Public Health 150
John R. Froines, PhD
Department of Environmental
Health Sciences
.
EPA’s “Environmental Public
Health Continuum”
Study Designs
Ecologic
Study
Individual
Study
Laboratory
Study
Modified from EPA RFA
ENVIRONMENTAL & OCCUPATIONAL DISEASE PROCESS
INTERNAL
EXTERNAL
Uptake &
Transport
Absorbed
Dose
Exposure
Mechanism
Metabolism
Effective
Dose
Early
Responses
Disease
Route of
Entry
Genetic Modifiers
Exposure-Dose Relationship
Poorly Characterized
Dose-Disease Relationship
National Research Council
1983, 1989
ENVIRONMENTAL HEALTH
• “Environmental health comprises those
aspects of human health, including quality
of life, that are determined by physical,
chemical, biological, social, and
psychosocial processes in the
environment” (WHO).
• The science and knowledge we bring to
the looming environmental crises must
evolve to enable prevention/control and
protection of public health.
Environmental Health
• Environmental health problems were local in
their effects and short in duration
• Todays problems are persistent and global
• Examples: global warming, population growth,
habitat destruction and resource depletion
• Problems not amenable to quick technical fixes
• Problems require fundamental shift in culture,
politics and attitudes including consumption
THE ENVIRONMENT IS
A POWERFUL DETERMINANT OF HEALTH,
As Nations Develop, Patterns of Disease Change
Profoundly
• Infectious diseases decline in frequency and severity
(AIDS and tuberculosis notwithstanding)
• Life expectancy increases
• Infant mortality declines
• Chronic diseases such as cancer and cardiovascular,
become increasingly prevalent
The Epidemiologic Transition
Patterns of Disease Change with Development
Environmental Change is the Driving Force
Environmental successes during the past
century???
• What were the key environmental
successes during the past century?
– Decline in infectious disease
– Smoking and cancer
– Cholesterol as a marker for risk of
cardiovascular disease
– Elimination of lead from gasoline and other
products
– What else and what are the implications of
these successes?
Organic Chemical Production has Risen Dramatically
Number of Chemicals Known and In Use
Total number in ACS registry
>14 million
New chemicals per week
6,000
(more than half synthetic versions of
natural compounds)
Chemicals in the environment/use
50,000
Pesticides
1,000
Food additives
5,500
Drugs
6,000
Total in Common Use
63,000
In commerce-10,000lbs
15,000
Products of combustion
Atmospheric chemistry
Metabolites
Multiple exposures
Thousands
Thousands
Thousands
Common
Relevant tools at our disposal for studying
sourceÆhealth effect
• Exposure assessment including physical/chemical
characterization of toxic agents
• Structure-activity relationships
• Toxicology including chemical, biological toxicology and
in vivo studies
• Epidemiology including genetic epidemiology and
molecular epidemiology
• Biological and chemical mechanisms
Four Major Elements of Risk Assessment
Policy related issues
• Decisions, decisions decisions-how do we decide
whether a chemical is toxic, poses a risk to humans, and
what are intervention strategies for control?
• What is the level of proof required for intervention and
control to protect public health?
• What are the criteria for these decisions?
• Do we wish to protect against false negative conclusions
or false positive conclusions.
• Example of all this: what is a carcinogen? Once we
decide what is our policy for addressing it.
IARC Carcinogens
•
•
•
•
•
Total number of agents evaluated
Proven human carcinogens
Probable human carcinogens
Possible human carcinogens
Number of animal carcinogens
836
74
56
225
287
Risk Assessment
Key question:
• What is an acceptable risk? How much
death and disease in a society is
acceptable?
• Who decides?
Chemical Regulation: Options Exist to Improve EPA’s Ability to Assess Health Risks and
Manage Its Chemical Review Program
GAO Report to Congressional Requestors
• EPA lacks sufficient data to ensure that potential health and
environmental risks of new chemicals are identified
• EPA does not routinely assess existing chemicals, has limited
information on their health and environmental risks , and has
issued few regulations controlling such chemicals
• EPA has limited toxicity and exposure data with which to review
existing chemicals
• EPA has had difficulty proving that chemicals pose unreasonable
risks and has regulated few existing chemicals under TSCA.
When an activity raises threat of harm
to human health or the environment,
precautionary measures should be
taken even if some cause and effect
relationships are not fully established
scientifically.
Wingspread Statement
Innovation on chemical strategies in Europe and Canada
• Facing a similar set of problems, the 27-nation European Union is
implementing sweeping new policies governing chemicals and
products. These policies are expected to spur innovation globally
in cleaner technologies, including green chemistry.
• The Registration, Evaluation and Authorization of Chemicals
(REACH) regulation requires chemical producers and importers in
the E.U. to register most chemicals that are widely used, identifies
substances most likely to present a hazard, and places restrictions
on the use of chemicals of very high concern.
• Canada has recently completed an assessment of 23,000 chemicals
currently in commercial circulation and is implementing steps to
reduce the use of those posing the greatest risk to human and
environmental health.
Increases in concentration of lead in Greenland*
*shown on a logarithmic scale.
McMichael, T. (2001). Human frontiers, environments, and disease. Cambridge, UK, Cambridge University Press.
Key World Statistics 2003
Top Mining Countries
Largest Lead
Producers
Major Users of Lead
Main Recyclers of Lead
Australia
654,000
USA
1,488,000
China
1,533,000
USA
China
618,000
China
1,050,000
USA
1,338,000
USA
464,000
Germany
392,000
Germany
Peru
308,000
Korea Rep
342,000
Mexico
152,000
UK
Total
2,196,000
Total
% in the world
73
% in the
world
Recycle rate
(%)
1,098,000
82
Germany
222,000
63
352,000
Japan
190,000
-
UK
338,000
UK
176,000
52
330,000
Australia
304,000
Italy
153,000
3,602,000
Total
3,865,000
Total
1,839,000
55
% in the
world
* Values shown in tons
* Data from Lead Development Association International (LDA).
59
% in the
world
61
Child Behavior
and Pb Levels
Adapted from Needleman
and Rabinowitz
Score
Childhood Lead Exposure and
Intelligence
120
115
110
105
100
95
90
85
80
75
70
IQ: Stanford-Binet
British Ability Scale
0
10
20
30
40
50
Lead in Blood (ug/dl)
Grant and Davis, 1989
Lead in gasoline and lead in blood
NHANES II, 1976-1980
17
100
16
90
15
80
14
Gasoline lead
70
13
12
60
11
50
Blood lead
10
40
9
30
1975
1976
1977
Source: Annest, Pirkle, Makuc, et al., Chronological
trend in blood lead levels between 1976 and 1980.
NEJM 1983; 308;1373-7.
1978
Year
1979
1980
1981
Blood lead levels (μg/dL)
Lead used In gasoline
(1000 tons)
110
Carcinogenicity Evidence for CrVI
• Cr VI is known to cause lung, nasal and/or
sinus cavity cancers in humans (30
occupational studies)
• There is suggestive evidence of distant
tumors in humans (bladder-stomach)
• Cr VI causes tumors in laboratory animal
studies by multiple exposure routes
• Cr VI is genotoxic animals and cells,
inducing DNA damage, gene mutation,
chromosomal damage
• IARC: “Cr VI is carcinogenic to humans”
Cancer Potencies/(ug/m3)
• Chromium VI
1.5 x 10-1
• Diesel exhaust
3.0 x 10-4
• Methylene chloride
1.0 x 10-6
• (1 x 10-6 == 1 excess cancer/million
people/ug/m3)
Key issue
• CHROMIUM VI (CARCINOGEN) IS REDUCED TO
CHROMIUM III (NON-CARCINOGEN) IN BODY
TISSUES AND FLUIDS
• There is evidence of bioavailability
• “Nonetheless, it is clear, based on total
urinary chromium excretion, that a
consistently greater percentage of the Cr(VI)
than of the Cr(III) was absorbed. This implies
that some Cr(VI) escaped reduction in the
stomach and entered portal venous blood.”
•
Key issue
• “The greater absorption of Cr(VI) than
of Cr(III) implies that absorption from
the gastrointestinal tract is so rapid
that it is able to compete effectively
with reduction in the stomach.”
• O’flaherty et al., Toxicological Sciences, 60, 196213, 2001
Chromium VI and cancer
• Results of a study by the National
Toxicology Program reported May 16,
2007
• Male and female rats and mice
• Significant increases in tumors at sites
rarely seen in lab animals
• Oral cavity and (mice) small intestine
(dose-response
Where’s Arsenic Found?
• Air
– Burning fossil fuels
• Food
– Vegetables and fruits (Due to pesticides/herbicides)
– Meat consumption esp. seafood.
• Water
– Weathering of Rocks
– Non-ferrous metal smelting
• Soil
–
–
–
–
Same as water
Wood preservatives
California example: Owen’s lake
Reclaimed water – San Diego (vs Colorado River)
Taiwan
Chile
Argentina
As. “Hotspots”
2002
Brief history of ingested inorganic arsenic (As)
and health effects
•
1880s -- Skin cancer associated with inorganic arsenic
medications
•
1942 – U.S. drinking water standard set at 50 μg/L
•
1980s -- Taiwan studies showed associations with internal
cancers
•
1980s & 1990s –High As levels found in Bangladesh well water
•
Late 1990s – Argentina and Chile studies confirm Taiwan
results
•
2001 (January) -- Clinton lowers U.S. standard to 10 μg/L
•
2001 (March) -- Bush EPA delays lowering the standard
•
2001 (October) – EPA adopts 10 μg/L
•
2006 – Compliance date for new U.S. standard
Arsenic in Bangladesh and
West Bengal
• 1970s and 1980s - International aid to drill
tube wells and improve water supplies
• 1983 - First skin lesions detected
• Estimated populations exposed:
– Bangladesh: 35-77 million (of 125 million)
– West Bengal: 1.5 million
Hyperkeratosis
Arsenic carcinogenicity by
ingestion in drinking water
Valley of the Moon
1000
Arsenic in μg/L
900
800
Antofagasta/Mejillones
700
Rest of Region II
600
500
400
300
200
100
0
1950-1954
1955-1959
1960-1964
1965-1969
1970-1974
1975-1979
1980-1984
1985-1989
1990-1994
Lung cancer standardized mortality ratios for men and
women, by exposure sub-region of Region II, for 1989-98.
7
Antofagasta/Mejillones - Males
Antofagasta/Mejillones - Females
Rest of Region II - Males
Rest of Region II - Female
6
5
SMR
4
3
2
1
0
1989
1989
1990
1991
1992
1993
Years
1994
1995
1996
1997
1998
Comparison of Smith and
Cal/EPA
As exp. for risk As exp. for risk
of 10-3
of 10-6
(PHG)
Cal/EPA
Smith
4 μg/L
4 ppb
0.004 μg/L
4 ppt
2.5 μg/L
2.5 ppb
0.0025 μg/L
2.5 ppt
History
• First Air Pollution Commission: 1265-1306
– Recommended banning coal in London
– Implementation delayed for ~650 years
• The Great Air Pollution Disasters
– Meuse Valley, Belgium: 1930
– Donora, Pennsylvania: 1948
– London, UK: 1952 (Smoke + Fog = Smog)
The Particle Story
• Dust and droplets suspended in air
• “Oldest” air pollutant, first measured and
regulated
• Primary particles released as products of
incomplete combustion
• Newest” air pollutant, mechanisms still
mysterious, new standards proposed,
ongoing research
How small are these
particles?
Hair cross section (60 μm)
Human Hair
(60 μm diameter)
PM10
(10 μm)
PM0.1 PM2.5
(0.1 μm) (2.5 μm)
Summary: Health effects
associated with PM exposure
• Effects on CNS and autonomic nervous
system
• Low birth weight/preterm babies
• Increase in asthma and other respiratory
disease in children and adults
• Decrease in lung development and
function in children
• Atherosclerosis in adults
• Cancer
Findings on Epidemiologic Studies on
Carcinogenicity of Diesel exhaust
• More than 40 studies
• These studies have found that long-term
occupational exposures were associated
with a 40% increase in risk of lung cancer.
• Findings are consistent and unlikely due to
chance.
• A causal relationship between occ. diesel
exhaust exposure and lung cancer.
• Risk about 1 excess cancer/10,000/ug/m3
MATES-II Assessment of
Cancer Risk in LA Basin
Basinwide Cancer Risks* ~1400 in a million
11%
3%
7%
Diesel Particulate
8%
1,3 Butadiene
Benzene
71%
Carbonyls
Other
710 Freeway - Trucks
• Today: 17,500 a day
• 2020: 42,000 a day
New Cancer Cluster Study
USC, School of Medicine
Professor T. M. Mack
• Examines cancer
clusters throughout
LA county over 25
year period
• Both LA and LB port
communities
identified having
high cancer rates
Mobile Source Studies
• Particle mass remains relatively
constant with distance from freeway;
size distribution changes
considerably.
• Concentrations of nanoparticles
(<20 nm) are much higher in winter
than summer, suggesting that these
particles are volatile, formed by
condensation of organic vapors after
they leave the tailpipe.
• Zhu, Y., Hinds, W.C., Kim, S., Shen,
Shen, S. and Sioutas*,
C. “Aerosol Science and Technology, 38, 55-13, 2004.
•Highway study found “Most of the
particles consisted of volatile
material.”
• Kittleson et al., Inhal.
Inhal. Tox.Tox.-16, 2004:
Deposition and Pathways of Particle Translocation Within and
Outside Respiratory Tract--Main Mechanism for UFP is Diffusion
Translocation of UFP from
NP and TB region along sensory
neurons to CNS (neurodegeneration)
•Translocation of UFP to
interstitium, capillaries, heart
•Uptake by endothelium; platelets
•Activation/interaction of endothelial
cells, platelets and leukocytes
Alveolar inflammation
Pathways of Oxidative Stress
Low
GSH/GSSG
Ratio
Level of
oxidative stress
High
GSH/GSSG
Ratio
Cell response pathway: Normal
Anti- Inflammation
oxidant
Defense
Dose
Source: Xiao, et al. 2003
Toxicity
Untreated
Mag. x 6000
Mag. x 21000
M
Coarse
M
P
P
Ultrafines lodge in and destroy mitochondria
Mag. x 6000
Mag. x 21000
RAW 267.4
P
P
M
M
M
M
OVA ± UFP
OVA ± UFP
OVA ± UFP
OVA ± UFP
OVA
OVA
Necropsy
Day:
UFP
Treatment Design
1
2
4
7
9
21
22
23
Sites
for
of airway tissue selection
microscopic examination
OVA/UFP-Induced
Allergic Bronchiolitis
Saline
Control
OVA
Alone
OVA
UFP
What is the effect of ultrafine particles
on atherosclerosis?
Hypothesis: PM synergizes with known
proatherogenic stimuli and mediators in their
ability to elicit oxidative stress and promote
atherosclerosis.
Most of the proatherogenic potential resides in
the ultrafine particles fraction, highly enriched
in redox cycling or electrophilic PM chemicals
Experimental Design: apoE-/- on chow
diet
E-/Chow
Non-exposed
(NE)
Filtered air
(FA)
6-week-old male
Exposures: 5 hours/session
3x/week for 5 weeks
PM2.5
(FP)
PM0.1
(UFP)
* Aortic atherosclerosis assessment
* Lipid profile, plasma hydroperoxides, tissue gene expression
Aortic atherosclerotic
Aortic lesion area (μm2/section)
lesions
70000
P<0.0001
P= 0.002
60000
P= 0.02
P= 0.02
50000
40000
30000
20000
10000
0
NE
FA
Condition
FP
UFP
Summary
9 PM0.1-exposed mice develop greater atherosclerotic lesions
than all other mice (NE, FA, FP)
9 Ultrafine particles lead to the lost of the protective
antiinflammatory profile of plasma HDL without altering the
lipoprotein level.
9 PM0.1 exposure results in increased systemic oxidative and
systemic induction of Nrf2 and Nrf2-regulated antioxidant
genes.
9 The ultrafine particles fraction concentrates the air pollutionrelated proatherogenic effects.
9 Ulftrafine particles lead to a systemic effect characterized by
increased oxidative stress and lost of the antiinflammatory
properties of HDL.
Recent Studies of
Freeway Exposures and Mobile Source Effects:
Children’s Health Study - Lung Development and
Exposure to Air Pollution
Proportion
of 18-year
olds with
FEV1
below 80%
of the
predicted
value
Gauderman,
Gauderman, et al. 2004 New England Journal of Medicine
Results: More asthma within 150 m of
major roads
Asthma Odds Ratio
2.5
2
1.5
1
0.5
0
<75
75-150
150-300
>300
Distance to Major Road (meters)
McConnell, et. al. AJRCCM 2005;2:A522
Recent Studies of
Freeway Exposures and Mobile Source Effects:
Residential Proximity to Freeway Truck Traffic
and Pre-term and LBW Babies
Infants born between 1997-2000 in Los Angeles County
Number of freeway trucks passing
within 750 feet of a home per day
Odds Ratio (95% Cl)
(n=4,346; 26,606)
≥ 13,290 trucks
1.23 (1.06-1.43)
≥ 8,684 heavy-duty diesel vehicles
1.18 (1.02-1.37)
Model adjusted for all maternal risk factors as covariates, background air pollution
concentrations and census block-group level socio-economic status
Recent Studies of
Freeway Exposures and Mobile Source Effects:
Central Nervous System
Kleinman et al., in preparation, 2004
Major new issues
•
Nanotechnology
•
Acrylamide:
– Historical: powerful neurotoxicant in the workplace
– Discovery of high levels in starchy products, such as, french fries,
potato chips
– Carcinogen
– Highly controversial
•
Diacetyl: Flavoring agent-butter taste in popcorn
–
–
–
–
–
Bronchiolitis obliterans
Predicted toxicity from chemical structure
What other uses, other similar molecules
Orville Redenbacher-advertises that his popcorn contains no diacetyl
Example of precautionary principle
20 – Year Timeline for
Nanotechnology
Passive
Nanostructures
Active
Nanostructures
Systems of
Nanosystems
Molecular
Nanosystems
Coatings,
Polymers,
Ceramics
Transistors,
Targeted Drugs,
Actuators
Robotics,
3D Networks
Guided
Assemblers
Molecules by
Design,
Evolutionary
Systems
2001
2005
2010
2020
Recreated from: Breggin and Carothers, 2006
Carbon Nanotubes:
cylindrical arrangements of carbon atoms, 1 nanometer in diameter,
several micrometers long. 2 types:
single-walled (isolated cylinders) “SWCNT”, and
multi-walled (concentric cylinders) “MWCNT”.
Are they the “new asbestos”?
Different subsets of stakeholders:
Ideal
•
industry (Warheit-Dupont)
•
government (Shvedova-NIOSH, Lam-NASA)
•
academia (Muller-Catholic U, Belgium)
•
outside contractors (Mitchell-LRRI)
Real
Is there interaction between researchers? What do we
already know?:
From Lam 2004. Nanotubes being poured into a bucket from another bucket:
“Unprocessed nanotubes are light and could become airborne.”
Risk Assessment
Exposure Assessment
Acrylamide levels in foodstuffs were analyzed by a gas chromatographic-mass
spectrometric method by the Department of Environmental Chemistry at
Stockholm University in Sweden.
Risk Assessment
Risk Characterization
Data on acrylamide intake in the adult population was taken
from the national food survey NORKOST 1997 based on a
quantitative frequency questionnaire.
Offshoring: Imported electronic waste, Lianjiang River,
Guiyu, China All China photos copyright 2001, Basel Action Network
Electronic waste recovery workers, Guiyu, China
Toner recovery worker, Guiyu, China
Carbon black (IARC 2A carcinogen); cartridge dumping
Risk assessment