Webinar

Nanotoxicology Specialty Section

Society of Toxicology

December 14, 2011

Thomas W. Hesterberg, PhD, MBA

Director, Product Stewardship, Sustainability,

and Environmental Health

Navistar, Inc.

Chicago, USA

Studies with Diesel Exhaust Particulate:

Implications for the Potential Human Health

Hazards of Nanoparticles

Introduction

2

• At early stages of assessing human health risks of

nanoparticles

• Animal and in vitro studies of nanoparticles

• Substantial uncertainties

• May not be relevant to humans

• Nanoparticles are a major constituent of diesel exhaust

• Many animal inhalation and human epidemiology studies

of DE over last 30 years

• More recent human volunteer exposure studies

Diesel Exhaust Particles

3

Traditional Diesel Exhaust (TDE)

Exhaust from engines utilizing old technologies:

– Pre-1988 diesel engines sold and in use prior to the

US EPA diesel particulate standards

– “Transitional“ 1988-2006 diesel engines

• Progressive improvements in engine design, but

• Prior to the full-scale implementation of multi-component

after-treatment systems

4

Diesel Particle Size Distribution

5

6

Occupational Exposures to Diesel PM

Exposure Group DPM (ug/m3)

Ambient < 4

Truckers 10

Railroad works 70

Surface miners 88

Underground miners 830

7

Lung Cancer in Railroad Workers

• Small elevation in lung cancer risk, but cause

is uncertain

• Cancer risk does not increase with exposure

or duration of employment

• Lack of exposure measurements

• Possible confounding from cigarette smoking

8

Lung Cancer in Truck Drivers

No change in

lung cancer risk

after truck

dieselization

9

Lung Cancer in Underground Miners

Despite

underground

miners having

the highest

occupational

exposures to

diesel exhaust,

no change in

lung cancer risk

10

Chronic Animal Studies of Diesel

Exhaust and Carcinogenicity

• No tumors observed in mice or hamsters

• Tumors in rats only at very high exposures(1,000 ug/m3)

• Thought to be non-specific response to “lung overload”

• Seen with inert dusts, e.g., talc, TiO2, carbon black, that are not in

the nanoparticle size range

• Lung overload-related tumors not observed in humans,

even in coal miners exposed to overload levels of coal dust

• Inflammation and other lung effects observed were similar

to what is seen with larger particles, e.g. amorphous silica

Lung Tumor Excess in Rats Seen Only

Above Lung Overload Exposures

Threshold for Lung Overload

12

Mutagenicity Studies

• Diesel particulate matter contains mutagenic

compounds, but

• Mutagenic compounds are not bioavailable

• Explains why tumors not seen in animal studies,

except above overload levels in rats

• Whole diesel exhaust not likely to be mutagenic

13

Summary

Diesel Exhaust Lung Cancer Studies

• Human workplace studies show small increase in lung

cancer, but no exposure-response demonstrated

• Miners, who have highest DE exposures show no

increase in lung cancer

• Lung cancer not found in mice or hamsters and only at

very high “lung overload” exposures in rats

• No unusual toxicity noted in the lungs of animals

exposed chronically to diesel exhaust nanoparticles

(Hesterberg et al. Critical Reviews in Toxicology 36:727-726, 2006)

Human Volunteer Exposures to TDE

14

• Reviewed 30 human volunteer studies

• Studies used exposure chambers

• Allows control and precise measurement of exposure

conditions

• Exposed 2-3 hours to diesel exhaust

• Studies performed in UK, Sweden, and USA

• Traditional Diesel Exhaust (TDE) engines

• Many used 20 year old diesel engine

• No exhaust after treatment which has been required since

2007

(Hesterberg et al. Inhalation Toxicology 22(8):679-694, 2010)

Some Caveats

15

• Diesel exhaust (DE) exposure also contains:

• Larger-sized particles in the fine range

• Gases: carbon monoxide, nitrogen dioxide, nitric acid,

carbon dioxide

• Volatile organic compounds

• Other nanoparticles (NPs) may have properties

different diesel exhaust NPs

• DE particles may be less toxic than other

nanoparticles

16

Controlled and Ambient Exposure to

Diesel Particulate Matter

Controlled

diesel

exposures 5 to

10 times

higher than

ambient

exposures

17

Controlled and Ambient Exposure

to Diesel Particles

18

Workplace Nanoparticles vs. DE Studies

CNT

Handling

Metal Oxide

Handling

CNT

Machining

Metal Oxide

Reactor Cleanout

19

Lung Function

20

Lung Inflammation

21

Lung Inflammation

and Blood Clotting

22

Cardiovascular System

ET-1)

Diesel Exhaust Studies and NP Toxicity

• High diesel exhaust nanoparticle exposures may elicit

transient, subclinical effects in human volunteers

• Effects generally less or not seen at lower exposure levels

• Responses similar to those observed with larger particles

• These studies do not provide evidence of a unique toxicity

of nanoparticles compared to larger particles

23

Hesterberg et al. Inhalation Toxicology 22(8):679-694, 2010

Evolution of US Heavy Duty Diesel

On-Road Emission Standards

0.01 0.10

0.2

1.2

2.5

4.0

5.0

0.0

NO

x [

g/

BH

P-h

r]

PM [g/BHP-hr]

1994

0.0

1998

2002

2007 (NTDE)

2010 (NTDE)

ULSD 15 PPM (10/06)

500 PPM (10/93)

FUEL SULFUR

Fuel Sulfur

24

New Technology Diesel Exhaust

(NTDE)

Exhaust from engines utilizing new technologies:

– Meets EPA & CARB 2007 emissions standards

– Fully integrated electronic control systems

– Ultra low sulfur diesel fuel (< 15 ppm)

– Oxidation catalysts

– Wall-flow diesel particulate filters (DPFs)

– Applies to both new and retrofitted engines

25

Key to Emissions Reductions in NTDE Wall-flow Diesel Particulate Filter

26

Trapped PM Cell Plugs

Exhaust (PM, CO, HC) Enter

Porous Ceramic Wall

Exhaust (CO2, H2O) Out

Adapted from MECA , 2000

Reductions: 95+% PM 80 to 100% HC, CO 80 to 99+% toxins

100.

2.09 1.94 1.19 0.90 0.15 0.45 0

10

20

30

40

50

60

70

80

90

100

Veh1-baseline Veh1-DPF1 Veh1-DPF1+SCR1 Veh1-DPF1+SCR2 Veh2-DPF2 Veh3-DPF3 Veh4-DPF4

NTDE: Lower Particulate Emissions

CARB Study: Herner et al., EST 43:5928-5933, 2009, data from Table 2. Transit Buses: UDDS Test Cycle

TDE

NTDE Pe

rce

nt

of

TD

E

27

Most Toxic Air Contaminants (TACs)

in TDE are Not Found in NTDE — Others Reduced to Near-Zero Levels —

• Aniline

• Antimony compounds

• Arsenic

• Beryllium compounds

• Cadmium

• Chlorine (chloride)

• Chlorobenzene and derivatives

• Chromium compounds

• Cobalt compounds

• Ethylbenzene

• Inorganic lead

• Manganese

• Mercury

• 4-Nitrobiphenyl

• Nickel

• Selenium

• Styrene

• Xylene isomers and mixtures

• o-Xylenes

• p-Xylenes

• m-Xylenes

28

Ullman et al, SAE 2003-01-1381, 2003

NTDE Reduces Emissions Across a

Broad Spectrum of Compounds Category Reduction Relative to TDE

Single Ring Aromatics 82%

PAH 79%

Alkanes 85%

Hopanes/Steranes 99%

Alcohols & Organic Acids 81%

Nitro-PAHs 81%

Carbonyls 98%

Inorganic Ions 71%

Metals & Elements 98%

Organic Carbon 96%

Elemental Carbon 99%

Dioxins/Furans 99% 29

Khalek et al., JAWMA 2011.

PM Composition and Mass Comparisons

30

100.0

2.3 2.5

0

10

20

30

40

50

60

70

80

90

100

TDE NTDE CNG

Pe

rce

nt

TDE

PM Mass

Lev-On et al., SAE 2002-01-0432,

2002. Transit Bus.

TDE

OC

EC

Sulfate

Nitrate

NTDE

CNG

PM Composition and Mass Comparisons

31

100

2.3

8.9

0

10

20

30

40

50

60

70

80

90

100

TDE NTDE Gasoline

Pe

rce

nt

of

TDE

PM Mass TDE

OC

EC

WSOC

Nitrate

Cheung et al., Env. Sc. Tech. 43:6334-6340, 2009. Passenger

Gasoline

NTDE

0

100

200

300

400

500

600

700

CO PM NOx HC NMHC CO2

Pe

rce

nt

of

TDE

NTDE

CNG

Gasoline

NTDE: Lower Regulated Emissions Also Similar or Better than CNG or Gasoline

32 Hesterberg et al., ES&T 42:6437-45, 2008.

TDE

(2010 Std)

Recent NTDE Nanoparticle Study In Vitro Test Results

33 33

• Catalytic after-treatment results in higher number of nanoparticles

• More nanoparticles associated with lower ―toxicity‖ in DTT and macrophage assays

Herner et al. ES&T 45:2413-19, 2011

34

McDonald et al., Env Health Perspectives 112:1307-12, 2004, developed from Figures 2-4.

3

1.8

1.5

1.8

1

0

1 1 1

0

1 1

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Viral Burden Histopathology Inflammation (TNFa) Oxidative Stress

Re

lati

ve R

esp

on

se

TDE

NTDE

Filtered Air

Animal Inhalation Study Traditional Diesel Exhaust (TDE) vs

New Technology Diesel Exhaust (NTDE)

35

Recent Human Volunteer Studies Traditional Diesel Exhaust (TDE) vs

New Technology Diesel Exhaust (NTDE)

50

60

70

80

90

100

110

120

130

Ex Vivo Thrombus Formation

Acetylcholine Vasodilation

Pe

rce

nt

Filte

red

Air

TDE

NTDE

Filtered Air

NTDE gave same response as

Filtered Air

Lucking et al. Circulation 123:1721-1728, 2011.

Research In Progress

Advanced Collaborative Emissions Study (ACES)

• Managed by the Health Effects Institute

• Funded by government agencies and industry

• Lifespan inhalation study in rodents

• Lung disease and cancer are main endpoints

• Two more years to complete

36

Summary on NTDE vs TDE

• PM levels in NTDE are 100-fold lower than in TDE

• NTDE PM is chemically very different from TDE

• Similar to CNG and gasoline PM

• NTDE emissions generally lower than CNG or gasoline

• Biological effects of TDE were not observed with NTDE

• NTDE should be evaluated separately from TDE

37

Hesterberg et al, JAWMA, 61:894–913, 2011.

NTDE and NP Toxicity

• High diesel exhaust nanoparticle exposures may elicit transient, subclinical effects in human volunteers

• Effects generally less or not seen at lower exposure levels

• Responses similar to those observed with larger particles

• Effects not observed with New Technology Diesel Exhaust

• These studies do not provide evidence of a unique toxicity of nanoparticles compared to larger particles

38

Hesterberg et al., Inhalation Toxicology 22(8):679-694, 2010.

Hesterberg et al., JAWMA, 61:894–913, 2011.