophilic and • Many nanomaterials are made from elements for which thecharged molecules from one side to the other. The impermeability toxicology of the bulk material is relatively well defined, suchof the BBB has impeded the study and treatment of various as heavy metals. This is the toxicity that is the most straightfor-diseases, from CNS infections and neoplasms to chronic degenera- ward and easiest to measure.tive diseases. • The fact that the electrical properties of nanoparticles differ

There have been many attempts to alter penetration into the from the bulk material has tremendous impact in their industrialCNS. Most of these efforts have focused on either increasing the usefulness, but also might affect their toxicological effects. Thepermeability of the BBB or chemically increasing the lipophilicity potential for nanomaterials to create or scavenge reactive oxy-of the drugs. Either approach has significant drawbacks, since not gen species and free radicals may well be important in theirall drugs are amenable to chemical alteration while globally in- ability to create or to ameliorate toxicity.creasing BBB permeability is potentially dangerous in that it could • Toxicity could arise as a function of the extremely small size ofdisrupt brain homeostasis and allow the entrance of harmful nanoparticles. This is suggested by the relatively well studiedmaterials. Carriers therefore offer an attractive solution to the inhalational toxicology of ultrafine particles (UFPs), for whichproblem of drug delivery to the CNS. The unaltered drug, growth a large body of literature indicates that respiratory distributionfactor or peptide can be selectively transported across the BBB and toxicological effects are primarily determined by the size ofwithout compromising the barrier’s physiological function. Na- the individual particles and their propensity to agglomerate.noparticles have been shown to enhance entry into the CNS for a However, when dealing with materials on the nanoscale, othernumber of drugs in a number of ways. For example, polysorbate size-related properties become important, such as the ability of80-coated poly(butyl cyanoacrylate) nanoparticles have been very small particles to pass through biological barriers, includ-shown to facilitate the translocation of many drugs. In one study, ing the skin, vascular endothelium and the BBB. This coulddoxorubicin bound to such coated nanoparticles increased the dramatically affect the absorption, distribution and excretion ofsurvival rate in rats with an aggressive glioblastoma, with 20% these particles.achieving long-term remission.[30] Other techniques have focused • As with larger materials, the overall shape of a nanoscaleon using endogenous transporters to translocate drugs into the

product may be an important factor in determining its toxicity.CNS from the blood. For instance, loperamide, an opioid agonist,

This may be a concern for CNTs, whose toxicity differs fromwhich does not normally cross the BBB, was shown to induce an

that of particulate carbon in other shapes, perhaps due to theantinociceptive response when attached to albumin nanoparticles

lung’s response to inhaled fibres.linked to apolipoprotein E (ApoE). This effect was lost when using

• Although they are generally too small to be directly allergenic,ApoE variants that do not bind to lipoprotein receptors, indicatingthere is the concern that haptens composed partly of thesethat receptor binding played a key role in translocation into thematerials could engender an immune response.CNS.[31]

From a human toxicology standpoint, significant exposures3.1.2 Biosensing would most likely be occupational and result from either dermal orNanowires or CNTs can be coupled to proteins or antibodies to inhalational exposure to nanoproducts in a manufacturing or re-

create ultrafine probes. Chemical interaction of the tip of the probe search setting. Oral and parenteral exposures would be expected towith the designated ligand results in a change in electrical proper- result from the use of nanotechnology in a medical setting. Issuesties of the probe, which can then be detected. This technology, related to potential environmental exposures and effects are dis-used in arrays of probes, has allowed detection of less than a cussed in section 5.1.picogram of several cancer-specific antigens in small amounts ofundiluted blood.[32] The hoped-for end product of the commercial-

4.1 Inhalational and Pulmonary Toxicityisation of this technology would be fantastically specific detectionof a variety of cancer markers (or other analytes of interest) from a

While there are no studies addressing the specific effects ofsingle drop of blood, such as the sample used by a commonengineered nanomaterials on the human lung, there is a large bodyglucometer today.[1]

of literature that deals with the injurious effects of inhaled particu-late matter. In addition, a strong correlation has been found be-4. Toxicity of Nanomaterialstween the size of the inhaled particles and the health effects that

There are several mechanisms by which nanoparticles and result, and many of the particles studied are certainly small enoughmaterials might cause adverse effects: to be considered nanoparticles.



Convention divides particulate pollution into several categories particles, and it has been postulated that the increased inflammato-based on size. PM(10) and PM(2.5) describe particles <10μm ry potential of UFPs may be a result of their tremendously large(10 000nm) and 2.5μm (2500nm), respectively. PM(10) particles surface area per unit mass.are of the size typically produced by diesel combustion.[33] The In rat lungs instilled with fine particles versus UFPs of titaniumdesignation fine refers to PM(2.5) and less, while ultrafine refers dioxide and carbon black, the UFPs induced more inflammation,to particles <100nm in diameter. It should be noted that PM(10) cell death, epithelial damage and increased lung permeability moreincludes fine and ultrafine particles as well as the larger particles than the fine counterparts of both materials.[42] Further, agglomer-between 2.5 and 10μm. ates of UFPs induced the production of various lipid mediators

(arachidonic acid derivatives) by isolated canine alveolar macro-UFPs <100nm in diameter make up the majority of particles inphages. The character of the inflammatory response seemed to beurban air pollution. Although similar in size, they differ frommore closely related to the surface area of the agglomerates than toengineered nanoparticles in their complex, variable, and generallythe overall mass (amount) of the agglomerates.[47] The balanceill-defined composition. A series of ecological or semi-ecologicalbetween pro- and anti-inflammatory mediators was also related toepidemiological timer series studies have demonstrated a weak butsurface area, in both carbon and titanium-dioxide particles, withconsistent temporal association between urban air pollution insmaller particles (with greater surface area) shifting arachidonicgeneral (and UFPs in particular) and decreased peak flows inacid metabolites towards 5-lipo-oxygenase products (leukotrienes)patients with asthma,[34] increases in cardiorespiratory mortali-at the expense of cyclo-oxygenase products (prostaglandins).[47]ty,[35] alterations in cardiovascular function,[36] impaired lung

function in children[37] and adults,[38] and perhaps an increase in The greater surface area of UFPs provides more potentialthe risk of ventricular dysrhythmias (as measured in those with reactive sites for any given mass-dose; and several studies haveautomated internal cardiac defibrillators).[39] Recent studies of observed that the increased toxicity results from an increasedcommunity mortality data indicate once again an effect of particle exposure to transition metals on the surface of particles and thesize, with PM(2.5) causing greater increases in mortality than consequent oxidative stress.[48,49] Studies of UFPs treated withthose associated with PM(10) particulate air pollution.[40] Several chelators to remove residual metals, however, suggest a pro-studies have indicated that UFPs are more toxic than larger parti- inflammatory effect of UFPs that is not mediated by transitioncles of similar make-up,[41,42] although some recent results suggest metals.[41] However, even for particles that do not contain metals,that this relationship may not be general.[43] reactive sites on the surfaces of inhaled particles may induce

inflammation by altering the normal iron homeostasis. ReactiveDeposition of particles in the lung depends at least partially onsites on the inhaled particles may interact with endogenous iron,the size of the inhaled particle. Larger particles may be filtered outfacilitating the generation of reactive oxygen species.[50]in the upper airways, whereas small particles may more efficiently

reach the distal airways. The retained fraction of particles is also Not only the size of nanoengineered materials, but also theirsize dependent – with studies of inhaled zinc oxide showing shape and structure can predispose to inhalational toxicity. Themarkedly increased retention of smaller UFPs. Of note, the mea- importance of shape and surface characteristics in pulmonarysured deposition of the smallest particles was much greater than toxicology is exemplified by the health problems caused by anoth-that predicted by mathematical models.[44] There also seem to be er inhaled fibre: asbestos. For asbestos, the diameter, length andsmall differences in the ways that healthy and diseased lungs surface characteristics of the fibre have been shown to be impor-process inhaled UFPs. In studies of technetium-labelled agglomer- tant in exerting its harmful effects.[51,52] A reactive surface, a smallates of UFPs, subjects with chronic obstructive pulmonary disease enough diameter to enter the distal airspaces in the lung, andhad slightly increased central-to-peripheral lung deposition ratios. sufficient length to prevent effective elimination all contribute toIn addition, while the deposited fraction of particles was smaller the development of inflammation, fibrosis and eventually carcino-than that of healthy subjects, the increased basal respiratory rate genesis.led to an increased deposition rate for a given exposure concentra- These properties are, to a degree, all satisfied by CNTs, whichtion.[45] has raised concerns that they may have similar pulmonary toxici-

Once inside the lung, inhaled particles may cause direct ty.[4,53] Structural effects seem to be pronounced in the case ofcytotoxicity, induction of an allergic response, or inflammation. In CNTs: while carbon black and graphite[54] also have lung toxicity,addition, some inhaled UFPs can cross cell membranes by non- CNTs with similar chemical make-up seem to have distinct pul-endocytic mechanisms and as a result be found distributed in the monary effects, presumably due to their structure. Some of thebody – leading to the potential for systemic effects.[46] Initiation of qualities that make CNTs so attractive to industry are theiran inflammatory process seems to be a prominent effect of inhaled strength, stability, and the ability of CNTs to assemble into rope-


252 Curtis et al.

like fibres. However, this stability and structure may be exactly Cytotoxicity of various nanomaterials to lung cells has alsowhat predisposes them to pulmonary toxicity, and it has been been demonstrated. SWCNTs were found to be markedly cytotox-shown that the toxicity of man-made fibres is proportional to their ic to alveolar macrophages, while MWCNTs were less so and C60

biopersistence.[55-58] was practically non-cytotoxic.[63]

Thus, there are many potential harmful effects from the inhala-Recent animal studies have reported that intratracheal instilla-tion of nanomaterials. The first is related to particle size. Nanopar-tion of mice with high concentrations of CNTs experienced aticulates function similarly to carbon-based UFPs, inducing in-variety of health effects. The CNTs were markedly more harmfulflammation and at high concentrations causing cell death. Second-than carbon black. Both were taken up by lung macrophages, butly, the structural characteristics of both SWCNTs and MWCNTsthe macrophages that ingested carbon black remained in the alveo-seem to be capable of producing pulmonary effects similar to otherlar space, presumably to be cleared by the mucociliary escalatorbiopersistent inhaled fibres. Thirdly, carbon nanoparticles mayand removed from the lungs, while macrophages that ingestedincrease the lungs’ response to allergens, resulting in greater levelsCNTs migrated to centrilobular locations and caused interstitialof inflammation and mucous production. Finally, nanoparticlesgranulomas.[5] This was true even for purified CNTs that containedmay be directly cytotoxic to cells in the lung, resulting in cell deathonly trace amounts of residual metal catalysts. Another in vivoand consequent inflammation.study of mice that modelled inhalation through pharyngeal aspira-

The relevance of many of these early studies is, as yet, unclear.tion of SWCNTs found increased inflammation and cell damage,Tracheal instillation is often used due to the difficulties associatedas well as two distinct patterns of lung remodelling: granulomawith exposing the animal subjects to aerosolised products. Thisformation and interstitial fibrosis, perhaps related to whethercan result in unrealistic scenarios, such as conglomerates of carbonSWCNTs formed aggregates or were distributed throughout thenanotubes physically obstructing the airways,[60] or markedly une-lung space.[59]

ven distribution in the lungs. Further calling into question theIn one intratracheal instillation experiment comparing

relevance of these studies are preliminary environmental andSWCNTs to various controls, including silica, SWCNTs only

occupational studies that report that there are relatively low levelscaused acute toxicity in concentrations high enough for the CNT

of aerosols created by handling or even vigorously agitating bulkagglomerates to physically block the airways. In lower doses, or in

quantities of SWCNTs, with estimates of aerosol concentrationsanimals receiving a high dose that did not asphyxiate, SWCNTs

from various processes all reported as <53 μg/m3.[64,65] Clearly, thecreated only a brief inflammatory response, while quartz resulted

expected level of occupational exposure needs to be accuratelyin sustained elevation of inflammatory markers and eventual fibro-

defined, and relevant experimental protocols developed to bettersis. Despite the seemingly low acute toxicity seen in this study, the

define the actual risk.rats developed non-uniform multifocal granulomata that seemed tooccur in areas where the CNTs had agglomerated into ‘na-noropes’.[60]

4.2 Toxicity Following Dermal Exposure

MWCNTs have been shown to have similar harmful effects.Much like asbestos, MWCNTs were shown to be highly bio- The second probable route of exposure to nanomaterials ispersistent, with >80% retained in rat lung 60 days following through contact with the skin. Some have speculated that dermalintratracheal administration. Chemical markers of inflammation contact will be the primary route of exposure for most popula-and a fibrotic response were increased by instilled asbestos and tions.[66] One study of the workplace environment showed that upMWCNTs, but not by carbon black. Furthermore, a granuloma- to 6mg of SWCNT could remain as residual on the gloves oftous response was noted on histopathological examination of the workers following handling of the bulk material.[64] These con-lungs following sacrifice of the animals.[61]

cerns have led to a number of studies evaluating the effect thatthese products have on cultured skin cells.The allergic pulmonary response seems to be increased by

nanoparticles as well. In another pulmonary lavage study in rats, The fullerene C60 has been shown to induce cytotoxicity inBAL cell counts and levels of various interleukins were increased human dermal fibroblasts through oxidative stress and lipid perox-by both nanoparticulates and allergens, but the combination of idation.[67] The cytotoxicity of fullerenes has been shown to de-both resulted in a much more vigorous response.[62] Once again, crease with increasing modifications to increase water solubili-smaller particle size was correlated with significantly more in- ty.[68] When applied to the skin in benzene at concentrations thatflammation and greater mucous production by pulmonary goblet might be used in an industrial setting, however, fullerenes did notcells. result in benign or malignant tumours in mice.[69]



While most nanotechnology designed for human use would be 4.4 Toxicity Due to Crossing of Biological Barriers

rendered water soluble through various chemical modifications,C60, as a highly lipophilic molecule, has the potential to crossthere is also the concern for occupational exposure to products

biological barriers. It has been shown to cross the placenta indesigned for non-biological purposes. Unmodified MWCNTs

rats.[83] Studies of fullerenes derivatives show a high degree ofwould be an example of such a product, and MWCNTs have been

protein binding in the serum, and the high volume of distributionshown to enter the cytoplasm of human epidermal keratinocytes

indicate that they are distributed into tissues.[84] Non-organic na-(HEK) and induce an inflammatory response, characterised by

noparticles may also cross biological barriers. Gold nanoparticlesincreased levels of interleukin-8 and a dose-related decrease in

administered orally are widely distributed to various body areas,viability.[70] In addition, studies of gene transcription show an including the brain, to an extent inversely proportional to size.[85]

upregulation of genes involved in immune and inflammatoryIn addition to crossing the BBB as specially designed carriers,

responses within human skin fibroblasts.[71]there are other potential means by which nanoparticles could enter

SWCNT have been shown to increase markers of oxidative the brain. In animal models, inhaled UFPs entered the brain,stress such as products of lipid peroxidation, result in morphologi- presumably by transport through olfactory nerves.[86] Water-solu-cal changes and to decrease viability in HEK in a dose-dependant ble fullerene derivatives not only persist in tissues, but have beenmanner.[72] SWCNTs inhibit HEK proliferation, presumably by shown to enter the brain when administered parenterally.[82] Wheninducing an oxidative stress thereby increasing levels of NFκB.[73] present in water at concentrations of 0.5 ppm, C60 has been shown

to induce lipid peroxidation in the brains of largemouth bass afterHowever, these two in vitro studies are perhaps in conflict withonly 48 hours of exposure.[87] Similar results have been shown inlimited in vivo data that carbon nanotubes in a filter applied to skinother aquatic species.[88] Furthermore, in vitro studies have showndid not result in noticeable irritation.[74]

that fullerenes damage cultured human astrocytes through lipidVarious inorganic nanoparticles have also been investigated.peroxidation.[67] In contrast, while CNTs have been shown to beQdots have been shown to enter HEK, regardless of differences indistributed throughout various compartments in the body, andtheir coatings.[75] Cytotoxicity, however, was found to be depen-concentrated in bone, SWCNTs do not seem to enter the braindant on the particular coating used, with PEG-coated Qdots caus-when administered orally or parenterally.[89]

ing the least cell damage.[76] As mentioned in section 3, TiO2Fullerenes have been shown to induce morphological changes,nanoparticles are common components of sunscreens. Studies

and at high enough doses cause cytotoxicity in vascular endotheli-have shown that these particles are not significantly absorbed.[77]

al cells. Since nanoparticles used elsewhere may translocate intoThis seems to be true regardless of the size to the applied parti-

the bloodstream, this has raised concerns that fullerenes couldcles.[78] Even without systemic absorption, inorganic nanoparticles

predispose to cardiovascular disease.[90]

could cause local irritation or cell death. Silver nanoparticles, forexample, have been reported to greatly reduce the viability of 4.5 Health Effects Due to Chemical Compositioncultured keratinocytes.[79]

Much of the utility of nanotechnology relies on being able toprecisely control the molecular arrangements of nanostructures.4.3 Toxicity Following IngestionFor many applications, such as metallofullerenes and Qdots, thisincludes controlling chemical structures of both the surface (which

Relatively few studies examining the effects of ingested na-would be exposed to the external environment) and the interior or

noparticles have been performed. In gavage studies comparing thecore. It is expected that the surface characteristics will be an

acute toxicity of copper particles at various sizes, nanocopperimportant determinant of the toxicological effects. The contribu-

(23.5nm) was found to have an LD50 (i.e. the dose that was lethal tion of the materials inside the core would be less important into 50% of animals tested) in mice of 413 mg/kg, versus >5000 mg/ determining potential toxicity – as long as the structure remainedkg for copper of 17μm in diameter, with copper nanoparticles stable.producing damage to the liver, kidney and spleen.[80]

Indeed, some research has shown that the cytotoxicity andWater solubilised fullerenes have been shown to be non-toxic genotoxicity of Qdots applied to cells is directly related to the

when administered orally to rats in doses >2 g/kg.[81] This is surface modifications, rather than the core luminescent materi-perhaps because there seems to be low oral bioavailability of some als.[7] In other studies, it is the release of core material that seemsof these compounds, with most of an administered dose excreted to be more important in mediating cytotoxicity.[91] Even if thein the faeces.[82] surface coatings are designed to prevent the release of toxic core


254 Curtis et al.

materials, these shells have been shown to be sensitive to environ- the fullerenes, and some populations of antibodies were found thatmental conditions. The cytotoxicity of Qdots increase when they cross-reacted with other (C70) fullerenes as well.[96]

are exposed to air or ultraviolet radiation prior to administra-4.7 Genotoxicity and Effects on Developmenttion.[92]

Harmful effects due to metals are not limited solely to the There are mixed results in the few basic studies available tochemicals intended to be contained in a product, but also can arise determine the genotoxicity of fullerenes derivatives. There seemsfrom materials used in their manufacture. As mentioned in section to be low potential for genotoxicity and carcinogenicity based on a2.2, CNTs contain some amount of residual catalyst metal, of limited number of in vivo studies in lower order organisms such asvarying types and quantities depending on the manufacturing Salmonella and Drosophila.[97,98] An in vitro analysis of Salmonel-process used. In rat inhalational studies, animals displayed health la, however, noted DNA damage, probably through generation ofeffects, including weight-loss, lethargy and death that seemed to oxygen radicals.[99]

be related to the content of the residual metal catalyst. This wasThere seems to be a potential for fullerenes to be fetotoxic, with

particularly true for CNTs containing large amounts of nickel.[5]harmful developmental effects seen in rats injected intraper-

Similar results have been shown in cytotoxicity studies involvingitoneally.[83] C60 has been seen to both promote[100] and sup-

Qdots, in which there were marked differences in toxicity betweenpress[83] cell differentiation in various models.

the ‘crude’ and ‘purified’ nanocrystals.[7]

As mentioned in sections 3.1.1 and 4.2, SWCNTs can cross cellCytotoxicity through redox reactivity is not limited to inorganic

membranes in fibroblasts and enter the nucleus.[27] It is of un-nanoparticles. Carbon-based nanostructures have been shown to

known significance that single-stranded DNA has been shown toinduce the formation of reactive oxygen species and several cell

bind to appropriately sized nanotubes.[101]

lines, including human keratinocytes.[72,73] Lipid peroxidation hasWater-soluble Qdots have been reported to induce free-radical

been shown to be the primary cause of some fullerene cytotoxici-mediated DNA nicking,[102] while Qdot photosensitised TiO2 films

ty.[67] MWCNT have been shown to induce apoptosis in human T-were shown to induce free-radical mediated damage to bacteria

lymphocytes. Oxidised MWCNTs were shown to be more harmfuland DNA.[103] Several other inorganic nanoparticles, particularly

than pristine (unoxidised) structures, which were in turn moresilver nanoparticles, have been reported to cause in vitro male

harmful than simple carbon, but even so the concentrations re-germline toxicity in mice.[104]

quired to induce apoptosis were relatively high – in the order of 10million nanotubes per cell.[93]

5. Environmental and Regulatory Issues

4.6 Antigenicity of Carbon Nanomaterials5.1 Potential Environmental Effects

As mentioned in section 4.1, inhaled nanomaterials can be Concerns over the lack of understanding of the potential envi-shown in some instances to enhance the pulmonary allergic re- ronmental impact of nanotechnologies has led to some groups,sponse. However, uncertainty remains regarding the ability of such as The Action Group on Erosion, Technology, and Concen-these small carbon-based structures to engender a specific immune tration (ETC Group), to call for a moratorium on the use andresponse (i.e. antigen formation rather than nonspecific inflamma- manufacture of nanomaterials.[105] Others agree that a precautiona-tion). ry approach is necessary, lamenting the “almost complete absence

Carbon nanotubes may be functionalised with peptides for of scientific literature on environmental toxicity or exposure.”[106]

various purposes, including intracellular delivery. These com- Major environmental groups such as Environmental Defense andplexes are immunogenic, although the antibodies produced were the Natural Resources Defense Council, as well as the ETC, havespecific for the peptide and did not cross-react with the carbon refused to attend meetings on the subject, based on what they feltnanotubes.[94,95] In fact, the ability of CNTs to enhance antibody was undue industry influence.[107] Perhaps due to a much lessresponse to these peptides has led to interest in their potential uses enthusiastic view of nanotechnology by the European populacein vaccine creation. compared with that of the US,[108] Britain’s Royal Society and

Royal Academy of Engineering have argued that manufacturedIn contrast, C60 fullerenes have been shown to induce annanoparticles should be assumed dangerous until proven safe.[109]immune response following inoculation of rats with fullerenes

conjugated with bovine thyroglobulin. In this study, inoculation While this view is certainly not unanimous, there is recognitionwith C-60-thyroglobulin resulted in a polyclonal immunoglobulin by most authorities that there are many gaps in our knowledgeG response. Antibodies were formed that reacted specifically with about the environmental fate and occupational hazards associated



with nanotechnology. From 2000–04, an estimated $US88 million tion from more efficient energy use or lower net use of materials. Itin grant money organised by the NNI has been devoted to environ- has also been suggested that nanomaterials could be potent cat-mental research, but the majority of that money has gone into alysers of environmental degradation of other pollutants, thusresearching environmental applications of nanotechnology, rather having a positive environmental impact.[66] In addition, na-than into better defining the environmental impact of the materials notechnology is foreseen to be useful in monitoring ecosystems,themselves.[12] It was estimated that only about 0.5% of the total detecting and remediating pollution.[113,114]

research budget was spent on the areas that most directly addressthe environmental concerns.[12]

5.2 US Regulatory Statutes and ImplicationsWhile research is still in preliminary stages, there is some

evidence that, if left uncontrolled, there could be negative environ-Novel materials bring exciting opportunities for technological

mental impacts associated with the release of various nanomateri-advancement, but they also bring the need for new regulations and

als.[110] Carbon-based nanomaterials are hydrophobic, but manysafety precautions. EPA, OSHA, NIOSH and FDA all have certain

applications require that they be made water soluble by variousmandates to impose guidelines, and are participants in the NNI.

chemical alterations. Even in their natural state, low water solubil-Individual agencies, as well as the NNI, have set forth ambitiousity does not mean that these particles will not enter the waterresearch agendas. However, it is unclear how nanomaterials andsupply. For example, C60 fullerenes will enter water as a colloidalproducts will fit into the existing regulatory structures. In thesolution, with concentrations reaching 10 ppm, a concentrationStrategic Plan for NIOSH Nanotechnology Research released inthat exceeds the solubility of several other known environmental2005 by NIOSH, most of the research necessary to define thecontaminants, such as polyaromatic hydrocarbons, which are onlytoxicity of nanomaterials will not be undertaken for another 3 or 4about 1% as soluble.[111] In aquatic studies of fullerenes, acuteyears. Thus, evidence-based exposure recommendations may be intoxicity does not seem to be much of a concern. Due to the lowthe even more distant future. In the meantime, the EPA haswater solubility, an LC50 (the concentration resulting in the deathconsidered asking for voluntary reporting by manufacturers andof 50% of exposed animals) could not be calculated; however,researchers to track the nature and quantities of the productsconcentrations were reached that significantly altered reproductiveproduced and their potential uses.[115]

rates of several fish species were tested.[112] As mentioned insection 4.4, fullerenes have been shown to enter the nervous One of the key regulatory issues is whether the new configura-system of fish and potentially alter the bacterial content of water at tions of existing chemicals at the nanoscale can be considered aconcentrations of <1 ppm.[87] new chemical or a significant new use of a chemical, which would

potentially give the EPA authority to regulate production under theIn evaluating the overall environmental impact of a new tech-Toxic Substances Control Act. Additionally, if considered newnology, it is important to consider not only the direct effects of thechemicals, new Chemical Abstracts Service numbers and chemi-materials that the technology releases into the environment, butcal descriptions would need to be generated by the appropriatealso the effects that will occur from the replacement of olderbodies.technologies. Nanotechnology might result in lower rates of pollu-

Table I. National ambient air quality standards for particle pollution[118]

Pollutant Averaging times Primary standards (μg/m3) Secondary standards

PM10 Annual (arithmetic mean)a Revokeda

24-hourb 150

PM2.5 Annual (arithmetic mean)c 15 Same as primary

24-hourd 35

a Due to a lack of evidence linking health problems to long-term exposure to coarse particle pollution, the agency revoked the annual PM10

standard in 2006.

b Not to be exceeded more than once per year.

c To attain this standard, the 3-year average of the weighted annual mean PM2.5 concentrations from single or multiple community-oriented monitorsmust not exceed 15 μg/m3.

d To attain this standard, the 3-year average of the 98th percentile of 24-hour concentrations at each population-oriented monitor within an areamust not exceed 35 μg/m3.

PM2.5 = 2.5μm (2500nm); PM10 = <10μm (10 000nm).


256 Curtis et al.

Table II. Limits for air contaminants (combination of the Occupational Safety and Health tables Z-1,2,3)[120-122]

Substance CAS no. ppm mg/m3

Asbestos 1910.1001 0.1 fibre/cm3

Carbon black 1333-86-4 3.5

Iron oxide fume 1309-37-1 10

Nickel carbonyl (as Ni) 13463-39-3 0.001 0.007

Nickel, metal and insoluble compounds (as Ni) 7440-02-0 1

Nickel, soluble compounds (as Ni) 7440-02-0 1

Particulates Not Otherwise Regulated (PNOR)

total dust 15

respirable fraction 5

Titanium dioxide 13463-67-7

total dust 15

Graphite (natural) 529.7 particles/cm3

Coal dust

respirable fraction <5% SiO2 2.4

respirable fraction >5% SiO2 10 mg/m3

%SiO2 + 2

Inert or nuisance dust 15 5

respirable fraction 50 15

CAS = Chemical Abstracts Service.

Respirable particulate matter (as PM10 [‘coarse’ particles with mandated. Carbon nanotubes, for example, are regulated as anoth-aerodynamic diameters ≤10μm] and PM2.5 [‘fine’ particles with er form of graphite, although the physical properties and potentialaerodynamic diameters <2.5μm]) is one of the six ‘criteria’ air health effects are quite different.[119]

pollutants for which the EPA promulgates National Ambient Air OSHA sets permissible exposure limits (PELs) to protect work-Quality Standards (NAAQS) in accordance with Sections 108 and ers against the health effects of exposure to hazardous substances.109 of the Clean Air Act. The largest database on the toxicity of PELs are regulatory limits regarding the concentration of a sub-nanoparticles has originated from the voluminous international stance in the air, typically expressed as an 8-hour time-weightedliterature pertaining to PM10 and PM2.5, and as discussed in average. All inert or nuisance dusts not listed specifically aresection 4.1, toxicological and epidemiological data support the covered by Particulates Not Otherwise Regulated (PNOR). Tablecontention that nanoparticles in inhaled air are important drivers of II is a compilation of applicable OSHA inhalation exposure limitsthe adverse effects attributed to particulate matter. As noted in the for various particles.EPAs draft Nanotechnology White Paper,[116] of the most recent While it is expected that the inhalational toxicity of nanopar-Air Quality Criteria for Particulate Matter document[117] cites ticulates would vary from that of the bulk material, fortunatelynumerous references describing the health effects of UFPs. Cur- most organic nanoparticles would be expected to only reach veryrent NAAQS for particulate matter are presented in table I. low concentrations in air due to their tendency to agglomerate.[64]

Recognising the distinction between the complex and variable However, the ability of standard particulate respirators to removemixture of ambient UFPs and engineered nanoparticles, EPA has such small airborne particles should not be assumed. It is perhapsoutlined recommendations for research into the human and eco- more concerning that these regulatory statutes for the most partlogical health risks and benefits, as well as information needs for address only workplace air concentrations, without a skin designa-risk assessment of nanomaterials (EPA, 2005). tion. As mentioned in section 4.2, some studies have already

suggested that dermal contact could be the most important sourceOSHA creates and enforces workplace safety legislation in theof workplace exposure.US. Since the short- and long-term toxicity of most nanoparticu-

lates are unknown for the majority of biological systems, the NIOSH, the federal agency that conducts research in occupa-current regulatory approach has been to use standards for the tional safety and health and makes recommendations for prevent-similar bulk materials until material-specific standards can be ing work-related injuries and illnesses, has identified ten critical



topic areas to guide in addressing knowledge gaps, developing Secondly, the scientific community must agree upon appropri-strategies and providing recommendations (NIOSH, 2005). NI- ate and relevant experimental protocols. This would allow moreOSH is also working with other agencies to address health issues accurate characterisation of the acute and chronic toxicity of theseassociated with nanotechnology via participation in the NNI and products in concentrations and by the routes that are most likely tothe Nanoscale Science, Engineering and Technology subcommit- be relevant to human experience.tee of the National Science and Technology Council committee on Finally, environmental and occupational monitoring must betechnology. A NIOSH Nanotechnology Research Center is being conducted. Concentrations reached and persistence in the environ-developed that will coordinate institute-wide nanotechnology-re- ment must be determined. Also, it is important to document thelated activities. functional changes occurring in released nanoparticles due to

Another regulatory body that will struggle with an array of new environmental effects such as exposure to air, water, heat andproducts is the FDA. The FDA’s current categorisation scheme radiation. These data will be essential in designing the experimentshas been seen as poorly suited to classifying nanomedical drugs necessary to more fully define the potential health and environ-and devices.[123] A common theme in much of nanotechnological mental consequences of a maturing nanotechnology industry.regulation, modern medical devices will tend to straddle some ofthe traditional boundaries between regulatory and standardising Acknowledgementsbodies.[124]

John Curtis, MD, reports that he was compensated for his time byNewfields, LLC, Atlanta, GA, USA. No other sources of funding were used to6. Conclusionsassist in the preparation of this review. The authors have no conflicts ofinterest that are directly relevant to the content of this review. The authors

Nanotechnology is a diverse field that is still in its infancy. would like to thank Benjamin Legum for his contributions to the review.While the eventual impact of nanotechnology cannot be estimatedat this time, it is fully expected to revolutionise many fields.

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