Download - Lovelace Respiratory Research Institute
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Lovelace Respiratory Research Institute
www.LRRI.org
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2010Short-2
EPIDEMIOLOGY FINDS ASSOCIATIONS BETWEEN PM AND NUMEROUS HEALTH EFFECTS
Mortality (non-accidental, non-homicide deaths)
Daily mortality rates (time series studies)
Shortened life span (cohort studies)
Morbidity (illness)
Respiratory
Symptoms
Reduced lung function
Lung inflammation
Exacerbation of asthma
Incidence of infections
Allergic sensitization
Reduced rate of lung growth
Medication use, physician visits and hospital admissions
Cardiovascular
ECG abnormalities
Implanted cardioverter events
Heart attacks
Athersclerosis
The list is growing !
Other
Premature birth
Low birth weight
Altered maternal hormones
Developmental effects:
Reduced thymus size
Reproductive system
CNS Inflammation
Cognitive defects
Metabolic Disorders
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2010Short-3
Tools for Evaluation of Toxicity
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2010Short-4
SOURCE APPORTIONMENT OF IMPACT OF PM10 ON RESPIRATORY AND
CARDIOVASCULAR HOSPITAL ADMISSIONS Janssen et al., Environ. Health Perspect. 110: 43, 2002
Time series study of PM10 vs. hospital admissions in 14 U.S. cities
1985 –1994, adjusted for weather, day, season, and air conditioning
Proportional source contributions from Emission Inventory EstimatesVehicle and oil combustion-derived PM had the greatest impact
% change in regression coefficient for interquartile change in PM10 (*p<0.05)
PM10 Source CVD COPD Pneumonia
Highway vehicles +58* +48 +61
Highway diesels +56* +47 +56
Oil combustion +38* +2 +27
Wood burning +3 +1 +2
Coal combustion +1 +0 +2
Metal processing +29* +3 +12
Fugitive dust 49* 11 31
*P < .05
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2010Short-5
EFFECTS OF PROXIMITY TO TRAFFIC ON LUNG FUNCTION OF CHILDREN
Brunekreef et al., Epidemiology 8:298, 1997
Lung function of 877 9 yr olds and air pollution at schools in 6 locations
Measured black smoke (proxy for diesel), PM10, and NO2
Traffic counts (cars & trucks), distance from motorway, & wind direction
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2010Short-6
IF MOBILE SOURCE COMBUSTION IS IMPLICATED, WHAT PART OF EMISSIONS ARE MOST IMPORTANT?
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2010Short-7
C57Bl6N Male Mice Exposed by Inhalation 6h/day 7 daysExposed to whole exhaust with PM range from 30-3000 µg/m3
Exhaust generated from Yanmar Genset: No 2 fuel, steady stateComposition of exhaust varied by change in engine operation
Group 1: Implanted with telemeters to monitor heart rate/varianceGroup 2: Challenged with respiratory syncytial virus at end of exposure
Evaluated 4 days later for viral persistance/pathology
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2010Short-8
ENGINE OPERATION CONDITIONS HAD MARKED IMPACT ON COMPOSITION
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2010Short-9
HIGH BLACK CARBON CONTENT/LOW ORGANICS LED TO INCREASED SUSCEPTIBILITY TO INFECTION
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2010Short-10
HIGH ORGANIC (VOLATILE AND NON) HAD LARGEST IMPACT ON CARDIOVASCULARPHYSIOLOGY
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2010Short-11
THE BEHAVIOR OF ULTRAFINES AND NANOPARTICLES WILL DEPEND ON THEIR COMPOSITION, AS WELL AS THEIR SIZE
Solubility determines whether mass or number/surface area is the most important dose metric
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2010Short-12
BOTTOM LINES1. Epidemiology associations have been found with environmental
Pollution and many health outcomes
2. Mobile-Source PM appears to be especially important
3. Careful consideration of the composition and type of exhaust
Needs to be considered when interpreting results
Modern diesel is much different than old diesel
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2010Short-13
1. Collected PM and vapor-phase SVOCs during urban driving cycle
2. Analyzed composition in detail
3. Tested the re-combined fractions by instillation into rat lungs
IDENTIFYING TOXIC COMPONENTS OF ENGINE EMISSION
SAMPLES
[Seagrave et al. Toxicol. Sci. 70: 212-226, 2002]
[Zielinska et al., J. Air Waste Man. Assoc. 54: 1138-1150, 2004]
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2010Short-14
SAMPLES HAD A 5-FOLD RANGE OF POTENCY
Lung Inflammation
(5 parameters)
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2010Short-15
Laboratory Results Also Suggest SOA NOT More Toxic than Primary Sources
Collected Ambient Samples
Explored as Described for Motor Vehicle Study
Source ApportionmentToxicity
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2010Short-16
-0.40
-0.30
-0.20
-0.10
0.00
0.10
0.20
0.30
0.40
-0.20 -0.10 0.00 0.10 0.20 0.30
Seco
nd C
ompo
nent
First Component
Loadings plot - 2 components
NH4
NitrateSulfate
EC
OC
As
Cu
Earth Me
Mn
Pb
SeZn
aromatic
branch a
carboxyl
Choleste
dioic ac
Hop and
Levogluc
n-alkane
Nonanal
PAH < 25PAH>252
resin ac
ALP
Cells
LDHlung:BW
LYMPH
MACSPMN
Protein
PCA/PLS Reveals Composition:Toxicity Associations
SOA “Indicators”
Methods reported in McDonald et al.,2004
(diacids)
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2010Short-17
“The Working Group found that diesel exhaust is a cause of lung cancer (sufficient evidence) and also noted a positive association (limited evidence) with an increased risk of bladder cancer (Group 1).
The Working Group concluded that gasoline exhaust was possibly carcinogenic to humans (Group 2B), a finding unchanged from the previous evaluation in 1989.”
IARC press release, 2012
IARC: Diesel Exhaust Carcinogenic
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2010Short-18
CANCER HAZARD
Mutagenicity
Interest heightened in 1970s with application of Ames testReverse mutations in Salmonella bacteria
Many labs studied many variables through 1980s (huge literature)
Biodirected fractionation pointed toward nitro-aromatic compounds
Carcinogenicity
Several large-scale gasoline and diesel rodent inhalation studiesU.S., Germany, Switzerland, Japan
Results generally consistent across studies
Extreme exposures increased lung tumors in rats
No increase in mice or Syrian hamsters
Gasoline studies did not cause cancer in any species
Led to recognition of “particle overload” phenomenon
Kotin et al., Indust. Health 11:113, 1955 (USC)Solvent extracts of diesel and gasoline emissions caused tumors in mouse skin
painting assay
Related to source, operating condition, and aromatic hydrocarbons
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2010Short-19
ORIGINAL LOVELACE DIESEL STUDY (early 1980s)Mauderly et al. Fundam. Appl. Toxicol. 9:208-221, 1987
Male & female F344 rats, n=221-230 examined for tumors/group
Exposed 7 hr/day, 5 days/wk for up to 30 mo1980 5.7L GM engines on FTP, burning certification fuel 0, 350, 3470, or 7080 µg total chamber PM/m3 (control 10
µg/m3 )
High level = 30 ppm CO, 11 ppm NOx, 13 ppm HC
Results:No effect on clinical signs, body weight, or survivalProgressive accumulation of soot in lung at mid & high levelsProgressive inflammatory and fibrotic lung disease at mid &
high levelsLung tumor incidences (benign + malignant)
C = 0.9%, L = 1.3%, M = 3.6%, H = 12.8%
Low level (340 µg exhaust PM/m3): No progressive lung disease or increase in lung tumors
No significant effects on hematology, serum chemistry, bronchoalveolar lavage, pulmonary function, lymphocyte function
in bronchial lymph odes, or histopathology (except for PM in some macrophages)
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2010Short-20
ORIGINAL LRRI CARCINOGENICITY STUDY
Mauderly et al. Fundam. Appl. Toxicol. 9:208-221, 1987
Rats exposed 7 hr/day, 5 days/wk x 30 mo to whole diesel exhaust
10
0
0
20
100 200 300
Some estimated risks for humans exposed at much lower levels by linear extrapolation of these data
No significant carcinogenicity in CD-1 mice exposed simultaneously
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2010Short-21
THE LACK OF CARCINOGENICITY FROM LOW EXPOSURES WAS TOO READILY IGNORED
Mauderly, in Environmental Toxicants , Lippmann Ed., Wiley, 2000
Increased tumors resulted only from exposures that caused preceding, chronic-active inflammation and progressive epithelial hyperplasia-metaplasia
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2010Short-22
RAT LUNG TUMORS IN OLD DIESEL STUDIES WERE PRIMARILY DUE TO LUNG LOADING WITH PM
Nikula et al., Fundam. Appl. Toxicol. 25: 80-94, 1995
Male & Female F344 rats exposed to diesel exhaust (DE) or carbon black (CB)16 hr/day, 5 days/wk at 2 PM concentrations
1988 6.2L GM engine on FTP burning certification fuel
2390 & 6280 µg PM/m3 exhaust PM
10 & 27 ppm CO
9.5 & 27.2 ppm NOx (0.7 & 3.8 ppm NO2)
6.5 & 8.1 ppm HC
Cabot Elftex-122410 & 6500 µg PM/m3 CB
Control
50 µg PM/m3
Lung tumor results (n = 210-213):
DE CB
High level 17.9% 15.2%Low level 6.2% 4.7%Control 1.4%
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2010Short-23
THE LUNG “OVERLOADING” CONCEPT EVOLVED
Heinrich et al. Inhal. Toxicol. 7:533-556, 1995
Other poorly-soluble, respirable PM fell on the same exposure-response line
Same exposures were not tumorigenic in normal test strains of mice
Mutagen-free carbon blacks gave same result in two studies
Consensus evolved that results from “overloaded” rats should not be used to estimate risks to humans
Patterns of particle retention in the lung differ between rats and humans
Threshold Nonspecific Not reliable for estimating human risk Species-specific
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2010Short-24
Bigchanges!
OLD DIESEL NEW DIESEL
Pre-1990
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2010Short-25
NTDE: Less PM and Composition Very Different
TDE NTDE
[Kittelson, 1998] [ACES, 2009]
25
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2010Short-26
Pre-Trap Post-Trap
Sulfate/Nitrate
Hydrocarbons (Fuel + Lube derived)
Elemental Carbon + Ash
≥0.1 g/bhp-hr
0.01 g/bhp-hr
Particulate Matter Composition Breakdown
Cummins ISM 2007; Liu et al. , Aerosol Science and Technology, 43/11: 1142-52 2009
-99%Mass
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2010Short-27
Combustion and dilution Air Supply
Engine Dynamometer
Engine Cooling heat Exchanger
Primary Dilution Tunnel
Dynamometer Power Supply and Controls
Fuel “Day Tank”
Engine Exhaust Injection Point
Diluted Exhaust Extraction Point
ACES Engine and Primary Dilution System
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2010Short-28
28
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2010Short-29
CORE BIOSCREENING STUDY DESIGN
Chronic Carcinogenicity Bioassay of Wistar Han Rats:
Expose 288/group 16 hr/day, 5 days/wk for 24-30 months
3 dilutions of whole emissions + clean air controls
166/group committed to carcinogenesis bioassay
122/group allocated for interim evaluations at 1, 3, 12, & 24 months Pulmonary function (3, 12, & 24 mo)Lung lavage, lung tissue & cell proliferation
Hematology & serum chemistry (3, 12, & 24 mo)
Histopathology
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2010Short-30
MAIN EXHAUST DUCT
MAIN SUPPLY AIR DUCT
H-2000 EXPOSURE CHAMBER
2ndary CHAMBER DILUTION
Muffler
MAIN CHAMBER DILUTION
Diesel Dilution Tunnel
(Note: Drawing is not to scale)
Sampling Probe flange
CompressedAir
Air-Vac
Primary Dilution Tunnel
Extraction probe flange
Compressed air
Exhaust Extraction and Secondary Dilution Systems
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2010Short-31
31
ATMOSPHERE COMPOSITION
Real-time particle mass
Real-time particle number
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2010Short-32
Biological Response in Rats
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2010Short-33
Histopathology in Rats at 3 Months:
Higher Power View of Previous Slide
Control
High
Thickening of alveolar ductseptae
Macrophage
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2010Short-34
3 months
12 months
Enhanced epithelial hyperplasia at 12 months. Only observed at high level, but in both sexes.
Histopathology in Rats at 3 and 12 Months:
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2010Short-35
ACES Findings
In a nutshell; we did not observe any exposure related evidence of cancer