Policy Analysis The Impact of Toxicity Testing Costs on Nanomaterial Regulation JAE-YOUNG CHOI,† GURUMURTHY RAMACHANDRAN,‡ AND M I L I N D K A N D L I K A R * ,§ Division of Health Policy and Management and Division of Environmental Health Science, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, and The Liu Institute for Global Issues & Institute for Asian Research, University of British Columbia, Vancouver, British Columbia V6T 1Z2, Canada
Received August 26, 2008. Revised manuscript received January 25, 2009. Accepted January 30, 2009.
Information about the toxicity of nanoparticles is important in determining how nanoparticles will be regulated. In the U.S., the burden of collecting this information and conducting risk assessment is placed on regulatory agencies without the budgetary means to carry out this mandate. In this paper, we analyze the impact of testing costs on society’s ability to gather information about nanoparticle toxicity and whether such costs can reasonably be borne by an emerging industry. We show for the United States that costs for testing existing nanoparticles ranges from $249 million for optimistic assumptions about nanoparticle hazards (i.e., they are primarily safe and mainly require simpler screening assays) to $1.18 billion for a more comprehensive precautionary approach (i.e., all nanomaterials require long-term in vivo testing). At midlevel estimates of total corporate R&D spending, and assuming plausible levels of spending on hazard testing, the time taken to complete testing is likely to be very high (34-53 years) if all existing nanomaterials are to be thoroughly tested. These delays will only increase with time as new nanomaterials are introduced. The delays are considerably less if less-stringent yet risk-averse perspectives are used. Our results support a tiered risk-assessment strategy similar to the EU’s REACH legislation for regulating toxic chemicals.
1. Introduction Although it is well-recognized that health risks of exposures to nanoparticles are poorly understood and need to be quantified (1), nanomaterial production and use are effectively unregulated in the workplace and in the environment (2). At the same time, new nanoparticles are being created at a rapid rate and being incorporated into consumer products, highlighting the need for oversight mechanisms. Additionally, innovations in nanotechnology will likely emerge from research groups and firms that are small businesses and startups and consequently are more sensitive * Corresponding author phone: (604) 822-6722; fax: (604) 8225207; e-mail:
[email protected]. † Division of Health Policy and Management, School of Public Health, University of Minnesota. ‡ Division of Environmental Health Science, School of Public Health, University of Minnesota. § University of British Columbia. 3030
9
ENVIRONMENTAL SCIENCE & TECHNOLOGY / VOL. 43, NO. 9, 2009
to signaling from regulatory bodies and costs associated with increased oversight (3). Health and safety regulations will need to pay careful consideration to the cost burden of regulatory testing. These costs will play an important role in prioritizing nanoparticle risks (4). In the United States, regulation of the human health risks is primarily the responsibility of the Occupational Safety and Health Administration (OSHA) for occupational risks and the U.S. Environmental Protection Agency (EPA) for nonoccupational risks under the OSHAct and the Toxic Substance Control Act (TSCA), respectively. A series of court rulings has resulted in the burden of health risk assessment for any substance being placed on the under-resourced OSHA (5). This has led to a standard setting process that is so slow that thousands of chemicals have no defined occupational exposure limits. Any new nanomaterial would likely meet the same fate (6). A similar paralysis besets the oversight of chemicals in the environment by TSCA, where the EPA faces a Catch-22 (7). Before the EPA can ask the producer to provide data to help in risk assessment of a chemical, the agency needs to show that the chemical presents an unreasonable risk to human health or the environment. EPA thus needs toxicity and exposure data that producers are not obligated to provide unless the EPA can first show that a risk exists! As a result, by the mid-1990s, the EPA had managed to review the risks of about 1200 (2%) of the 62 000 “1979 existing chemicals” (8). High production volume (HPV) chemicals accounted for more than 90% of these; since 1979 the EPA has run a voluntary program whereby firms can provide screeninglevel data for these chemicals. Although such information has been submitted for most of these chemicals, it is not sufficient to support risk-based decision-making. For premanufacture notification (PMN) of new chemicals, TSCA requires only that producers submit toxicity testing information that is “in their possession” when they file the PMN; it does not require new testing. Not surprisingly, 85% of PMNs lack data on chemical health effects (9). The common theme running through the OSHA and TSCA examples is that the entire burden of data collection and risk assessment is placed on agencies without the budgetary means to carry out this mandate, while firms have little incentive to reveal toxicity or exposure information. EPA has taken the initial steps for nanoparticle regulation through the implementation of a voluntary nanotechnology stewardship program. In the light of oversight of existing chemicals in the United States, it is reasonable to assume that the voluntary program will fail even as thousands of new nanoproducts enter the market in the coming decade (10). It is, therefore, important to consider alternative approaches that may show better performance in terms of the efficiency (using fewer resources) and effectiveness (extent of coverage of new nanomaterials) of producing information essential for risk assessment. Limitations of regulatory oversight are also evident in private sector R&D related to nanoparticles. Despite the large and rising investments in nanotechnology research, corresponding private investments in studying the health and safety aspects have been limited. Although some firms may conduct acute toxicological studies (11), industry fears penalties and is less willing to conduct long-term studies on chronic health and environmental effects (12). Wagner (13) delineates several reasons why the private sector is reluctant to voluntarily undertake long-term safety testing of their products. First, direct costs associated with assessing risks 10.1021/es802388s CCC: $40.75
2009 American Chemical Society
Published on Web 02/20/2009
are expensive and may not produce definitive results, especially if tests have low specificity. Second, virtually no market benefits accrue to actors who produce research on the long-term safety of products. As a result, firms do not consider the assessment of long-term risks from chemicals to be an attractive business investment. Knowledge about risks from specific nanoparticles will continue to be a bottleneck in the coming decade, particularly in the United States under current oversight mechanisms. In this paper, we estimate the costs of risk assessment of nanoparticles drawing inspiration from the new REACH program recently promulgated in the European Union (EU) as well as Proposition 65 in the state of California. We explore the consequences of placing the burden on firms to provide relevant exposure and toxicity information (like Proposition 65 does), while simultaneously using a tiered toxicity testing strategy to most efficiently and effectively use scarce resources (like REACH does). Tiered strategies begin with an initial screening tier comprising relatively simple and inexpensive tests; the outcomes of simple tests are used to prioritize substances for further, more resource-intensive and complex testing with increasing degrees of selectivity for adverse effect (14). Assessing whether such a system might be able to fill the enormous data gap for untested nanoparticles requires that we understand how costly it is likely to be, especially if the burden of providing environmental health and safety data falls on an emerging industry. To develop plausible estimates for private R&D spending on nanomaterial hazard testing, we construct a data set for publicly traded and private firms manufacturing or using nanomaterials that includes annual revenues and reported or estimated expenditures on nanomaterial-specific research and development (section 2). Next, we develop estimates for the costs of hazard assessment for nanomaterials currently in use using various tiers of toxicity testing, from simple assays to long-term in vivo laboratory studies (section 3). In section 4, we compare testing costs with R&D spending and ask a series of “what if” questions: What are the industry-wide costs of testing nanoparticles if new nanomaterials are subjected to simple “screening” tests? What are the costs of testing if a full-blown hazard assessment based on the entire complement of currently available testing procedures are performed? Finally, at current levels of investment, how long might it take to clear the backlog of nanoparticles currently in use that need to be tested?
2. Estimating Funds Available for Nanomaterial Hazard Evaluation The database of U.S. nanomaterial firms is compiled from several sources: Nanomaterial Database (15), Corporate Annual Reports (henceforth, CARs), and The Nanotech Report (16). This database includes a total of 329 firms: 53 publicly traded firms and 276 privately owned firms. A list of privately held firms and publicly traded firms that are engaged in making nanomaterials was excerpted from the Nanomaterial Database and The Nanotech Report. For the publicly traded firms, we identified the number of employees, total revenue, and the amount of R&D spending from their 2006 CARs, an audited document required by the U.S. Security and Exchanges Commission. For privately traded firms, we were able to identify the number of employees and revenues for a sample of 62 privately traded firms (16). Firms were categorized into four sizes: macro, >10 000 employees; large, 1000-9999 employees; medium, 100-999 employees; small, 100 employees. Firms in these categories have mean R&D spending of $1372M, $55M, $30M, and $6M, with an average of 79500, 4650, 330, and 49 employees respectively. Data on privately traded firms are scarce and total revenue and R&D spending for these firms is not widely
TABLE 1. Estimated Amount of R&D Funds Spent Annually on Nanomaterial Hazard Evaluation Research for the Three Different R&D Scenarios (in millions of US dollars)a percentage of nanomaterial R&D spent on hazard evaluation
nanomaterial R&D spending
10%
5%
1%
R&D scenario 1 R&D scenario 2 R&D scenario 3
$325.53 $224.00 $349.57
$162.77 $112.00 $174.79
$32.55 $22.40 $34.96
a Scenario 1 assumes 10% current R&D expenditures are devoted to nanomaterial R&D by all firms independent of size. Scenario 2 assumes 10% current R&D expenditures are devoted to nanomaterial R&D by macro firms, 20% by large firms, 80% by medium firms, and 90% by small firms. Scenario 3 assumes 15% current R&D expenditure are devoted to nanomaterial R&D by macro firms, 20% by large firms, 50% by medium firms, and 100% by small firms.
available. On the basis of our sample, we assumed that the average size of privately owned firms is 60% of the average size of private firms in the publicly traded “small” category. In addition to determining the size of U.S. corporations manufacturing nanomaterials, there is the additional challenge of assessing the firms’ R&D spending related to nanomaterial hazard testing. Though several firms reveal product segmentation, none of the firms provide information on the magnitude and composition of R&D spending. Nanomaterial hazard expenditures are characterized by two variables (i) the fraction of R&D that firms in the nanomaterial manufacturing sector devote to nanomaterial research (R&D scenarios) and (ii) the proportion of nanomaterial research spending devoted to hazard testing. We devise the following three R&D scenarios: Scenario I: 10% of current R&D expenditures are devoted to nanomaterial R&D by all firms independent of size. Scenario II: 10% of current R&D expenditures are devoted to nanomaterial R&D by macro firms, 20% by large firms, 80% by medium firms, and 90% by small firms. Scenario III: 15% of current R&D expenditures are devoted to nanomaterial R&D by firms, 20% by large firms, 50% by medium firms, and 100% by small firms. These R&D scenarios are consistent with patterns of spending we calculated from publicly traded firms in our database. For small firms engaged in nanomaterial research, our data show that R&D spending far exceeds revenues. For example, median spending on R&D for small firms exceeds revenues by a factor of 7, whereas macro and large firms spend only 2 and 3% of revenues on R&D, respectively. Clearly, small and medium-sized nanomaterial firms tend to spend considerably greater portion of their budgets on R&D than macro and large firms do. Data on the portion of R&D spending devoted to hazard testing is proprietary and difficult to access. Hence it was not possible to estimate nanohazard R&D spending as a function of company size. Consequently, we assume three different investment fractions for all companies (10, 5, and 1% of R&D spending) devoted to nanomaterial hazard assessment and estimate a range for R&D funds targeted to nanomaterial hazard assessment. In Table 1, we present the estimated amount of R&D funds spent annually on nanomaterial hazards research for the three different R&D scenarios. The range of numbers should be seen as an attempt to provide upper and lower bounds for current expenditures for nanomaterial hazard testing; they should not be seen as precise estimates. VOL. 43, NO. 9, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
9
3031
TABLE 2. Estimated Costs of Toxicity Testing for Four Scenarios That Differ in the Proportion of Nanomaterials That Need to Undergo Different Levels of Testing (all costs are in millions of US dollars)a
optimistic neutral risk averse precautionary
testing cost per substance distribution number of materials costs of testing distribution number of materials costs of testing distribution number of materials costs of testing distribution number of materials costs of testing
level I
level II
level III
level IV
total
$0.07 0.60 159 $11.4 0.25 66 $4.7 0.10 27 $1.9 0.00 0 $0.0
$0.83 0.15 40 $33.0 0.25 66 $55.0 0.20 53 $44.0 0.00 0 $0.0
$2.15 0.15 40 $85.6 0.25 66 $142.7 0.20 53 $114.1 0.00 0 $0.0
$4.48 0.10 27 $118.8 0.25 66 $296.9 0.50 133 $593.9 1.00 265 $1187.70
1.00 265 $249 1.00 265 $500 1.00 265 $754 1.00 265 $1188
a Cost of testing is calculated as follows: number of nanomaterials multiplied by cost of testing for each level (e.g., cost of level I testing for the optimistic perspective is 150 × 0.07 ) $11.4; total costs of testing from an optimistic perspective is sum of the costs at levels I, II, III, and IV).
3. Estimating the Cost of Nanoparticle Hazard Evaluation In the absence of both regulatory standards and a commonly accepted set of assays, it is difficult to quantify the costs of nanomaterial testing. Here we use costs of toxicity testing for conventional chemicals as a proxy for nanomaterial testing costs. The use of chemical toxicity tests may serve as a lower bound for the true costs of testing nanomaterial toxicity, since some of the tools and techniques will likely be new and require additional analytical infrastructure. We then develop plausible estimates for escalating costs associated with increasingly complex assays and test procedure using recently published estimates. Employing a cross-sectional survey design using a questionnaire, Fleischer (17) reported prices for laboratory testing services for the 76 test categories, in particular toxicological and eco-toxicological tests as required by EU REACH, from 28 independent and corporate laboratories in 2004. We used these reported prices in our analysis. Detailed information of testing costs from Flesicher (17) and comparison across sources (18, 19) is provided in the Supporting Information section. REACH tiers the testing requirements into four levels on physicochemical, toxicological, and eco-toxicological properties according to the volume of use: substances produced or imported in quantities of 1-10 tons/year require level I testing at an estimated average cost per chemical of $70 000; substances produced or imported in quantities of 10-100 tons/year require level II testing with an estimated average cost per chemical of $830 000; substances produced or imported in quantities of 10-100 tons/year require level III testing with an estimated average cost per chemical of $2.15 million; substances produced or imported in quantities of 10-100 tons/year require level IV testing with an estimated average cost per chemical of $4.48 million. In what follows, we use these testing levels as a proxy for the level of safety for a nanoparticle. Thus, in what follows, we assume that nanoparticles requiring level I testing alone are “safe”, whereas those requiring level IV tests have the highest hazard potential. We begin by estimating the total number of nanomaterials manufactured to date that need to be tested. We estimate the number of nanomaterials from Nanomaterial Database provided by Nanowerk LLC that has 265 nanomaterials in 9 categories. The database includes only nanoparticles that can be identified using a search of manufacturers’ Web sites providing detailed particle description. In total, of the 190 nanoparticle manufacturers identified, roughly two-thirds provide particle descriptions and hence are included in the 3032
9
ENVIRONMENTAL SCIENCE & TECHNOLOGY / VOL. 43, NO. 9, 2009
database (18). Consequently, the number of nanoparticles should be seen as a lower bound. We propose four perspectives on levels of testing that capture subjective views on nanoparticle hazards - optimistic, neutral, risk-averse, and precautionary - and estimate the cost of nanomaterial testing for each perspective. The perspectives range from the largely safe (optimistic) to the primarily unsafe (precautionary), with two perspectives (neutral and risk-averse) in between. The degree to which a nanomaterial is considered “safe” or “hazardous” has a direct effect on the level of testing. In the optimistic perspective, only 10% of nanomaterials need testing at level IV, with a majority (60%) needing only level I testing. In other words, 60% of the nanomaterials are deemed safe based on level I tests, and 10% of the nanomaterials could not be deemed safe on the basis of levels I, II, and III tests, and therefore had to also be tested at level IV. The precautionary scenario on the other hand requires all nanomaterials to be tested at level IV, the most extensive testing level. The neutral perspective assumes nanomaterials to be distributed roughly equally in all four categories, whereas the risk-averse perspective assumes 50% of all nanomaterials to be tested at level IV. Details of how nanomaterials are distributed across testing categories for each perspective are provided in Table 2. Table 2 presents the estimated costs of risk assessment for the different perspectives on the toxicity of nanoparticles. Using assessment costs developed by Fleischer (17), we estimate $0.07 million as the cost of testing at level I, $0.83 million at level II, $2.15 million at level III, and $4.48 million at level IV. Because a given material would require testing at a certain level only if it fails to be judged safe on the basis of lower testing levels, the cost at any level is the sum of the costs of all levels up to that level. Total estimated cost of testing for a perspective is determined by multiplying the number of materials at each level by the cost of testing for each level, and aggregating across all materials.
4. Adequacy of Available Funds for Hazard Evaluation We compare the costs of testing for each perspective with the availability of R&D funds at current levels for nanohazards research, and express the comparison in terms of years needed to complete hazard assessment for the nanomaterials currently available. Time to completion is calculated by dividing costs of hazard evaluation for different perspectives (from Table 2) by the annual R&D funds available for testing for different scenarios (from
TABLE 3. Estimated Time (in years) Needed to Assess the Hazards from Existing Nanoparticles for Different R&D Scenariosa spending on hazards research (%) scenario I 10% 5% optimistic neutral risk averse precautionary
0.8 1.5 2.3 3.6
1%
1.5 7.6 3.1 15.3 4.6 23.2 7.3 36.5
scenario II 10%
5%
1%
1.1 2.2 3.4 5.3
2.2 4.5 6.7 10.6
11.1 22.3 33.7 53.0
scenario III 10% 5% 0.7 1.4 2.2 3.4
1%
1.4 7.1 2.9 14.3 4.3 21.6 6.8 34.0
a Each entry is indexed by spending on nano-hazard research (10%, 5%, 1% of total R&D), as well as a subjective perspective (optimistic, neutral, risk averse, precautionary) on the distribution of risk levels from nanoparticles across particle types.
Table 1). The numbers in Table 3 reveal the significant impact of spending on nanohazard related R&D, as well as the importance of the different perspectives on nanohazards; the fraction of R&D investments that firms in the nanomaterial manufacturing sector devote to nanomaterial research appear to have a smaller impact. From an optimistic perspective (when most of the nanomaterials require only level I testing and only 10% of the nanomaterials require level IV testing), it should be possible to complete all testing in a year or less if firms spend a substantial amount (i.e., 10%) of their R&D spending on nanohazard research. However, if firms spend a smaller amount (i.e., 1%) the time taken to complete nanohazard testing can be quite long (∼7-11 years). From the precautionary perspective (that requires all nanomaterials to be tested at level IV), however, very high R&D (e.g., 10%) investment in nanohazard research results in clearing of the current backlog in 3-5 years, whereas smaller investments in nanohazard R&D of 1% sees the time taken balloon to a much greater range of 34-53 years. The analysis above does not differentiate between the producers of the nanomaterials. It simply calculates the ratio of potential sector-wide spending on R&D to costs of testing from different perspectives. It is possible that the costs may fall on the individual producer of nanoparticles who may disproportionately be smaller and privately owned firms. This will further skew the analysis toward greater delays in hazard evaluation, because smaller firms have smaller R&D budgets relative to large and macro firms. Current investments in nanohazard evaluation are likely on the low side and probably less than 1% of nano R&D. Under such conditions, evaluating hazards may take much more time than the highest estimate in Table 3. As the number of nanoparticles increase with time, this problem will be exacerbated. Our results show that the range of the total estimated cost of hazard evaluation for nanomaterials depend primarily on the distribution of nanomaterials into testing categories. All the perspectives exhibit an element of tiered testing with the exception of the precautionary perspective, which demands that all particles be tested at the highest and therefore most expensive level of testing. Further, lessstringent risk-averse perspectives that nonetheless do take seriously the question of nanomaterial health risks reduce total costs by about 40%. Consequently, these results point to the plausibility of a tiered testing for risk assessment of nanoparticles, provided the lower tiers have sufficiently specificity. In EU’s REACH legislation, testing tiers are based on amounts released to the environment; in this work, we assumed the existence of testing tiers for nanoparticles
analogous to those specified under REACH. Ideally, testing tiers should be based on hazard characterization that captures potential exposures and toxicity. Schemas for classifying nanoparticles into categories that map onto hierarchical testing levels will be needed for tiered testing approaches to work. Testing tiers for nanoparticles prior to their widespread use and release will require information on exposures and toxicity to help in classifying the particles. Recent efforts in this direction (21) suggest that it may possible to do rapid in vitro profiling of nanoparticles that will help in classifying nanoparticles according to toxicity.
Acknowledgments This work was, in part, supported by the U.S. National Science Foundation (NSF) through the NIRT Grant SES0608791 (G.R.), and the Cooperative Agreement 0531184 between NSF and Center for Nanotechnology in Society at University of California, Santa Barbara (M.K.). M.K. would also like to acknowledge support from the Center for Environmental Implications of Nanotechnology at UCLA which is funded by the US National Science Foundation and the Environmental Protection Agency under Cooperative Agreement Number EF 0830117. The authors thank the two anonymous reviewers for their comments. Any opinions, findings, and conclusions or recommendations expressed in this article are those of the authors and do not necessarily reflect the views of the National Science Foundation.
Supporting Information Available Additional details provided include data on company size and R&D investments. Data on R&D investment estimates corresponding to the three scenarios are provided inTables S1, S2, and S3. Table S4 shows the tests included in a toxicity testing tier and their respective costs. This material is available free of charge via the Internet at http:// pubs.acs.org.
Literature Cited (1) Kandlikar, M.; Ramachandran, G.; Maynard, A. D.; Murdock, B.; Toscano, W. A. Health risk assessment for nanoparticles: A case for using expert judgment. J. Nanopart. Res. 2007, 9, 137– 156. (2) Wardak, A.; Gorman, M. E.; Swami, N.; Rejeski, D. Environmental Regulation of Nanotechnology and the TSCA. Technol. Soc. Mag., IEEE 2007, 26, 48–56. (3) Monica Jr, J. C.; Heintz, M. E.; Lewis, P. T. The perils of preemptive regulation. Nat. Nanotechnol. 2007, 2, 68–70. (4) Owen, R.; Handy, R. Formulating the problems for environmental risk assessment of nanomaterials. Environ. Sci. Technol. 2007, 41, 5582–5588. (5) Ashford, N. A.; Caldart, C. C. Technology, Law and the Working Environment; Island Press: Washington, D.C., 1996. (6) Balbus, J. M.; Florini, K.; Denison, R. A.; Walsh, S. A. Protecting workers and the environment: an environmental NGO’s perspective on nanotechnology. J. Nanopart. Res. 2007, 9, 11– 22. (7) Chatterjee, R. The Challenge of Regulating Nanomaterials. Environ. Sci. Technol. 2008, 42, 339–343. (8) United States General Accounting Office. Toxic Substances Control Act: Legislative Changes Could Make the Act More Effective (GAO/RCED-94-103); U.S. Government Printing Office: Washington, D.C., 1994; available at http://archive.gao.gov/ t2pbat2/152799.pdf. (9) United States General Accounting Office. Options Exist to Improve EPA’s Ability to Assess Health Risks and Manage Its Chemical Review Program, (GAO-05-458); U.S. Government Printing Office: Washington, D.C., 2005; available at http:// www.gao.gov/new.items/d05458.pdf. (10) Bowman, D.; Hodge, G. Nanotechnology and public interest dialogue some international observations. Bull. Sci. Technol. Soc. 2007, 27, 118–132. (11) Davies, J. C. EPA and Nanotechnology: Oversight for the 21st Century; Project on Emerging Nanotechnologies; Woodrow VOL. 43, NO. 9, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
9
3033
(12) (13) (14)
(15) (16) (17)
3034
Wilson International Center for Scholars: Washington, D.C., 2007. Lyndon, M. L. Information economics and chemical toxicity: designing laws to produce and use data. Mich. Law. Rev. 1989, 87, 1795–1861. Wagner, W. E. Common ignorance: the failure of environmental law to produce needed information on health and the environment. Duke Law J. 2004, 53, 1619–1745. Becker, R. A.; Borgert, C. J.; Webb, S.; Ansell, J.; et al. Report of an ISRTP Workshop: Progress and barriers to incorporating alternative toxicological methods in the U.S. Regul. Toxicol. Pharmacol. 200646, 18–22. Nanowerk, LLC Home Page; http://www.nanowerk.com/(last accessed Jan 20, 2009). Lux Research. The Nanotech Report, 5th ed.; Lux Research Inc.: New York, 2007. Fleischer, M. Testing Costs and Testing Capacity According to the REACH Requirements-Results of a Survey of Independent and Corporate GLP laboratories in the EU and Switzerland. J. Bus. Chem. 20074, 96–114.
9
ENVIRONMENTAL SCIENCE & TECHNOLOGY / VOL. 43, NO. 9, 2009
(18) Bundesanstalt fu ¨ r Arbeitschutz und Arbeitsmedizin. Kosten fu ¨r eine Anmeldung nach dem Chemikaliengesetz; Bundesanstalt fu ¨ r Arbeitschutz und Arbeitsmedizin: Dortmund, Germany, 2004. (19) U. S. Environmental Protection Agency. Chemical hazard data availability study: What do we really know about the safety of high production volume chemicals; EPA: Washington, D.C., 1998; available at http://www.epa.gov/hpv/pubs/general/hazchem. htm. (20) Berger, M. Nanowerk LLC. 2008, personal communication. (21) Shaw, S. Y.; Westly, E. C.; Pittet, M. J.; Subramanian, A.; Schreiber, S. L.; Weissleder, R. Perturbational profiling of nanomaterial biologic activity. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 7387–7392.
ES802388S