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October 11, 2011
TABLE OF CONTENTS
1.0 INTRODUCTION ................................................................................................................................. 1
2.0 METHODS .......................................................................................................................................... 1
2.1 Literature Search ........................................................................................................................... 1
2.1.1 English Language ................................................................................................................... 1
2.1.2 Foreign Language .................................................................................................................. 2
2.2 Literature Selection ....................................................................................................................... 2
2.2.1 English Language ................................................................................................................... 2
2.2.2 Foreign Language .................................................................................................................. 5
2.3 Literature Review .......................................................................................................................... 5
3.0 RESULTS............................................................................................................................................. 6
3.1 General Characteristics of Selected Literature ............................................................................. 6
3.2 Summary of Key Information Obtained from the Literature ........................................................ 9
3.2.1 Human Health Toxicity .......................................................................................................... 9
3.2.2 Occupational Practices ........................................................................................................ 12
3.2.3 Risk Assessment .................................................................................................................. 17
3.2.4 Occupational Exposure ....................................................................................................... 18
3.2.5 Environment ........................................................................................................................ 19
3.2.6 Ecotoxicity ........................................................................................................................... 19
3.2.7 Regulatory ........................................................................................................................... 20
3.3 Summary of Key Information Obtained from Amorphous Silica Papers .................................... 20
3.3.1 Literature on Amorphous Silica........................................................................................... 21
3.3.2 Literature on Nano‐Sized Amorphous Silica ....................................................................... 21
3.4 Summary of key information from Carbon Black Papers............................................................ 22
3.4.1 Literature Specific to Nano‐sized Carbon Black .................................................................. 23
4.0 CONCLUSIONS ................................................................................................................................. 25
4.1 Conclusions on General Literature Review ................................................................................. 25
4.2 Conclusions on Amorphous Silica and Carbon Black Literature Review ..................................... 26
6.0 REFERENCES .................................................................................................................................... 27
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1.0 INTRODUCTION
Under the Tire Industry Project (TIP), the Nanomaterials Working Group (NWG) launched a
project aimed to support the continued use of nanostructured materials (namely, carbon black
and precipitated silica) and the development of new nanomaterials for use in the tire
manufacturing process. Under these broad goals, a review of the scientific literature was
conducted to identify studies pertaining to environmental risk assessment for nanomaterials,
with a focus on amorphous silica and carbon black.
In accordance with the goals of the project, the purpose of the literature search and review was
to identify key literature related to the known properties and the history of safe use of
amorphous silica and carbon black and to provide information to the industry to aid in moving
forward in the development of new nanomaterials for use in the tire manufacturing process.
This report summarizes some of the basic information gained from the review of papers
addressing these two broad topics including the methods used to identify and review the
literature, information about the literature, brief summaries of key points on important topics, and
recommendations for moving forward.
2.0 METHODS
The literature search was conducted using a combination of standard internet search engines
(i.e. Yahoo! and Google) and targeted scientific journal databases (ScienceDirect and PubMed).
All combinations of the following terms were used to conduct the search. The combinations
represent one word from each “material type” and “topic”.
For example, the search terms included: nanomaterial AND risk assessment; nanomaterial AND
risk management; etc. In addition to these search terms, combinations including amorphous
silica AND toxicity AND nano*; carbon black AND toxicity AND nano*; amorphous silica AND
exposure AND nano*; and carbon black AND exposure AND nano*, such that the asterisk can
represent any appropriate word (e.g. material, particle, technology), were used to identify
literature specific to amorphous silica and carbon black.
In addition to these search terms, additional relevant regulatory and stakeholder papers
provided by TIPG member companies were incorporated into the review process as
appropriate. Also, ChemRisk had a database of literature on amorphous silica and carbon black
from other projects that were consulted for relevant studies. Supplemental targeted searches
for publications relevant to the project (e.g. ‘gray’ literature obtained from searching websites of
key stakeholders) were also conducted.
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European language searches were conducted along with English language sources, as
ScienceDirect and PubMed include European language sources. Japanese, Chinese, Korean,
and Indian language searches were conducted by local scientists.
2.2 LITERATURE SELECTION
2.2.1 English Language
In the interest of cost and time, the literature review was limited to review of 250 papers. Based
on the large number of responses from use of the search terms (see Table 1), each article title
was reviewed for relevancy to the project1. In reviewing article titles for relevancy, we
considered the subject matter of the paper (i.e. exposure, toxicity, etc.), the material studied in
the paper and its relevance to the project, and other key criteria. Based on this review, we
selected a subset of the search results to evaluate further, including abstract review, article
characterization and prioritization.2
1
ScienceDirect only permits the viewing of the top 1,000 search results; for all ScienceDirect searches, the results
were sorted by relevance and the top 1,000 article titles reviewed for potential inclusion.
2
These search results are valid through July 31, 2010. Papers published since that time are not included in this
literature review.
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PubMed ScienceDirect
Search Term Combination
Results Results
nano* AND risk assessment 388 3220
nano* AND risk management 321 2580
nano* AND exposure 2067 14,001
nano* AND rubber OR tire 122 3406
nano* AND toxicity 3328 8,269
nano* AND occupational 279 913
amorphous silica AND risk assessment AND nano* 2 253
amorphous silica AND risk management AND nano* 1 162
amorphous silica AND exposure AND nano* 15 1191
amorphous silica AND (rubber OR tire) AND nano* 1 498
amorphous silica AND toxicity AND nano* 19 579
amorphous silica AND occupational AND nano* 3 75
carbon black AND risk assessment AND nano* 9 655
carbon black AND risk management AND nano* 7 463
carbon black AND exposure AND nano* 79 2,420
carbon black AND (rubber OR tire) AND nano* 5 839
carbon black AND toxicity AND nano* 80 1446
carbon black AND occupational AND nano* 23 288
* Suffixes included material(s), technology, and particle.
Once the article titles were screened and appropriate articles selected, each abstract was
reviewed and information from the abstract entered into a spreadsheet database to allow for
prioritization. Specific characteristics of each paper were identified to prioritize the articles for
review. Prioritization was conducted using the analytical hierarchy process (AHP), a method for
ranking different papers based on relative comparisons between the papers based on the
importance of specified properties. The process for conducting the prioritization using AHP is
multi-step:
1. Rank properties relative to one another (i.e. how important are papers that evaluate
human health toxicity versus those that evaluate materials development, how important
are papers that investigate inhalation versus oral exposure, etc.)
2. For each property, rank the papers in order of relative importance
3. Combine rankings of each property for every study to generate an overall weight
Table 2 outlines the rankings within each property that were assigned to those characteristics.
Each property was weighted equivalently with the exception of material type, which was given
the highest importance to ensure that within the prioritization, all carbon black and amorphous
silica papers were identified in the subset of papers to be reviewed. In addition, we also
included the year of publication in the ranking, with papers published since 2005 weighted more
heavily than those published prior to 2005. However, of the papers identified as relevant after
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prioritization, over 90% were published during that time window, indicating that this metric did
not appreciably impact the overall selection of papers. For any paper where information was
not available for a given property, the average value was assigned to that property to ensure
that an absence of a value did not skew the results of the prioritization towards non-inclusion.
b
Includes: atmospheric particulate, carbon based particles, fullerene, gold particles, silver particles, crystalline silica
particles, non-specified materials.
c
Includes: Intravenous injection, intraperitoneal injection, oral, unknown
Composite scores were created for each paper based on the rankings by each property as
detailed in Table 2. These scores were then used to select the most important papers for
review. In total, 189 papers were reviewed in the English language. Based on the project
goals, it was determined that we would not review any articles specific only to materials
development.
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Upon selection of the relevant articles, each article was reviewed. Non-English papers were
read by translators and English summaries prepared. All reviewers used the same review
spreadsheet for summarizing comments on each paper.
Upon review of each article and preparation of a summary, each paper was ranked with respect
to relevance to the project. To ensure consistency, a base set of rules was used to establish
the relative importance of the papers. Table 3 outlines these rules used to assign the ranking.
Where the paper description did not match the ranking criteria, professional judgment was used
to assign the ranking.
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3.0 RESULTS
3.1 GENERAL CHARACTERISTICS OF SELECTED LITERATURE
In total 258 articles were reviewed; 189 in English language, 2 in Russian, 2 in Polish, 2 in
Italian, 1 in French, 21 in Chinese, 18 in Korean, 13 in Indian and 10 in Japanese. Table 4
provides a summary of the characteristics of the reviewed literature by topic. The majority of the
literature reviewed addressed aspects of human health toxicity. However, within the gray
literature, the primary topic addressed in the reviewed literature was occupational practices,
which included papers addressing methods for best practices in industry. Furthermore, our
literature review did not focus on a single industry; rather most papers were either related to the
rubber and tire industry (many of the amorphous silica papers, some carbon black papers) or
were generally applicable to all industries using nanomaterials.
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Dose Response
Human Health
Occupational
Occupational
Assessment/
Management
Environment
Ecotoxicity
Regulatory
Exposure
Practices
Toxicity
Total
Risk
157 5 20 6 14 26 2 30 260
2005-2010 143 5 20 6 14 26 2 29 245
Year
Pre 2005 14 0 0 0 0 0 0 1 15
Scientific Literature 141 5 20 4 11 10 2 25 218
Gray Literature 6 0 0 2 3 16 0 4 31
Source
Conference
5 0 0 0 0 0 0 0 5
Proceedings
Other 5 0 0 0 0 0 0 1 6
R&D 1 0 0 0 0 2 0 0 3
Rubber/Tire 35 0 0 0 0 0 0 1 36
General 36 1 5 3 11 22 1 22 101
Industry
Cosmetics/ Consumer
1 0 0 0 0 0 0 0 1
Product
Manufacturing 0 2 0 0 2 1 0 0 5
Pharmaceutical/Medici
7 0 0 0 0 0 0 0 7
nea
Other 77 2 15 0 1 1 1 10 107
a
The initial screening process included eliminating papers related to pharmaceutical or medicinal uses for nanomaterials. Most
papers on pharmaceutical or medicinal uses of nanomaterials relate to the efficacy of these materials as drug delivery systems for
chemotherapy and thus may meet the search terms based on toxicity to the cancer cell. The remaining papers were retained as
they discussed toxicity of nanomaterials that may be targeted for use as medicines to normal cells and are therefore relevant for
considering the weight of evidence on toxicity of nanomaterials.
Ranking of priority revealed that there were 130 papers of high priority, 95 of medium priority,
and 33 of low priority. A more detailed profile of the high priority papers is presented in Table 5.
High priority papers were primarily associated with human health toxicity and occupational
practices. A more detailed discussion of the focus within these topics is found in Section 3.2,
along with a brief discussion on what is known about the other topics as well. Because
specific focus on amorphous silica and carbon black was necessary to meet the objectives of
the project, a large number of papers were reviewed on each material (amorphous silica = 50;
carbon black = 53). Details of these papers can be found in Tables 6 and 7, respectively and
in Sections 3.3 and 3.4.
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Primary Topic
Risk 5
Assessment/Management
Human Health Toxicity; 2
Occupational Practices
Dose Response 1
Environment 1
Regulatory 1
Not Specified/Applicable 54
General 39
Industry
Rubber/Tire 34
Research and Development 2
Pharmaceutical/Medicine 1
aSiO2 41
Carbon Black 30
Material Type
General 30
Various; Includes Carbon 21
Black
Various; Includes aSiO2 5
Various 2
aSiO2; Carbon Black 1
Scientific Literature 102
Source
Gray Literature 18
Other 6
Conference Proceedings 4
Ecotoxicity 3
Risk 1
Assessment/Management
Environment 1
Scientific Literature 40
Source
Gray Literature 4
Conference Proceedings 3
Other 3
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Source
Other 2
Conference Proceedings 1
Assessment/Management
General 1
Dose Response 1
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the most appropriate/most sensitive metrics for understand toxicity from nanomaterial exposure,
researchers are focusing their attention on particle characteristics as they relate to toxicity. For
instance, identification of the type of nanomaterial to which people are exposed to may not be
sufficient for characterizing the potential for an adverse effect to occur; some studies indicate
that, for example, carbon nanotubes with slightly different surface coatings or characteristics
may behave very differently when introduced into biological systems (Kayat, Gajbhiye et al.
2010).
Indications are that smaller particles (even within the nanometer size range) are often more
potent toxicants than larger particles. Furthermore, some suggest that exposure metrics such
as number of particles and total particle surface area are better correlated with adverse health
effects than mass particle concentration. However, currently there is no consensus on the best
metric for estimating toxicity, and therefore researchers are continuing to investigate this
question extensively. With most toxicity studies, researchers are careful to characterize a
variety of properties of their particles and monitor important dose metrics such as particle
number and particle surface area alongside of particle mass concentration. It should be noted
that OECD acknowledges this data gap, but recommends the traditional mass based toxicity
evaluation for risk assessment until additional information is available to clarify the appropriate
dose metric (OECD, 2010).
Within the scope of studies addressing the relationship between particle characteristics and
toxicity are those that quantitatively assess the dose response relationship. Studies addressing
issues of dose response primarily focused on dosimetry and methods for modeling lung
deposition and estimating internal doses of different nanomaterials, including carbon nanotubes
and titanium dioxide (Kuempel, Tran et al. 2006; Kleinstreuer, Zhang et al. 2008; Liao, Chiang et
al. 2008; Liao, Chiang et al. 2009; Pauluhn 2010). While these papers are related to those
toxicity papers which discuss the best metric by which to estimate toxicity, they are focused
specifically on lung dosimetry. With one exception, these studies are very specific to the
materials investigated in the individual studies, and therefore, are not considered of high priority.
The exception was a paper that discusses general methods for using lung dosimetry models
and other tools for dose response assessment to estimate risk in the workplace (Kuempel, Tran
et al. 2006). However, while the authors state that their proposed methods offer a useful tool for
evaluating risk from nanoparticles in the work place, the lung dosimetry models need to be
validated for different types of nanoparticles and that translocation of particles must also be
considered when understanding worker risk.
Key health effects such as inflammation and cytotoxicity, particularly in models of inhalation
The vast majority of papers that review or assess the toxicity of nanomaterials address two
specific endpoints of toxicity: inflammation and cytotoxicity (cell damage/death) (Bergamaschi,
Bussolati et al. 2006; Lanone and Boczkowski 2006; Wittmaack 2006; Fischer and Chan 2007;
Warheit, Sayes et al. 2009; Chang 2010; Johnston, Hutchinson et al. 2010; Kayat, Gajbhiye et
al. 2010). Many researchers propose that these effects are related to the ability of the
nanomaterial to induce oxidative stress, which ultimately causes inflammation and cell damage
(Bergamaschi, Bussolati et al. 2006; Lanone and Boczkowski 2006; Chang 2010; Johnston,
Hutchinson et al. 2010; Kayat, Gajbhiye et al. 2010). However, it is important to note that with
respect to these endpoints, not all nanomaterials behave the same. For example, titanium
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dioxide was found to be relatively inert with respect to causing pulmonary inflammation and
cytotoxicity (Warheit, Sayes et al. 2008). Furthermore, results may differ depending on the
method used to study the endpoint of toxicity; multiple researchers have demonstrated that
results from in vitro and in vivo studies of identical materials are not always consistent, although
in vitro models are more frequently used to study nanomaterials (Fischer and Chan 2007;
Warheit, Sayes et al. 2009). This finding is consistent with the evaluation of non-nano particle
matter where the in vitro models are poor predictors of the relative in vivo responses of different
particles in mammalian systems (Cullen, Miller et al. 1997; Seagrave, Mauderly et al. 2003).
Therefore, care must be taken in drawing conclusions about relative toxicity of materials based
on in vitro studies.
Genotoxicity of nanomaterials
Genotoxicity is deleterious action on a cell's genetic material affecting its integrity, including
mutations in DNA, DNA damage, chromosomal damage, etc. Several papers review
genotoxicity studies on various nanomaterials (Maeng, Park et al. 2006; Balasubramanyam,
Sailaja et al. 2009; Landsiedel, Kapp et al. 2009; Singh, Manshian et al. 2009; Patlolla, Hussain
et al. 2010). Three of the review papers concluded that while there may be some evidence of
genotoxicity with certain materials, differences in study design (e.g. selection of screening
method), material type, dose metric and other parameters affecting the study design and the
inconsistency in result that accompanies these differences prevents one from drawing
conclusions regarding genotoxicity that are applicable to all nanomaterials (Maeng, Park et al.
2006; Landsiedel, Kapp et al. 2009; Singh, Manshian et al. 2009). Additional studies conducted
in an effort to assess individual material properties with respect to genotoxicity are consistent
with this conclusion. Patolla, et al. 2010 concluded that multi-walled carbon nanotubes
(MWCNTs) were genotoxic in mice following intraperitoneal injection; however, the state of
functionalization of the MWCNTs affected the outcome of the study. Nonfunctionalized
MWCNTs were less toxic than functionalized MWCNTs. Balasubramanyam, et al. 2009
evaluated the potential for genotoxicity of different sizes of aluminum oxide nanoparticles
following oral exposure in rats. They concluded that while there was evidence of genotoxicity
with exposure to the nanoparticles, the distribution of the particles in vivo and the genotoxicity
was dependent on particle size.
It is worthwhile to note that one study evaluated markers of DNA damage (micronuclei and
sister chromatid exchange) in workers at a rubber production facility (Joao Teixeira, Laffon et al.
2006). In this study, the authors investigated the potential genotoxic effects from exposure that
occur in the rubber industry, including amorphous silica and carbon black, and found there was
no increased incidence of either micronuclei or sister chromatid exchange in the rubber workers
compared to the control population, indicating that even if nanomaterials are genotoxic in some
models, those materials used in the rubber industry do not result an increase in adverse effects
in people working with the materials.
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• 66% of organizations reported using fume hoods with exhaust filtration, HEPA filters, or
wet scrubbers. Another engineering control used was an in-line conveyor to transfer dry
powders from bags to reactors that also disposed of bags.
• 82% of organizations reported having nano-specific PPE requirements, which were
usually associated with other EHS practices. Respiratory protection recommendations
were prevalent among these organizations, with P100 filters being the most commonly
recommended respirator type. Other forms of PPE included gloves, eye protection,
plastic body coverings during periods of high concentration, long gloves pulled over
sleeves, antistatic shoes to prevent ignition, and sticky mats at lab entrances. Most
respondents indicated that PPE recommendations were based on conventional
chemical hygiene practices or cost factors.
• 68% of organizations reported monitoring the air for nanoparticles; measurement of
number concentration was most common. Instruments used included condensation
particle counters, scanning mobility particle sizers, witness plates, and portable
respirometers.
• 60% of organizations reported disposing of nanomaterial as hazardous waste.
• 67% of organizations reported providing guidance to customers or other users on safe
use of nanomaterials, most commonly in the form of MSDSs.
These studies can be useful for understanding what is currently being done to protect against
worker exposure to nanomaterials and may be useful in informing other companies how to
design their own best practices guidelines.
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Author(s) or Authoring
Year Scenario Covered Overarching Principle Key Aspects Unique Aspects
Organization
With respect to worker exposure, recommend that programs begin by
identifying potential exposure (where/how exposure could occur). Following
exposure identification, the following actions should be considered to
Office of Technical Any workplace
minimize exposure: elimination/substitution of the hazards; engineering
Assistance and 2010 exposure to Precautionary principle Guidance was written to help industries develop best practices
controls; administrative controls; and PPE. The authors note that PPE
Technology (MA) nanomaterials
should be required when containment cannot prevent exposure to
nanomaterials.
(Office of Technical Assistance and Technology (MA) 2010)
Facilities should institute risk management programs that include evaluation
of hazard, evaluation of worker exposure, education of workers on good
Any workplace
practices, evaluating engineering controls effectiveness (LEV with HEPA
NIOSH 2009 exposure to Precautionary principle Recommend professional judgment in determining the necessity of using respirators
filter, isolation), designating criteria for selecting PPE, and evaluating
nanomaterials
exposures to ensure control measures are working.
(NIOSH 2009)
Recommend hazard elimination through effective process design,
substitution of raw materials products, processes or equipment that may lead
to undue exposure or hazard, the implementation of engineering controls in
Any workplace
accordance with the level of risk (e.g. in accordance with the UK COSHH
ISO 2008 exposure to Precautionary principle None identified
Essentials approach), and administrative measures to control workplace
nanomaterials
exposure (e.g. modifying work practices, keeping good records, training
employees, etc.).
(ISO 2008)
Four categories or "bands" of hazards, with different control levels specified
for each band. The placement of factors into bands depends on the severity
of adverse effects and probability of exposure. For factors where nothing was Probability scores were given based on amount of nanomaterial used, frequency and
Paik 2008 Use of nanomaterials Control Banding known (i.e. many types of nanoparticles), 75% of the point value for "high" duration of the operation, dustiness/mistiness, and number of employees with
was given to that factor, automatically placing it in at least the control band potential for exposure.
requiring containment.
(Paik, Zalk et al. 2008)
Recommend using the hierarchy of controls, including engineering
Not specified; Control banding (containment and LEV), administrative, and PPE control to manage hazards
Schulte 2008 Use of nanomaterials None identified
discussed of nanoparticles.
(Schulte, Geraci et al. 2008)
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Elimination is the practice of removing the hazard from the industrial operation in an effort to
eliminate worker exposure. This is not often a practical consideration, particularly in the case of
nanomaterials where these materials are under new development and the true hazard is not
often known. Substitution, an alternative approach, is the replacement of a hazardous material
with a similar but less hazardous material. In the absence of information about toxicity for some
of these materials, those that advocate the substitution approach do so from the standpoint of
exposure and recommend using materials that have a reduced propensity for aerosolization
(e.g. binding the nanomaterials in a liquid or solid media) (BAUA 2007).
Isolation is the practice of preventing exposure by minimizing worker contact with the material
through the use of physical barriers such as enclosure or other forms of containment. Nearly all
guidance that propose recommendations for managing exposure to nanomaterials advocate for
the use of isolation, particularly closed processes or containment rooms, to minimize worker
exposure (ASTM 2007; BAUA 2007; ISO 2008; Schulte, Geraci et al. 2008; USDOE 2008;
AFNOR 2009; Japan MHLW 2009; NIOSH 2009; Office of Technical Assistance and
Technology (MA) 2010). By isolating the nanomaterial, it may be possible to reduce the
necessity of other engineering controls or PPE to minimize exposure.
Administrative controls are changes in work procedures such as written safety policies, rules,
supervision, schedules, and training with the goal of reducing the duration, frequency, and
severity of exposure to hazardous chemicals. As another layer intended to protect worker
exposures, most groups offering recommendations on best practices incorporate administrative
controls including worker education, housekeeping practices, worker scheduling, and other
standard industrial hygiene practices.
The last recommended layer of protection for worker exposure is the use of PPE, including
gloves, protective clothing, and respirators. Because respirator use is typically triggered by
exposure concentration, and there is, as yet, no occupational exposure limit established for
nanomaterials that can aid in identification of an appropriate action level, several of the unique
aspects related to the recommended best practices are centered around when respirator use
should be required. Some advocate using respirators where there is any exposure potential or
where nanomaterials have been detected in the air (when engineering and administrative
controls do not fully protect against exposure) or using professional judgment to determine if
respirator use is required (NIOSH 2009). ASTM and the British Standards Institute have both
made recommendations on how to define an OEL to aid in decision making regarding the use of
respirators. ASTM proposes using existing particulate-based standards, such as ambient air
quality standards, standards for asbestos, etc. to establish occupational exposure limits for
nanomaterials (ASTM 2007). British Standards Institute defines four categories of materials
based on particle characteristics and/or characteristics of the bulk compound and makes
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In an effort to address the issue of measuring filter efficiency, Steffens and Coury evaluated the
efficiency of a fibrous polyester filter with fibers of uniform diameter (Steffens and Coury 2007).
Particle number concentrations were measured using a condensation particle counter, and filter
samples were analyzed by TEM for size determination. Measured collection efficiencies varied
from nearly 100% for particles around 10 nm in diameter down to less than 40% for particle
diameters around 95 nm. In general, collection efficiency was greater for lower flow rates. There
was good agreement between calculated collection efficiencies and those observed
experimentally. They also evaluated the effectiveness of HEPA filters with homogenous filter
diameters (Steffens and Coury 2007). Measured collection efficiencies were greater than 99%
for all particles diameters tested (10 nm-100 nm), indicating that particle size does not affect the
efficiency of the HEPA filter.
Few studies were identified that discuss approaches for assessing risks of nanomaterials. Most
of the risk assessment papers discuss nanomaterials qualitatively, and review the current gaps
in knowledge that prevent nanomaterials from being assessed appropriately (e.g. methods for
exposure assessment, dose metric for estimating exposure-toxicity relationship, etc.). Of those
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papers that address methods for assessing risks of nanomaterials, there are divergent
viewpoints. The OECD Working Party concluded in their workshop on risk assessment of
nanomaterials that current methods for risk assessment are applicable to nanomaterials based
on current knowledge (OECD 2010). They do, however, recommend regular evaluation of
existing assumptions and estimations employed in the risk assessment process. In particular,
they note that research is needed to determine what characteristics result in hazard and
whether uncertainty factors can be applied according to existing practices. Further, until
additional research is conclusive, empirical results from monitoring efforts should continue to be
reported in terms of mass based units, although this limitation should be discussed in risk
assessment.
Chen, et al. 2007 suggests that new methods should be developed to assess the risks of
nanomaterials because current methods may not be sufficient (Chen, Mu et al. 2007). Kim, et
al. 2007 recommends that additional research is needed to understand the dose-response
relationship in order to establish safe levels for exposure to nanomaterials (Kim, Choi et al.
2007). Zhang, et al. 2009 recommended a framework to weigh the benefits of using
nanomaterials with the potential hazard using a mathematical process, although specifics
regarding this proposed method were not discussed in detail.
Papers on occupational exposure address the primary issue of methods for measuring
nanomaterial concentrations in the workplace. Measurement methods exist for most dose
metrics (e.g. particle concentration, particle number, particle surface area) (Marconi 2006; Yu,
Lee et al. 2008; OECD 2009; Ono-Ogasawara and Takaya 2009; Lee, Moon et al. 2010).
However, as yet, no method allows for simultaneous measurement of all metrics. Further, most
of the available methods are not applicable to personal measurements. While the methods for
monitoring worker exposures are not yet well developed (in so far as they are adaptable for the
work environment), because of the uncertainty regarding the appropriate dose metric for
conducting risk assessment, monitoring for multiple metrics is important.
Few studies were available that measured nanomaterial levels during industrial operations; only
exposure data during nanomaterial manufacturing and treatment of end-products containing
nanomaterials were reviewed (Brouwer 2010). This review indicated that that nanoparticles can
rapidly attach to large background particles or coagulate with themselves. Further treatment of
nanomaterial-containing products (e.g. polymers), such as through high-speed grinding or high-
speed milling, has also been shown to produce nanoparticles. Although most of these reviewed
studies focused on nanomaterial production, several addressed end uses in research settings.
In general, it was found that particle number or mass concentrations were different during
periods of various activities, although differences were not significant. However, the absence of
primary engineered nanomaterials was indicated during end-product uses such as bagging,
reactor cleaning, and pouring. In both experimental simulations and actual workplaces, it has
been shown that the lifetime of primary nanoparticles is limited by coagulation or attachment of
nanoparticles to larger particles. Therefore, it may be possible that exposure assessments of
particles in the 400-500 nm range may be of equal importance to the nano-size range. The
existing literature indicated that primary engineered nanomaterials may not be prevalent in
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workplaces, and that it may be more important to understand whether the agglomerates and
aggregates are present and if they become bioavailable as single particles after entrance into
the body through inhalation or dermal contact.
Of the papers that discussed occupational exposures, one was notable for its inclusion of the
rubber and tire industry. Boccuni, et al. 2008 estimated the number of workers in Italy
“potentially exposed” to nanomaterials by industry, including the rubber and tire industry
(Boccuni, Rondinone et al. 2008). They identified 7489 employees that worked in research and
development (manufacture of man-made fibers/carbon black) and 48,334 employees in powder
handling (carbon black/manufacture of rubber products). Additionally, 13,798 employees were
identified as manufacturing rubber tires and tubes, and 2,206 employees were identified as
working in retreading and rebuilding of rubber tires. Although this paper was intended to identify
the numbers of workers by industry that were potentially at risk from exposure to nanomaterials,
it did not offer any qualitative or quantitative assessment of their potential from risk nor did it
discuss the risks associated with specific materials (e.g. carbon black).
3.2.5 Environment
The studies identified for this topic addressed a variety of issues, including methods for
detecting nanomaterials in environmental media, sources of release from products containing
nanomaterials, methods for preventing environmental release during manufacturing/industrial
use of nanomaterials, and environmental fate and exposure via the environment. In reviewing
what is known about the methods for measuring nanomaterials in environmental media, several
authors discuss the variety of options for measuring nanomaterials in the environment and their
associated challenges, including particle agglomeration in aqueous media and adsorption to
other materials (Nowack and Bucheli 2007; Tiede, Boxall et al. 2008; Tiede, Hassellov et al.
2009). Reijinders (2009) evaluated the potential for amorphous silica and titanium dioxide to be
released throughout the life cycle of composites such as polymers (Reijinders 2009). Included
in this discussion is a consideration for tires and the potential for amorphous silica to be
released from tires. No quantitative estimates of release rates were provided, but life cycle
stages at which emissions may occur were discussed, including release following degradation
or weathering and release during recycling activities. The Japanese Ministry of the Environment
has released recommendations on methods for minimizing release of nanomaterials to the
environment during industrial use or manufacturing (Ministry of Economy 2009), whereas, the
U.S. EPA has published a white paper outlining what still needs to be addressed in order to
assess environmental risks associated with the use of nanomaterials (USEPA 2007).
3.2.6 Ecotoxicity
Of the identified studies, ecotoxicity studies from a variety of materials, including titanium
dioxide and fullerenes were identified. The authors of several of these papers, indicated there is
a lack of published literature assessing ecotoxicity of nanomaterials in general (Moore 2006;
Baun, Hartmann et al. 2008; Farré, Gajda-Schrantz et al. 2008). However, several studies
provide a quantitative (e.g. EC/LC50s) or qualitative understanding of the toxicity of some
nanomaterials in the environment (Baun, Hartmann et al. 2008; Farré, Gajda-Schrantz et al.
2008; Handy, Henry et al. 2008; Handy, Kammer et al. 2008; Handy, Owen et al. 2008; Klaine,
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Alvarez et al. 2008; Kahru and Dubourguier 2010). Nano-silver and zinc oxide were identified
as the most potent and titanium oxide as the least potent ecotoxicants (Kahru and Dubourguier
2010). However, most of these reviews indicate that of the literature that is available,
nanomaterials are typically of low toxicity (adverse effects begin to occur at levels in mg/L).
Unfortunately, because little information is available on the levels of nanomaterials in the
environment, it is difficult to put these concentrations into perspective of environmental levels
(Klaine, Alvarez et al. 2008). In addition, authors note that issues related to the insoluble nature
of nanomaterials and their potential for agglomeration and aggregation affects the ability to
deliver nanomaterials in an aqueous testing system, thus making interpretation of some of the
results difficult (Baun, Hartmann et al. 2008; Farré, Gajda-Schrantz et al. 2008).
3.2.7 Regulatory
There were only two papers addressing regulation of nanomaterials, likely due to the fact that
nanomaterial regulations are still under development. Of the two papers, only one was of high
priority as it discussed data gaps regarding risk assessment of nanomaterials and how these
data gaps affect the ability to regulate nanomaterials (Powell, Griffin et al. 2008). The identified
data gaps included: lack of detection, monitoring, control techniques, toxicological data, as well
as information about production and emissions. The authors conclude that the identified data
gaps will make local, state, and federal regulation difficult.
Nearly all of the amorphous silica papers addressed human health toxicity. Because of the
importance of these studies to the overall goal of the project, particularly with respect to
supporting the continued use of these nanostructured materials in the rubber industry, these
studies are reviewed separately here.
When considering papers addressing amorphous silica, it is important to recognize that studies
specifically assessing effects of nano-sized amorphous silica may not accurately reflect the
material that is used in the tire industry. While the precipitated silica (a form of amorphous
silica) used in tire manufacturing has a primary particle size in the nanometer size range, the
form used as a filler in the tire industry is typically aggregated, such that the actual particle size
appears to be larger (ETRMA 2010). In fact, the ETRMA argues that precipitated silica as used
as filler does not need to be managed based on its properties as a nanomaterial. Arts, et al.
2007 state that the respirable portion of the synthetic amorphous silicas represent only a "very
minor part" of the commercial product. The authors stated that the particle size of commercial
products handled under normal conditions is approximately 100 um MMAD (mass median
aerodynamic diameter).
Amorphous silica comes in different forms, and many of the studies evaluating nano-sized
amorphous silica focus on materials that are engineered specifically to have primary particle
size that is the nanometer size range. These studies may not necessarily be reflective of
precipitated amorphous silica. However, it is still important to consider the studies on nano-
sized amorphous silica, particularly as this distinction is not often recognized by those outside of
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the rubber and tire industry. Therefore, the literature on amorphous silica and nano-specific
amorphous silica are presented separately.
Two comprehensive reviews of amorphous silica toxicity data were conducted by the U.S. EPA
and the OECD (USEPA 1996; OECD 2004). The U.S. EPA conducted this review within the
context of ambient exposure to silica. OECD summarized data specific to synthetic amorphous
silicas for their SIDS Initial Assessment Report (SIAR) for SIAM 19. In general, these
documents support the notion that in animal models of inhalation toxicity, the effects of
amorphous silica are transient; initial inflammatory responses occur with exposure to particles,
but these effects generally resolve with cessation of exposure (USEPA 1996; OECD 2004).
Furthermore, in the SIAR, OECD reviews health effects in workers who manufacture synthetic
amorphous silicas. These workers have no adverse pathological effects in the lung, indicating
that regular exposure in the workplace is not likely to lead to the transient effects seen in animal
models. The conclusions regarding toxicity of amorphous silica reached by the U.S. EPA and
the OECD are supported by other studies in the published literature (Swensson 1965; Jahr
1981; Reuzel, Bruijntjes et al. 1991; Warheit, Carakostas et al. 1991; Merget, Bauer et al. 2002;
Arts, Muijser et al. 2007).
The Synthetic Amorphous Silica and Silicates Industry Association (SASSI) has voluntarily
submitted a package under the U.S. EPA’s Nanoscale Materials Stewardship Program in
support of the continued use of synthetic amorphous silicas. This voluntary program has
several goals, including to "gather existing data and information from manufacturers, importers,
processors, and users of existing chemical nanoscale materials," to "identify and encourage use
of risk management practices in developing and commercializing nanoscale materials," to
"encourage the development of additional test data," and to "encourage responsible
development of nanoscale materials." With respect to these goals, SASSI formulated four major
conclusions including: 1) synthetic amorphous silicas are not nanoparticles or nano-objects
because of agglomeration and aggregation, 2) the potential for exposure to nano-sized synthetic
amorphous silicas during use is low, 3) synthetic amorphous silica is of low toxicity to human
health and 4) current exposure standards for synthetic amorphous silicas are health protective.
The literature on nano-sized amorphous silica focuses primarily on endpoints of human health
toxicity. The results of these studies indicate several key things: effects in vitro and in vivo can
differ, with in vivo effects mimicking the effects of studies on commercially available amorphous
silicas, like precipitated silica. In vitro toxicity studies indicate that amorphous silicas may cause
cytotoxicity and inflammation through the generation of reactive oxygen species; the toxicity was
size dependent, with smaller size being more potent.
Studies of amorphous silica exposures in vivo indicate that, in general, inhalation of nano-sized
amorphous silica causes a transient inflammatory reaction that typically resolves with cessation
of exposure (Kaewamatawong, Shimada et al. 2006; Cho, Choi et al. 2007; Sayes, Reed et al.
2007; Choi, Cho et al. 2008; Park and Park 2009; Sayes, Reed et al. 2010). This is consistent
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with the effects described above for commercially available amorphous silicas but contradicts
what is indicated by studies on amorphous silica nanoparticles in vitro. In vitro studies of
amorphous silica nanoparticles in a variety of cell types, including lung epithelial cells, alveolar
macrophages, keratinocytes, and myocardial cells, found that particle exposure results in an
inflammatory reaction and cytotoxicity, effects that some authors suggest are related to the
formation of reactive oxygen species (Lin, Huang et al. 2006; Chang, Chang et al. 2007; Sayes,
Reed et al. 2007; Lison, Thomassen et al. 2008; Kasper, Hermanns et al. 2009; Park and Park
2009; Waters, Masiello et al. 2009; Akhtar, Ahamed et al. 2010; Nabeshi, Yoshikawa et al.
2010; Shi, Yadav et al. 2010; Yang, Liu et al. 2010; Ye, Liu et al. 2010; Ye, Liu et al. 2010).
Similarly, those studies that address both in vivo and in vitro effects of the same materials find
that there is no correlation between what occurs in vitro with what occurs in vivo, indicating that
it will be important to keep the results from in vitro studies in context, for amorphous silica and
other nanomaterials (Sayes, Reed et al. 2007).
Several studies evaluated particles of multiple sizes. Yang, et al. 2010 and Nabeshi, et al. 2010
tested both micro- and nano-sized amorphous silica using in vitro models. Both found that
micro-sized amorphous silica was demonstrably less potent at inducing cytotoxicity and/or the
generation of oxidative stress in skin cells than nano-sized amorphous silicas. Similar
conclusions were made from studies that evaluated different sized amorphous silica
nanoparticles (Waters, Masiello et al. 2009; Ye, Liu et al. 2010; Ye, Liu et al. 2010). These
results can also be used to support the notion that the materials that are used in the tire
industry, which following aggregation and agglomeration form particles of larger size than these
manufactured nanomaterials, are less potent at inducing adverse effects than these traditionally
studied amorphous silica nanoparticles.
Nearly all of the carbon black papers addressed human health toxicity. Because of the
importance of these studies to the overall goal of the project, particularly with respect to
supporting the continued use of these nanostructured materials in the rubber industry, these
studies are reviewed separately here.
Carbon black (CB) refers to a group of industrial products including thermal, furnace, channel
and acetylene blacks. CB consists of elemental carbon and is obtained by the partial
combustion or thermal decomposition of hydrocarbons. The different types of carbon black have
a wide range of particle sizes, high surface areas per unit mass, quite low contents of ash and
toluene-extractable materials and varying degrees of particle aggregation.(Donnet 1993).
Carbon black is widely used as a filler in elastomers, plastics and paints to modify the
mechanical, electrical and the optical properties of the materials in which they are dispersed.
Carbon black used in rubber changes the fracture behavior and improves abrasion and failure
properties. About 90% of the worldwide production of carbon black is used by the tire industry
where the carbon black enhances tear strength and improves modulus and wear characteristics
of the tires.
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Due to the source materials, the production methods, and their large surface areas and surface
characteristics, carbon blacks typically contain varying quantities of adsorbed by-products from
the production process. In particular, these by-products consist of polynuclear aromatic
hydrocarbons (PAHs) (Nutt 1984; Donnet 1993). The specific chemicals detected in carbon
black extracts and their relative quantities vary widely from sample to sample. Extraction
method, type and grade of carbon black and after-treatments all appear to be factors that affect
the types and quantities of impurities obtained. Among the PAHs frequently found at the highest
levels in carbon black extracts are benzo[ghi]perylene, coronene, cyclopenta[cd]pyrene,
fluoranthene and pyrene. Of greater interest are the carcinogenic PAHs like e.g. benzo[a]pyrene
or benzo[e]pyrene. Observed ranges in concentration for ten compounds which account for
most of the PAH fraction in solvent extracts of carbon black are shown in Table 9. Currently
produced furnace and thermal blacks tend to have PAH contents near the low end of the
observed range (World Health Organization 1996).
Carbon black is not acutely toxic, but is a skin and eye irritant in humans (European Chemicals
Bureau 2000). In studies of long-term exposure to carbon black, the respiratory and
cardiovascular systems were impacted (European Chemicals Bureau 2000; Carter, Corson et
al. 2006). In vitro mutagenicity studies on carbon black were generally negative and
carcinogenicity studies utilizing various routes of exposure were negative in all mammalian
species tested (European Chemicals Bureau 2000). Additionally recent epidemiology studies of
carbon black workers did not find a positive dose response between carbon black exposure and
any type of cancer (Buchte, Morfeld et al. 2006; Dell, Mundt et al. 2006; Morfeld, Buchte et al.
2006; Morfeld, Buchte et al. 2006; Valberg, Long et al. 2006). The IARC classification for
carbon black is “possibly carcinogenic to humans” (Group 2B), based on insufficient evidence of
carcinogenicity in humans and sufficient evidence of carcinogenicity in animals.
As with amorphous silica, the large majority of the studies on nano-sized carbon black are
focused on human health toxicity. The results of these studies indicate a few key items:
researchers are using ultrafine carbon black as a surrogate for understanding toxicity of ambient
ultrafine particulate matter (UFPM), key health effects from exposure to carbon black include
inflammation and cytotoxicity, possibly as a result of oxidative stress, and smaller sized particles
of carbon black have a greater inflammatory effect in pulmonary systems than larger particles.
In addition, studies addressing reproductive toxicity and cancer were also reviewed.
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study showed that while urban PM impaired nitric oxide responsiveness, ultrafine carbon black
did not (Courtois, Andujar et al. 2008). However, another study showed that nitric oxide levels
were reduced with CB treatment (Yamawaki and Iwai 2006). Therefore, it is not clear whether or
not carbon black, as a model for ultrafine particulate matter, results in the adverse effects
typically associated with fluctuations in ambient particulate levels, such as acute cardiovascular
events.
One study, conducted by the Korean Occupational Safety and Health Administration (KOSHA),
specifically evaluated the toxicity from inhalation of nano-sized carbon black using a subacute
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inhalation study (Kim, Cho, et al., 2010)3. KOSHA generated carbon black under controlled
conditions to achieve average particle sizes under 100 nm, and exposed rats via inhalation for
four hours per day, five days per week for four weeks to the particles at three different dose
levels; animals were sacrificed for evaluation both immediately after (24 hours after the last
exposure) and 4 weeks after the cessation of exposure. Evaluations included pulmonary
function testing, pathology, biochemical analysis of bronchoalevolar lavage fluid, clot testing and
other cardiovascular endpoints. Based on the results of the KOSHA study, the authors
concluded that carbon black caused no significant adverse effects at the doses tested. The
highest dose from this study, 0.931 μg/m3, could be used as a no-observed adverse effect level
(NOAEL) for nano-sized carbon black.
Potential for carcinogenicity has also been evaluated both in vitro and in vivo. A study found
that long term exposure at sub-cytotoxic concentrations of carbon black produced a weak
mutagenic response in lung epithelial cells (Jacobsen, Saber et al. 2007). Another study using
in vivo and in vitro methods demonstrated that carbon black was genotoxic in mouse lung based
on results from the Comet assay and micronuclei formation (Totsuka, Higuchi et al. 2009).
4.0 CONCLUSIONS
3
The Kim, Cho, et al., 2010 study was not originally part of the literature review; because of the importance of the
results for the goals of the project, this was added as part of the report.
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The literature on amorphous silica and carbon black reviewed here include studies on both bulk
amorphous silica and carbon black (as is relevant to use in the industry) and nano-sized
amorphous silica and carbon black (used to understand the potential for nanomaterials-related
toxicity). Because results of these studies can differ, it is important to make a distinction
between the material used in the tire industry and the studies that are being conducted to
investigate amorphous silica and carbon black as nanomaterials. Forms of amorphous silica, in
particular, are regularly being used in studies of nanomaterials. While these particles are not
equivalent to the materials used in the tire industry, they may be interpreted as being related by
the public or regulators unless clear distinctions are made for the relevant parameters, such as
characteristics and toxicity. To address this potential misperception, the TIPG has recently
published a white paper that provides a summary of key issues regarding the characteristics
and toxicity of carbon black and amorphous silica as these materials are used in the tire
industry. This paper can be found at the World Business Council for Sustainable Development
website (www.wbcsd.org).
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