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Exploring the Biotic-Abiotic Interface:

Implications for Nano Toxicity

December 16, 2013

National Capitol Area Chapter

Society of Toxicology

Christopher P. Weis, Ph.D., DABT.

National Institutes of Environmental health Science

Objectives

• What’s going on at the Biotic – Abiotic interface?

• Why is the Biotic-Abiotic interface important?

• What are the implications for Health Risks and Regulations?

Basic Respiratory Anatomy

Images developed under contract to the National Institutes of Health

Anatomy of the bronchiolar alveolus clusters

Bronchiole Alveolar Structure Maina & van Gils (2001) Comp. Biochem and Physiol. 130(4)781-798.

Gas exchange in the lung

The alveolar- capillary membrane is just 0.2 microns thick!

Blood volume in capillary space Is about 70 mL.

Blood flow through the lung is about 5L/min.

Water: the molecule of life

Solid – Liquid Interface

Nel et

al. (2

00

9)

Nat

. M

ater.

8:5

43

Qiao, R. et al. (2007) Nano Lett. 7(3):614

“C60 molecule can readily “jump” into the bilayer and translocate the membrane within a few milliseconds”

“The simulation results indicate that, although a pristine C60 molecule can readily “jump” into the bilayer and translocate the membrane within a few milliseconds, the C60(OH)20 molecule can barely penetrate the bilayer.”

Small chemical modifications Can have big Consequences

Qiao, R. et al. (2007) Nano Lett. 7(3):614

ENM – Biomolecule Interactions

Nel et al. (2009) Nat. Mater. 8:543

Nel et al. (2009) Nat. Mater. 8:543

Nanoparticle endocytosis at the cell membrane: The clathrin-coated vessicle

Clathrin coated vessicles transporting materials across the cell

membrane

Attribution: University of British Columbia Dept. of Zoology (Permission requested)

Objectives

• What’s going on at the Biotic – Abiotic interface?

• Why is the Biotic-Abiotic interface important?

• What are the implications for OELs?

Attribution: F.A. Murphy, Univ.Texas Medical Branch

Coronavirus on a Mouse epithelial cell ~40,000X mag.

Coronavirus

(~70 - 200nm)

Corona Virus on Cultured Cell Surface Attribution: Dr. Steve Patterson

Targeted Docetaxel Nanoparticle

Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile.

Hrkach et al. (2012) Sci. Trans. Med 4:128ra39

~90 nm

Docetaxel MW=807

Strain-specific differential response to TOPO-PMAT Cd-

Se/ZnS QDs

Oropharyngeal aspiration 10 nM solution, 8 h PE

BALF Neutrophils

Mouse Strains

Univ. Washington Nanotoxicology Center

Ceria nanowires introduced

shape-dependent toxicity

Inflammasome activation

N

pro-IL-1β IL-1β

lysosome

IL-1β NALP3

Macrophage AR 0= 1

Ф = 7 nm

AR 7>200

L = 1~2 μm

0

50

100

150

200

250

300

0 25 50 75 100 125

IL-1

β a

cti

vit

y (

pg

/mL

)

Concentration (µg/mL)

R0R1R2R3R4

AR 6

AR 0-5

AR7

THP-1 cells

AR7

Lysosomal Damage

AR7

SEM TEM

Frustrated endocytosis

AR: aspect ratio

IL-1β T

HP

-1 c

ell

s

TH

P-1

cell

s

Ceria nanowires introduced shape-dependent toxicity NIEHS-funded Center for Nanobiology and Predictive Toxicology

Objectives

• What’s going on at the Biotic – Abiotic interface?

• Why is the Biotic-Abiotic interface important?

• What are the implications for Risks and Regulations?

Att

ribut

ion:

CP

Weis

Nano-sized mineral fibrils from Western Montana A

ttribu

tion:

Phagocytosis of asbestos fibers

pulmonary alveolar macrophage cell attempting to engulf and ingest several long mineral fibers incomplete ingestion of bio-persistent fibers can lead to extensive ‘selective release’ of proteolytic enzymes and ROS from the ‘frustrated’ PAMs

Microscopic and macroscopic lung abnormalities caused by durable fibers

‘mineral bodies’

‘ferruginous bodies’

Radiograph of Pleural plaques

Anatomy of Pleural plaques

Attribution: Med. Digital Library. Univ. of Michigan

High Resolution Computed Tomography (HRCT) of a pleural plaque

HRCT scan of a 45 Y.O. female with secondary (take home) exposure to nano particle taconite dust in the Upper Peninsula of Michigan.

Harbut et al. (2009) Int J Occup Environ Health 15(3):269-

273.

“Fibres shorter than 5 mm have traditionally not been counted by methods used for regulatory standards for asbestos because these methods were developed to provide a reproducible index of fibre exposure. The findings from our analysis show that cumulative exposures to all fibre size indices, including fibres <5 mm in length, were highly statistically significant predictors of lung cancer or asbestosis mortality.”

Stayner et al. (2008) Occ. Env. Med 65(9):613

Size–based Risk Management: a good idea?

Summary

• Biophysical chemistry at the abiotic-biotic

interface is critical to understanding

toxicity of engineered nanomaterials;

• Characterization of nanomaterials

(especially effects on the A-B interface) is

key;

• Toxicity studies for nanomaterials must

include minimal physico-chemical

characterization.