Getting It Right the First Time : Developing Nanotechnology while Protecting Workers, Public Health, and the Environment

Getting It Right the First Time

Developing Nanotechnology while ProtectingWorkers, Public Health, and the Environment

JOHN M. BALBUS, KAREN FLORINI, RICHARD A. DENISON,AND SCOTT A. WALSH

Environmental Defense, Washington, DC 20009

ABSTRACT: Nanotechnology, the design and manipulation of materialsat the atomic scale, may well revolutionize many of the ways our soci-ety manufactures products, produces energy, and treats diseases. Inno-vative nanotechnology products are already reaching the market in awide variety of consumer products. Some of the observed properties ofnanomaterials call into question the adequacy of current methods fordetermining hazard and exposure, and for controlling resulting risks.Given the limitations of existing regulatory tools and policies, two dis-tinct kinds of initiatives are urgently needed: first, a major increase inthe federal investment nanomaterial risk research, and second, rapid de-velopment and implementation of voluntary standards of care pendingdevelopment of adequate regulatory safeguards. The U.S. governmentshould increase federal funding for nanomaterial risk research under theNational Nanotechnology Initiative to at least $100 million annually forthe next several years. Several voluntary programs are currently at var-ious stages of evolution, though the eventual outputs of each of these arestill far from clear. Ultimately, effective regulatory safeguards, harmo-nized globally, are necessary to provide a level playing field for industrywhile adequately protecting human health and the environment.

KEYWORDS: nanotechnology; nanoparticles; nanotoxicology; risk assess-ment; risk management; occupational health; environmental health

INTRODUCTION

Nanotechnology, the design and manipulation of materials at the atomicscale, may well revolutionize many of the ways our society manufacturesproducts, produces energy, and treats diseases. Hundreds of large and smallnanotechnology companies are developing a wide variety of materials for use

Address for correspondence : John M. Balbus, M.D., M.P.H., 1875 Connecticut Avenue, N.W. Suite600, Washington, DC 20009. Voice: 202-387-3500; fax: 202-234-6049.

e-mail: [email protected]

Ann. N.Y. Acad. Sci. 1076: 331–342 (2006). C© 2006 New York Academy of Sciences.doi: 10.1196/annals.1371.027

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in electronics, medical diagnostic tools and therapies, construction materials,personal care products, paints and coatings, environmental cleanup, energyproduction and conservation, environmental sensors, and many other impor-tant applications.

Deliberate exploitation of properties that only become evident at thenanoscale is central to these applications. Such properties include highly spe-cific binding over a huge surface that arises from tiny particle size, absorption,and radiation of specific wavelengths of light, penetration of cellular barriers,and high tensile strength and durability. Carefully controlled, these propertiesmay provide highly beneficial products. But these new and enhanced propertiesalso raise the possibility of unintended adverse consequences for human healthand the environment. The same binding properties that deliver therapeutics tocancer cells might also, for example, deliver toxic substances to aquatic organ-isms if similar materials are released or used in the ambient environment. Theelectrical properties that drive applications in computers may lead to oxidativedamage in living tissues. It is essential that these potential harms are identifiedprospectively and mitigated—ideally through material design, or where that isnot feasible through use restrictions.

NANOTECHNOLOGY EXPOSURES AND RISKS–A LIFECYCLE VIEW

Innovative nanotechnology products are already reaching the market in awide variety of consumer products, and the National Science Foundation pre-dicts that the global market for nanomaterials could reach $1 trillion within adecade.1 Some of these products, and others now in the pipeline, will result inhuman and environmental exposures to nanoparticles. Examples include drugsand cosmetics, and uses for remediation of groundwater contamination. Otherproducts may also entail substantial exposures, though not necessarily during aproduct’s useful life. For example, tennis rackets, automobile running boards,and other products contain carbon nanotubes embedded within resins or othermatrices. While exposure to individual nanoparticles during the product’s in-tended use seems unlikely, a product’s life cycle includes not just the product’suseful life, but also its manufacture (and manufacture of its components) and itsdisposal or recycling/reclamation. Human or environmental exposures duringthese other stages may be substantial. For instance, although computer usersare highly unlikely to inhale carbon nanotubes bound in their computer screen,exposure potential may dramatically increase when recyclers ultimately grindup those screens for use as road aggregate. Human exposures are most obviousfor the workers doing the grinding, but may also occur in road constructionworkers, and perhaps to travelers and neighbors as the road surface weatherswith time and traffic. One study has shown that finely ground carbon nan-otubes can damage lung tissues,2 illustrating the importance of considering a

BALBUS et al.: DEVELOPING NANOTECHNOLOGY 333

product’s complete life cycle to understand exposures, tailor toxicity testing,and thus address risks effectively.

With commercialization of more products containing or comprising nanoma-terials comes growing opportunities for human and environmental exposure,lending urgency to the need to understand the potential hazards of nanoma-terials. It also raises the question of whether and how carefully regulators arereviewing these new materials before they reach the market.

Numerous examples demonstrate that failure to sufficiently consider thepotential adverse effects of technological advances can lead to immensecosts, from human and environmental as well as financial perspectives. Thewidespread use of tetraethyl lead in motor fuels has left a legacy of impairedcognitive function and shortened life span,3 as well as persistent environmentalcontamination. Similarly, widespread use of asbestos has created a tremen-dous human burden of lung disease and mesothelioma—and has also resultedin massive litigation and cleanup costs for many companies that mined as-bestos and manufactured asbestos products, as well as for building owners thatinstalled such products. The total cost of liability for asbestos-related lossescould reach $200 billion.4 Finally, failure to address potential harms proac-tively could lead to a repeat of what is occurring in the biotechnology sector,where European consumers’ resistance to genetically modified foodstuffs issaid to cost the U.S. agricultural sector $300 million annually in lost cropexport revenues.5

HOW DO NANOMATERIALS DIFFERFROM CONVENTIONAL SUBSTANCES?

In some cases, the very properties that make nanomaterials uniquely use-ful in biomedical or other commercial applications also raise the potentialfor novel mechanisms and targets of toxicity. For example, the ability of cer-tain nanoparticles to penetrate cell membranes, which new applications todeliver targeted therapies exploit, suggests that nanoparticles will also beable to cross physiologic barriers and enter body compartments that largerparticles and smaller molecules do not readily access. Particles of differentsizes gain entry into cells via very different mechanisms. Those larger than500 nm primarily gain entry through active endocytosis; those smaller than200 nm gain entry through a variety of active and nonactive mechanisms.6

One study of 20 nm polystyrene beads suggests that they enter cells by pass-ing directly through membranes without requiring specific transport mecha-nisms. Once inside the cells, the nanoparticles distributed throughout the cy-toplasm and appeared to bind to a variety of structures, including endosomesand cytoskeletal elements. Aggregation after entry occurred and was inhibitedby blockers of microtubules, suggesting a role for active transport processesintracellularly.7


The manner in which different individual and aggregated nanoparticles mayinteract with critical cellular substructures, such as cytoskeletal and motile el-ements is poorly understood, and cannot be inferred from studies of chemicalagents or randomly generated nanoparticles. Surface modifications may allownanoparticles to bind to cell-surface receptors and avoid internalization8 or betaken up by specific transport mechanisms, allowing cell targeting for thera-peutic agents. It is clear that subtle variations in nanoparticle surfaces, whetherdue to intentional coating prior to entry into the body or unintentional surfacebinding or coating degradation once inside the body, can have dramatic impactson where and how nanoparticles gain entry into cells, as well as where and howthey are transported within cells after entry. Understanding the implications ofsuch transport as well as assuring the stability of surface properties throughoutthe life span of manufactured nanoparticles will be critical to assuring safety.

Preliminary efforts to use nanoparticles for therapeutic interventions indi-cate that at least some nanomaterials have unanticipated toxic effects—effectsthat have been detected only because of the testing that routinely occurs in thecourse of drug development. In one example, researchers developing nanopar-ticles designed to target gliosarcoma tumor cells noted that, of 20 such ma-terials, all caused adverse effects on the reticular endothelial system and thekidneys.9 No papers documenting this example of unintended consequenceshave been published as yet; study of these events is crucial to understandingpotential structure–activity relationships for nanomaterials.

Understanding the behavior of nanoparticles requires careful characteriza-tion of their surface properties. For a given mass of particles, surface areaincreases exponentially with decreasing diameter (and increasing number).This increased surface-area-to-mass ratio may be a critical feature in under-standing the toxicity of nanomaterials. For example, in a study comparing thetoxicity of conventional versus nano-sized particles of titanium dioxide, thenanoparticles appeared significantly more toxic when the dose was reportedon a mass basis, but the distinction essentially disappeared when the dose wasreported on a surface area basis.10 The higher surface area to volume ratioalso leads to higher particle surface energy, which may translate into higherreactivity.11 Last, the combination of high surface area and small size may givenanoparticles unusual catalytic reactivity due to quantum effects, such as thoseseen with gold nanoparticles.12 This combination of enhanced surface area andenhanced surface activity lends far greater complexity to the characterizationof nanoparticles, and also precludes easy extrapolation about potential toxicity.

No studies on reproductive toxicity, immunotoxicity, or chronic health ef-fects, such as cancer or developmental toxicity, have yet been published.13 Ofthe limited number of short-term studies completed to date, several have founda variety of adverse effects. Studies in which single-walled carbon nanotubes(SWCNTs) were instilled into the lungs of rodents have consistently demon-strated that SWCNTs cause unusual lung granulomas and other signs of lunginflammation,14–16 and one16 found that SWCNTs also cause dose-dependent,


diffuse interstitial fibrosis. One study of multiwalled carbon nanotubes(MWCNTs) showed similar lung toxicity, especially after the MWCNTs werefinely ground.2 SWCNT and MWCNT have also been shown to induce oxida-tive stress in skin cells.17–19 These studies raise questions of potential toxicityat the beginning or end of the carbon nanotube (CNT) life cycle, through work-place exposures or if CNT-containing products undergo weathering, erosion,or grinding during recycling or disposal.

C60 fullerenes (commonly known as buckyballs) have been less well stud-ied in mammalian models. They have been shown to be potent bactericidesin water20 as well as capable of being transported via the gills from waterto the brains of fish, where they can cause oxidative damage to brain cellmembranes.21 Buckyballs also have caused oxidative stress in in vitro testingsystems.22

Quantum dots can be made of a variety of inherently toxic materials, in-cluding cadmium and lead. As some of the key applications of quantum dotsinclude diagnostic imaging and medical therapeutics, quantum dots have beenstudied relatively extensively in biological systems, although only a small por-tion of this research has focused on potential toxicity. Studies performed to datehave mainly been in vitro cytotoxicity assays. While results have been some-what inconsistent, studies that used longer exposure times were more likely todemonstrate significant toxicity.23 Quantum dots typically have a core made ofinorganic elements, but they are generally coated with organic materials, suchas polyethylene glycol to enhance their biocompatibility or target them to spe-cific organs or cells. Some coatings initially decrease toxicity by one or moreorders of magnitude, but the coatings are known to degrade when exposed toair or ultraviolet light, after which toxicity increases. While the presumptionhas been that this cytotoxicity was caused by leakage of cadmium or seleniumfrom the core, there is evidence that some of the molecules used as coatingsmay have independent toxicity.23 Significant questions remain about the safetyof quantum dots based on the available in vitro studies.

HOW WELL WILL CURRENT REGULATORY FRAMEWORKSPROTECT WORKERS, THE PUBLIC, AND THE

ENVIRONMENT FROM NANOMATERIAL RISKS?

Effectively managing nanomaterials’ potential risks will prove a challengefor existing occupational and environmental regulatory frameworks for at leastfour reasons. First, in most current regulatory programs, standards (and exemp-tions from them) are based on mass and mass concentration. Because of theirhigh surface-area-to-mass ratios and enhanced surface activity, nanomaterialsare likely to prove potent at far lower concentration levels than those envisionedwhen threshold standards were initially set. Second, although regulators canoften reasonably predict at least some types of toxicity for new conventional


materials based on extrapolation from related materials, too little is currentlyknown about nanomaterials to enable such extrapolation.

Third, it appears many nanomaterials are being developed in a decentral-ized fashion, with a significant percentage of production coming from small,dispersed facilities. As a result, obtaining information on which materials arebeing produced and used, by what processes and for what applications—anddirecting any compliance and enforcement efforts to where they are needed—will be hampered by the sheer number of facilities involved. By the same token,a great deal of production, processing, and use will take place in facilities thatmay lack expertise and resources to understand and comply with environmentaland occupational safeguards.

Last, the pace of the regulatory process lags far behind the speed withwhich nanomaterials are being brought to market. While substances marketedas drugs, food additives, and pesticides regularly receive significant scrutinywhen first brought to market, most others do not. As a result, occupationaland environmental protections generally must be developed after problemsare identified or suspected, and then in regulatory proceedings that typicallytake several years to complete. The opportunity exists to recognize and controlproblems more proactively with nanotechnology. A more detailed discussionof specific regulatory issues under two key U.S. laws follows.

OCCUPATIONAL SAFETY AND HEALTH ACT

Under the Occupational Safety and Health Act (OSHAct), four types ofregulatory mechanisms are most likely relevant for protecting workers fromoverexposure to nanomaterials: substance-specific standards, general respira-tory protection standards, the hazard communication standard, and the “generalduty clause.” Each is examined below.

As a practical matter, substance-specific occupational standards are unlikelyto be set in the absence of extensive toxicology data. The majority of standardshave been based on findings of human epidemiology studies, which by defi-nition follow widespread exposure and take even more time to conduct. Giventhe relative paucity of health data on nanoparticles, it is unlikely that anynanoparticle-specific standards will be put in place in the reasonable future.In their absence, inhalable nanoparticles will automatically be covered by the5 mg/m3 standard that applies to “particulates not otherwise regulated,” some-times called “nuisance dust” (29 CFR 1910.1000 Table Z-1). These mass-basedstandards, developed for conventional particles, are unlikely to protect work-ers from adverse effects of nanoparticle exposures: One author 14 has sugg-ested that exposures to carbon nanotubes at 5 mg/m3 for several weeks wouldbe analogous to exposure levels he found to cause lung granulomas and inflam-mation in rats.


Second, the respiratory protection standard (CFR 1910.134) requires em-ployers to provide workers with respirators or other protective devices whenengineering controls are not adequate to protect health. The standard providesguidance in selecting specific personal protective equipment and in imple-menting workplace respiratory protection programs. Only respirators certifiedby the National Institute of Occupational Safety and Health (NIOSH) may beused, and employers must assess the effectiveness of the respirators they sup-ply. The current lack of validated means to measure and characterize the formand size of nanoparticles in the air, as well as uncertainties regarding respiratorperformance with particles less than 30 nm and potential agglomerates around300 nm,24 will complicate implementation of this standard.

Third, OSHA’s hazard communication standard (CFR 1910.1200) stipulatesthat all producers or importers of chemicals are obligated to develop materialsafety data sheets (“MSDSs”), which are intended to provide workers withavailable information on hazardous ingredients in products they handle andeducate them on safe handling practices. However, even when accurate andup-to-date, MSDSs have significant limitations—most notably, there is norequirement to either generate data on potential hazards, or to disclose theabsence of data. Moreover, in some instances a nanomaterial’s MSDS hassimply adopted the hazard profile for a supposedly related bulk material. Forexample, an MSDS for carbon nanotubes identifies the primary component asgraphite, and goes on to cite information on the hazards of graphite withoutacknowledging any dissimilarity between the two substances.25

Finally, OSHAct’s general duty clause [Section 5(a)(1)] is intended as abackstop to protect workers from exposures that are widely known to resultin toxic effects but are not addressed specifically by an OSHA standard. Thegeneral duty clause, however, applies only to “recognized” hazards, a difficultcriterion to meet in light of the current paucity of toxicity data on specificnanomaterials.

TOXIC SUBSTANCES CONTROL ACT

Beyond the occupational realm, the array of potential environmental reg-ulatory authorities initially appears impressive, including the Clean Air Act,Clean Water Act, Resources Conservation and Recovery Act (RCRA, whichaddresses management of hazardous and other solid wastes), and the ToxicSubstances Control Act (TSCA, which covers chemicals other than drugs,food additives, cosmetics, and pesticides). However, with the exception ofsome provisions of TSCA, existing regulations under these statutes are notdirectly relevant to nanomaterials, and adopting such standards would requirethe Environmental Protection Agency (EPA) to launch a lengthy, data-intensiverulemaking process that would take years to complete.26


Certain provisions of TSCA, however, do currently apply. Specifically, sec-tion 5 of TSCA requires the producer of a “new” chemical substance to sendEPA a “Pre-Manufacture Notification” (PMN) before beginning to produce asubstance. Unfortunately, there are no baseline data requirements for PMNs,and 85% of PMNs are submitted without any health data.27 EPA can requestadditional data, but rarely does so; it typically conducts its review based on useof structure–activity relationship models, through which toxicological proper-ties of an unstudied substance are estimated based on the extent of molecularstructural similarity to substances with known toxicological properties. Be-cause the models are based on the properties of bulk forms of conventionalchemical substances, and because nanomaterials’ novel and enhanced proper-ties result from characteristics (e.g., size, shape) in addition to their molecularstructure, existing models have little applicability to nanomaterials. It remainsto be seen whether EPA will make more vigorous use of its authority to re-quire actual toxicity data on nanomaterials to be generated and included inPMNs.

Other key questions also remain unresolved, including the extent to whichnanomaterials qualify as “new” chemicals (thereby triggering PMN require-ments). Under TSCA, a “new” chemical is one that is not already listed onthe TSCA Inventory of chemicals in commerce, and a chemical is defined asa substance with “a particular molecular identity” [TSCA section 3, 15 USCsection 2602(2)]. While nanomaterials whose molecular formula is not alreadyincluded on the TSCA Inventory obviously constitute “new” materials, someparties appear to be assuming that other nanomaterials—those with a molecu-lar structure identical to a substance already on the Inventory—do not qualifyas new.

In October 2005, EPA announced plans to issue guidance on distinguishing“new” from “existing” nanomaterials. Environmental Defense has urged EPAto clarify that nanomaterials constitute “new” substances unless their chemicaland physical properties are demonstrably identical to those of the conventionalsubstance, on the grounds that only substances with the same properties aswell as the same molecular structure share “a particular molecular identity.”Environmental Defense also urged EPA not to apply mass based and otherexemptions in the PMN program unless the underlying scientific rationale isappropriate when applied to nanomaterials.

TSCA also provides certain information gathering authorities. Under Sec-tion 8(a), EPA can require manufacturers to provide certain use and exposureinformation. Section 8(e) requires manufacturers to submit any informationindicating that a substance poses a “significant risk” to health or the environ-ment, while Section 8(d) allows EPA to require manufacturers to submit alltoxicity-related data already in their possession. As further discussed below,EPA is currently conducting a multistakeholder process that is both designinga voluntary initiative to address nanomaterial risks and considering possibleuse of TSCA authorities.


ADDRESSING NANOMATERIAL RISKS: NEXT STEPS

Given the limitations of existing regulatory tools and policies, two distinctkinds of initiatives are urgently needed: first, a major increase in the federalinvestment nanomaterial risk research, and second, rapid development and im-plementation of voluntary standards of care pending development of adequateregulatory safeguards. A wide array of stakeholders must be involved in allcomponents of the latter process, not only large and small businesses and theacademic community, but also labor groups, health organizations, consumeradvocates, community groups, and environmental organizations.

INCREASE GOVERNMENTAL INVESTMENT INRISK RESEARCH

The U.S. government, as the largest single investor in nanotechnology re-search and development, needs to spend more to assess the health and envi-ronmental implications of nanotechnology and ensure that the critical researchneeded to identify potential risks is done expeditiously. Through the NationalNanotechnology Initiative, the federal government spends roughly $1 billionannually on nanotechnology research and development. Of this, environmentaland health implications research accounted for only $8.5 million (<1%) inFY 2004, and is expected to increase to only $38.5 million (<4%) in FY 2006.

The U.S. government should spend at least $100 million annually on hazardand exposure research for the next several years. While an annual expenditureof $100 million represents a significant increase over current levels, it is stillless than 10% of the overall federal budget for nanotechnology development.Moreover, it is a modest investment compared to the potential benefits ofrisk avoidance and to the $1 trillion role that nanotechnology is projectedto play in the world economy by 2015. The call for greatly expanded healthand environmental research spending is buttressed by experts’ assessments, aswell as by testing costs associated with hazard characterization programs forconventional chemicals, and the research budgets for a roughly analogous riskcharacterization effort on risks of airborne particulate matter.28

But the U.S. government should not be the sole, or even the principal, funderof nanomaterial risk research. Other governments are also spending heavilyto promote nanotechnology research and development, and they too shouldallocate some portion of their spending to address nanotechnology risks. Andalthough government risk research has a critical role to play in developing thebasic knowledge and methods to characterize and assess the risks of nanoma-terials, private industry should fund the majority of the research and testing onthe products they are planning to bring to market. Clearly, all parties will ben-efit if governments and industry coordinate their research to avoid redundancyand optimize efficiency.


DEVELOP VOLUNTARY STANDARDS OF CARE

Because federal agencies are unlikely to be able to put into place adequateprovisions for nanomaterials quickly enough to address the products now enter-ing or poised to enter the market, voluntary “standards of care” for nanomate-rials must play a role in guiding the safe use of nanomaterials in the meantime.These standards should include a framework and a process by which to iden-tify and manage nanomaterials’ risks across a product’s full life cycle, takinginto account worker safety, manufacturing releases and wastes, product use,and product disposal. Such standards should be developed and implementedin a transparent and accountable manner, including public disclosure of theassumptions, processes, and results of the risk identification and risk manage-ment systems.

Several voluntary programs are currently at various stages of evolution,though the eventual outputs of each of these are still far from clear. InOctober 2005, a workgroup of an EPA advisory committee proposed a frame-work for a voluntary program aimed at producers, processors, and users ofnanomaterials. The group also recommended using certain TSCA regulatoryauthorities to address nanomaterial risks.29 In addition, Environmental Defenseis working directly with industry to develop a framework for the responsibledevelopment, production, use, and disposal of nanoscale materials. Once de-veloped, the framework will be pilot tested on specific nanoscale materialsor applications of commercial interest to the company. Other U.S. multistake-holder efforts to develop voluntary standards are also under way through ASTMInternational 30 and the American National Standards Institute.31 In addition,the International Standards Organization is convening a new Technical Com-mittee on Nanotechnologies.32

Regulatory programs are essential to securing long-term public confidencein and support for nanotechnology.33 In an ideal world, ample data on nano-materials toxicity and exposures would already exist, allowing governmentsto establish appropriate safeguards. In reality such data are extremely limitedand regulatory programs almost nonexistent. Significantly more federal sup-port for research into the health and environmental effects of nanomaterials isurgently needed, along with rapid development of voluntary standards of carethat can help provide interim protection for workers, the general public, andthe environment until meaningful regulations can be put into place.

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Getting It Right the First Time : Developing Nanotechnology while Protecting Workers, Public Health, and the Environment