Moving beyond Mass: The Unmet Need to Consider Dose Metrics in Environmental Nanotoxicology Studies
The field of nanotechnology has rapidly developed due to recognition that nanoscale particles often exhibit properties that differ substantially from comparable bulk phases. Given this fact it is unfortunate that the environmental nanotoxicology community continues to rely heavily upon mass-based dose-metrics. To truly evaluate if nanoscale particles elicit toxicological responses that differ from those of bulk phases then alternative dose-metrics must be simultaneously considered.
Despite previous calls to report characterization information sufficient to evaluate the toxicity of engineered nanomaterials against dose-metrics other than mass,(1) most environmental nanotoxicology studies continue to report dosimetry exclusively on a mass basis. We sampled 25 representative studies (most of which were published in 2010–2011) investigating the ecotoxicological effects of unbound engineered nanomaterials. All reported dosimetry exclusively in terms of mass, and less than 20% reported characterization information sufficient to transform mass concentrations to particle number, particle number density (N, particles per unit volume), or suspension surface area. Transforming from mass concentration requires knowledge of the particle size, shape, and crystallinity, which were reported in 60%, 48%, and 20% of the manuscripts, respectively. Only 8% of the studies reported that characterization was performed in the experimental media used to measure a toxicological response and none reported the fraction of dissolved ions present.
Focused efforts to relate dosimetry to biological effects are required to better understand the ecotoxicological profiles of engineered nanomaterials and to allow risk assessors to more reliably relate exposure to effect. We challenge the research community to better address the dosimetry issue in future toxicological studies with engineered nanomaterials, and to report characterization information sufficient to convert mass-based concentration data to other dose-metrics.
When Mass Misleads
The reliance of nanoparticle environmental risk studies in aqueous systems on mass-based dose-metrics is likely attributable to (i) convention—most water quality standards are presented in terms of mass concentration, (ii) ease of measurement, and (iii) an inherent need to compare toxicity of particulate versus dissolved species to delineate potential “nano” effects. The principal assumption behind mass concentration, that the molar mass of a solute is equivalent to 6.022 × 1023 “particles” per mole, is violated at the nanoscale. At a given mass, decreasing particle size exponentially increases particle number, and suspension surface area (by several orders of magnitude) available to interact with biological receptors.(2) Differences in particle number or surface area can dictate a toxicological response and thus the indiscriminate application of mass-only dosimetry discards critical information that may determine toxicity, in particular, the degree to which receptors are saturated with nanoparticles.
Lessons Learned from Aerosol Science and Immune System Responses: Number and Surface Area Matter
The importance of dosimetry in the aerosolized particulate literature is well established. In a study investigating the effects of nanoscale particles on rat alveolar macrophages, Oberdörster(3) reported that surface area concentrations correlate better to inflammatory response and lung tumor incidence than does mass concentration. Donaldson et al.(4) suggested that increasing particle number and surface area may overwhelm macrophage defenses and enhance interfacial interactions between reactive particle surfaces and epithelial cells, leading to an increase in the incidence of inflammation and oxidative damage within the lung. In these instances where the mechanism of toxicity is driven primarily by particle number and available surface area, traditional mass-based approaches to dosimetry may misrepresent dose–response relationships. These observations presumably apply to aquatic toxicity studies as well, but the current emphasis on mass-based dosimetry coupled with limited characterization data preclude our ability to confirm this hypothesis.