Grantee Research Project Results
2008 Progress Report: Impact of Physiochemical Properties on Skin Absorption of Manufactured Nanomaterials
EPA Grant Number: R833328Title: Impact of Physiochemical Properties on Skin Absorption of Manufactured Nanomaterials
Investigators: Xia, Xin-Rui , Monteiro-Riviere, Nancy A. , Riviere, Jim E.
Institution: North Carolina State University
EPA Project Officer: Hahn, Intaek
Project Period: September 1, 2006 through August 31, 2009
Project Period Covered by this Report: September 1, 2007 through August 31,2008
Project Amount: $391,617
RFA: Exploratory Research: Nanotechnology Research Grants Investigating Environmental and Human Health Effects of Manufactured Nanomaterials: a Joint Research Solicitation-EPA, NSF, NIOSH, NIEHS (2006) RFA Text | Recipients Lists
Research Category: Nanotechnology , Safer Chemicals
Objective:
The wide applications of manufactured nanomaterials will create enormous potential for human exposure and environmental release. Skin, as the largest organ protecting the body from exogenous toxins and particulates, could be a major portal of entry for nanomaterials. Our preliminary study has shown that fullerene nanoparticles can penetrate deep into the stratum corneum (the primary barrier of the skin) and be modulated by solvents and ion-pairing agents. Currently, there is no method available for quantitative assessment of the skin absorption of the manufactured nanomaterials.
The objective of this project is to establish a structure-permeability relationship for skin absorption of manufactured nanomaterials for safety evaluation and risk assessment. Four dominant physiochemical properties (particle size, surface charge, hydrophobicity and solvent effects) in skin absorption will be studied. Fullerene and its derivatives will be used as model nanomaterials. The absorption and disposition kinetics and dose-response relationships will be measured experimentally for quantitative model development. Four specific aims will be delivered: Aim I. ion-pairing effects on skin absorption of charged nanomaterials; Aim II. Effects of particle size on skin absorption; Aim III . Impact of lipophilicity of nanomaterials on skin absorption; and Aim IV. Solvent effects on skin absorption of carbon nanomaterials.
Progress Summary:
The first year of this project was designed to deliver specific Aim I. Ion-pairing effects on skin absorption of charged nanomaterials.
We have developed a novel method to prepare water soluble fullerene nanoparticles (nC60) with a narrow size distribution at 43.8 nm and a Zeta-potential of -43 mV. This method does not use tetrahydrofuran (THF), which has led to many false toxicity reports on water fullerene nanoparticles. The nC60 nanoparticles are formed in a SDS aqueous solution, then SDS is removed via dialysis. After exhaustive dialysis, the nC60 nanoparticles were stable in water for years. This method provided the highest concentration ofnC60 nanoparticles (about 100 times higher than the currently used THF method) with narrow size distribution.
We have discovered a "superwrap" polymer to increase nC60 nanoparticle colloidal stability. The starting polymer is an industrial dispersion agent; it became water soluble after hydrolysis. When nC60 nanoparticles were mixed with the polymer solution, the particle size increased to about 52 nm. Amazingly, the polymer wrapped nC60 nanoparticles (ANnC60) had a superior colloidal stability over a wide pH range from I to i3; would not be aggregated by strong electrolyte (e.g., 2 M KCI) or any of the ion-pairing agents. Therefore, ANnC60 nanoparticles can be used for studying the ion-pairing effects on skin absorption of charged nanomaterials.
The concentrated nC60 nanoparticles allow us to study the ion-pairing effects on skin absorption of charged nanomaterials in vitro and in vivo. When nC60 in designated formulations were dosed on dermatomed pig skin, no fullerene was detected in the receptor solutions using thc conventional diffusion cell experiments (in vitro). The detection limit of our HPLC analysis method was I ng/mL C60/nC60 in media, which is the most sensitive method for fullerenes detection in biological fluids. The possible reasons could be (i) the diffusion rate of the nanomaterials within SC was very slow; not enough time to reach the receptor solution in 8 hr or 24 br experiments or due to the reservoir effects or the SC.
A tape-stripping method was developed to directly measure the quantity of nanomaterials in the SC. The amount of nanomaterials on the tape-strip was analyzed with our trace HPLC analytical method and the quantity of SC on the tape was measured by Lowry total protein method. The tape-strip data for a give dose time-period were processed to generate the concentration of nanomaterial in the SC (Cn) and relative location of Cn as a function of depth in the SC (x,IL). The partition coefficient of nanomaterial between SC and dose vehicle (K) and diffusion coefficient of nanomaterial in SC (D) were obtained via regression analysis of (Cn - xn/L) data following Fick's second law, which can be used for predictive model development for safety evaluation and risk assessment of the manufactured nanomaterials. When nC60 formulations dosed on pig skin (in vivo) daily for 4 days, significant nanomaterials were detected deep in the skin. Nanomaterial depth profiles in the stratum corneum and absorption kinetics were obtained.
Many experimental difficulties have been encountered. We have tested many nanoparticle formulations to conduct the 8 hr or 24 hr diffusion cell experiments; no nanomaterial was detected in the receptor solutions. Fortunately, the tape-stripping method proposed in the project can directly measure the quantity of nanomaterials in the skin. The nanomaterials (nC60 and ANnC60) have diameters from 43.8 and 52 !lm, respectively, which could be too big to permeate through skin. The fullerene nanomaterials were detected deep in skin only after repeated doses to simulate the worst case scenarios in occupational exposures. In our following study, we will investigate the effects of particle size, hydrophobicity and solvents on skin absorption of nanomaterials, in which smaller nanoparticles (I to 10 nm) will be used. The ion-pairing effects on skin absorption of the small nanoparticles will be tested.
Journal Articles on this Report : 4 Displayed | Download in RIS Format
Other project views: | All 11 publications | 4 publications in selected types | All 4 journal articles |
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Xia XR, Monteiro-Riviere NA, Riviere JE. Intrinsic biological property of colloidal fullerene nanoparticles (nC60): lack of lethality after high dose exposure to human epidermal and bacterial cells. Toxicology Letters 2010;197(2):128-134. |
R833328 (2008) |
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Xia XR, Monteiro-Riviere NA, Riviere JE. Skin penetration and kinetics of pristine fullerenes (C60) topically exposed in industrial organic solvents. Toxicology and Applied Pharmacology 2010;242(1):29-37. |
R833328 (2008) |
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Xia XR, Monteiro-Riviere NA, Riviere JE. An index for characterization of nanomaterials in biological systems. Nature Nanotechnology 2010;5(9):671-675. |
R833328 (2008) |
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Xia XR, Monteiro-Riviere NA, Mathur S, Song X, Xiao L, Oldenberg SJ, Fadeel B, Riviere JE. Mapping the surface adsorption forces of nanomaterials in biological systems. ACS nano 2011;5(11):9074-9081. |
R833328 (2008) |
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Supplemental Keywords:
nanoparticles, skin absorption, dermal exposure, percutaneous absorption, skin permeability, ion-pairing, solvent effect, hydrophobicity, charged nanoparticle, safety evaluation, risk assessment, disposition kinetics,, Health, Scientific Discipline, Health Risk Assessment, Risk Assessments, Biochemistry, biological pathways, nanochemistry, bioavailability, nanotechnology, environmental risks, manufactured nanomaterials, nanomaterials, toxicologic assessment, biogeochemistry, nanoparticle toxicity, cellular response to nanoparticles, bioaccumulationProgress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.