Risk Assessment for Manufactured Nanoparticles Used in Consumer Products (RAMNUC)

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute


Most recent scientific efforts have focused on examining toxicities of manufactured nano-particles (MNPs) only in source materials. By not evaluating MNPs at the point of exposure, these efforts fail to address the relevant question of whether or not consumer-product-derived MNPs are of concern to public health and the environment. The proposed US-UK consortium, 'Risk Assessment for Manufactured Nanoparticles Used in Consumer Products (RAMNUC)', provides a systematic, multidisciplinary approach, including both experimental and computational tools and projects, for predicting potential human and environmental risks associated with the use of selected consumer products that respectively incorporatezinc oxide, silver, and cerium dioxide nanoparticles. The overall hypothesis of the RAMNUC project is that MNPs at the point of exposure for both humans and aquatic animals will substantially differ in both physicochemical and toxicological properties from MNPs at the source (synthesized in the laboratory or acquired commercially). These differences may have significant consequences with respect to MNPs' bioavailability, alterations of immunity, induction of oxidative stress, inflammation, disease processes, and other toxicity measures. We will assess intracellular and extracellular bioavailability and toxicity of the selected MNPs, as synthesized and as incorporated in consumer products, using both in vitro and in vivo experiments. Tested MNPs will be controlled or well characterized for their physical (e.g., size, shape, state of agglomeration/aggregation) and chemical properties (e.g., composition, functionalization, surface chemistry). Hence, our proposed in vitro and in vivo studies will produce mechanism-based results relating toxic effects to MNP physicochemical properties. The RAMNUC Consortium will also include a novel human exposure simulation study that will produce realistic estimates of MNP exposures to consumers. Data generated from these mechanistic experiments will be integrated into the mechanism-based computational modules of two existing source-to-exposure-dose-to-effects modeling systems, allowing for rational extrapolation and generalization in MNP risk assessment. Built upon the inter-institutional expert structure, the RAMNUC consortium serves as a model for systematically addressing complex problems associated with MNP risk assessment and will generate results that will contribute to our very limited knowledge about health risks associated with the use of nano-technology based consumer products.


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Leo BF (2013) The stability of silver nanoparticles in a model of pulmonary surfactant. in Environmental science & technology

Description 1. Fate and behaviour of NMS in the environment
(i) Nanotechnology-based and consumer spray products containing nano-materials.
We provided a quantitative assessment of inhalation exposure and deposited aerosol dose in the 14 nm to 20 µm particle size range based on the aerosol measurements conducted during realistic usage simulation of five nanotechnology-based and five regular spray products matching the nano-products by purpose of application. In seven out of ten sprays, the highest inhalation exposure was observed for the coarse (2.5-10 µm) particles while being minimal or below the detection limit for the remaining three sprays. Nanosized aerosol particles (14-100 nm) were released, which resulted in low but measurable inhalation exposures from all of the investigated consumer sprays. Eight out of ten products produced high total deposited aerosol doses on the order of 101-103 ng kg-1 bw per application, ~85-88% of which were in the head airways, only <10% in the alveolar region and <8% in the tracheobronchial region.
In a simulation study, we applied the cosmetic powders studied to the face of a human mannequin head and found that that a user would be exposed to nanomaterial predominantly through nanoparticle-containing agglomerates larger than the 1-100-nm aerosol fraction. Based on this, we concluded that predominant deposition of nanomaterial(s) will occur in the tracheobronchial and head airways--not in the alveolar region as would be expected based on the size of primary nanoparticles.
( Nazarenko Y, Lioy PJ, Mainelis GQuantitative Assessment of Inhaled and Deposited Doses of Aerosol from Nanotechnology-Based Consumer Sprays, Environ. Sci:Nano, 2014, 1, 161-171. ; Nazarenko, Y., Zhen, H., Han, T., Lioy, P.J., Mainelis, G. Potential for inhalation exposure to engineered nanoparticles from nanotechnology-based cosmetic powders, Environ Health Perspect, 2012, 120(6):885-92.

(ii) Impacts of a Nanosized Ceria Additive on Diesel Engine Emissions of Particulate and Gaseous Pollutants
We reported on the impact of fuel additives incorporating nanosized ceria used in diesel engines as combustion promoters on pollutant emissions by systematically comparing emission rates of particulate and gaseous pollutants from a single-cylinder, four-cycle diesel engine using fuel mixes containing nanoceria of varying concentrations. The addition of a commercial fuel additive Envirox into an ultralow-sulfur diesel fuel resulted in ceria-concentration-dependent emission reductions of CO2, CO, total particulate mass, formaldehyde, acetaldehyde, acrolein, and several polycyclic aromatic hydrocarbons. These reductions at the manufacturer-recommended doping concentration of 0.5 mL Envirox per liter of fuel., however, were accompanied by a substantial increase of certain other air pollutants, specifically the number of ultrafine particles (+32%), NO(x) (+9.3%), and the particle-phase benzo[a]pyrene toxic equivalence quotient (+35%). Increasing fuel ceria concentrations also led to decreases in the size of emitted particles.
(Zhang, J., Y. Nazarenko, L., Zhang, L., Calderon, K.L, Garfunkel, E., Schwander, S., Tetley, T.D., Chung F.K., Porter, A., Ryan, M., Lioy, P.J., Mainelis. Impacts of a Nanosized Ceria Additive on Diesel Engine Emissions of Particulate and Gaseous Pollutants, Environ. Sci. Technol, 2013, 47 (22):13077-13085. )

2. Interaction with biological targets
? Nanotechnology-based and consumer spray products containing nano-materials.
In studies of spray products containing silver and zinc "nanoparticle", we discovered that the bioreactivity of the product varied, depending on the type of particle and the carrier solution. Thus neither the silver particles, nor the diluent of Mesosilver was toxic to respiratory lung cells in vitro. In contrast, for Nanofix, which also contained silver particles, the silver particles were toxic alone, as was high concentration of the diluent alone, and the mixture was extremely toxic. Therazinc was also found to be very toxic, largely due to the diluent, but also at high particle concentrations. Conversely, Dermazinc which was also very toxic, it was the particles that were most toxic, whilst the diluent was toxic only at high concentrations. These studies of sprays indicate that even if these sprays are used for other purposes (eg cleaning and skin conditions), unintended inhalation could have adverse health effects as we show in our mouse models exposed to these products.
? Impacts of a Nanosized Ceria Additive on Diesel Engine Emissions of Particulate and Gaseous Pollutants
We investigated the effect of addition of cerium oxide (as Envirox) to diesel at 0x, 0.1x, 1.0x and 10.0x the manufacturer's recommended level on the physicochemical properties of the diesel exhaust particles (DEP), and on their bioreactivity with human lung cells from the respiratory unit, where a significant proportion of inhaled nanoparticles deposit. Interestingly, the data so far suggest that the pro-inflammatory effect of DEP containing 10x cerium oxide was significantly less than for the other condition.
Stuies in mice instilled with DEP collected from combustion of diesel containing addition of Envirox indicated that there was less inflammatory response with the use of envirox at 1.0x as added in diesel.

(i) Development of models and validation
We have developed a module-based modelling system that can be used to estimate population exposures to the engineered nanoparticles described above particularly silver nanoparticles contained in consumer products and to describe/predict biological responses to ENM exposure at the cellular level and at the organ function level including interactions with pulmonary lining fluid.
?We reported that population distributions of intakes are consistent with published individual-based intake estimates, demonstrating that PRoTEGE is capable of capturing realistic exposure scenarios for the US population. Distributions of intakes are also used to calculate biologically-relevant population distributions of uptakes and target tissue doses through human airway dosimetry modeling that takes into account product MNP size distributions and age-relevant physiological parameters. (Royce, SG., Mukherjee, D., Cai, T., Xu, SS., Alexander, JA., Mi, Z., Calderon, L., Mainelis, G., Lee, K., Lioy, PJ., Tetley, TD., Chung, KF., Zhang, J., Georgopoulos, PG. Modeling Population Exposures to Silver Nanoparticles Present in Consumer Products, J Nanoparticle Research, 2014 Nov;16(11). pii: 2724.)
?We have developed a model that quantifies ENM transformation and transport in the alveolar air to liquid interface and estimates eventual alveolar cell dosimetry. This formulation brings together established concepts from colloidal and surface science, physics, and biochemistry to provide a stochastic framework capable of capturing essential in vivo processes in the pulmonary alveolar lining layer. We have presented applications for four different ENMs, and relevant kinetic rates are estimated, demonstrating an approach for improving human in vivo pulmonary dosimetry. (Mukherjee, D., Royce, SG., Sarkar, S., Thorley, A., Schwander S., Ryan, MP., Porter, AE., Chung, KF., Tetley, TD., Zhang, J., Georgopoulos, PG,. Modeling in vitro cellular responses to silver nanoparticles. J Toxicol, 2014;2014:852890.)
?We have developed a model for predicting agglomeration and dissolution compared with in vitro measurements for various types of ENMs, coating materials, and incubation media. The model has been implemented for an in vitro case in cell culture systems to inform in vitro dosimetry for toxicology studies, and can be directly extended to other biological systems, including in vivo tissue subsystems by suitably modifying system geometry.(Mukherjee D, Leo BF, Royce SG, Porter AE, Ryan MP, Schwander S, Chung KF, Tetley TD, Zhang J, Georgopoulos PG. Modeling physicochemical interactions affecting in vitro cellular dosimetry of engineered nanomaterials: application to nanosilver. J Nanopart Res. 2014 Oct 1;16(10):2616.).
? We developed a detailed biologically based computational model of cellular interactions with NPs, utilising measurements performed in human cell culture systems in vitro, to develop a mechanistic mathematical model that can support analysis and prediction of in vivo effects of NPs. The model considers basic cellular mechanisms including proliferation, apoptosis, and production of cytokines in response to NPs. (Mukherjee D, Royce SG, Sarkar S, Thorley A, Schwander S, Ryan MP, Porter AE, Chung KF, Tetley TD, Zhang J, Georgopoulos PG. Modeling in vitro cellular responses to silver nanoparticles.
J Toxicol. 2014;2014:852890.)
?We have developed a computational, multiscale toxicodynamic model to quantify and predict pulmonary effects due to uptake of engineered nanomaterials (ENMs) in mice. The model consists of a collection of coupled toxicodynamic modules, that were independently developed and tested using information obtained from the literature. The modules were developed to describe the dynamics of tissue with explicit focus on the cells and the surfactant chemicals that regulate the process of breathing, as well as the response of the pulmonary system to xenobiotics. (Mukherjee D, Botelho D, Gow A, Zhang J and Georgopoulos PG.Computational multiscale toxicodynamic modeling of silver and carbon nanoparticle effects on mouse lung function. 2013, PLOS One 8(12):e80917.)
Exploitation Route 1. Our results are of use to organisations that regulate consumer products that contain nanoparticles as to their potential pulmonary toxicity.
2. The results regarding the use of CeO2 in diesel are reassuring from their potential toxicity and this could be further exploited in terms of their wider use.
3. Further extension of this work would be welcome given the increasing use of nanoparticles in consumer products not only restricted to silver and zinc nanoparticles. Studies of other nanoparticle are warranted.
Sectors Environment,Healthcare,Leisure Activities, including Sports, Recreation and Tourism

Description The PIs in thsi program published an article summarising the positive putcomes from this Joint program. Lasat MM1, Chung KF2, Lead J3,4, McGrath S5, Owen RJ6, Rocks S7, Unrine J8, Zhang J9. Advancing the Understanding of Environmental Transformations, Bioavailability and Effects of Nanomaterials, an International US Environmental Protection Agency-UK Environmental Nanoscience Initiative Joint Program.J Environ Prot (Irvine, Calif). 2018 Apr 2;9(4):385-404. doi: 10.4236/jep.2018.94025.
First Year Of Impact 2018
Sector Environment,Healthcare
Impact Types Societal,Economic,Policy & public services

Description Ambient exposure to diesel traffic particles and exacerbations of cardiovascular and chronic pulmonary disease: mechanistic explanations for epidemiological observations.
Amount £300,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2012 
End 10/2014
Description Nanoparticles, sensory irritation and the lung: environmental influences on biological processes.
Amount £80,000 (GBP)
Funding ID 1243159 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2012 
End 09/2015
Description Collaboration with Dr Mark Wiesner at Duke University 
Organisation Duke University
Country United States 
Sector Academic/University 
PI Contribution Prof. Mark Wiesner is Director for the Environmental Implications of NanoTechnology (CEINT) funded by US NSF and EPA. The near-term collaboration with Prof. Wiesner?s group will strengthen the ecotoxicity component (especially modeling) of our current RAMNUC program.
Collaborator Contribution Has contributed to the modelling of RAMNUC project
Impact Nil.
Start Year 2013
Description Collaboration with Dr Rachel Smith at PHE for doiing exposure studies of nanoparticles and DEP 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution Provide expertise in animal lung function
Collaborator Contribution Provide dosimetry and exposure facility
Impact Papers in press.
Start Year 2010
Description Final Environmental Nanoscience Initiative 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Discuss the findings and legacy of the research funded under the Environmental Nanoscience Initiative in parallel with other funded projects with scientists, funders and politicians.
Year(s) Of Engagement Activity 2015
Description Presentation at the 8th ICEENN Nano2014 meeting in Columbia, South Carolina, US on 10th September 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talked sparked a lot of interest about toxicity of nanoparticles of silver and zinc in consumer products

Discussion about potential further funding to continue work
Year(s) Of Engagement Activity 2014