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Risk Assessment/Management

Development of Common Approaches to the Risk Assessment of Nanomaterials

Nanoparticle Human Health Screening Assessment Framework

Following the analysis and discussions that occurred during the case study/comparative analysis exercises, a common approach for assessing and identifying additional testing requirements for nanoparticles was developed by the two countries, based on current knowledge of particle toxicology. This common framework is summarized here, and represents an effort to systematically focus human health concerns and additional testing requirements for nanoparticles based on physical-chemical characteristics (e.g., particle shape, aspect ratio, particle/fibre size, solubility, composition and surface chemistry).  (Refer to Appendix F for a more detailed discussion.)

The manipulation of matter at the nano-scale is creating many novel substances with characteristics which are not always easily predicted from current knowledge. For example, a substance with a fixed composition can be engineered into many different forms (e.g., spheres, fibres, or sheets) with varying physical characteristics (e.g., size, shape, and surface properties).  Though these different forms possess identical composition, the effects of changing the physical-chemical parameters may alter the substance’s behaviour in environmental and biological media. The near-limitless diversity of substances that can be engineered from one particular composition can also have a near-limitless spectrum of toxicity: some particles may confer health benefits, others may be harmless, some become toxic, and some may retain the toxicity profile of the original bulk counterpart. 

Nanoparticles come in all sorts of sizes, shapes, and composition. Currently, nanoparticles are identified by name and by their Chemical Abstract Services Registry Number (CASRN), which are nomenclature methods primarily based on composition. One name and/or CASRN may represent a wide array of substances with the same composition. For example, a material of one composition will have a size distribution that can vary depending on manufacture and processing methods, and, can exhibit varied crystal structure, shape, surface chemistry, aggregation/agglomeration and other characteristics.

Particle toxicology is different from molecular toxicology in that the physical characteristics of the particles are most often the primary drivers of toxicity rather than their composition alone. Consequently, different paradigms are required in nanoparticle risk assessment than in molecular risk assessment.

Traditionally, classification of particles has been conducted on the basis of size based on the principle that as particle size decreases, the greater the potential impact on human health because the particles can be more easily inhaled[1]. Additionally, numerous reports exist in published literature showing that the toxicity of particles (on a mass basis) generally increases as their size decreases. The terms nanoparticles (NPs) and ultrafine particles (UFP) describe particles in the same size range (less than 100 nm), but nanoparticles usually refer to manufactured/engineered materials while ultrafine particles are defined as naturally occurring or those arising in ambient air (Donaldson et al. 2013)[2].


Figure 1: Important characteristics affecting particle toxicology (from Hristozov et al. 2012)

Characteristics affecting particle toxicology.

It has been demonstrated in literature that changes in a particle’s physical characteristics (e.g., size, shape, aspect ratio, surface area, surface coatings, chemical composition, impurities and crystalline structure) will influence the particle’s environmental fate (Klaine et al. 2008)[3] and toxicological properties (Figure 1; ENMs- Engineered Nanomaterials)[4]. The surface chemistry parameters of a nanomaterial (e.g., composition, coatings, charge, placement of ligands and wettability) affect cellular fate, uptake, and interactions with ions and various biomolecules (Zhu et al. 2013)[5]. The relationship between a particle’s physical characteristics and toxicity has been further emphasized in a mini-review by Warheit (2013)[6] that describes measuring hazard/risks following exposures to nanoscale or pigment-grade titanium dioxide particles:

It is important to note that particle-types of different TiO2 compositions may have variable toxicity potencies, depending upon crystal structure, particle size, particle surface characteristics and surface coatings.

The magnitude and specificity of this influence on the toxicokinetics and environmental fate of a manufactured nanoparticle are currently impossible to predict in the absence of particle-specific test data - a viewpoint that is highlighted in a paper by Ma-Hock et al. (2013)[7] which investigates the comparative inhalation toxicity of multi-wall carbon nanotubes, graphene, graphite nanoplatelets and low surface carbon black. Nevertheless, currently existing particle toxicology paradigms are being applied in an effort to focus human health hazard concerns for nanoparticles (Donaldson & Poland 2012)[8].

This document summarizes a proposed approach to systematically focus human health concerns and additional testing requirements for nanoparticles based on their physical characteristics, including size, particle shape, aspect ratio, composition and surface chemistry.  

The schematic presented in Figure 2 assumes that the nanoparticle is novel and that this approach will be applied prior to conducting or requesting toxicity testing.

As scientific knowledge evolves and mechanisms of action are better understood, existing toxicity information could be used to further identify concerns and/or additional relevant nanoparticle-specific toxicity testing. For example, available information on nanoparticles with similar physical characteristics and composition could be used as analogue/read-across information.  Depending on the nanoparticle in question, various physical and chemical characteristics will need to be considered in order to make direct or indirect correlations between relevant data sets, especially for nanoparticles where significant uncertainty exists in regards to the degree of influence slight changes in physical and chemical characteristics may exert in determining toxicity.

For example, following the framework described in Figure 2, the testing strategies for “Insoluble Biopersistent” nanoparticles should also consider their surface characteristics/reactivity/composition, so that different testing would be required for those nanoparticles that, based on available information, are expected to display “low reactivity/toxicity” and those that are expected to display some inherent toxicity.

Using the approach outlined herein should lead to more focused toxicological testing and a more tailored risk assessment of new nanomaterials.

Figure 2: Schematic for focusing concerns and additional testing requirement for novel nanoparticles

Diagram showing testing requirements for novel nanoparticles


Common Outlook on the Environmental Fate and Ecological Effects of Nanomaterials

In general, an ecological risk assessment takes into account the fate and effects of a substance in air, water, soil, and sediment compartments. As well, the behaviour of the substance in wastewater treatment plants is also considered as this has an impact on environmental fate. This approach is depicted in Figure 3 below.

Figure 3: A general framework for ecological risk assessment[1]

A general framework for ecological risk assessment

There remain many uncertainties in accurately determining the environmental fate and ecological effects of nanomaterials.  Traditionally, chemicals (typically organics) undergo partitioning between water, sediment, soil and air depending on their physical-chemical parameters (See section 3.2). Nanomaterials are, however, more complex than traditional chemicals. As seen in Figure 3, nanomaterials can undergo a variety of transformations once in the environment including (bio)degradation, dissolution, hetero- and homo-aggregation, and speciation. It is currently not always possible to predict these processes and to then properly quantify the environmental fate and effects, however, which makes risk evaluation challenging.

During discussions within the RCC context, these uncertainties were primarily attributed to the fact that this is an emerging science, and that the application of chemically-based regulatory regimes to nanomaterials is challenged by the fact that nanomaterials have modifying factors such as size, shape, and reactivity.     

As was highlighted from the joint case-study analysis on MWCNTs, in the face of uncertainty the Canada/US Programs use similar approaches and safety factors to assess the environmental fate and ecological effects of nanomaterials. 

While the outcomes in Section 3.2 summarize the major findings arising from the case-study and the current thinking of the Canada/US Programs, some common assumptions in dealing with environmental fate and ecological effects are presented below; these will be refined as better scientific information becomes available. Common approaches to physical-chemical endpoints and characterization techniques for environmental fate and effects are not proposed since these depend on the type of material being tested, the media, and measurement needs, and are captured under the nano-specific OECD Guidance on Sample Preparation and Dosimetry.

Environmental Fate:

  • Due to the uncertainties associated with predicting partitioning behaviour of nanomaterials, the Canada/US Programs will continue to assume that they may end up in all compartments: water, soil, sediment, and air.
  • The potential for long-range transport of is expected to be low; however, vectorization (i.e., nanoparticles binding to other particulates and undergoing transport) is still considered possible. 
  • The Log octanol-water partitioning (Log Kow) coefficient is not a useful predictor for bioconcentration/ bioaccumulation.
  • While agreeing that the concentration of nanomaterials in the environment is important, the Canada/US Programs will be considering the bioavailable fractions of these substances in the environment. These take into account interactions with environmental media, such as humic/fulvic acids.
  • Environmental exposure will consider two worst-case scenarios:  100% release to the aquatic compartment from wastewater treatment (i.e., no removal from treatment) and 100% release to biosolids (i.e., 100% removal from treatment). These two extremes will allow for the development of conservative scenarios to calculate predicted environmental concentrations.

Ecological toxicity:

  • Physical-chemical characterization is critical for adequately assessing the ecotoxicity of nanomaterials. The Canada/US Programs will continue to require this information, including separation of the ionic and particulate species.[2]
  • The OECD Test Guidelines will continue to be considered adequate for nanomaterials; the OECD is currently considering appropriate modifications to address specific properties of nanomaterials.[3]
  • Due to the lack of predictability for bioconcentration (log octanol-water (Log Kow)), the OECD test guideline on bioconcentration (TG 305) may apply to nanomaterials, but only when conducted through the dietary route.
  • In addition to traditional safety/uncertainty factors when extrapolating from acute to chronic environmental effects, additional factors will be used when appropriate to take into account the interaction with organic matter.
  • Both Programs will use the OECD nano-specific Guidance on Sample Preparation and Dosimetry[4] to help identify appropriate methods and measurement techniques for the testing of nanomaterials.

[1] Batley, G.E., Kirby, J.K., McLaughlin, M.J., Acc. Chem. Res, 2013, 46 (3), 854-862

[2] Meesters, J. A.J., Veltman, K., Hendriks, A.J., van de Meent, D. Integr Environ Assess Manag, 2013, 9, e15-e26

[4] ENV/JM/MONO(2012)40. Guidance on Sample Preparation and Dosimetry for the Safety Testing of Manufactured Nanomaterials. Series on the Safety of Manufactured Nanomaterials No. 36.


[2] Donaldson K, Duffin R, Langrish JP, Miller MR, Mills NL, Poland CA, Raftis J, Shah A, Shaw CA, Newby DE. 2013. Nanoparticles and the cardiovascular system: a critical review. Nanomedicine 8(3): 403-423

[3] Klaine SJ, Alvarez PJJ, Batley GE, Fernandes TF, Handy RD, Lyon DY, Mahendra S, McLaughlin MJ, Lead JR. 2008. Nanomaterials in the environment: behavior, fate, bioavailability, and effects. Environ Toxicol Chem  27(9):1825-1851

[4] Hristozov DR, Gottardo S, Critto A, Marcomini A. 2012. Risk assessment of engineered nanomaterials: a review of available data and approaches from a regulatory perspective. Nanotoxicology 6(8):880-898

[5]  Zhu M, Nie G, Meng H, Xia T, Nel A, Zhao Y. 2013. Physicochemical properties determine nanomaterial cellular uptake, transport, and fate.  Accounts of Chemical Research 46 (3):622-631

[6] Warheit DB. 2013. How to measure hazards/risks following exposures to nanoscale or pigment-grade titanium dioxide particles.  Toxicol Lett  220(2):193-204

[7] Ma-Hock L, Strauss V, Treumann S, Küttler K, Wohlleben W, Hofmann T, Gröters S, Wiench K, van Ravenzwaay B, Landsiedel R. 2013. Comparative inhalation toxicity of multi-wall carbon nanotubes, graphene, graphite nanoplatelets and low surface carbon black. Part Fibre Toxicol 10(1):23

[8] Donaldson K, Poland CA. 2012. Inhaled nanoparticles and lung cancer - what we can learn from conventional particle toxicology. Swiss Med Wkly 142: 13547