nanomaterials in fda regulated products: moving forward with

Nanomaterials in FDA regulated products: moving forward with science-based risk assessment

Paul C. Howard, Ph.D.

Director, Office of Scientific Coordination,Acting Director, NCTR/ORA Nanotechnology

Core Facility (NanoCore),National Center for Toxicological Research,

U.S. Food & Drug Administration, Jefferson AR USA

Disclaimer:The presenter, and not the FDA, is responsible for the accuracy of this presentation.

The views, opinions, and/or conclusions are those of the presenter only, and should not be considered as current or future official position or policy of the U.S. Food & Drug Administration (FDA), or any component of the U.S. Government. Any mention of commercial organizations or trade names is not intended as endorsement.

FDA Mission

- Protect public health by ensuring safety, efficacy and security of human and animal drugs, biological products, medical devices, food supply, cosmetics, and products that emit radiation.- Advance public health by speeding innovations for more effective, safe and affordable medicines and food.- Provide public with accurate, science-based information. Underlined for emphasis only;

related to food or food safety

Products Regulated by FDA

Foods• All interstate domestic

and imported; includingproduce, fish, shellfish,shell eggs, milk; exceptmeat and poultry.

• Bottled water.• Wine (<7% alcohol).• Infant formula

Food Additives• Colors• Food containers

Cosmetics

Dietary SupplementsAnimal FeedsPharmaceuticals

• Human (safety, efficacy)• Animal (safety, efficacy)

Medical DevicesRadiation Producing DevicesVaccinesBlood ProductsTissuesSterilantsTobacco

Center for Biologics and Experimental Research, CBER

Center for Drugs and Experimental Research, CDER

Center for Devices and Radiological

Health, CDRH

Center for Veterinary

Medicine, CVM

Center for Food Safety and Applied Nutrition, CFSAN

National Center for Toxicological

Research, NCTR

Center for Drugs and Experimental Research, CDER

FDA

Office of the Commissioner

Center for Tobacco Regulation, CTR

Office of Regulatory Affairs

NCTR Mission

FDA’s National Center for Toxicological Research(NCTR, Jefferson, AR)

- Conduct peer-reviewed toxicological research in support of FDA mission for science-based regulatory decisions to improve health of US public:- Understand critical biological events in toxicity;- Develop and characterize methods and incorporate new technologies to improve assessment of human exposure, susceptibility and risk;- Increase understanding of interaction between genetics, metabolism and nutrition. Underlined for emphasis only;

related to food or food safety

Nanotechnology = enabling the synthesis of materials with unique and controllable properties; nanotechnology-based materials ≈ 1~100 nm;

Nanomaterials are, or are reportedly, being included into many FDA-regulated products.

Products Regulated by FDA

Foods• All interstate domestic

and imported; includingproduce, fish, shellfish,shell eggs, milk; exceptmeat and poultry.

• Bottled water.• Wine (<7% alcohol).• Infant formula

Food Additives• Colors• Food containers

Cosmetics

Dietary SupplementsAnimal FeedsPharmaceuticals

• Human (safety, efficacy)• Animal (safety, efficacy)

Medical DevicesRadiation Producing DevicesVaccinesBlood ProductsTissuesSterilantsTobacco

Underlined and highlighted for emphasis only; related to food or food safety

Risk Assessment and Risk Management

Public HealthRisk Management

Risk Assessment

Hazard Identification

Dose Response

Exposure Quantification

Chemical Identification

Absorption, Distribution, Metabolism, Elimination (ADME)

Toxicity

Immunotoxicity

Genotoxicity

Carcinogenicity

Human Exposure

Systemic/Organospecific

Photo-toxicity, -carcinogenicity

“there are many challenges associated with each of these modules that feed into any risk assessment model; these challenges are exacerbated when studying nanomaterials”

Risk Assessment and Risk Management

Public HealthRisk Management

Risk Assessment

Hazard Identification

Dose Response

Exposure Quantification

Chemical Identification

Absorption, Distribution, Metabolism, Elimination (ADME)

Toxicity

Immunotoxicity

Genotoxicity

Carcinogenicity

Human Exposure

Systemic/Organospecific

Photo-toxicity, -carcinogenicity

What type of characterization is needed?

Should nanomaterial characterization differ from characterization of conventional materials?

How much characterization of nanomaterials is enough for understanding interaction with biological systems and consistency in manufacturing?

Challenges of Nanomaterial Characterization

Minimum characterization:

Agglomeration/aggregationChemical composition Crystal structure/crystallinityParticle size/size distributionPurityShapeSurface areaSurface chargeSurface chemistry (composition and reactivity)

Challenges of Nanomaterial Characterization

Card and Magnuson, J. Food Sci., 74, vi-vii, 2009MinCHAR project; www.characterizationmatters.org

Risk Assessment and Risk Management

Public HealthRisk Management

Risk Assessment

Hazard Identification

Dose Response

Exposure Quantification

Chemical Identification

Absorption, Distribution, Metabolism, Elimination (ADME)

Toxicity (in vitro, in vivo)

Immunotoxicity

Genotoxicity

Carcinogenicity

Human Exposure

Systemic/Organospecific

Photo-toxicity, -carcinogenicity

What is the behavior of nanomaterials in the traditional in vitro and in vivotoxicity assays?

If a nanomaterial is toxic, will it be detected in the current ‘battery’ used by regulatory agencies (false negative; false positive)?

Will nanoparticle and nanomaterial behavior interfere with toxicity assays?

Toxicity

Example: “Method for Analysis of Nanoparticle Hemolytic Properties In Vitro”, Dobrovolskaia et al., NanoLetters 8, 2180-2187, 2008

“… 50 nm nanoparticles, absord hemoglobin .. and the adsorbed hemoglobin precipitates with the particles upon centrifugation, yielding a false negative result…”

“The most common mechanism of interference is due to the nanoparticle absorbance at or close to the assay wavelength (540 nm).”

Toxicity assay interference

Risk Assessment and Risk Management

Public HealthRisk Management

Risk Assessment

Hazard Identification

Dose Response

Exposure Quantification

Chemical Identification

Absorption, Distribution, Metabolism, Elimination (ADME)

Toxicity

Immunotoxicity

Genotoxicity

Carcinogenicity

Human Exposure

Systemic/Organospecific

Photo-toxicity, -carcinogenicity

Key requirement for hazard-assessment studies is to measure nanoparticles or nanomaterials in biological matrices and water/food matrices.

Examples from FDA/NCTR laboratories:ADME of quantum dots applied to mouse skin (acute; Gopee et al.; Tox. Sciences 111, 37-48, 2009; Tox. Sciences 98, 248-256, 2007).

ADME of TiO2 applied to pig skin (subchronic; Gopee et al., Tox. Sciences 115, 156-166, 2010).

Exposure, Detection, and ADME

Quantum dots

CdSe coreCdS shell

PEG coated

QD solutions were:19 µM QD particles (TEM);38 mM Cd, 6 mM Se

(Cd:Se, 6.3:1) (ICP-MS);QD = ~ 2000 Cd, ~316 Se atoms

Gopee et al., 2007, Tox. Sciences 98, 249-257.

(TEM)

Total particle size:37 nm (DLS, PCS; SE-HPLC-DLS)

Normal versus Dermabraded Skin

Gopee et al., 2009, Tox. Sciences 111, 37-48.Also addressing the in vivo experimental model.

ICP-MS Quantitative Analysis: Lymph Nodes

Gopee et al., 2009, Tox. Sciences 111, 37-48.

- No penetration from emulsion except where epidermis compromized.

ICP-MS Quantitative Analysis: Liver

Gopee et al., 2009, Tox. Sciences 111, 37-48.

-Dermal penetration measured using sentinel organ approach, confirmed with confocal fluorescence microscopy (next slide).

-Conclusion: condition of skin is critical (question: what is the appropriate model)

Confocal Microscopy*: Dermabraded skin

Gopee et al., 2009, Tox. Sciences 111, 37-48.

A DC

B

*621 nm QDots

Topical application of creams (4 weeks) containing TiO2: uncoated, nano (30-50 nm); coated nano (20-30 x 50-150 nm); uncoated submicron (300-500 nm).

TiO2 and minipig: dermal penetration

Sadrieh et al., 2010, Tox. Sciences 115, 156-166.

TiO2 and minipig: dermal penetration

Sadrieh et al., 2010, Tox. Sciences 115, 156-166.

-Used sentinel organ appoach, ICP-MS results confirmed with electron microscopy (EDS).

-Scattered TiO2 below stratum corneum.

- Detection of 10 TiO2 particles by EM would equate to 0.0008-0.0023 % applied dose.

Risk Assessment and Risk Management

Public HealthRisk Management

Risk Assessment

Hazard Identification

Dose Response

Exposure Quantification

Chemical Identification

Absorption, Distribution, Metabolism, Elimination (ADME)

Toxicity

Immunotoxicity

Genotoxicity

Carcinogenicity

Human Exposure

Systemic/Organospecific

Photo-toxicity, -carcinogenicity

Dose Response

Adapted from Oberdorster et al., 2005 EHP 113, 823-839.

% n

eutro

phils

Should dosimetric expression be mass (response/mg), particle number (response/106

particles), area (response/m2) or volume (response/m3) for nanoparticles?

TiO2 mass (μg) TiO2 surface area (cm2)

250 nm

20 nm

Summary

Public HealthRisk Management

Risk Assessment

Hazard Identification

Dose Response

Exposure Quantification

Chemical Identification

Absorption, Distribution, Metabolism, Elimination (ADME)

Toxicity

ImmunotoxicityGenotoxicity

Carcinogenicity

Human Exposure

Systemic/Organospecific

Photocarcino-genicity

Nanomaterials present additional requirements: hazard identification, hazard quantification (toxicity assays, exposure assessment), and dose-response determination.

FDA, as part of NNI, is addressing data-gaps through applied research (animal model, sentinel organs, toxicity data).

NanoCore: core facilities at NCTR, ORA/ARL to provide FDA investigators with tools to characterize and detect nanomaterials in toxicity studies and in FDA-regulated products.

Acknowledgements

NCTR/ORA Nanotechnology Core Facility:S Linder, B Miller, T Mudalige, Y Jones

Gopee et al. (FDA/NCTR; Rice Univ.; National Toxicology Program)N Gopee, D Roberts, P Webb, C Cozart, P Siitonen, J Latendresse, A Warbritton, W Yu, V Colvin, N Walker, P Howard

Sadrieh et al. (FDA/NCTR; FDA/CDER; NCI/NCL)N Sadrieh, A Wokovich, N Gopee, J Zheng, D Haines, D Parmiter, P Siitonen, C Cozart, A Patri, S McNeil, P Howard, W Doub, L Buhse