Evaluation of Exposure Concentrations Used in Assessing

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Critical Review

Evaluation of Exposure Concentrations Used in Assessing Manufactured Nanomaterial Environmental Hazards: Are They Relevant? Patricia Ann Holden, Fred Klaessig, Ronald F Turco, John Priester, Cyren M. Rico, Helena Avila Arias, Monika Mortimer, Kathleen Pacpaco, and Jorge L Gardea-Torresdey Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/es502440s • Publication Date (Web): 26 Aug 2014 Downloaded from http://pubs.acs.org on August 31, 2014

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Environmental Science & Technology

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Evaluation of Exposure Concentrations Used in Assessing Manufactured

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Nanomaterial Environmental Hazards: Are They Relevant?

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Patricia A. Holden a,e, Frederick Klaessig c,e, Ronald F. Turco b, John H. Priester a,e, Cyren M. Rico d,e,

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Helena Avila-Arias b, Monika Mortimera,e, Kathleen Pacpaco a,e, Jorge L. Gardea-Torresdey d,e

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a Bren

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Barbara, Santa Barbara, California 93106-5131, USA

School of Environmental Science & Management, University of California Santa

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b

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Lafayette, Indiana 47907, USA

College of Agriculture − Laboratory for Soil Microbiology, Purdue University, West

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c

Pennsylvania Bio Nano Systems, Doylestown, Pennsylvania 18901, USA

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d Department

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University of Texas at El Paso, El Paso, TX

of Chemistry and Environmental Science & Engineering PhD Program, The

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e University

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CEIN)

of California Center for Environmental Implications of Nanotechnology (UC

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Corresponding author: Holden, PA Email: [email protected]. Tel: 805-893-3195

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ACS Paragon Plus Environment

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Abstract

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Manufactured nanomaterials (MNMs) are increasingly produced and used in consumer

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goods, yet our knowledge regarding their environmental risks is limited. Environmental

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risks are assessed by characterizing exposure levels and biological receptor effects. As

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MNMs have rarely been quantified in environmental samples, our understanding of

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exposure level is limited. Absent direct measurements, environmental MNM

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concentrations are estimated from exposure modeling. Hazard, the potential for effects on

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biological receptors, is measured in the laboratory using a range of administered MNM

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concentrations. Yet concerns have been raised regarding the “relevancy” of hazard

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assessments, particularly when the administered MNM concentrations exceed those

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predicted to occur in the environment. What MNM concentrations are administered in

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hazard assessments, and which are “environmentally relevant”? This review regards MNM

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concentrations in hazard assessments, from over 600 peer-reviewed articles published

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between 2008 and 2013. Some administered MNM concentrations overlap with, but many

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diverge from, predicted environmental concentrations. Other uncertainties influence the

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environmental relevance of current hazard assessments and exposure models, including

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test conditions, bioavailable concentrations, mode of action, MNM production volumes, and

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model validation. Therefore, it may be premature for MNM risk research to sanction

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information on the basis of concentration “environmental relevance”.

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Introduction For over a decade, there have been concerns regarding the potential for

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manufactured nanomaterials (MNMs) to cause environmental impacts.1 To inform MNM

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use and disposal,2 and to guide industry towards innovating safer MNMs,3, 4 hazards are

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assessed for a range of biological receptors. However, the relevance of hazard assessment

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research is questioned, including how it facilitates understanding real risks of MNMs

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released into the environment.5 Similar issues arise with human health hazard assessment,

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including what constitutes “realistic exposure scenarios”6 and how to improve toxicity

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testing relevancy.7 For critically evaluating in vitro MNM dosing in human health risk

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assessment, airborne occupational MNM exposures, plus deposition and retention in the

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lung environment, have been modeled.8 This forms a strong basis for evaluating how

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relevant in vitro hazard tests have been to date, and what MNM concentrations should be

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tested in the future for assessing human health risk.8 A critical examination of MNM dosing

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regimes, juxtaposed against expected concentrations at receptors, would also be useful for

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guiding MNM environmental risk assessment.

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Environmental risk assessment requires understanding hazards to environmental

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receptors, but also exposure magnitudes.5 Yet, relatively little research has been conducted

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on exposure assessment, including few reports of MNMs measured in environmental

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samples.9 Detecting and quantifying MNMs in complex environmental matrices remains

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challenging.10 Without directly knowing MNM concentrations in the environment, most

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exposure assessments have been developed from model predictions, including material

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flow analysis (MFA).9, 11 Models are used to estimate MNM concentrations in various

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environmental compartments,9, 12, 13 and such models are increasingly validated against


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measurements, when available.9, 14, 15 Meanwhile, MNM hazard assessment research—

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typically planned and performed independently of exposure modeling—involves testing

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MNM toxicity magnitudes and mechanisms, using various organisms and conditions,

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including various MNM concentrations.16, 17 Even when ecology drives MNM hazard

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assessments,18 are study designs meaningful for environmental risk assessment? What

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chemical concentrations are used in MNM hazard assessments? Are such concentrations

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“environmentally relevant”?

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To address these questions, MNM exposure modeling and measurement results can

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be co-evaluated alongside MNM hazard assessment exposure conditions. Such co-

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evaluation would be useful for several reasons. First, co-evaluation could assist with

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defining “environmental relevance” and thereby inform future nanotoxicology to better

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support environmental risk assessment. Relatedly, without carefully defining

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“environmental relevance”, risk estimates may arbitrarily disregard hazard assessments

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performed at MNM concentrations exceeding model estimates.5 High environmental MNM

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concentrations (“hot spots”) could occur, and risks should be understood. Further, even

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peer reviewing for publication is affected, since some journals recommend scoring for

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“environmental relevance”. Since “environmental relevance” is not defined, such criteria

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could bias peer reviews.

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Herein, we illustrate MNM concentrations administered in environmental hazard

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research, juxtaposed against those measured and modeled. We ask: what MNM

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concentrations have been used in hazard assessments, and are they “environmentally

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relevant”? Related to conventional pollution risk assessment: what constitutes

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“environmental relevance”, and is there precedence for confining hazard assessment


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regimes to modeled environmental concentrations? If the MNM hazard assessment

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enterprise self-sanctions, i.e. discounting studies that utilize greater than predicted

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exposure concentrations, could planning for long-term environmental protection be

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constrained? We conclude with a synthetic perspective, towards stimulating dialog across

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the nascent endeavors of MNM exposure and hazard assessments.

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Methods Used in Data Collection and Interpretation

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MNM Exposure Concentrations Used in Environmental Hazard Assessments

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To evaluate MNM exposures in experimental hazard assessments, we extracted

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concentration values from peer-reviewed articles, mostly from 2008 through 2013 (SI

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Table S1). Over 600 articles were identified via the Web of Science (WOS) for several

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environmental receptors or compartments: aquatic organisms (algae and macro-

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organisms); microorganisms (bacteria, protozoa and fungi); soil, sediments, and

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wastewater; terrestrial plants. We also noted food web studies. Details are in the

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Supporting Information. Although articles regard many MNM types, they were classified

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into the following MNM categories: metal oxides (e.g. nano-ZnO, -TiO2, -CeO2, SiO2, etc.);

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metals (nano-Ag, -Au, -Fe, and other); carbonaceous (multi- or single-walled carbon

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nanotubes or CNTs, graphene, fullerenes, and carbon black); quantum dots (e.g. CdSe or

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CdTe). Articles were not categorized further, e.g. by MNM characteristics (e.g. primary

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particle size or coating chemistry), aqueous media type, MNM physicochemical properties

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such as charge or agglomeration state, endpoint metrics, toxicity, mode of action, and

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toxicant concentration at the damage site(s). Other exposure variables were recognized

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(e.g. temperature or oxygenation), but mainly concentration data were extracted. While


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other issues are also important, such as the toxicant concentration and form at the site of

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effects in organisms, the most relevant comparison—based on the in-common spatial scale

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of simulation versus MNM administration—is between modeled exposure concentration

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and the nominal concentration employed in toxicity tests.

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Extracted concentration data were organized into spreadsheets according to

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receptor or compartment, and MNM category. Toxicity results were not tabulated, mainly

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because of the disparate measurement and interpretation methods used across the studies,

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making their results comparisons difficult or incredible. Mostly, each article generated one

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entry that regarded one receptor or compartment type, and one MNM category. However,

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some articles regarded multiple MNM categories or receptor types; in such cases, one entry

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was created for each combination of MNM category and environmental receptor or

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compartment. Because we sought to understand how frequently MNM concentrations

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were researched across MNM categories and various environmental receptors or

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compartments, this approach mostly resulted in one table entry per article (i.e. individual

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research study). Still, 693 entries resulted from 615 articles (Table S1, Supporting

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Information) because some articles regarded more than one biological receptor or

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compartment, or MNM category.

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For each entry, concentration units were converted to parts per million (ppm) for

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comparing across aqueous, versus solid (e.g. soil or sediment), exposures. The mode,

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median and mean exposure concentrations were calculated—across all MNM categories.

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Concentration data were then used to score (1 or 0, for presence or absence, respectively)

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range “bins” spanning ≤0.001 to >1000 ppm at order of magnitude intervals. This

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classification enabled examining which concentration ranges had been more studied for


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each receptor or compartment and MNM category. For each receptor or compartment and

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MNM category, the numbers of publications reporting exposure concentrations within the

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bin levels were graphed as histograms.

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Estimated or Measured Environmental MNM Concentrations The binning process was also applied to modeled or measured environmental

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concentrations. Environmental concentration sources included a comprehensive

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compilation9 of modeling results that were graphed alongside direct environmental

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measurements19, 20 for water, soil, sediments, and biosolids. Two other recent modeling

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studies13, 21 were additional sources. During the revision of this manuscript, another

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modeling study was published,15 but the predicted concentrations were very similar to

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prior studies and thus the comparisons herein were unchanged.

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All three sources regarded the MNM categories: metal oxide, metals, and

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carbonaceous; none regarded quantum dots. Compartment categories were similar to

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those in hazard assessments: water, wastewater treatment plant (WWTP) effluent, WWTP

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biosolids, soils, and sediments. After tabulating the modeled and measured MNM

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environmental concentrations, then binning the concentration values using the same

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approach that was used for classifying hazard assessment MNM concentrations, we

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annotated the hazard assessment MNM concentration histograms to co-display, for the

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aquatic and also the soil/ sediment/ wastewater receptors, the predicted MNM

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environmental concentration ranges.

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Results

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Estimated or Measured Environmental MNM Concentrations

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Measured or modeled MNM environmental concentrations ranged from a low of

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≤0.001 ppm to a high of >1000 ppm, i.e. spanning all concentration “bins” used for

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classifying hazard assessment concentrations (Table 1). Across environmental

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compartments of water (surface water or WWTP effluent), and solid media (soil,

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sediments, and biosolids), the lowest MNM concentration estimates are ≤0.001 ppm. The

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highest for water are in WWTP effluent (0.11 to 1 ppm) and the highest overall are for

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biosolids (>1000 ppm; Table 1). However, many of the estimated surface water

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concentrations are orders of magnitude lower than the lowest concentration bin used

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herein, i.e. sub parts per trillion (ppt). Other reported environmental measurements, i.e.

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that were either more recent or not included in Gottschalk et al.9, either overlap22, 23 or, in

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one case (sediments), greatly exceed24 the compiled ranges. Still, given the currency and

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comprehensiveness of the consulted review,9 and the consistency across the main three

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consulted articles,9, 13, 21 the summarized modeled or measured MNM concentration ranges

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represent current available information (Table 1).

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Exposure Concentrations Used in MNM Hazard Assessments

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Aquatic, including Benthic, Organisms

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Across all MNM categories and for all aquatic, terrestrial plant or microbial

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receptors, or receptors in soils, sediment, or wastewater, there were 1692 concentration

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data points evaluated (Table 2) from the 615 surveyed articles (Table S1). The numbers of

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studies regarding aquatic organisms (271 total) were, by organism (Table S1, Supporting


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Information): algae (13), daphnia (76), fish (119 total, including 20 medaka, 64 zebrafish,

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12 carp, 18 trout, and 5 minnow), mollusc (42, including 7 gastropod, 20 mussel, 5 oyster, 5

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clam, 1 scallop, 2 bivalve, 2 abalone), echinoderm (5, all urchin), crustacean (14, including 4

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shrimp or mysid, 3 crab, 1 copepod, and 6 amphipod), and polychaete (2). Since studies

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used multiple doses, the number of concentration data points exceeded the number of

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studies, i.e. totaling 733 (Table 2).

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Across aquatic organism and MNM categories, the mean MNM concentration, and

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the concentration most frequently administered (mode), were 71 ppm and 5 ppm,

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respectively (Table 2). Thus, across the receptor categories, the lowest overall MNM

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concentrations were for aquatic organisms (Table 2). The administered MNM

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concentrations spanned the concentration range from ≤0.001 to >1000 ppm (Fig. 1a).

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While a more detailed analysis by MNM was not warranted—mainly because of the uneven

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study count per MNM—concentrations appeared to be similar across MNM categories, as

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indicated by similarly shaped histograms (Fig. 1a, Fig. S1). Administered MNM

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concentration ranges differed by organism: except for echinoderms, crustaceans and

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polychaetes, most aquatic organisms were tested at MNM concentrations up to 1000 ppm

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(Fig. S2); MNM concentrations >1000 ppm were administered for only two receptor types

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(Daphnia sp. and fish, Fig. S2b and c, respectively); the highest administered MNM

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concentration range for echinoderm studies (1.1 to 10 ppm) was lower than the highest

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concentration for the other aquatic receptors, except for polychaetes (Fig. S2); studies of

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molluscs appeared to use mostly lower MNM concentrations, as indicated by the left-

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skewed histogram (Fig. S2d).


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In comparing modeled or measured environmental MNM concentration ranges

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(Table 1, and blue shaded regions of Fig. 1a and Fig. S1) to the ranges (all of Fig. 1a and Fig.

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S1) and to the median (0.6 ppm, Table 2) of administered concentrations, half of the

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aquatic hazard studies reported using administered concentrations that were greater than

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predicted environmental concentrations. This comparison does not differentiate surface

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waters from the slightly more MNM-concentrated WWTP effluents (Table 1, and Fig. 1a),

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because WWTP effluent receiving streams can be “effluent-dominated”.25 On face value, the

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range of MNM concentrations administered in hazard assessments would seem ideal, i.e.

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that half are above, and half are within, predicted environmental MNM concentrations.

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However, one might be concerned if many publications only report toxicity testing over

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high concentration ranges.

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To assess the latter, the spreadsheet of aquatic entries (Excel document, Supporting

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Information) can be sorted, finding that 229 of the 271 hazard studies administered

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concentrations only above the lowest concentration bin. In other words, nearly 85 percent

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of all aquatic studies excluded testing in the sub-ppb concentration range. Further, 66%

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(180 studies) only tested concentration ranges exceeding 0.01 ppm. Nearly half (43%, or

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116 studies) only tested MNMs at concentrations exceeding 0.1 ppm, and 22% (50 studies)

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only tested MNMs at concentrations exceeding the median test concentration (i.e. at ranges

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at or above 1.1 to 10 ppm). Nearly 6% of the studies only tested aquatic toxicity at

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concentrations exceeding 10.1 ppm, and 2% of studies excluded test concentrations below

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100 ppm. These statistics would suggest that there is, at the level of the individual study, a

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large disparity between predicted environmental, versus tested, MNM concentrations.

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While there is general overlap (Fig. 1a and Fig. S1), individual study concentration ranges


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mostly exceed those predicted. It would seem that this situation could be rectified if future

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toxicity studies routinely tested low concentrations.

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Microorganisms Hazard assessments were classified into the “microorganism” category if they

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regarded MNM effects on bacteria, protozoa, or fungi. The few articles concerning MNM

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effects on viruses were not evaluated as they were clinically, not environmentally, oriented.

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The numbers of entries were: 220 (bacteria), 14 (protozoa), 9 (fungi). Most environmental

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nanotoxicology publications regarded bacteria. For 2013, the topics “bacter* and

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nanomaterial*” yielded 174 publications (Table S2), but the topics “plant* and

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nanomaterial*” and “fish* and nanomaterial*” yielded only 111 and 31 publications,

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respectively (ISI Web of Science Search, January 1, 2014). However, many MNM-bacterial

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studies are clinically-oriented: out of over 600 identified publications from 2008-2013, ca.

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62% are oriented towards antibacterial or disinfection applications (235 of 623, Table S2),

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with others regarding the environment. Of the 220 bacterial studies recovered, 75 were

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regarding testing MNMs for antibacterial or disinfection properties, and 145 regarded

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environmental toxicity. Thus, the total entries related to bacterial environmental toxicology

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(as above, 145) is significant and, given the lack of bias in recovering sources (Supporting

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Information), representative. All of the entries for protozoa regarded environmental

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toxicity, as did five out of nine studies with fungi.

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While not a comprehensive test of the hypothesis, we examined administered MNM

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concentration ranges for antibacterial (e.g. disinfection) versus environmental hazard

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assessments to determine if the former tended to be higher. Not surprisingly, studies


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targeting MNM antibacterial, including disinfection, properties used relatively higher

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exposure concentrations, particularly for carbonaceous, metal (including nano-Ag) and

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metal oxide MNMs (Fig. S3). Further analysis only regarded the environmental bacterial

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nanotoxicology studies.

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The distributions of administered MNM concentrations for microorganisms appear

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similar to those for aquatic organisms (Fig. 1b versus 1a), and similar between MNM

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categories, across all microorganisms (Fig. S4). As expected, given the greater number of

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entries for bacteria relative to other microorganisms, the distribution of administered

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MNM concentrations for all microbes (Fig. 1b) appears very similar to that for bacteria (Fig.

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S5a). Still, protozoan and fungal testing apparently involved higher MNM concentrations,

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relative to bacterial testing (Fig. S5).

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The reported toxicity magnitudes are not summarized or interpreted here, as there

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are many reviews regarding bacterial-nanomaterial interactions, including across several

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MNMs,26 for nano-Ag27-30 and quantum dots,31, 32 and regarding effects mechanisms33, 34 and

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sensitivities compared to higher organisms.35 Further, based on our literature survey, a

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different analysis would be required to compare across bacterial studies, owing to

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disparate MNM preparations, toxicity endpoints, and experimental methods, including use

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of positive and negative controls. This point also applies to the other compartments and

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organisms, i.e. aquatic, soil/sediment/wastewater, and terrestrial plants. For evaluating the

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realism of administered MNM concentrations, frequency distributions are informative.

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Because microbial nanotoxicity studies were conducted in aqueous media, the

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environmental relevance of tested MNM concentrations should be compared to the MNM

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concentration ranges predicted, or measured, for surface water or WWTP effluent (Table 1,


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and blue shaded bars in Fig. 1a). One can readily see, comparing Fig. 1a and 1b, that the

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concentrations of MNMs used in microorganism toxicity testing are at ranges exceeding

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those used in aquatic organism toxicity testing, and so the microbial test ranges well exceed

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those predicted for water. The descriptive statistics (Table 2) confirm: the mean, and most

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frequently studied (mode) concentrations across all microbes and MNMs were

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approximately 362 and 55 ppm, respectively. Half of the entries are for concentrations

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exceeding approximately 6 ppm (Table 2), i.e. not even within range of predicted

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environmental concentrations in water (Fig. 1a and 1b). Thus, it would appear that most

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environmental microorganism nanotoxicology studies have utilized overly high MNM

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concentrations. Because the publication pace in microbial nanotoxicology appears to be

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accelerating (Table S2), it would be important to include low MNM concentrations in future

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studies, so that the growing field addresses a full range of possibly relevant concentrations.

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Soils, Sediments and Wastewater After landfills, soils are predicted to be significant destinations for MNMs released

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into the environment.12 For soils, there are concerns that MNMs could disrupt nutrient

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cycling, a high value ecosystem service,36 via impacts on the microbial community. Nutrient

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cycling is substantially carried out by diverse microbial communities whose interacting

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populations and biogeochemical functions are practically inseparable from the physical

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matrix with its environmental factors (e.g. water potential, pH, redox, etc.). That, coupled

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with the possibility that soil sorption reactions will lower MNM bioavailability,37

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necessitates studying soils—and, similarly, sediments—in microcosms where MNMs are

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amended to the matrix with its intact microbial communities. Similarly, wastewater is


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comprised of complex microbial communities whose biogeochemical functions, whether

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specialized or broad, are best studied within the matrix, i.e. activated or anaerobic sludges.

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Therefore, we distinctly categorized articles that addressed nanotoxicology for soils,

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sediments or wastewater, with the latter including various biological unit processes in

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WWTPs.

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Of the 84 studies sourced, 57, 21, and 6 regarded soils, wastewater, and sediments,

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respectively. As per the histogram (Fig. 1c), most tested MNM concentrations were in the

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high ranges, with none in the sub-ppb range. Few studies regarded quantum dots, and

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most regarded metal MNMs (Fig. 1c, Fig. S6). No studies of sediments regarded metal

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oxides (Fig. S7b). The administered MNM concentrations were not normally distributed,

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but rather were skewed to the right: more studies utilized higher than lower

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concentrations (Fig. 1c, Fig. S6). This was particularly the case for soil studies (Fig. S7a).

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Overall, across the three media types, the mean and most frequently studied

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concentrations were approximately 1200 and 550 ppm, respectively (Table 2).

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Neither activated sludge nor anaerobic digester sludge MNM concentrations were

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specifically predicted by exposure modeling. Still, MNM concentrations in sludge studies

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can be compared to the concentration ranges predicted, or measured, for soils, sediments,

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and biosolids (Table 1), particularly because both sludge types are converted to biosolids

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in WWTPs. While many of the exposure modeling outcomes predict sub-ppb levels (Table

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1), it is notable that none of the sourced toxicity studies employed such low MNM

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concentrations (Fig. 1c). Further, only three studies employed concentrations below 100

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ppb, and many employed MNM concentrations exceeding 1000 ppm (Fig. 1c). Based on the

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median MNM concentration across soils, sediments or wastewater (55 ppm, Table 2), half


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of the studies administered MNM concentrations within the highest ranges of predicted, or

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measured, environmental MNM concentrations (100.1-1000 and >1000 ppm, Table 1 and

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Fig. 1c). Thus, there is a large disparity when comparing exposure modeling results to

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experimental nanotoxicity test conditions: models often predict very low MNM

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concentrations in soils, sediments, and biosolids (Table 1), yet microcosm exposures

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employ concentrations that are orders of magnitude higher (Fig. 1). One measurement of

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nano-TiO2 in sediments near a WWTP effluent outfall would support the realism of high-

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end MNM concentration testing,24 yet there is only one such report. Further, it is unknown

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if the reported Ti nanomaterial was manufactured or natural, i.e. indigenous to that

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environment.9

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Terrestrial Plants

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There is great concern regarding the possible entry of MNMs into the food chain, via

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agricultural crops grown, for example, in soils fertilized with MNM-containing biosolids.38,

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biomass40 in the WWTP activated sludge precursors to biosolids, and thus land application

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of biosolids is a certain route by which MNMs can enter soils. MNMs can genetically

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damage food crops,41 affect food crop nutrient content,42 and interfere with nutrient cycling

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including nitrogen fixation in root nodule symbioses.43 Further, many vegetables are grown

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hydroponically, and thus MNM uptake via aqueous plant growth media is of concern.38

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Not all biosolids are land-applied to agriculture. However, MNMs sorb to microbial

Overall, 134 studies were examined regarding MNM concentrations used in plant

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nanotoxicity testing. Because more than one MNM concentration was often tested, this

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resulted in 294 data points (i.e. an MNM concentration for a given plant, within an


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individual study, Table 2). One can observe that, across the range of administered MNM

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concentrations, the tendency with plant exposures is to use higher MNM concentrations

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(Fig, 1d, Fig. S8). As such, the mean actual concentration was approximately 860 ppm, and

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the most frequently studied concentration (mode) was 55 ppm. Similarly to the

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publications regarding aquatic organisms (Fig. 1a) and microorganisms (Fig. 1b), the

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frequencies of tested concentrations did not appear to vary significantly by MNM category

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(Fig. 1d) except that there were few studies using quantum dots (Fig. S8). Across the lower

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end concentration ranges, only one study reported using MNMs at sub-ppb (≤0.001 ppm)

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levels, and eight studies tested MNMs at the next highest range (0.0011 – 0.01 ppm, Fig.

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1d). Over 90% of the sourced studies did not test MNMs across the lowest three

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concentration ranges (i.e. below 0.10 ppm), and over 80% did not test MNMs at

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concentrations below 1.1 ppm.

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Food Webs As summarized in the Supporting Information, there are few studies of food webs,

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i.e. using mesocosms, and all ten sourced were published since 2011. While one might

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assume that food web studies would employ the lowest MNM concentrations, the studies

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report a wide range of administered concentrations (Fig. S9). No studies used MNM

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concentrations exceeding 1000 ppm, and most studies—which were mainly aquatic

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mesocosms—appeared to use MNM concentrations below 1 ppm. Thus, there is a tendency

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with food web studies to employ MNM concentrations more reflecting those measured or

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predicted in water (as in Fig. 1a).

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Summary of Modeled or Measured, vs. Administered, Exposure Concentrations

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In summary, across the major compartments of water (surface water and WWTP

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effluent) and solid media (soil, sediments, and biosolids), and across major receptors of

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aquatic organisms, microorganisms, complex communities (in soils, sediments or

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wastewater) and terrestrial plants, there are some overlaps in modeled and measured

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MNM concentrations, versus those administered in toxicity studies. However, there are also

371

large disparities, with much higher MNM concentrations being routinely tested as

372

compared to what are predicted for, or measured in, the environment. There are few

373

patterns that differ across MNMs, but there are some differences across receptors. Future

374

hazard assessment studies would be improved by strategically incorporating concentration

375

ranges that overlap with those modeled or predicted (Table 1, Fig. 1). In the following

376

sections, we discuss uncertainties in hazard assessment that transcend MNM

377

concentration, and some major uncertainties currently inherent to exposure modeling.

378 379 380

Uncertainties When Defining Environmental Relevance of MNM Hazard Assessments Ideally, hazard assessment research would be performed under conditions that

381

mimic the environments in which biological receptors are exposed. Therefore, how to

382

define and incorporate “realism” into MNM hazard assessment studies is an important

383

issue. As above, on the basis of administered MNM concentrations, there appears to be a

384

broad lack of environmental realism in MNM hazard assessment research to date—that is,

385

if one assumes that the modeled and measured MNM environmental concentrations are

386

themselves “realistic”. What other factors, besides administered MNM concentrations, may


17


387

influence hazard assessment “environmental relevance”? Further, what are the key

388

uncertainties in predicted MNM environmental concentrations?

Page 18 of 39

389 390 391

Uncertainties regarding environmental relevance in MNM hazard assessment There are many factors, besides MNM test concentration, that influence hazard

392

assessment “environmental relevance”. On one hand, to be most environmentally-relevant,

393

instead of only testing standard organisms studied out of an ecological context, hazard

394

assessment research should regard MNM impacts in systems that are sufficiently complex

395

to include all relevant ecological interactions.18, 44 This is particularly true for ecosystem

396

processes that require multiple populations interacting as communities, as is the case for

397

biological N2 fixation within plant root-bacterial symbioses.43 However, assessing MNM

398

hazards by only using mesocosms is impractical and slow, and alternative test strategies

399

proposed for accelerating human health hazard assessments45 could also have a role in

400

environmental nanotoxicology if such alternative tests employ “environmentally relevant”

401

receptors.18, 46 Regardless of the receptor, a wide range of MNM exposure concentrations

402

may be required to allow for resolving MNM bioavailability mechanisms, uptake,

403

bioaccumulation, and organismal internal concentrations at sites of toxicity.

404

Media choice would also be an important consideration, since aqueous chemistry

405

significantly affects biological population responses to MNMs,47 and since defined media

406

could conceivably be formulated to closely represent nutrient-depleted soil or water

407

environments. Further, depending on the media, MNM dissolution, speciation and

408

complexation can interfere with differentiating particle versus ion toxicity, e.g. in the case


18

Page 19 of 39


409

of Ag ions dissolved from Ag MNMs but then complexing with chloride, leading to an

410

underestimate of dissolution-mediated Ag MNM toxicity.48

411

In addition to receptor type and media, “environmental realism” is also affected by

412

MNM delivery choice, e.g. whether to administer and study as-produced, “neat” MNM

413

particles, versus “aged” MNMs. On one hand, MNMs that are relatively stable may exert

414

similar toxicities over prolonged exposure, including MNM “aging” periods,49 while other

415

MNMs may acquire a mitigating cap, as in Ag MNMs becoming sulfidated.50 Still, how fast

416

aging occurs, relative to hazard assessment study periods, is an important consideration.

417

For example, nano-ZnO can dissolve quickly in environmental waters,51 including the soil

418

solution.38 If plants grow slowly in soils43 relative to MNMs dissolving in the soil solution,

419

then administering neat MNMs may be reasonably “environmentally relevant”. Fully

420

exploring how fast MNMs physicochemically transform in situ, relative to how fast

421

biological receptors respond, would assist resolving when it is “environmentally relevant”

422

to administer “neat”, as-produced, MNM powders during environmental hazard

423

assessment. For MNMs that are embedded in composites with polymers, conducting hazard

424

assessments using neat MNMs may still be “relevant”, if MNMs can release from

425

composites.52

426

Thus, in addition to MNM concentrations, other factors affecting “environmental

427

realism” during MNM hazard assessment include: choice of biological receptors, choice of

428

test conditions including media chemistry and ecological complexity, and what MNM forms

429

should be used, including aged or neat. Given these multiple factors, it is uncertain if the

430

choice of MNM concentration overwhelmingly determines MNM hazard assessment

431

“environmental relevance”.


19


432 433

Page 20 of 39

Uncertainties regarding predicted environmental MNM concentrations Uncertainties associated with modeling environmental MNM concentrations also

434

contribute to the ambiguity in what comprises “environmentally relevant” MNM

435

concentrations for MNM hazard assessment. For example, modeling requires

436

understanding the source magnitude, i.e. MNM production volumes. Yet, accurate

437

quantifications of production volumes are not readily available. At industry trade

438

association meetings, colleagues are reminded of antitrust law requirements such as,

439

“Don’t, in fact or appearance, discuss or exchange information on:… company data on costs,

440

production, capacity inventories, sales, etc….”.53 Not complying can lead to allegations of

441

price-signaling, as in the pigment TiO2 suit recently settled for $163.5 million.54, 55 Industry

442

insiders understand that consolidated nanomaterial production volumes are difficult to

443

obtain or that intermediaries, such as market research firms, provide only estimates. This

444

is because market research relies on information gained via interviews, financial reports,

445

trade show handouts, and other sources.

446

However, academic researchers have used market research estimates of production

447

volumes as starting points for modeling environmental MNM concentrations. These, along

448

with other sources, can result in a wide variety of production volume estimates. For

449

example, silver production volume estimates vary greatly (Table S3), i.e. 500 t/a stemming

450

from personal communication;11 1230 t/a via trade association analysis;11 55 t/a, and a

451

range of 5.5 to 550 t/a from a survey of experts;56 2.8 to 20 t/a in the U.S., using “creative

452

approaches” combining order inquiries with proxy parameters.57 Keller, et al.12 and the

453

European Commission’s (EC’s) staff58 cite market research reports for 450 t/a and 22 t/a,

454

respectively. Given that production volume estimates can vary by two to three orders of


20

Page 21 of 39


455

magnitude (Table S3), estimates of MNM environmental concentrations are rather

456

uncertain (Table 1).

457

What MNM production information is most reliable? Market research practitioners

458

utilize superior access to supply chain resources and their detailed knowledge of end use

459

markets to arrive at self-consistent findings. (For a discussion of financial reporters

460

operating in the nanotechnology environment, see Ebeling et al.59) However, industry

461

insiders temper market research report findings with their own market knowledge. In

462

proposing production volumes herein (Table S3), weight has been given to market

463

estimates having some level of government review, i.e., an imprimatur of relevance to

464

nanomaterial environmental health and safety. However, the EC’s definition is relatively

465

recent and may be a surprise to some market segments. For those material suppliers,

466

reported volumes will reflect an increasing awareness of definitions rather than a market

467

growth.

468

We illustrate the challenge with a compilation of global production estimates for

469

eleven nanomaterials (Fig. 2). Details on sources, volumes and interpretations are found

470

with Table S3 in the Supporting Information. Major marketplace segments are identified, as

471

are their alignments with specific nanomaterials. Symbols () indicate uncertainties in

472

volume and likely growth trends. As shown in the following discussion, the definition of

473

“nanoscale”, and a knowledge covering the many market segments, can significantly affect

474

the reliability of market research estimates, which influence estimates of environmental

475

concentration through the modeling of likely release scenarios.

476 477

Volume ranking highlights the older, passive fillers that often have mineralogical counterparts (Fig 2, Table S3). Carbon black, carbon nanofibers and carbon nanotubes


21


Page 22 of 39

478

share markets for reinforcement, electrical conductivity and thermal conductivity. 60

479

Silicon dioxide has sub-categories (and CAS-numbers61)—diatomaceous earth, synthetic

480

amorphous silica, silica fume, and quartz—that also span descriptors such as natural,

481

incidental and engineered. All are “manufactured” when processed into commercial

482

products leading to a combined volume (Fig. 2). Adjusting the upper boundary of nanoscale

483

to above 100 nm would affect TiO2 estimates greatly, due to the 5 million t/a of pigment

484

grade TiO2 for which the mean primary particle size found in aggregates is between 250

485

and 300 nm.62, 63 Carbon black (CB), SiO2, Al2O3 and TiO2 describe a class of “large volume,

486

long-term-use” materials relative to the remaining particles including future novel

487

compositions, and such “large volume, long-term-use” nanomaterials are used in several

488

markets. For example, the tire industry, known for CB, is also a significant market for

489

precipitated silica. The paper industry utilizes process additives (antifoams, retention aids)

490

and paper fillers (alumina, silica, calcium carbonate) that can be nanoscale, and is also a

491

source of nanocellulose, which may displace carbon nanotubes and nanofibers in

492

reinforcement. Elastomer and polymer compounders, and the paint and coatings

493

industries, use fillers extensively. For some markets, e.g. optical fiber ferrules for zirconia

494

or catalyst carriers for TiO2, nanomaterials are converted into much larger objects, and

495

there are others, such as chemical mechanical planarization (CMP), where MNM

496

consumption occurs within a closed-loop industrial context (workplace and waste

497

treatment). Other MNM uses, such as pesticides in an agricultural setting, and in food,

498

personal and household care products, offer considerable opportunity for widely dispersed

499

environmental exposure.


22

Page 23 of 39

500


Several authors and organizations utilize patent claims and product formulations to

501

suggest environmental concentrations.64, 65 In many respects, these efforts responded to

502

the public’s early questions about consumer and environmental exposures. Silver

503

illustrates a pitfall in that many authors mistook prominence for large production volumes

504

when using the Project on Emerging Nanotechnologies (PEN) listing, even though verifying

505

the products’ commercial status was difficult.66 Yet, formulated household products lead to

506

immediate human exposure and, for silver, there is past medical experience to consider.67

507

Lorenz, et al.68 and the Magic Nano incident69 demonstrate the very real exposure potential

508

with aerosol sprays.

509

Life cycle analyses track a material from production through to disposal,11, 12 and

510

production volumes allow for calculating general background exposure levels. Specific

511

production site knowledge is useful for estimating localized environmental exposure such

512

as along a river system, and there are also generic scenarios for point sources.70 Total

513

production volumes also act as surrogates for the frequency of everyday incidents such as

514

spills, broken bags, accidental exposures and their locations. However, anticipated

515

environmental background levels are distinct from the frequency and duration of acute

516

exposures.71

517

Therefore, the investigator interested in establishing a “realistic” or

518

“environmentally relevant” exposure level for nanomaterial testing faces several

519

challenges. There are distinctions to draw among environmental concentration, exposure

520

level, and dose; there are several assessment methods with accompanying nuances: risk

521

assessment, life cycle analysis (and its sub-category of life cycle impact assessment),

522

comprehensive environmental assessments and multi-criteria decision analysis.72 Whether


23


523

as narratives used to set research priorities73 or as computer models calculating a

524

predicted environmental concentration,11 these methods establish material (mass) flows

525

passing from production-to-use-to-disposal.

526

Page 24 of 39

Practitioners utilize mapping to identify life cycle stages or ”hot spots”, allowing

527

scenario-specific information to be applied to material flows to estimate releases and

528

concentrations. However, estimating environmental exposure for a nanomaterial is more

529

challenging due to the definition. Nanoscale materials are defined by size and not by

530

property.74 Without recognized properties or known effects, it becomes difficult to verify

531

life cycle models, leading to over- or underestimates of exposure.9 Recent articles20, 24, 75

532

report on nanoscale TiO2 content in biosolids exceeding nearby production or consumption

533

with paint as an apparent source, i.e., non-nano-pigment grade TiO2.9, 20 which does have a

534

nanoscale component.76 Additionally, particles respond to environmental conditions, which

535

for silver can entail repeated dissolution and re-precipitation, as well as sulfide

536

formation.77-79 While silver sulfide does not readily re-oxidize, other metals and metal

537

sulfides do.79 Effectively, non-nano sources, sinks, changes in surface chemistry and

538

chemical transformations, all meeting the definition of nanomaterial, are possible at each

539

environmentally relevant stage of the life cycle, and they are not necessarily included in the

540

mass balance assumptions of many life cycle models.

541

Thus, major uncertainties in MNM environmental concentration modeling include

542

understanding production volumes of actual nanoscale materials that can be released into

543

the environment and, as above, accounting for transformations that would affect not only

544

toxicity but also integrity and retention of properties conferring nano-specific reactivity

545

and hazard.


24

Page 25 of 39

546 547


Conclusions Herein, upon reviewing administered concentrations reported in more than 600

548

articles concerning MNM environmental hazards, we show that there is some overlap, but

549

also disparity, as compared with modeled or measured environmental MNM

550

concentrations (Fig. 1 vs. Table 1). There are uncertainties in modeling environmental

551

MNM concentrations, mainly stemming from limited production volume information, but

552

also in accounting for MNM release and environmental transformation. Further, there are

553

great uncertainties regarding MNM bioavailability, and the effective concentrations that

554

cause toxicity by a particular mode of action within a receptor. This limits defining with any

555

degree of detail, the MNM doses that are most realistic for the myriad environmental

556

receptors and their exposure conditions. Although human occupational exposure by

557

inhalation and MNM deposition into the lung have been modeled for improving in vitro

558

hazard assessment,8 MNM environmental exposure and hazard assessment endeavors do

559

not yet account for bioavailability, bioaccumulation, biotransformation, and mode of action.

560

Actual concentrations in, and around, biological receptors may be much higher than

561

average ambient concentrations of toxicants that are modeled or measured in bulk.

562

However, even if the concentrations near receptors are not high, it may be necessary to

563

default to administering higher MNM exposure concentrations in bioaccumulation studies,

564

since many common methods for quantifying MNMs in tissues or similarly complex

565

matrices have relatively high detection limits.10 For all of these reasons, it is premature to

566

discount MNM hazard assessment research on the basis of “environmental relevance”.

567

Further, while modeling results are compared and comparable to the limited

568

measurements of MNM environmental concentrations, it is important to validate models,


25


Page 26 of 39

569

perhaps even for their abilities to predict conventional pollutant concentrations. This could

570

serve as a good “check” on model performance when reapplied to predicting future MNM

571

environmental concentrations.

572

To maximize environmental realism, hazard assessment should, as closely as

573

possible, be conducted to include ecologically relevant receptors and exposure conditions.

574

Extremely low to rather high MNM concentrations could be routinely administered in

575

toxicity assessments. What MNM exposure conditions, including concentrations, are

576

“environmentally relevant”, especially given that predicted concentrations are averages

577

and thus do not capture “hot spots”, i.e. environmental locations where MNMs may hyper-

578

concentrate? By comparison, pharmaceutical pollutants are expected to occur at low

579

concentrations in the environment,80 yet pharmaceutical aquatic toxicity is studied under

580

acute (high concentration) exposure conditions expected with spills or highly unregulated

581

situations.80, 81. The MNM hazard and exposure assessment communities are prudent to

582

design their studies carefully, particularly since the nanotechnology industry with its many

583

anticipated societal and environmental benefits could be unduly thwarted if great risks are

584

inaccurately predicted or perceived82. Yet, in the absence of careful consideration of such

585

questions, conservatism within the MNM hazard and exposure assessment communities

586

may lead to “self-sanctioning” that itself could constrain research and thereby prevent

587

necessary and full discovery.

588 589

Acknowledgements

590

This work was supported by the National Science Foundation and the

591

Environmental Protection Agency under Cooperative Agreement DBI-1266377 and


26

Page 27 of 39


592

Purdue-Colciencias agreement under Colombia-Purdue Institute for Advanced Scientific

593

Research – (CPIASR). Any opinions, findings, and conclusions are those of the authors and

594

do not necessarily reflect the views of the National Science Foundation or the

595

Environmental Protection Agency. This work has not been subjected to EPA review and no

596

official endorsement should be inferred.

597 598

Supporting Information Available

599

There are two Supporting Information files: an Excel workbook containing binned

600

concentration data for each MNM hazard assessment study that was sourced, and a Word

601

document containing additional methods, results, and a table plus references of the Excel

602

spreadsheet entries. This information is available free of charge via the Internet at

603

http://pubs.acs.org/.

604 605


27


606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651

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890 891 892 893 894 895


Table 1. Modeled or measured MNM concentration magnitudes by MNM category for two environmental compartments (separated by a bold line): water (surface water or WWTP effluent), and solid media (biosolids, soil, sediments). Concentration ranges (bins) span ≤0.001 to >1000 ppm, with intervening 10-fold ranges. These match the hazard assessment MNM concentration data categorization described in the Methods, and in Table S1. Modeled versus measured concentrations are not distinguished where “both” are indicated (2nd column from left). WWTP= wastewater treatment plant. The lowest and highest bin magnitudes for each compartment, across MNM categories, appear in “bold” font. Bins in brackets were gaps in the source data. Modeled Modeled or Measured MNM Environmental Concentration Ranges According to Compartment or MNM Category (ppm) Source measured Metal oxides Metals Carbonaceous ≤0.001; 0.0011-0.01 ≤0.001 ≤0.001 water: surface both Gottschalk water et al.9 ≤0.001 ≤0.001 ≤0.001 modeled Liu and water: WWTP effluent

≤0.001; [0.0011-0.01]; 0.0110.10; 0.11-1 ≤0.001; 0.0011-0.01; 0.0110.10

≤0.001; [0.0011-0.01]; 0.011-0.10 ≤0.001; 0.0011-0.01; 0.0110.10

≤0.001; 0.0011-0.01; 0.011-0.10 ≤0.001

≤0.001; [0.0011-0.01]; 0.0110.1; 0.11-1; 1.1-10; 10.1100; 100.1-1000; >1000 1.1-10; 10.1-100; 100.1-1000

0.0011-0.01; 0.0110.1

modeled

≤0.001; [0.0011-0.01]; [0.011-0.10]; 0.11-1; 1.1-10 ≤0.001

≤0.001; 0.0011- 0.01; 0.011-0.1; 0.11-1; 1.1-10; 10.1-100 0.0011-0.01; 0.011-0.1; 0.11-1; 1.1-10; 10.1-100; 100.1-1000 ≤0.001; 0.0011-0.01; 0.0110.10 ≤0.001

both

0.011-1; 1.1-10; 10.1-100

0.0011-0.01; 0.011-0.10

modeled

0.0011-0.01; 0.011-0.10; 0.11-1; 1.1-10

≤0.001

≤0.001; 0.0011-0.01; 0.011-0.10; 0.11-1; 1.1-10 ≤0.001; 0.0011-0.01; 0.011-0.1

both modeled

solid media: biosolids

both

modeled

solid media: soil

solid media: sediments

both


Cohen13 Gottschalk et al.9 Keller and Lazareva21 Gottschalk et al.9

0.11-1; 1.1-10

Keller and Lazareva21

≤0.001; 0.0011- 0.01

Gottschalk et al.9 Liu and Cohen13 Gottschalk et al.9

≤0.001

Liu and Cohen13

35


896 897 898 899 900

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Table 2. Mode, median and mean exposure values (ppm), by receptor or compartment and across all MNMs, calculated from administered MNM concentrations used in published nanotoxicology hazard assessments (Table S1). The number of individual concentrations excerpted across the surveyed 615 published articles is indicated by “n”. Receptor or compartment

n

Aquatic organisms Microorganisms Soil/Sediment/Wastewater Terrestrial plants

733 575 90 294

Calculated MNM concentration statistic (ppm) mode Median mean 5.1 0.6 71.0 55.1 5.6 361.6 550.1 55.1 1183.5 55.1 55.1 860.2

901 902


36

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903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948


Figure 1. Histograms of the number of nanotoxicology hazard assessment publications over the period 2008-2013 that report administering MNMs at various MNM concentrations, binned by orders of magnitude from ≤0.001 to >1000 ppm. Distributions are for: aquatic organisms (a), microorganisms (b), soil/sediment/wastewater (c) and terrestrial plants (d). Bar shading denotes MNM material category: dark solid = metal oxide; light solid = metal; diagonal lines = carbonaceous; and unfilled = quantum dots. Blue coloring of bars in parts a) and c) denote ranges for which MNM environmental concentrations have been modeled or measured for waters (surface water and WWTP effluent) and solid media (soils, sediments, and biosolids), respectively (Table 1). These ranges are not overlain in b) or d), since modeled water concentrations (Table 1) can more readily be compared to aquatic organisms exposure levels in toxicity testing (a); similarly, modeled solid media concentrations (i.e. soils, sediments and biosolids, Table 1) can be more readily compared to the soil/sediment/wastewater exposure levels in toxicity assessments (c).


37


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949 950

951 952 953 954 955 956 957 958 959

Figure 2. Global production volumes (tons per year), growth expectations (relative to gross domestic product or GDP), and primary uses for selected nanomaterials (left and right, colored arrows with sector or product labels). Arrows are differently colored for readability; otherwise, the colors have no specific meaning. The development of volume data is discussed in more detail in the Supporting Information and in Table S3.


38

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960 961

962 963 964 965 966 967

TOC Art

968 969 970 971 972 973 974


39

Evaluation of Exposure Concentrations Used in Assessing

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