SoH FULLEDITION 0120b PDF

A Story
of Health
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A Story of Health Help Page Reunion Asthma Cancer Learning/ Diabetes Infertility Cognitive References Go Back
Home (Childhood Developmental Decline
Acknowledgements
Leukemia) Disabilities
Contributing Authors Reviewers

We gratefully acknowledge the following people who
Christine Zachek, Victoria Leonard, UCSF
reviewed draft sections of a Story of Health, noting that
Pediatric Environmental Health Specialty Unit their review does not constitute an endorsement of the
findings or conclusions. Any errors or misrepresentations
Art Team that remain are entirely the responsibility of the authors.
Illustrations and eBook design, production Introduction and Asthma (Brett’s Story):
Stephen Burdick, Stephen Burdick Design Polly Hoppin; Catherine Karr; Brian Linde;
Maria Mirabelli; Madeleine Scammell;
Illustrations Rebecca Wolf
Dan Higgins, Visual Information Specialist, Developmental Disabilities (Amelia’s Story):
Primary Development Organizations Primary Authors/Development Team Centers for Disease Control and Prevention David Bellinger; Lucy Crain; Katherine Herz;
Brian Linde; Elise Miller; Leslie Rubin;
The Agency for Toxic Substances and Disease Mark Miller MD MPH, Director, Other contributors Madeleine Scammell; Maureen Swanson
Registry (ATSDR), the Collaborative on UCSF Pediatric Environmental Childhood Cancer (Stephen’s Story):
Health and the Environment (CHE), the Agency for Toxic Substances and Myles Abbott; Gary Dahl; Maida Galvez; Catherine
Health Specialty Unit
Office of Environmental Health Hazard Disease Registry: Metayer; Elizabeth Raetz; Joshua Schiffman; Oscar
Director, Children’s Environmental Health Tarrago; Christopher Vlasses; Joseph Wiemels
Assessment, California Environmental Online course development and video editing:
Program, Office of Environmental Health
Protection Agency (OEHHA), the Science and Amanda Cadore Funders
Hazard Assessment, California EPA
Environmental Health Network (SEHN), and Copyright and Editing: Diana Cronin In addition to significant in-kind contributions from all of
the University of California, San Francisco, Ted Schettler MD MPH, Science Director, Geographic Information Services Team: the primary development organizations, we are grateful to
Pediatric Environmental Health Specialty Science and Environmental Health Network Charlton Coles; Stephanie Foster; the following funders who have made this project possible:
Unit (UCSF PEHSU) teamed up to leverage Science Director, Collaborative on Health and Melissa M. Smith; Shannon Graham, Agency for Toxic Substances and Disease
our combined resources to develop and the Environment Julia Bryant Registry (ATSDR)
produce A Story of Health. The John Merck Fund
Brian Tencza MEd, Team Lead Education University of California, Berkeley:
Services, Agency for Toxic Substances and The Jacob & Valeria Langeloth Foundation
For more information: Berkeley/Stanford Children’s Environmental The Office of Environmental Health Hazard
Disease Registry (ATSDR)
Brian Tencza: bht1@cdc.gov Health Center Assessment, California Environmental
Maria Valenti, National Coordinator, Healthy Center for Integrative Research for Protection Agency (OEHHA)
Maria Valenti: mvalenti@igc.org Aging and the Environment Initiative, Childhood Leukemia and the Environment > The UCSF PEHSU
Collaborative on Health and the Environment Educational Technology Services – The US Environmental Protection Agency
Jon Schainker and Scott Vento
Disclaimers:
Copyright: Portions of this document may Suggested citation: Miller M, Schettler T, University of California, Davis: 1. The UCSF Regional Pediatric Environmental Health
be subject to the copyright act. Graphics and Tencza B, Valenti M. A Story of Health. Specialty Unit (PEHSU) prepared A Story of Health on
Brenda M. Giddings, California Cancer Registry, behalf of the American College of Medical Toxicology
illustrations by Stephen Burdick Design may Agency for Toxic Substances and Disease
Institute for Population Health Improvement, (ACMT) and funded as part of the cooperative agreement
not be reproduced without permission. Before Registry, Collaborative on Health and the award number 1U61TS000238-01from the Agency for Toxic
U.C. Davis Health System
reproducing and or modifying any content Environment, Science and Environmental Substances and Disease Registry (ATSDR).
or illustration, contact Brian Tencza at ATSDR Health Network, University of California, Videos – Speakers: 2. The findings and conclusions in this report are those of
bht1@cdc.gov. Any permitted reproduction San Francisco, Pediatric Environmental the author(s) and do not necessarily represent the official
of content or illustrations must be properly Health Specialty Unit. PDF file online.
John Balmes; Patricia Buffler; position of the organizations listed (above) as funders.
acknowledged. Gary Dahl; Mark Miller; Catherine Metayer; 3. The ATSDR, US EPA, and Cal EPA/OEHHA do not endorse
Lawrence Rosen; Joseph Wiemels; the purchase of any commercial products or services
Dedication: Thomas Whitehead; Rosalind Wright mentioned in this publication.
This eBook is dedicated to our designer Stephen Burdick for his extraordinary talent and vision.
- The authors.
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help page
How to Navigate Our eBook
Our eBook Navigation: Click on selections If you lose your place, use
Adobe Acrobat Tools The individual stories in the bar at the top of each page to move the ‘Go Back’ selection in the
This interactive pdf document is best
of health in this eBook between stories, navigate back to this navigation bar to return to
your previous screen.
viewed on a laptop or desktop, down- are written to address many ‘Help Page’, and to find out more in the
loaded and opened in a current version of
audiences. For example, some References section.
Adobe Acrobat Reader. Refer to the top
Adobe menu bar for features including: sections are more technical Icons
Magnify - If you want to enlarge a than others – you can skip Click on icons that appear throughout the Skip this section - If you wish to skip a
diagram or some text, click (+) button.
sections if you wish. stories for pop-ups, videos, and links to technical section, choose the “Skip this
more information as described. section” arrow and you will jump to the
(Note: underlined words or page after the technical sections ends.
phrases link to online information,
prompt down-loads or navigate
Move through pages - You can use the up to a related page.)
and down arrows to move through pages.
You can also move through pages using the Each of the eBook stories key watch a additional technical skip this definition
scroll up and down feature to the right of is embedded with a wide range concept video resources, details section
your screen.
of resources. These help further tools for health
explain possible environmental professionals
Table of Contents and/or genetic “risk factors” –
Use the sidebar (contributors to the development Resources include videos, slides You can skip
Bookmark Tools as of a disease, or factors that might with audio commentary, tables, this section and
a table of contents make a disease worse) – and
to skip to a section
charts, and graphics. Some ‘pop- continue to the
how these factors interact. We up’ in the story, and some connect
of interest, find your Story of Health
place, or return to this also provide links for additional online. Through these links, you
Help page. introduction.
resources, including actions you can choose to dig deeper and learn
can take to prevent disease, and more. Refer to the icons (above)
“tools you can use.” for guidance.
References and Citations: Certain

references are cited in the text where
we believe they are most warranted.
Full references by topic can be found
at the end of each story.
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Introduction
This is a story about health.

It is a story of how our own health is
intimately connected with the health of
our families, friends and communities.
It is a story about how human health is
interdependent with our surroundings.
Volunteer
Our overall story is told through the personal
stories of a number of fictional people of Live
various ages attending a family reunion. Play
These individual stories highlight the many
ways our health is influenced by the complex
environments where we live, eat, work, play,
volunteer, gather and socialize.
Gather Work
Socialize
Eat
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Introduction
built and natural

Our stories explore how many aspects of environments
finances
our lives, and what we are exposed to in chemical
exposure
our environments, influence health across
stressors
the lifespan—from the beginning of fetal education
development to elder years—and how they
can promote health and resilience, or disease
and disability. access to
healthcare social
Important determinants of health support
come from the natural, built,

chemical, food, economic, and
© Stephen Burdick Design

social environments.
nutrition occupation
These environments are further
expressed through such things
as education, housing, nutrition, Watch: Pediatrician
access to health care, social supports Larry Rosen
and more. addresses the Complex interactions occur among many
environment and variables and across individual, community,
Many of them interact to create the family health.
(2 min.) and societal levels. These aspects of our lives
conditions for health and wellness, or
Lawrence D. Rosen MD are not independent of one and other.
vulnerability to disease. is an integrative
pediatrician and Rarely is one particular thing responsible
founder of the Whole for health or disease, so we refer to this as
Child Center.
a multifactorial (or ecological) approach,
the best way to promote health and
prevent disease.
←
Introduction
Ecological Health Framework
The ecological framework can include community society

ecosystem
family
multiple levels from sub-cellular to
relationships
societal.
It is not hierarchical in the sense that
individual
one level is more important than
another, but rather in the sense that
individual biology is progressively
nested within the person, family,
community, society and ecosystem.
The interactions and feedback loops
within, across, and among these levels T I M E D I M E N S I O N
are complex and variable. They exert timing of

exposures
effects of multilevel
variables over lifespan
recent historic/
evolutionary time
their influences on health across time.

individual organ
system
cell
organelle
cell
signaling
The ecological health

framework also extends
to the sub-cellular level.
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Introduction
Focus on Six Diseases
Following are stories of people like you and

me, our partners, families and friends, our
Asthma
mothers and fathers, sisters and brothers, Diabetes
children, grandparents, cousins, and aunts
and uncles.
The personal health stories we will explore
include some of the most common and
troubling diseases and disorders of our time. Cancer
They include: Cognitive
• Asthma decline
• Cancer (childhood leukemia)
• Diabetes
• Infertility
• Learning and developmental disabilities
• Cognitive decline
Infertility Learning and

developmental
disabilities
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Introduction Our Stories

These stories are not meant to

be an exhaustive accounting of
every variation of a disease or
every possible cause.
Rather, we present current,
authoritative scientific evidence to
enable you to better understand
environmental contributors and
make more informed decisions
and take action to help improve
your health, and the health of
your family, friends, community,
and patients.
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A Family Reunion Six Stories

This page is your portal to

six stories of health.
It is recommended that
you read through the
introduction first and
then choose stories in
the order you wish.
Health professionals can

receive CE credits for
completing A Story of Health.
Click here for more details.
Choose stories in the order you wish. Asthma Cancer Learning/ Diabetes Infertility Cognitive Decline
Select a disease term to highlight Developmental
the affected person. Click the arrow Disabilities
button to read his or her fictional
story of health.
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Introduction Free Continuing Education

Information on free continuing education Review these

learning objectives
offered from the Centers for Disease for each story:
Control and Prevention/Agency for
Toxic Substances and Disease Registry Brett’s Story
Free Con tin u in g Edu catio n
(Asthma) > Continuing education available

Each of the fictional stories in
by specialty
A Story of Health offers free
Stephen’s Story
continuing education (CE). On the (Cancer/Childhood • Continuing Medical Education
“Final Thoughts” page of the last Leukemia) > (CME) for Physicians
story of the entire eBook, or of • Continuing Nursing Education
each story (if you download them Amelia’s Story
(CNE) for Nurses
(Developmental
separately), you will be prompted to Disabilities) > • Continuing Education Units (CEU)
register for CE through a hyperlink. for other Professionals
This hyperlink links to the CDC/ • Continuing Education Contact
ATSDR CE page where you can Hours (CECH) for Certified Health
register and take the test for CE Education Specialists (CHES)
credits for each story (credits are
offered by story). Before you begin
each story, please review the learning
objectives at right. These will help
you focus as you read each story,
and prepare you for each CE test.
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Asthma: Brett’s Story (a fictional case)

Brett is a nine year old boy who lives with his mom,
Karen in an urban area in southern California. They live in
an apartment near a busy street, and Brett takes the bus to
public school. He plays several sports including baseball,
soccer, and basketball, and likes to go out with his friends.
Unfortunately, today, many kids like Brett also have asthma.
Basic information: Health professionals: Asthma resources and

Click here to find out Click here to read more more information from
more about asthma. about asthma. the CDC .
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Asthma: Brett’s Story (a fictional case)

Asthma Information for Health

Brett is a nine year old boy who lives with his mom, Professionals
Karen in an urban area in southern California. They live in “By definition, all asthmatics share common physiologic
an apartment near a busy street, and Brett takes the bus to abnormalities of airflow limitation such as obstruction
on spirometry, airway hyper-responsiveness to
public school. He plays several sports including baseball, methacholine challenge, and symptoms that can include
soccer, and basketball, and likes to go out with his friends. shortness of breath, chest tightness, wheezing, and
coughing. Despite these shared features, clinicians
Unfortunately, today, many kids like Brett also have asthma. have long recognized the great heterogeneity in the
severity of airway obstruction and symptoms, degree
of reversibility, and the amount of improvement in
Basic information: Health professionals: Asthma resources and response to medications.”
Click here to find our Click here to read more more information from (Bhakta, 2011; Holgate, 2010)
more about asthma. about asthma. the CDC .
From more information check out these online links:
CDC’s health care guidelines
ATSDR’s CASE study, Environmental Triggers of Asthma
National Environmental Education Foundation –
Environmental Management of Pediatric Asthma:
Guidelines for Health Care Providers.
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Asthma: A Multifactorial Disease

Brett’s mother sometimes wonders what

caused Brett’s asthma, and why so many
of his friends have it.
The causes of asthma in Brett may differ
considerably from the causes of asthma in
another person, or the prevalent causes of
asthma in a population.
Key Concept: Addressing disease risks in
individuals and populations
In general, asthma is a multifactorial disease

although in some individuals, a single factor
may be predominantly responsible for
its onset. For example, an exposure to a
chemical airway sensitizer like formalde-
hyde, or exposure to secondhand smoke.
Graphic reproduced with permission.
After asthma develops, various exposures can
trigger or exacerbate an asthmatic episode.
Watch this short informative
Key Concept: Causation and Association video by Dr. John Balmes that
explains the many risk factors for
developing asthma. (1.5 min.)
John Balmes MD, Professor and Division

Chief of Occupational and Environmental
Medicine at San Francisco General Hospital,
University of California, San Francisco
←

Key Concept:
Brett’s mother sometimes wonders what Addressing Disease Risks in Individuals and Populations
H
ealth care practitioners generally provide would help reduce cardiovascular risk factors
advice and care to people and their across the entire population. This involved
of his friends have it. families, based on individual histories and campaigns and activities in partnerships with the
circumstances. Public health practice widens media, supermarkets, food manufacturers, and
The causes of asthma in Brett may differ the lens to include the health of groups or
populations of people. Public health practices
others, to make healthier choices more readily
available to everyone.
considerably from the causes of asthma in include advocating for and helping to create and The results were dramatic. In 35 years the annual
maintain the conditions that promote health for
another person, or the prevalent causes of entire communities. Public health practitioners
age-adjusted coronary heart disease mortality rate
among 35-64 year-old men declined 85 percent.
have long recognized the benefits—or risks—
asthma in a population. associated with small shifts in determinants of
Cancer-related mortality was also reduced, and
all-cause mortality reduced for men and women.
health within populations.
Key Concept: Addressing disease risks in One early commentary on the North
individuals and populations In 1985, epidemiologist Geoffrey Rose was Karelia project critically called it “shot-gun
interested in strategies for disease prevention. He prevention.”[ii] But, it worked. It showed the
recognized that small downward population-
In general, asthma is a multifactorial disease wide shifts in blood pressure where hypertension
value of multi-level interventions in a population
rather than focusing solely on individuals at
was common could have large public health
although in some individuals, a single factor benefits. Community-level interventions differed
highest risk. Data from five different surveys
showed that an estimated 20 percent of the
may be predominantly responsible for from what individuals could do to accomplish the
same goal.
coronary heart disease mortality could be
prevented by reducing cholesterol levels in the
its onset. For example, an exposure to a The North Karelia project in Finland put these entire population by 10 percent, while a 25
chemical airway sensitizer like formalde- ideas to work about 25 years after demographer,
Vaino Kannisto, published his doctoral thesis
percent cholesterol reduction in only those with
the highest levels would reduce morality by only
hyde, or exposure to secondhand smoke. pointing out that eastern Finland had the highest five percent. Lifestyle changes, they concluded,
heart disease mortality in the world.[i] By this are not just responsibilities of individuals but also
time, the Framingham Heart Study, started in of communities.
After asthma develops, various exposures can 1948, had begun to identify risk factors that We often debate which public health
trigger or exacerbate an asthmatic episode. contribute to cardiovascular disease by following
its development over a long period of time in a
interventions should be directed at entire
populations or focused more on individuals at
Key Concept: Causation and Association large group of participants. Based on its findings, risk to address disorders such as cancer, diabetes,
efforts to reduce smoking, cholesterol, and blood cardiovascular disease, obesity, and dementia,
pressure, and to increase physical activity, were among others. But it’s undeniably clear that
undertaken in N. Karelia. These efforts did not disease prevention and response after diagnosis is
focus entirely on educating at-risk individuals not just an individual responsibility. It belongs to
in order to change their behavior with respect the community as well.
to physical activity, diet, and smoking, but also
included community-level interventions that
Rose G. Sick individuals and sick populations.
i.
Editorial: Shot-gun prevention? Int J Epidemiol.
iii.
Int J Epidemiol. 1985; 14(1):32-38. 1973; 2(3):219-220.

Puska P. From Framingham to North Karelia:
ii.
Schettler T. The ecology of breast cancer: The promise of prevention,
from descriptive epidemiology to public health action. and the hope for healing. Science and Environmental Health Network and
Prog Cardiovasc Dis. 2010; 53(1):15-20. the Collaborative on Health and the Environment. October, 2013.
←

Key Concept:
Brett’s mother sometimes wonders what Causation and Association
Epidemiologic studies identify asso- intentional medical interventions,
of his friends have it. ciations between an exposure and a are typically not applicable or pos-
health outcome of interest. Identify- sible when studying the origins of
The causes of asthma in Brett may differ
ing the risk factors causally related environmentally-related diseases.
considerably from the causes of asthma in to a disease is a difficult task for re- A randomized controlled trial that
another person, or the prevalent causes of searchers. Origins of individual cases would expose subjects to hazardous
asthma in a population. of a disease may result from different chemicals raises ethical concerns.
combinations of risk factors. Human studies should be supported
Key Concept: Addressing disease risks in
individuals and populations Carefully designed studies can help by strong biologic explanations and/
establish cause and effect relation- or animal experiments. Still, it is hard
In general, asthma is a multifactorial disease ships, but ultimately causation must to be certain of the causal relation-
although in some individuals, a single factor be inferred from available epidemio- ship and its strength, especially when
may be predominantly responsible for logic and laboratory data. Random- many complicated factors contribute
its onset. For example, an exposure to a ized controlled double blind studies to a particular disease. Associations
(where neither the subjects of the ex- between exposures and health out-
chemical airway sensitizer like formalde- periment nor the persons administer- comes are frequently robust enough
hyde, or exposure to secondhand smoke. ing the experiment know the critical to support recommendations. In fact,
aspects of the experiment), which are much preventive medicine depends on
After asthma develops, various exposures can often used for evaluating making those judgments regularly.
trigger or exacerbate an asthmatic episode.
Key Concept: Causation and Association
←
Asthmagens: Risk factors for the development of asthma

There are hundreds of substances

known or suspected to cause asthma
(“asthmagens”). Some are encountered Causes vs.
in the workplace as well as at home, Triggers
school, and elsewhere – such as of Asthma
formaldehyde (in certain furnishings and
building materials like cabinets),vinyl
flooring, carpeting, phthalates (in plastic
toys and other plastic products), bleach,
More details: Asthma in the
natural gas combustion products, workplace and elsewhere
cleaning solutions and other products.
Brett has likely been exposed to many
asthmagens in his life. Prevention Strategies –
Home Checklists:
Our main character Brett is not yet in Better Home Visits for Asthma,
the workforce but occupational causes Lessons Learned from the Seattle–
of asthma should be considered when King County Asthma Program (pdf)
treating adults and children. Do-it-yourself Home Environmental
Assessment List (HEAL)(pdf)
Though many chemicals shown to cause EPA’s Asthma Home Environment
asthma in workers may not have been Checklist
studied in children, it is likely that they For Clinicians:
are capable of causing asthma in the Pediatric Environmental History
general population including children. Forms, National Environmental
And, working parents can bring Education Foundation
exposures home to kids on clothing
and in other ways, so pediatricians
and parents of kids with asthma should View a database list of asthmagens
also consider occupational exposures The Association of Occupational
and Environmental Clinics
of parents. (AOEC). Includes those
encountered in the workplace,
home, school, etc. (Click ‘display
all asthmagens’ on site page.)
←

There are hundreds of substances Asthma in the Workplace and Elsewhere

known or suspected to cause asthma Epidemiologic studies have found that Occupational asthma. This diagnosis is
(“asthmagens”). Some are encountered Causes vs. children face increased risks of develop- appropriate when a worker develops new
in the workplace as well as at home, Triggers ing asthma after early life exposure to respiratory symptoms and obstructive
chemicals that have also been found to airway physiology consistent with asthma
school, and elsewhere – such as of Asthma
cause asthma in workers like, for example, and an exposure in the workplace is likely
formaldehyde (in certain furnishings and formaldehyde. to have contributed to its onset. Occupa-
building materials like cabinets),vinyl In a study of > 4,000 children in South- tional asthma is often sub-classified as:
flooring, carpeting, phthalates (in plastic ern California, exposure during the first - Sensitizer-induced (90% of cases)
toys and other plastic products), bleach, year of life to 1) wood or fossil fuel - Irritant induced asthma (10% of cases),
More details: Asthma in the smoke, soot, or exhaust 2) herbicides 3)
natural gas combustion products, workplace and elsewhere
including reactive airway dysfunction
pesticides or 4) cockroaches was associ- syndrome (RADS).
cleaning solutions and other products. ated with 74%, 450%, 230% and 200%
Brett has likely been exposed to many respectively increased risk for being di- Some cases are mixed or unclassifiable.
asthmagens in his life. Prevention Strategies – agnosed with asthma by 5 years of age. Work-exacerbated asthma. This occurs
Home Checklists: Risks noted for asthma after exposure to when a worker’s previously diagnosed
Our main character Brett is not yet in Better Home Visits for Asthma,
some pollutants were similar or greater asthma is worsened, but not caused, by
the workforce but occupational causes than that of another well established agents in the workplace.
Lessons Learned from the Seattle–
causal risk factor, cockroaches. (Salam
of asthma should be considered when King County Asthma Program (pdf)
et al., 2004)
At risk occupations include:
treating adults and children. Do-it-yourself Home Environmental
From the American College of Chest
• bakers • hair stylists
Assessment List (HEAL)(pdf) • building • laboratory
Physicians 2008 consensus statement
Though many chemicals shown to cause EPA’s Asthma Home Environment on the Diagnosis and Management of custodians workers
asthma in workers may not have been Checklist Work-Related Asthma: • detergent • nurses
studied in children, it is likely that they manufacturers • metal workers
For Clinicians: Work-related asthma has two categories.
are capable of causing asthma in the They are often clinically indistinguishable, • drug • millers
Pediatric Environmental History manufacturers
general population including children. Forms, National Environmental but the distinction can impact treatment • plastics and other
strategies and medico-legal decisions. • farmers chemical workers
And, working parents can bring Education Foundation
• grain elevator • woodworkers
exposures home to kids on clothing workers
and in other ways, so pediatricians
and parents of kids with asthma should View a database list of asthmagens
also consider occupational exposures The Association of Occupational
and Environmental Clinics
of parents. (AOEC). Includes those
encountered in the workplace,
home, school, etc. (Click ‘display
all asthmagens’ on site page.)
←

Some early life environmental risk factors

have been identified.
More information
For example, prenatal and early life on acetaminophen
exposure to social stressors, such as
violence, can increase the risk of asthma as
well as increase the impacts on respiratory
health from allergens, air
pollution, and tobacco smoke.
Secondhand smoke alone is a risk
factor for new cases of asthma in
preschool-aged children.
Karen was surprised to learn that
some doctors are even concerned
about acetaminophen and its Stress affects
relationship to asthma. our health. Watch
this video by
Brett has experienced many of these risk Dr. Rosalind Wright
factors in his short life. More details about to see how social
stressors, along
these can be found as you read his story. with environmental
factors, can be linked
to asthma. (5 min.)
Rosalind J. Wright,
MD MPH, Horace W.
Goldsmith Professor of
Pediatrics, Vice-chair,
Clinical and Translational
Research, Department of
Pediatrics, Icahn School of
Medicine at Mount Sinai
←
Asthma: Prenatal and Early Life Exposures

Karen also thinks about what her doctors

told her when she was pregnant about
exposure to tobacco smoke, and
how she tried to get her husband to
quit which was another source of
fighting between them.
In her discussions with her
OB/GYN she also learned about
keeping her weight down and
the importance of Vitamin D. Watch: Dr. John
Balmes presents
Additional Information: About Vitamin D powerful evidence
on the detrimental
Some prenatal variables are well-established effects of air
as risk factors for asthma, alone or in pollution and
smoking on
combination with postnatal exposures. prenatal and
For example, maternal obesity during early childhood
pregnancy is associated with increased development.
(5 min.)
risk of asthma in offspring.
←
Asthma: Prenatal and Early Life Exposures

Karen also thinks about what her doctors Vitamin D and Asthma
told her when she was pregnant about Higher cord blood levels of vitamin D The Centers for Disease Control and
exposure to tobacco smoke, and are associated with decreased risk of Prevention and the American Academy
transient childhood wheezing. Higher of Pediatrics (AAP) also find that
how she tried to get her husband to vitamin D intake during pregnancy most US infants and children are not
quit which was another source of is associated with decreased risk of consuming enough vitamin D according
wheeze in early childhood. Reduced to 2008 recommendations. The AAP
fighting between them. risk of wheezing may be due to reduced recommends that all infants, whether
frequency of respiratory infections. being breast fed or formula fed, receive
In her discussions with her a vitamin D supplement.
The American Congress of
OB/GYN she also learned about Obstetricians and Gynecologists Reference: Perrine C, Sharma A, Jeffers M, Serdula
M, Scanlon K. Adherence to vitamin D recom-
keeping her weight down and (ACOG) recommends testing pregnant
mendations among US infants. Pediatrics. 2010;
women who are at increased risk of
the importance of Vitamin D. Watch: Dr. John vitamin D deficiency (e.g., women with
125(4):627-632.
Balmes presents limited sun exposure, women with Other References:
Additional Information: About Vitamin D powerful evidence darker skin that limits absorption of
Carmago CA Jr, et al. References. Carmago CA Jr,
on the detrimental vitamin D). If a woman’s Vitamin D et al. Randomized Trial of Vitamin D Supplemen-
Some prenatal variables are well-established effects of air (25-hydroxy-D) level is 20 ng/mL (50 tation and Risk of Acute Respiratory Tract Infec-
nmol/L) or less, ACOG recommends tion in Mongolia. Pediatrics 2012. doi: 10.1542/
as risk factors for asthma, alone or in pollution and
vitamin D supplementation in a dosage peds. 2011-3029.
smoking on
combination with postnatal exposures. prenatal and
of 1,000 to 2,000 IU daily. Camargo CA Jr, Ingham T, Wickens K, Thadhani
Reference: ACOG Committee on Obstetric Prac- R, et al. Cord-blood 25-hydroxyvitamin D levels
For example, maternal obesity during early childhood tice. ACOG Committee Opinion No. 495: Vitamin and risk of respiratory infection, wheezing, and
pregnancy is associated with increased development. D: screening and supplementation during preg- asthma. Pediatrics. 2011 Jan;127(1):e180-7. doi:
(5 min.) nancy. Obstet Gynecol. 2011;118 (1):197-198. 10.1542/peds.2010-0442. Epub 2010 Dec 27.
risk of asthma in offspring. Hollams EM.Vitamin D and atopy and asthma
phenotypes in children. CurrOpin Allergy Clin-
Immunol. 2012 Jun;12(3):228-34.
Zosky GR, Berry LJ, Elliot JG, James AL, Gorman
S, Hart PH.Vitamin D deficiency causes deficits
in lung function and alters lung structure. Am J
RespirCrit Care Med. 2011 May 15;183(10):1336-
43. Epub 2011 Feb 4.
←
Asthma: Triggers
In someone like Brett who already has Potential Asthma Triggers

asthma, an asthma attack can be triggered
or set off by a wide range of many of foods pollen
the same environmental agents including
exposure to:
mold pet dander
• indoor air pollutants such as tobacco
spores
smoke, outdoor air pollution;
• other environmental chemicals including
pesticides, and; outdoor
indoor air air
• allergens including mold, pollen, pollution pollution
cockroach droppings and pet dander.
Exercise and cold weather can also
be triggers. These triggers vary from one
person to another.
It is sometimes called “allergic asthma” tobacco
smoke pesticides
when an individual wheezes in response

to exposure to an allergen such as pollen
or cat dander.
dust
mites environmental
chemicals
←
Asthma: Effects on the Lungs and Immune System

Brett’s doctor told him that the

reason he wheezes sometimes
is because of inflammation and
narrowing of the airways in Normal asthma
his lungs. Airway Airway
variable amounts
and kinds of
Watch: Dr. John normal
inflammation
airway lining
Balmes discusses airway lining
swollen
the many factors
that influence
airway
lung development

no muscle remodeling and
and the severity of tightening tightening
asthma. (Technical/ mucus
academic - 6 min.)
←
Asthma and Lung Development

The lung is susceptible to many influences

during early development.
Stages of Lung Development
Though the lung develops into a functioning organ
during the fetal period, important stages in lung
growth and development continue during early
childhood and may be altered by environmental
exposures.
Click here for more details. You may skip this section
and go to “Growing Problem
of Asthma”
Reference: Kajekar R. Environmental factors

and developmental outcomes in the lung.
Pharmacol Therap. 2007;114:129-145.
Graphic used with permission.
←


Though the lung develops into a functioning organ
during the fetal period, important stages in lung
growth and development continue during early
childhood and may be altered by environmental
exposures.
Click here for more details. You may skip this section
and go to “Growing Problem
of Asthma”
dular phase (6–16 weeks of gestation

Stages of lung development in humans), branching continues and
In humans, primary lung buds develop mesenchyme differentiates into carti-
during the fourth week of gestation lage, smooth muscle, and connective
from the endoderm of the foregut. Af- tissue around the epithelial tubules. By
ter early embryonic development, stag- the end of this time, major conducting
es in prenatal lung development are airways to the terminal bronchioles are
pseudoglandular, canalicular, saccular, developed. Respiratory bronchioles,
and alveolar, which are represented in develop in the canalicular period along
Figure 2, along with associated de- with a rich vascular supply. During the
velopmental features (Kajekar, 2007). saccular phase, first contact between
Only a portion of maturational events the air space and proliferating pulmo-
are required prenatally for successful nary capillaries takes place. During
survival, with most continuing postna- alveolarization, the primitive alveoli
tally during alveolarization (Pinkerton develop secondary septa that form the
and Joad, 2000). walls of the true alveoli, resulting in a Reference: Kajekar R. Environmental factors
During the embryonic period primary dramatic increase in surface area.

and developmental outcomes in the lung.
Pharmacol Therap. 2007;114:129-145.
bronchi develop from the primitive Chemicals that disrupt the cellular sig- Graphic used with permission.
gut, and elongate and divide into two naling important for these events may More Information: “Cellular,
main bronchi. During the pseudoglan- alter lung development. structural, and functional
impacts on lung development
of xenobiotics”
←

Examples of Chemicals that can Alter Lung Structure and Function During Development
during early development. Chemical Cellular and subcellular level
impacts
Structural or
functional impacts
Possible clinical impact

Nitrofen
2,4-dichloro-p-
GATA 6, Wnt7, BMP4, FGF,
retinal dehydrogenase2,
Decreased
branching, altered
Pulmonary hypoplasia,
immature lung
Though the lung develops into a functioning organ nitrophenyl-ether
(pesticide)
inhibition T3 receptor binding smooth muscle,
alteration in
during the fetal period, important stages in lung surfactant and
alveolar septation
growth and development continue during early TCDD Arylhydrocarbon receptor, Delayed lung Chronic bronchitis,
childhood and may be altered by environmental (dioxin) thyroid hormone development,
decreased total lung
decreased functional
capacity, COPD?
exposures. space, increased
septal area
Click here for more details. You may skip this section Nicotine Suppression glycolysis and Slower septal Emphysema, decreased
and go to “Growing Problem glycogenolysis, reduced formation, bleb functional capacity
of Asthma” synthesis phosphorylase and formation, decrease
phosphofructokinase, inhibition number alveoli,
+ +
Na K ATPase increase alveolar
dular phase (6–16 weeks of gestation
Stages of lung development
volume
in humans), branching continues and 4-ipomeanol, Bronchiolar cell differentiation Injury/loss of Clara Increased susceptibility to
In humans, primary lung buds develop mesenchyme differentiates into carti- naphthalene and repair inhibited cells inhaled toxicants,
alteration in surfactant
during the fourth week of gestation lage, smooth muscle, and connective Ozone Depletion proteoglycan and Altered bronchiolar Increase airway hyper-
from the endoderm of the foregut. Af- tissue around the epithelial tubules. By FGF-2, thinned basement growth reactivity, emphysema?
membrane zone (longer/decreased
ter early embryonic development, stag- the end of this time, major conducting diameter), fewer
es in prenatal lung development are airways to the terminal bronchioles are branches, alteration
in orientation
pseudoglandular, canalicular, saccular, developed. Respiratory bronchioles, bronchiolar smooth
and alveolar, which are represented in develop in the canalicular period along muscle
Figure 2, along with associated de- with a rich vascular supply. During the Arsenic Increase expression estrogen Alteration branching Cancer, bronchiectasis,
velopmental features (Kajekar, 2007). saccular phase, first contact between receptor alpha, alteration gene and cell migration, airway hyperreactivity
expression for extracellular decreased elasticity
Only a portion of maturational events the air space and proliferating pulmo- matrix (e.g. collagen type III), and structural
are required prenatally for successful nary capillaries takes place. During Sprouty-2, β-catenin, EGFR, L-
myc
support
survival, with most continuing postna- alveolarization, the primitive alveoli

tally during alveolarization (Pinkerton develop secondary septa that form the Di(2-ethylhexyl) phthalate
PPARγ, decrease type 2
pnuemocyte
Thickened primary
septa, fewer/more
Bronchopulmonary
dysplasia, altered lung
and Joad, 2000). walls of the true alveoli, resulting in a Kajekar 2007 Reference: Kajekar R. dilated airspace, mechanics
During the embryonic period primary dramatic increase in surface area.

Environmental factors and developmental increased Type II
outcomes in the lung. Pharmacol Therap. pneumocytes
bronchi develop from the primitive Chemicals that disrupt the cellular sig- 2007;114:129-145 Close Window
gut, and elongate and divide into two naling important for these events may More Information: “Cellular, From: Impact of Environmental Chemicals
on Lung Development - Miller et al., 2010
main bronchi. During the pseudoglan- alter lung development. structural, and functional
Online link - Table 1: Cellular, structural,
impacts on lung development and functional impacts on lung
of xenobiotics” development of xenobiotics

←

Environmental exposures at critical developmental

The lung is susceptible to many influences periods may permanently alter structure of airways
Environmental exposures during susceptible
developmental periods may produce lifelong
structural and functional alterations. Monkeys
exposed to ozone and house dust mite postnatally
develop longer, narrower, and fewer branches of
bronchioles along with other changes consistent
with increased risk for asthma development.
Click here for more details. You may skip this section and go to
“Growing Problem of Asthma”
Reference: Plopper CG, Smiley-Jewell SM, Miller LA,

Fanucchi MV, Evans MJ, Buckpitt AR, et al., 2007.
Asthma/allergic airways disease: does postnatal
exposure to environmental toxicants promote airway
pathobiology? (link) Graphic used with permission.
←

Environmental exposures at critical developmental

The lung is susceptible to many influences periods may permanently alter structure of airways
Environmental exposures during susceptible
developmental periods may produce lifelong
structural and functional alterations. Monkeys
exposed to ozone and house dust mite postnatally
develop longer, narrower, and fewer branches of
bronchioles along with other changes consistent
with increased risk for asthma development.
Click here for more details. You may skip this section and go to
“Growing Problem of Asthma”
Postnatal exposure to O3, alone

studies conducted at the or combined with house dust mite
University of California–Davis
antigen (HDMA), resulted in changes
evaluated the impact of ozone (O3)
in bronchiolar growth patterns,
and allergens on lung development
inhibiting growth in diameter and
in rhesus monkeys. These studies
promoting growth in length as well
integrated early-life exposures
as reducing the number of conducting
through multiple windows of
airway branches (by as many as
susceptibility to observe functional
six generations) (Fanucchi et al.,
and structural changes relevant
2006; Plopper et al., 2007). These
to human lung development and
changes are consistent with increased
lung disease. In 2004, Tran et
propensity to develop asthma and
al. described conducting airways
appeared to be permanent because
doubling in length and increasing by
they persisted at least 6 months after
33% in diameter between 1 and 6
exposure ended.
months of age.
Reference: Plopper CG, Smiley-Jewell SM, Miller LA,
Fanucchi MV, Evans MJ, Buckpitt AR, et al., 2007.
Asthma/allergic airways disease: does postnatal
exposure to environmental toxicants promote airway
pathobiology? (link) Graphic used with permission.
←
Asthma: The Growing Problem

When Brett gets an attack, he has a difficult time

10 -
breathing and sometimes feels as if he is going to Children
pass out. All Females
% with asthma
9-
He is careful to carry an inhaler with him at all TOTAL

8-
times. Lots of kids have them, so it seems common Adults
now even though his doctor says it wasn’t like this 7-
All Males
many years ago. The number of people with asthma,
continues to grow. 6-
From 2001 to 2010 overall asthma rates increased 5-

1.5% per year, to about 8.4%.
-
01
02
03
04
05
06
07
08
09
20
20
20
20
20
20
20
20
20
1 in 10 children, or 10%, now have asthma. Percentages are age-adjusted
In addition to the human costs, estimated monetary SOURCE: National Center for Health Statistics; 2010
From CDC “Vital Signs” on asthma
costs measured in 2007 dollars was $56 billion.
(CDC and Amer Children 3rd ed.)
←
Asthma: Racial and Socioeconomic Disparities

Percentage of children ages 0 to 17 years

Many of Brett’s friends who live in apartments in the reported to have current asthma, by race/
city also have asthma. ethnicity and family income, 2007-2010
Racial and socioeconomic disparities are dramatic All Races/Ethnicities
(see figure). About 1 in 9 (11%) of non-Hispanic All

White non-Hispanic
Black non-Hispanic
black persons of all ages and about 1 in 6 (17%) of Incomes Asian non-Hispanic
Hispanic
non-Hispanic black children had asthma in 2009, the All Other Races
highest rate among racial/ethnic groups.

All Races/Ethnicities
At or White non-Hispanic
Above Black non-Hispanic
The greatest rise in asthma rates was among black children Poverty Asian non-Hispanic
Hispanic
Level
(almost a 50% increase) from 2001 through 2009. Racial All Other Races
disparities (with increased asthma and hospital visits for Below

All Races/Ethnicities
White non-Hispanic
Poverty
asthma) are noted with increased risk for blacks compared Level
Black non-Hispanic
NA*
to whites even after controlling for factors such as economic Hispanic

All Other Races
status. The disparities hold true across economic strata and 0% 4% 8% 12% 16% 20%
in urban as well as rural communities. (McDaniel et al.. 2006) *Not available. The estimate is not reported because it has large uncertainty: the relative
standard error, RSE, is 40% or greater (RSE = standard error divided by the estimate).
Disparities may be explained by higher exposures to risk Data: Centers for Disease Control and Prevention, National Center for Health Statistics,
factors for asthma and lack of comprehensive asthma National Health Interview Survey, America’s Children and the Environment, Third Edition.
management, among other things.

←
Asthma: Family and Community Stressors

“Hi Mom,” says Brett. Brett’s mother,

Karen, comes over and gives him a hug.
Although Karen doesn‘t make a lot of
money, they have a stable home life now, but
it wasn’t that way when Brett was younger.
←

Karen sometimes wonders whether the

constant fights with her ex-husband Stress can add to and even magnify
the impacts of exposure to other
while she was pregnant and after Brett environmental conditions that
was born may have had an effect on foster the onset or increase the
Brett’s asthma. severity of asthma
She may be right.

Family stressors such as money
problems, exposure to violence, illnesses
and deaths, and divorce can make
kids more susceptible to many health Key Concept:
Allostatic Load
problems, including asthma.
Stress can add to and even magnify Key Concept:
Effect Modifiers
environmental conditions that
foster the onset or increase the
severity of asthma.
Watch: Dr. John Balmes

discusses how multiple
factors can interact
to increase the risk of
developing asthma
(effect modification).
(3 min.)
←


constant fights with her ex-husband
while she was pregnant and after Brett
was born may have had an effect on
Brett’s asthma.
She may be right.
Family stressors such as money
problems, exposure to violence, illnesses
and deaths, and divorce can make
kids more susceptible to many health Key Concept: Key Concept:
Allostatic Load Allostatic Load
problems, including asthma. Homeostasis is the body’s ability or tendency to maintain its normal equilibrium
Key Concept: by regularly adjusting the processes that influence blood pressure, temperature,
Stress can add to and even magnify blood sugar, and other functions. Allostasis is the body’s ability to change vital
Effect Modifiers
the impacts of exposure to other homeostatic functions in response to environmental changes. Like homeostasis,
allostasis is complex, and involves responses from the brain and other parts of
environmental conditions that the nervous system as well as the immune and cardiovascular systems. Allostatic
foster the onset or increase the load is the cumulative “wear and tear” on the body due to these systems actively
maintaining balance in response to stressors.
severity of asthma.
Real or perceived threats activate stress such as building muscle, bone, and brain
hormones and can lead to the following: cells are temporarily sacrificed to provide
• Constricted capillaries in the skin energy to respond to a threat or escape
(“fight or flight response”).
• Dilated bronchial tubes
Because we can experience stress from
• A release of sugar and fatty acids current events and ideas (remembering past
(for energy) stressful events and anticipating stressful
• Conversion of muscle protein to fat circumstances), our allostatic mechanisms
Watch: Dr. John Balmes • Blocked insulin action
may go into overdrive on a long-term
discusses how multiple basis. Exposures to various kinds of stress
• Release of minerals from bones (psychosocial, chemical, nutritional, etc.)
factors can interact during our early life can reprogram the
to increase the risk of • Changes to white blood cells
body’s mechanisms, resulting in chronic
developing asthma These actions (and others that are part of increased responses to stressors that affect
(effect modification). the stress response) help the body meet an our health negatively throughout our life.
immediate threat. Long-term functions
(3 min.)
Graphic: McEwen B., 2006, with permission
←


constant fights with her ex-husband
while she was pregnant and after Brett
was born may have had an effect on
Brett’s asthma.
She may be right.
Family stressors such as money Key concept:
problems, exposure to violence, illnesses Effect Modifier

and deaths, and divorce can make An effect modifier is a variable that differentially
kids more susceptible to many health Key Concept: modifies the observed effect of a risk factor on disease
Allostatic Load
problems, including asthma. status. Different groups have different risk estimates
Stress can add to and even magnify Key Concept: when effect modification is present. For example, stress
Effect Modifiers can increase the asthma risk associated with exposure
environmental conditions that to a given amount of traffic related air pollution
foster the onset or increase the addressed later in this story.
severity of asthma. An additional reference: Shankardass K, McConnell R, Jerrett M, Milam J, Richardson
J, Berhane K. Parental stress increases the effect of traffic-related air pollution on
childhood asthma incidence. Proc Natl Acad Sci USA. 2009 Jul 28;106(30):12406-11.

discusses how multiple
factors can interact
to increase the risk of
developing asthma
(effect modification).
(3 min.)
←

Because of all the prior family

problems, Karen pays a lot of
attention to Brett and tries to show
him how much she loves him in a lot
of ways, including making sure they Key Concept:
Windows of
eat dinner together every night. Vulnerability and
They have formed a close bond and Opportunity
Karen is happy about that, although
like many boys his age Brett usually
acts like he doesn’t know her when
they are in public.
Watch: Dr. Mark Miller
discusses early origins of
adult disease.
Mark Miller MD MPH, Director,

Children’s Environmental
Health Program, Office of
Environmental Health Hazard
Assessment, California EPA;
Director, UCSF Pediatric
Environmental Health
Specialty Unit
←

Windows of Vulnerability Example: Stress and Asthma

Development of Lung Function is
A window of vulnerability is a time
Affected by the Home Environment
window (s) during pregnancy or child
development when the fetus, infant,
or child is especially susceptible Key Concept:
to particular environmental Windows of
exposures, general environmental Vulnerability and
deprivation, suboptimal nutrition, Opportunity
or psychosocial stress. Exposures
during these time windows can disrupt
important developmental processes,
altering structural or functional
development of various organs or
physiologic systems, with potential Watch: Dr. Mark Miller
lifelong consequences. Time windows adult disease.
of vulnerability can be relatively long
and extend throughout fetal and infant
development or they can be relatively
short and precise. For example,
thalidomide can cause severe limb Graphic used with permission.
abnormalities if exposure occurs in In a prospective cohort study children were
the fetus 20-36 days after conception. followed from pregnancy through 3 years of age.
Alternatively, the manifestations If there was intimate partner violence (IPV) in
of fetal alcohol exposure can vary the home they had double the risk of developing
considerably depending on the timing asthma.
and extent of exposure. (continued >) Mark Miller MD MPH, Director, If there was IPV in the home and mother was less
Children’s Environmental interactive with the child/ played less with the
Health Program, Office of child/the child had few educational toys, the risk
Environmental Health Hazard went up to 2.5 times those without IPV.
Director, UCSF Pediatric If the home had IPV but mother was more interac-
Environmental Health tive, child had more toys etc., the risk was partially
Specialty Unit ameliorated to about 1.6 times those without IPV.
←

Windows of Opportunity Example: Stress and Asthma

Development of Lung Function is
A window of opportunity is a concept
Affected by the Home Environment
related to window of vulnerability. It
is a time window when structural or
functional developmental processes Key Concept:
in the body’s organs or physiologic Windows of
systems can be positively influenced by Vulnerability and
a rich, low hazard environment, with Opportunity
healthy nutrition, good education, a
positive home environment without
unrelenting chronic stress, etc. From
conception through the first few years
of life, development is rapid, and many
key developmental processes (e.g., Watch: Dr. Mark Miller
language acquisition) are programmed adult disease.
during this time. The functional effects
of this programming may be apparent
immediately or delayed until later in
life. Many functions remain plastic
(able to be changed) for prolonged Graphic used with permission.
periods, providing an opportunity In a prospective cohort study children were
for external influences to partially followed from pregnancy through 3 years of age.
remediate the potential effects of If there was intimate partner violence (IPV) in
earlier exposures. the home they had double the risk of developing
asthma.
Mark Miller MD MPH, Director, If there was IPV in the home and mother was less
Children’s Environmental interactive with the child/ played less with the
Health Program, Office of child/the child had few educational toys, the risk
Environmental Health Hazard went up to 2.5 times those without IPV.
Director, UCSF Pediatric If the home had IPV but mother was more interac-
Environmental Health tive, child had more toys etc., the risk was partially
Specialty Unit ameliorated to about 1.6 times those without IPV.
←

The impact of asthma on the

family can be substantial, from
emotional to economic.
Children suffer from days lost at
school and can be excluded from
certain activities.
Parents who need to work must
take time off or find adequate care Watch: Dr. Rosalind
for their children when they need to Wright discusses how
stay home. caregiver stress, early
childhood stress and
When a child has an acute attack, it community violence
can be very stressful and frightening all have an impact on
the development of
for parents. asthma. (5 min.)
More information:
Link to resources
on comprehensive
family asthma
management
programs – CDC
and medical legal
←
Asthma, Exercise and Air Pollution

Brett’s asthma is sometimes

triggered by exercising or
playing the sports he loves,
which is very frustrating
for him.
Some research shows that

playing multiple sports along
with higher exposures to air
pollution (ozone) can actually
cause the onset of asthma.
(McConnell et al., 2002)
For clinicians, link to

Dr. Jim Gauderman slide
show on Children’s Health
and Traffic Exposures.

presents compelling
scientific evidence that
clearly illustrates the
relationship between air
pollution and incidence
of asthma. (6 min.)
←
Asthma and Air Pollution

Industrial and Traffic Air Pollution

Make Asthma Worse
Adverse Effects of Regional and Traffic-
Related Air Pollutants on Children with Diesel emissions
Asthma and asthma
demographics
Pollutants in southern
California
• Ozone
• Nitrogen Oxide Asthma and near
roadway exposure
• Respirable particulate matter to air pollution
(PM - <10 and <2.5 μm)
• Vehicle exhaust (trucks, cars, Ozone and Particles Make Asthma Worse:
trains, ships, etc.)
• More symptoms
Health effects in children • More medications used
with asthma • More respiratory illnesses
• Respiratory symptoms • More clinic visits
• Wheezing (acute) • More emergency room visits
• Bronchitis (chronic) • More hospitalizations
• Increased rescue medication use (Sarnat JA, Holquin F. Asthma and air quality
• Decreased lung function Curr Opin Pulm Med. 2007; 13: 63-6.)
• Emergency department visits

• Hospitalizations
• School absences
←

Industrial and Traffic Air Pollution Diesel Emissions and Asthma Demographics in Southern California
Make Asthma Worse
Related Air Pollutants on Children with Diesel emissions
Asthma and asthma
demographics
California
• Ozone
roadway exposure
(PM - <10 and <2.5 μm)
• Vehicle exhaust (trucks, cars,
Health effects in children

with asthma
• Respiratory symptoms
• Wheezing (acute)
Graphic used
Credit: CalEnviroScreen, Office of Environmental
• Bronchitis (chronic) Health Hazard Assessment, California EPA
with permission.
• Increased rescue medication use

Link: California Environmental
• Decreased lung function Health Tracking Program Web Portaladway
exposure to air pollution
• Emergency department visits
• Hospitalizations
• School absences
←

Industrial and Traffic Air Pollution Asthma and Near Roadway Exposure to Air Pollution
Make Asthma Worse Children in neighborhoods with more traffic-related
air pollutants have increased risk of developing asthma and
Related Air Pollutants on Children with increased risk of bronchitis and asthma episodes
Diesel emissions
Asthma and asthma
demographics
California
• Ozone
roadway exposure
(PM - <10 and <2.5 μm)
• Vehicle exhaust (trucks, cars,
Health effects in children

with asthma
• Respiratory symptoms
• Wheezing (acute)
• Bronchitis (chronic)
• Increased rescue medication use
• Decreased lung function Slide 1: Air quality is worse Slide 2: Asthma risk increases
close to freeways. Air pollut- for children living closer than 150
• Emergency department visits ants are increased closer than meters from a major road.
150-300 meters downwind. McConnell et al., 2006
• Hospitalizations Zhu et al., 2002, 2006.
Graphics used with permission.
• School absences
←

Effect Modifiers – Air Pollution, Effect of traffic-related pollution on incident asthma

stress and Socioeconomics across parental stress quartiles
Brett lives in a low-income
neighborhood close to Los Angeles
and near a major roadway. Children
in relatively low-income families
and exposed to traffic-related air
pollution, such as in Brett’s case, are
at greater risk of frequent asthma
symptoms. Importantly, they are at
Examples: Air
greater risk than children in the same pollution and
neighborhood whose families are socioeconomics
financially better off.
(Meng et al., 2008, Shankardass et al., 2009, Link: National
Environmental
Clougherty et al., 2007)
Health Tracking
And, those with a lower income and Program
people of color are much more likely Asthma in Over a period of 3 years of follow up in a prospective cohort study of
to go to a school that has a heavily California 2,497 children aged 5-9 years with no previous history of asthma, the
trafficked roadway next to it. risk of new onset asthma attributable to traffic related air pollution
(TRP) was significantly higher for children whose parents were subject
to higher amounts of stress.
Stress was estimated using the Perceived Stress Scale (PSS), which is a
widely used measure of the degree to which respondents believed their
lives were unpredictable, uncontrollable, or overwhelming. Stress was
also associated with larger effects of in utero tobacco smoke exposure.
A similar pattern of increased risk of asthma was observed among chil-
dren from low SES families who also were exposed to either TRP or in
utero tobacco smoke. (Shankardass 2009)

←

Effect Modifiers – Air Pollution, Examples: Air pollution and socioeconomics

stress and Socioeconomics
in relatively low-income families
and exposed to traffic-related air
at greater risk of frequent asthma
symptoms. Importantly, they are at
Examples: Air
greater risk than children in the same pollution and
neighborhood whose families are socioeconomics
financially better off.
(Meng et al., 2008, Shankardass et al., 2009, Link: National
Environmental
Clougherty et al., 2007)
Health Tracking
people of color are much more likely Asthma in
to go to a school that has a heavily California
Slide 1: Slide 2 (rollover to view): Graphics used with permission.
trafficked roadway next to it. Economically disadvantaged Hispanic and non-Hispanic
students in CA Public Schools black children are more likely
have higher traffic exposure. to have high traffic exposure.
(Green et al., EHP 2004) (Green et al., EHP 2004)
←

Effect Modifiers – Air Pollution,

stress and Socioeconomics
Asthma in California
Childhood Rates of Asthma Emergency Room Visits* and Poverty, 2010
Childhood Rates of Asthma
Emergency Department Visits*

 

Rate of asthma
emergency visits per
10,000 residents¹
Percent of total
population
below poverty²
2010
Insufficient Data
0.1 - 52.7
in relatively low-income families    



Insufficient Data
0.1 - 52.7
7.0 - 11.8
11.9 - 16.0
52.8 - 72.2
72.3 - 101.6
and exposed to traffic-related air 
 52.8 - 72.2
16.1 - 19.8 101.7 - 199.6

 72.3 - 101.6

19.9 - 23.8


 

 

 101.7 - 199.6
at greater risk of frequent asthma 

symptoms. Importantly, they are at    
 

Examples: Air 
greater risk than children in the same   
 
pollution and 
neighborhood whose families are socioeconomics 


 
Active Asthma Prevalence**
financially better off.  All Ages, 2007
(Meng et al., 2008, Shankardass et al., 2009, Link: National    No Data

0.1% - 7.8%
Environmental
Clougherty et al., 2007) 
*An asthma Emergency 7.9% - 9.8%

Health Tracking Department (ED) visit is 9.9% - 11.9%

an admission to a licensed
ED in California with the
  12% - 14.4%
primary diagnosis of asthma.  
people of color are much more likely
The rate of asthma ED visits is
the number of visits per 10,000 residents,
Asthma in age-adjusted to the 2000 U.S. population.  
to go to a school that has a heavily
1
Rates based on numbers <12 are not reported.
California
trafficked roadway next to it.
**Active asthma prevalence is the proportion
of people in the population who have ever been
diagnosed with asthma and report they still have asthma
 
and/or report they had an epsiode within the past 12 months.
Data Source: 1Californiabreathing.org, CA Office of Statewide Health Planning and Development (OSHPD), 2US Census 2000, 3American Community Survey 2007- 2011 (5yr estimates)
Geospatial Research, Analysis & Services Program

←
Asthma Genetics and Air Pollution

Genetics Increase Susceptibility to Air Pollution

Exposure to oxidants in ambient air contributes
to inflammation in the lungs. Oxidants include
1) Variation in one
oxygen, ozone, particulate matter, polycyclic gene, epoxide
+ =
aromatic hydrocarbons (PAHs - a group of hydrolase (EPHX1) is
chemicals that occur primarily from burning associated with 50%
fuel), nitrogen oxides, and cigarette smoke. increase in asthma risk.
The genes glutathione (GST) and epoxide 1 increases by half

hydrolase (EPHX1) are important for detoxifica- Genetic variation is
associated with higher
tion and elimination of contributors to oxidative asthma susceptibility.
stress associated with asthma. Oxidative stress
and inflammation are fundamental to the 2) The combination of
origination and development of asthma. having two high risk
variants, EPHX1 and
Glutathione S Transferase
+ =
Key Concept: Inflammation
P1 (GST Val\Val) results in a
and Oxidative Stress four-fold increase in risk.
Certain genetic variants in GST and EPHX1 2

each are individually associated with increased A combination of two
genetic variations is
increases 4-fold
risk of developing asthma, as is living in close associated with even higher
asthma susceptibility.
proximity to a major roadway. Salam et al., 3) For children with both
found that being in the high risk group for all high risk variants (EPHX1
three resulted in nearly a nine-fold increase in and GST Val\Val) who live
risk for lifetime asthma. Ultrafine particulate close to a major roadway,
matter has strong oxidant properties and the risk is increased nine-fold.
+ + =
generates inflammatory responses (Li et al.,
2003).
Genes metabolizing PAHs have polymorphisms
(many forms) that affect how well they mediate
tissue damage via development of reactive 3
oxygen species. Two genetic variations AND
living in close proximity to a increases 9-fold
major roadway dramatically
increases asthma susceptibility!
Salam et al., Thorax 2007; 62:1050-1057

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Asthma Genetics and Air Pollution

Key Concept:
Exposure to oxidants in ambient air contributes Inflammation and Oxidative Stress
to inflammation in the lungs. Oxidants include Chronic inflammation and oxidative stress are two mechanisms
oxygen, ozone, particulate matter, polycyclic that underlie many common chronic diseases, including asthma,
aromatic hydrocarbons (PAHs - a group of diabetes, metabolic syndrome, obesity, cardiovascular disease, some
chemicals that occur primarily from burning neurodegenerative disorders, cancer, and other chronic illnesses.
fuel), nitrogen oxides, and cigarette smoke. Inflammation
The genes glutathione (GST) and epoxide Inflammation is the body’s attempt at self-protection in response to injury, infections,
hydrolase (EPHX1) are important for detoxifica- and other stresses - the aim being to remove harmful stimuli, including infectious
agents, damaged cells, or irritants - and begin the healing process. It can be acute
tion and elimination of contributors to oxidative and short-lived or chronic. The inflammatory response can affect blood vessels, the
stress associated with asthma. Oxidative stress immune system, and cells within involved tissue. Excessive, prolonged, or recurrent
inflammation is an aspect of many diseases. Various inflammatory “markers” are
and inflammation are fundamental to the involved, some of which can be measured through laboratory testing, for example,
origination and development of asthma. various cytokines.
An important contributor to inflammation is oxidative stress.

Key Concept: Inflammation
and Oxidative Stress EXTERNAL
Tobacco smoke
Industrial pollutants
Certain genetic variants in GST and EPHX1 Air pollution
each are individually associated with increased Pesticides Organic solvents
Radiation Some pharmaceuticals
risk of developing asthma, as is living in close Reactive Oxygen High oxygen
proximity to a major roadway. Salam et al., Species (ROS) Food*
found that being in the high risk group for all *Normal metabolism of

food for energy results in
three resulted in nearly a nine-fold increase in the production of ROS.
INTERNAL
risk for lifetime asthma. Ultrafine particulate Mitochondria
matter has strong oxidant properties and Activated Immune
Cells (phagocytes) Sufficient
generates inflammatory responses (Li et al., antioxidants from
biological and dietary
2003). sources keep this
process in check.
Genes metabolizing PAHs have polymorphisms
(many forms) that affect how well they mediate
tissue damage via development of reactive Oxidative Stress
oxygen species. Excessive oxidative stress (OS) occurs when levels of “reactive oxygen species” (ROS) are
chronically elevated, damage tissues, and increase disease risk. ROS are highly reactive oxygen
molecules, sometimes called free radicals, normally present in the body as a result of using
oxygen to metabolize food and create energy. They play an essential role in some aspects of
cell signaling. Antioxidants, including those from dietary sources, keep ROS at healthy levels.
Overproduction of ROS and/or insufficient antioxidants leads to excessive OS. Exposure to air
pollution, various industrial chemicals, pesticides, heavy metals, and radiation can also cause
excessive ROS. Certain people may be genetically predisposed to have a limited capacity to
Salam et al., Thorax 2007; 62:1050-1057 detoxify ROS.
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Asthma and Climate Change

Brett’s generation has heard a lot about It is easy to check the air quality in
your area on the weather channel
climate change. Climate change is expected to on television, in the newspaper,
increase ground level ozone through increases on the internet, or via your
smartphone. The EPA’s Air Quality
in temperature and wind patterns. As CO2 Index is a good resource.
levels rise and temperatures increase, airborne
pollen levels are also increasing.
The combination of higher levels of asthma-

related air pollutants associated with changes

in atmospheric conditions are expected
Watch: In this short
to continue to increase the frequency of video Dr. John Balmes
asthma attacks in people with asthma, clearly outlines how
and may also increase the prevalence of climate changes will
increase the incidence
asthma in populations. of asthma. (2 min.)
*pollutants
measured:
PM 2.5, ozone
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Asthma: Healthy Eating Habits

At the family reunion it is time to eat.

Brett grabs a sandwich off the buffet
table. Karen is glad that Brett has
chosen a sandwich on healthier whole
wheat bread, rather than processed
white bread.
Because of his asthma, Karen wants
Brett to stay as healthy as possible, and
also not to become overweight as it
could worsen his asthma. (Obesity can
also increase risk of developing asthma.)
His pediatrician regularly emphasizes
the importance of eating nutritious
foods high in antioxidants such as
colorful fruits and vegetables, and other
healthy foods including fish that have
omega-3 fatty acids.
←
Asthma
Hey, there comes Max, his cousin’s dog,

running right at him!
“Hey Max,” Brett says as he pets him

and holds him close, forgetting for a
minute that dogs can also cause him
to have an asthma attack, something
about their hair. (Hastert et al., 2007,
Popplewell et al., 2000)
Brett doesn’t care, Max is so friendly.

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Asthma: Brett’s Story

A wide range of
We have seen throughout the pages factors, and their
of Brett’s story that a wide range interactions across
of factors, and their interactions Brett’s lifespan, are
across his lifespan, are risk factors risk factors for both
for both the onset of asthma, as the onset of asthma,
well as triggering it. These include as well as triggering it.
environmental chemicals and other
contaminants, family and community
social stressors, diet and nutrition,
economics, and how these might
interact with each other and with
genetics.
Although Brett’s story is fictional, and

it is difficult to determine what risk
factors might be most important to
him, the circumstances of his life can
The
circumstances
be found in children throughout our
of Brett’s life
country.
can be found in
It is therefore critical that we consider children throughout
multiple environmental influences on our country
asthma when we design prevention
strategies and treatment.
It is critical that we consider multiple
environmental influences on asthma
when we design prevention strategies
Continue on to the next page to learn more and treatment.
about preventive strategies.
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Asthma: Management and Prevention Strategies

Children with asthma should:

• Not be exposed to secondhand smoke (SHS)
and other types of combustion smoke,
For clinicians - more
• Not exercise outdoors on bad air quality information on
days, but outdoor exercise should otherwise asthma management:
be encouraged, and,
Guidelines from
• Avoid allergens to which they the National
are sensitized. Environmental
Education
Other protective factors include Foundation
the following, if possible: Guidelines from the
National Heart, Lung
• Choosing homes and walking routes away and Blood Institute
from major roadways with heavy traffic, Asthma Management Strategies
• Improved access to health care, healthy
foods, and green space for disadvantaged
children with asthma,
• Dietary antioxidants, including vegetables,
• Avoidance of water-damaged environments, Avoid water Avoid Keep areas Use chemicals

damaged and tobacco free of dust and pesticides
• Improved ventilation in buildings to moldy areas smoke with care
discourage mold growth,
• Using household chemicals and pesticides
sparingly if at all, and with care, and,
• Replacing or retrofitting older diesel vehicles.
Promote and Improve Upgrade diesel Get regular
use greenspaces diet, include equipment checkups
such as parks antioxidants
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Asthma: Policy Initiatives to Protect Health

Policy initiatives to protect health Policy Initiatives for Cleaner Air - Reduction of diesel emissions
include: in California - On-road bus and truck rule
- Off-road construction vehicles
• Improved city and highway planning, California has instituted a number - Other surface goods
• Improved public transportation, of policy initiatives to improve movement efforts (ports
bicycle friendly streets, accessible air quality which other states and and rail yards)
sidewalks, communities could replicate. - Financial incentives
for cleaner trucks and
• Changes in zoning laws, where school buses
appropriate, to allow mixed use - Advanced Clean Cars
neighborhoods resulting in less rule - Smart growth =
decreased VMTs
driving,
- No-burn rules to limit
• Healthy building practices for wood smoke emissions
schools and public buildings,
including improved ventilation, reducing Watch: Public
use of toxic chemicals in building polices can help
improve health.
materials and maintenance, incentives for
Dr. John Balmes
green buildings, offers specific
• Increased use of renewable and less recommendations to
polluting energy, e.g. solar, reduce air pollution.
(7 min.)
• Chemical policy reform,
• Smoking ordinances,
• Asthma home visiting programs for
asthma education on trigger control and More on policies to
disease management, prevent asthma: Graphic used with permission.
• School sitings should be >500 meters CDC Asthma
from highways, and, EPA Indoor Air
• Regulations to limit wood burning and Pollustion
outdoor wood boilers. Asthma Community
Network
Continue to Final Thoughts >
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Burke H, Leonardi-Bee J, Hashim 106 no. 30 CDC. CDC: Health Care Guidelines
Bryant TN, Warner JO, Warner JA. ing, and asthma. Pediatrics. 2011 Database
A, Pine-Abata H, Chen Y, Cook Shonkoff JP, Garner AS, and the Jan;127(1):e180-7. doi: 10.1542/ National Environmental Education
The effect of high-efficiency and Mold video on EPA Asthma science ALA’s “State of the Air” search page
DG, Britton JR, McKeever Committee on Psychosocial As- peds.2010-0442. Epub 2010 Dec 27 Foundation: Pediatric Environmen-
standard vacuum-cleaners on mite, notebook
TM.Prenatal and passive smoke pects of Child and Family Health, (most relevant for CE course): tal History forms
cat and dog allergen levels and Hollams EM.Vitamin D and atopy
clinical progress. Pediatr Allergy
exposure and incidence of asthma Committee on Early Childhood, Phthalates
and wheeze: systematic review Adoption, and Dependent Care, and asthma phenotypes in children. EPA/NIEHS Children’s Centers Intervention Guidance
Immunol. 2000 Aug;11(3):142-8 CurrOpin Allergy ClinImmunol. Bornehag CG, NanbergE .Phthalate 2012 Webinar Series
and meta-analysis. Pediatrics. 2012 and Section on Developmental exposure and asthma in children.
2012 Jun;12(3):228-34 In particular: Krieger JW, Philby Miriam L,
Population Health Apr;129(4):735-44. doi: 10.1542/ and Behavioral Pediatrics. The Int J Androl. 2010 Apr;33(2):333- Brooks Marissa Z. Better Home
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North Karelia: from descriptive Stress Technical Report.Pediatrics.2012 D deficiency causes deficits in lung Hsu NY, Lee CC, Wang JY, Li YC, posure Health Effects - Richard
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Environmental Health Hazard Checklist
10.1111/j.1600-0668.2011.00753.x.
Epub 2011 Nov 16 Assessment, California EPA EPA Air Quality Index
←
Childhood Leukemia
Stephen’s Story *
Stephen is a 3-year-old boy

who lives with his parents
David and Tricia in a suburb in
Connecticut.
He is an only child, and his parents
spend as much time as they can with
him even though they manage a
successful plant nursery and
garden center.
He spends four days a week at child
care and is with his parents the other
three days, sometimes at their house
and sometimes at the garden center.
Stephen had been an active toddler,
but during the past month, Tricia
noticed that Stephen was not as live-
ly and energetic as usual. His child
care providers also mentioned this.
When he became listless and
started to run a fever, Tricia became
concerned. She took Stephen to
see his pediatrician, Dr. Jones.
(* a fictional case)
←
Childhood Leukemia
Stephen’s Story
After talking with Tricia and

examining Stephen, Dr. Jones was
also concerned. She confirmed that
Stephen appeared ill and that the
cause could be a number of things.
She said she needed laboratory tests
to make an accurate diagnosis.
Dr. Jones ordered blood tests that
could be done at the local hospital
and called to make an appointment
for Stephen to get his blood drawn
that same day.
Tricia was upset and called her
husband David with the news. She
started to ask a lot of questions. Dr.
Jones tried to calm her and said she
would call her as soon as she had
the results.
Tricia brought Stephen to the
hospital laboratory for the tests
and went home very worried.
←
Childhood Leukemia
Stephen’s Story
When Dr. Jones received the test

results she called Tricia and David
back into her office. She told them
that the test results showed a very
high white blood count and very
low platelet count.
Dr. Jones said that Stephen would
need to see a pediatric oncologist,
Dr. Baker. She said she would ar-
range the appointment for Stephen at
Dr. Baker’s office next to the hospital
and that he should go right over.
Tricia and David were shocked.
They knew that oncologists dealt
with cancer. Dr. Jones tried to reas-
sure them and said they should wait
to speak with Dr. Baker before
drawing any conclusions.
They left Dr. Jones office still very
worried.
“Diagnosing the Leukaemic Cells”
by Susan Macfarlane,
reproduced with permission.
About this painting, with words of
the artist in italics >
See this page for more information

on the artist.
←
Childhood Leukemia
Stephen’s Story
The pediatric oncologist, Dr. Baker,

looked at Stephen’s blood tests to
confirm the findings from the
laboratory.
Dr. Baker told Tricia and David that
he was concerned that Stephen may
have leukemia and needed to run
more tests to confirm the diagnosis.
Since Stephen had a fever and sup-
pressed immune system, Dr. Baker
admitted Stephen to the hospital to
start antibiotics and hydration thera-
py immediately.
Bone marrow
Dr. Baker explained to Tricia and aspiration >
David that he would return in the
morning to perform a bone marrow
aspirate.
“Typing the Leukaemic Cells”

by Susan Macfarlane,
About this painting, with words of
See this page for more information

on the artist.
←
Childhood Leukemia
Stephen’s Story
The next day when Dr. Baker came

to visit, Stephen looked well. He no
longer had a fever and was playing.
Dr. Baker explained the bone mar-
row procedure to Tricia and David
and then performed the aspirate in a
special room for procedures.
When he returned to discuss the
bone marrow test results, Dr. Baker
tried to calm Tricia and David, but
they were upset and imagined the
What is Leukemia?
worst.
Unfortunately, their fears were real-
ized when Dr. Baker told them that
Stephen’s test results confirmed that
he had leukemia. He said that fur-
ther tests were being done to find out
more about what type of leukemia he
had. He said they should know the
type of leukemia the following day,
and then they can begin treatment.
They were devastated.
←
Childhood Leukemia
Stephen’s Story
Dr. Baker discussed with them what

the course of treatment should be,
including intravenous (IV) hydration
(liquids), and initiating a course of
chemotherapy.
Stephen would need to be in the
hospital for this, since the initial
treatment is the riskiest time period.
Dr. Baker arranged for Stephen to
continue his hospital stay and begin
treatment immediately.
←
Childhood Leukemia
Stephen’s Story
Later Dr. Baker explained that the

type of leukemia Stephen had was
called acute lymphoblastic leukemia
(ALL). Dr. Baker told Stephen that
he was sick, and that he would have
to be in the hospital for a while so
that the doctors can give him
medicines to make him better. Leukemia Survival
Statistics
Dr. Baker also explained to Tricia
and David how the cure rate for
children has improved dramatically
Watch: Dr. Gary Dahl
over the past few decades. discusses types of
leukemia (4:13 mins.)
Gary Dahl MD, Professor

of Pediatrics (Hematology/
Oncology) at the Lucile
Salter Packard Children’s
Hospital, Stanford School
of Medicine
←
Childhood Leukemia
Stephen’s Story
Childhood leukemia is Leukemias originate in B and T cells, which have

important immune system functions.
not a single disease
Acute leukemias in childhood comprise a Types of leukemia
group of related but different diseases. In vary by age
the United States they represent 31% of
malignancies occurring among children
under the age of 15. Early life exposures are
important: age-specific
Eighty percent of acute childhood incidence chart
leukemias, including Stephen’s,
are acute lymphoblastic leukemia
(ALL). Approximately 17% are acute
More Detail on
myeloblastic leukemia (AML). ALL Subtypes
It is important to identify characteristics
of the leukemia at its presentation since Watch: Dr. Patricia Buffler
this information helps to determine the discusses leukemia
course of treatment as well as prognosis. classification (1:59 mins.)
The types of cells involved in the leukemia
(immunophenotype) are used to
determine whether a person has
ALL or AML.
Factors such as age, initial white blood
count at diagnosis, and cytogenetics
Graphic: Terese Winslow 2007.
(the specific differences or changes Graphic reproduced with permission.
in DNA) of the leukemic cells at
diagnosis are utilized to identify the Patricia Buffler PhD MPH,
most appropriate course of treatment. Professor of Epidemiology
and Dean Emerita
(deceased) of the School of
Public Health, University of
California-Berkeley
←
Childhood Leukemia
Stephen’s Story

not a single disease
Acute leukemias in childhood comprise a Types of leukemia
Types of leukemia vary by age
group of related but different diseases. In vary by age The two main types of leukemia based When grouped by underlying molecular
on cell histology are ALL and AML, but markers, certain leukemias occur
the United States they represent 31% of
even within these groups, there are more frequently at different ages.
malignancies occurring among children many different characteristics based on MLL (mixed leukemia or Myeloid/
under the age of 15. Early life exposures are the presence of abnormalities of the lymphoid leukemia) is the predominant
important: age-specific chromosomes, whether the number of form in infants but relatively rare in
Eighty percent of acute childhood incidence chart chromosomes is higher than expected older children. MLL is a particularly
leukemias, including Stephen’s, (hyperdiploidy), or whether or not aggressive form of leukemia.
are acute lymphoblastic leukemia we see translocation or deletion in a More details on translocations,
(ALL). Approximately 17% are acute specific chromosome. hyperdiploidy, and other genetic
More Detail on
These differences have practical implica- changes in childhood leukemia are
tions: subgroups may have very specific discussed later in this module.
It is important to identify characteristics risk factors. The leukemia subgroup also
of the leukemia at its presentation since Watch: Dr. Patricia Buffler impacts treatment decisions.
course of treatment as well as prognosis. classification (1:59 mins.) INFANTS CHILDREN
The types of cells involved in the leukemia TEL-AML1
other other
(immunophenotype) are used to TEL-AML1
Hyperdiploid
determine whether a person has BCR-ABL
ALL or AML.
Factors such as age, initial white blood
count at diagnosis, and cytogenetics
(the specific differences or changes
BCR-ABL
in DNA) of the leukemic cells at
MLL
diagnosis are utilized to identify the Patricia Buffler PhD MPH, MLL E2A-PBX1
most appropriate course of treatment. Professor of Epidemiology
and Dean Emerita
(deceased) of the School of Types other than MLL are identified by various
Public Health, University of acronyms that refer to other subtypes of leukemia.
California-Berkeley
←
Childhood Leukemia
Stephen’s Story

Early Life Exposures are Important
not a single disease There is a peak of incidence of child-
hood ALL between the ages of two and
In contrast to ALL, the childhood AML
rate seems to be more stable across
Acute leukemias in childhood comprise a Types of leukemia five. This has led researchers to think ages, which implies different risk
group of related but different diseases. In vary by age that critical windows of vulnerability factors, windows of vulnerability, or
the United States they represent 31% of to environmental exposures are very mechanisms that may lead to AML in
important before conception, during contrast to ALL.
malignancies occurring among children pregnancy, and in the early years of life.
under the age of 15. Early life exposures are
important: age-specific
Eighty percent of acute childhood incidence chart Age-Specific Incidence Rates of Acute Lymphocytic Leukemia (ALL) by Race/
leukemias, including Stephen’s, Ethnicity and Acute Myeloid Leukemia (AML) for All Races Combined
are acute lymphoblastic leukemia
(ALL). Approximately 17% are acute
More Detail on
It is important to identify characteristics
of the leukemia at its presentation since Watch: Dr. Patricia Buffler
course of treatment as well as prognosis. classification (1:59 mins.)
The types of cells involved in the leukemia
Rates are not shown
(immunophenotype) are used to when based on fewer
determine whether a person has than 25 cases. Data for
whites and blacks exclude
ALL or AML. Hispanic ethnicity. Due
to sparse data for ALL
Factors such as age, initial white blood in blacks for some ages,
count at diagnosis, and cytogenetics data are shown for
combined age groups:
(the specific differences or changes 7 to 10 years, 11 to 14
in DNA) of the leukemic cells at years, and 15 to 19 years
as marked by asterisks.
diagnosis are utilized to identify the Patricia Buffler PhD MPH, Source: Surveillance,
most appropriate course of treatment. Professor of Epidemiology Epidemiology, and End
and Dean Emerita Results (SEER) program,
(deceased) of the School of 18 SEER Registries,
Public Health, University of National Cancer Institute.
California-Berkeley
Ward, et al., 2014. Used with permission.
←
Childhood Leukemia
Stephen’s Story
Stephen spent the first two weeks

of his treatment in the hospital, Treatment information
then his protocol was continued on for the general public
outpatient status. The treatment
course would be up to three years
with induction, consolidation, and For clinicians
maintenance therapy stages.
Dr. Baker warned Tricia and David
that any time Stephen had a fever
he would need to be evaluated, and About the artist
if his white blood count was low he

would need to be hospitalized.
Dr. Baker, along with the rest of the
hospital team, carefully explained
how the chemotherapy medications
work and what side effects they
“Initial Blood Test”
might expect. Stephen’s hospital stay About this painting, with the words of artist Susan Macfarlane in italics >
was difficult for his parents. Stephen
hated being away from home and click a preview image to view above
the nausea and vomiting made him
uncomfortable.
Paintings by Susan Macfarlane, reproduced with permission.

←
Childhood Leukemia
Stephen’s Story
After the initial shock of the

diagnosis and while dealing with
Stephen’s first chemotherapy course,
Tricia and David began to ask Dr.
Baker and others more questions
about what might have been the
cause of Stephen’s disease.
Childhood leukemia is difficult to Changes to DNA that
cause leukemia:
study because it is relatively rare,
which limits the design of studies
intended to help clarify its etiology
Two-Hit Model Hypothesis
(cause). Nevertheless, substantial
evidence identifying a number of risk
factors has emerged over the past
two decades. The etiology is likely
TEL-AML1 Gene Fusion
to be attributable to a mixture of
genetic and environmental factors
and may vary by subtype or for ALL,
immunophenotype.
As with some cancers, it is thought
that childhood leukemia is a result of
distinct exposures during two time
periods.
←
Childhood Leukemia
Stephen’s Story
Changes to DNA that cause leukemia:
After the initial shock of the Two-Hit Model Hypothesis
Stephen’s first chemotherapy course, Childhood
Tricia and David began to ask Dr. leukemia results
Baker and others more questions from more than
about what might have been the one insult to DNA
Researchers consider
Childhood leukemia is difficult to Changes to DNA that cancer to often be a
cause leukemia: result of more than one
temporal event. For
which limits the design of studies childhood ALL and AML,
intended to help clarify its etiology there are two exposure
Two-Hit Model Hypothesis windows: one prenatal
(cause). Nevertheless, substantial
(before conception or in
evidence identifying a number of risk utero), when leukemia
factors has emerged over the past is commonly initiated
through chromosomal
two decades. The etiology is likely This model is supported by Note: 1% refers to an
TEL-AML1 Gene Fusion rearrangements, and evidence that the genetic estimated frequency of
to be attributable to a mixture of a second, postnatal changes are far more transition between covert
genetic and environmental factors window that is linked to frequent than the actual pre-leukemia and overt
the emergence of overt clinical leukemia. Infant ALL
and may vary by subtype or for ALL, disease. This suggests
and AML (<1 year of age) has
disease through secondary that initiation of leukemia
immunophenotype. genetic changes. may be a common event,
a much-abbreviated natural
history in which all the
As with some cancers, it is thought but the second “hit” that necessary genetic events are
transitions to ALL or AML thought to occur prenatally.
that childhood leukemia is a result of is rare (Greaves, 2006). Greaves, 2006, graphic used
distinct exposures during two time with permission.
periods.
←
Childhood Leukemia
Stephen’s Story
Changes to DNA that cause leukemia:
After the initial shock of the Translocations Associated with ALL Occur In Utero:
Stephen’s first chemotherapy course,
Tricia and David began to ask Dr. Chromosone 12, TEL gene
Baker and others more questions

about what might have been the Chromosone 21, AML-1 gene

Changes to DNA that Translocation (12:21)
Childhood leukemia is difficult to TEL/AML-1 fusion gene
cause leukemia:
which limits the design of studies
intended to help clarify its etiology Results from FISH (fluorescent in-situ hybridization) study • Occurs in approximately
Two-Hit Model Hypothesis
(cause). Nevertheless, substantial – Shows chromosomal fragments from 12 (green) and 21 20-25% of patients with pre
(red) switched. B-cell ALL (the most common
evidence identifying a number of risk type of childhood ALL) with
One of the common chromosomal abnormalities
factors has emerged over the past that has been identified is called the translocation
peak incidence between
ages 2 – 5 years.
two decades. The etiology is likely TEL-AML, where there is a shift of genes between • Strong evidence that this
to be attributable to a mixture of chromosome 12 and 21. occurs in utero.
genetic and environmental factors This translocation has been identified in blood • Frequency of this
specimens that are collected at birth. It indicates translocation at birth is
and may vary by subtype or for ALL, that there is an already ongoing process of DNA 100-fold greater than the
immunophenotype. insult; however we know that not all of the risk of developing the
children with this translocation at birth develop corresponding leukemia.
As with some cancers, it is thought childhood leukemia.
that childhood leukemia is a result of Therefore, there may be another process after birth
distinct exposures during two time that is necessary to lead to a full-blown childhood
periods. leukemia disease.
Graphics source: Greaves, 2000, used with permission.

←
Childhood Leukemia
Stephen’s Story
Since childhood leukemia is a rare

disease and it takes many cases
to identify environmental risk
factors, the Childhood Leukemia
International Consortium (CLIC)
was established in 2007 (locations
represented by the white dots on
the map at right). CLIC develops
and supports collaborations among
member groups to identify factors
that influence the risk of childhood
leukemia through epidemiological
studies and related research.
This consortium serves to strengthen
the available data set regarding the
role of environmental and genetic
risk factors and critical windows
of exposure, as well as to provide a
more robust translation to clinical
audiences worldwide.
←
Childhood Leukemia
Stephen’s Story
Factors associated with risk

for childhood leukemia
One of the hospital’s pediatric residents
asks Dr. Baker about the risk factors for
childhood leukemia.* Dr. Baker mentions
that this would be a great topic for
everyone to hear at rounds and asked
the resident to review the literature
and develop a presentation.
The resident reported that there
are many epidemiologic (human)
studies that find exposures to certain
groups of chemicals, air pollution,
tobacco smoke, and radiation to be
consistently associated with increased
risk for a child developing leukemia.
Additionally, some factors are
associated with a protective effect such
as early supplementation with folate.
*In the following pages of Stephen’s story we de-
scribe environmental and genetic factors signifi-
cantly associated with increased leukemia risk.
Keep in mind, however, that childhood leukemia
“Weekly Co-Ordinating Meeting”
is a relatively uncommon disease. Thus, even if a by Susan Macfarlane,
person were exposed to something that doubled reproduced with permission.
the risk of developing leukemia, the risk for that About this painting, with words of
person would remain quite low.
←
Childhood Leukemia
Stephen’s Story
Factors associated with risk

for childhood leukemia
Pesticides, solvents,
air pollution,
tobacco
Dr. Baker is careful to note that, “Scientists and smoke
Key Concept:
policy makers will continue to study and debate for Causation vs. radiation
years to come whether these associations are truly Association
causal. And, there are also ethnic and demographic nutrition
factors associated with leukemia risk. Interactions
among risk factors and their common co-occurrence toxicants
make it even more difficult to establish the cause
of leukemia in a particular person or to identify
the most important determinants of leukemia in a
population. But, many environmental exposures
associated with leukemia are also associated with
other health problems, such as neurodevelopmental social and
disabilities, asthma and other respiratory diseases, early childhood
and reproductive disorders. For all these reasons, environments infectious
most people would want to avoid exposure as agents
much as possible. The association with cancer is an
©stephenburdickdesign.com
additional reason.”
He adds, “Some of these exposures simply cannot be
Multiple Factors
reduced by individual action alone. Rather, in some Associated with Risk to
instances, policy interventions that reduce exposures genetics
across the entire population will be necessary and Childhood Leukemia
more effective.”
Childhood cancer risk also generally shares a
number of common themes that we have seen in
other disorders highlighted in A Story of Health,
such as greater susceptibility during certain periods
of development, underlying genetic risk factors, and
gene-environment interactions.
←
Childhood Leukemia
Stephen’s Story
Trends in the Age-Adjusted Incidence Rate of
Trends in the Age-‐Adjusted Incidence Rate of
Childhood Leukemia: Childhood Leukemia and Acute Lymphocytic
Childhood Leukemia and Acute Lymphoctyic
Leukemia, Ages 0-14, SEER 9, 1975-2011
Leukemia, Ages 00-‐14, SEER 9, 1975-‐2011
US Trends Leukemia (APC, 0.71*)
Acute Lymphocy?c Leukemia (APC, 0.81*)
Ethnic Trends
Although childhood leukemia is still 60
rare, Stephen is one of a growing

number of children with this cancer. 50
Childhood leukemia incidence has Genetic susceptibility

to leukemia in
been increasing in the US (0.8% per
Rate per 1,000,000

40
Hispanics
year) during the last two decades.
30
In the US, between 1975 and 2010,
the rate of leukemia among children
0-14 years increased 0.7% per year. 20
This adds up to a 55% increase over

35 years. 10
0
Year of Diagnosis
*The Annual Percent Change (APC) is significantly different from zero at

alpha=0.5
Source: Surveillance, Epidemiology, and End Results (SEER) Program
(www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs
Research Data, Nov 2013 Sub (1973-2011) <Katrina/Rita Population
Adjustment>

←
Childhood Leukemia
Stephen’s Story
Ethnic Trends:
Childhood leukemia is increasing more amongst
Childhood Leukemia: certain ethnic groups such as Hispanics
US Trends California with its large population and Hispanic Black children, it is increasing
excellent data collection on cancer is the at 1.7% per year amongst them. This is
Ethnic Trends location of one of the largest studies compared with an increase of 0.7% in non-
Although childhood leukemia is still designed to look at causes of childhood Hispanic White children. The rate seems to
rare, Stephen is one of a growing leukemia. Hispanic babies account for be stable among Asian/Pacific Islanders.
about half of all births in CA, making it a
number of children with this cancer. good place to examine possible genetic
These trends may represent an interaction
between predisposing genetics and
Childhood leukemia incidence has Genetic susceptibility and environmental interactions that may
underlie the recognized higher incidence
environmental exposures.
to leukemia in
been increasing in the US (0.8% per Hispanics of leukemia in children of Hispanic origin. Not only do Hispanic children have the
highest incidence of leukemia but it is
year) during the last two decades. On average, childhood leukemia has been growing faster than in the non-Hispanic
increasing 1.1% per year in Hispanics since White population.
In the US, between 1975 and 2010, 1988. Though much more rare in non-
the rate of leukemia among children
Trend in the Age-Adjusted Incidence Rate of Leukemia Among
0-14 years increased 0.7% per year. Children Aged 0-14 Years by Race/Ethnicity, CA, 1988-2009
This adds up to a 55% increase over
35 years.
Hispanic (AAPC, 1.1*)
All Races (AAPC, 1/1*)
Non-Hispanic White (AAPC, C.7)
Asian/Pacific Islander (AAPC, 0.1)
Non-Hispanic Black (AAPC, 1.7*)
*The Average Annual Percent

Change (AAPC) is significantly
different from zero at alpha = 0.05.
Source: California Cancer Registry,
California Dept. of Public Health,
Chronic Disease and Research Branch.
SEER*Database Incidence -
California, February, 2013,
(1988-2010) 4/15/2013.
Incidence rates per 100,000 of

leukemia in California Children 0-14,
by race, 1988-2009. Based on data
from the California Cancer Registry,
California Dept. of Public Health,
*Statistically significant result.
←
Childhood Leukemia
Stephen’s Story
Childhood Leukemia:
US Trends
Although childhood leukemia is still
Ethnic Trends Genetic susceptibility to leukemia in Hispanics
rare, Stephen is one of a growing Leukemia is more common among Hispanic factors varies by ethnicity: the frequency
Americans compared to other ethnicities. of many genetic factors is higher in Native
number of children with this cancer. While the causes of this are still uncertain, Americans and Hispanics than in whites
what is now clear is that part of the answer and blacks. These genetic polymorphisms
Childhood leukemia incidence has Genetic susceptibility
is genetics. There are several rare genetic in the genes, ARID5B, GATA3, PIP4K2A,
to leukemia in
been increasing in the US (0.8% per Hispanics
syndromes that predispose strongly for and CEBPE, collectively account for a
childhood leukemia, but account for only a large proportion of the increased risk of
year) during the last two decades. few cases among any ethnic group. There leukemia in Hispanics. There are also likely
are much more common genetic factors to be environmental risk factors that also
In the US, between 1975 and 2010, which contribute weakly to leukemia contribute to the increased risk in Hispanics
the rate of leukemia among children risk, but due to their high frequency they including lifestyle and exposures from
are responsible for a larger proportion occupation, which are known to vary in
0-14 years increased 0.7% per year. of leukemia incidence. Interestingly, the frequency between ethnicities.
This adds up to a 55% increase over proportion of these common genetic
35 years.
←
Childhood Leukemia
Stephen’s Story
Pesticides and leukemia

At their next visit to Dr. Baker,
Tricia mentions that she heard from
a friend that pesticides might cause
leukemia. This reminds Dr. Baker of
the information on environmental
exposures and childhood leukemia
Pesticide Exposure
that the pediatric resident presented in Children: Policy
during rounds. Dr. Baker asks Statement from the
if Stephen could have come into American Academy
of Pediatrics
contact with any pesticides and
specifically asks about pesticide use
in the home and garden. Tricia says
that they own a plant nursery and
garden center, and they use some
pesticides. Stephen sometimes visits
the nursery after preschool and on
weekends.
←
Childhood Leukemia
Stephen’s Story
Residential Pesticide Exposures
Pesticides
How to read and
interpret the figure
Tricia mentions to Dr. Baker that at right. What is a
other families in the neighborhood meta-analysis?
have regular pesticide applications to
Pesticide Regulation
the perimeter of their house and some
have lawn service, but they do not. Find a local Pediatric
Tricia thought that Stephen’s daycare Environmental Health
Specialty Unit (PEHSU):
might occasionally use pesticides to A respected network
spray for ants and flying insects. of experts in children’s
Dr. Baker consulted the pediatrician environmental health. In a meta-analysis by Turner et al. (2010), residential
at his regional Pediatric Environ- insecticide use during pregnancy was associated with a
Watch: Dr. Catherine doubling of risk for childhood leukemia (OR*=2.05). The
mental Health Specialty Unit, who association was somewhat stronger for ALL than AML, and
Metayer discusses
confirmed that many studies from insecticides and was found to be consistent over a variety of study designs.
around the world have found herbicides (4:15 mins.) Differences in leukemia risk associated with residential
statistically significant associations and occupational pesticide exposures may be due to
differences in chemical doses and co-exposures.
between pesticide exposure and
*OR= Odds ratio
childhood leukemia.
Turner, 2010. Graphic used with permission.
Catherine Metayer MD PhD, Associ-

ate Adjunct Professor, Epidemiol-
ogy/Biostatistics and Epidemiology,
University of California-Berkeley,
Principal Investigator, Center for
Integrative Research on Childhood
Leukemia and the Environment
←
Childhood Leukemia
Stephen’s Story
Residential Pesticide Exposures
Pesticides
How to read and
other families in the neighborhood meta-analysis?
have regular pesticide applications to
the perimeter of their house and some
have lawn service, but they do not. Find a local Pediatric
Tricia thought that Stephen’s daycare Environmental Health
Specialty Unit (PEHSU):
might occasionally use pesticides to A respected network
spray for ants and flying insects. of experts in children’s What is a meta-analysis?
Dr. Baker consulted the pediatrician environmental health. A meta-analysis uses statistical methods A graphic known as a Forest Plot
at his regional Pediatric Environ- to combine the results of different (shown above) is often used to display
Watch: Dr. Catherine studies in order to identify an overall the results of a meta-analysis. The size
mental Health Specialty Unit, who trend in the data. Generally, studies are of the square is proportional to the
Metayer discusses
confirmed that many studies from insecticides and grouped by a common measurement, weight assigned to the study.
around the world have found herbicides (4:15 mins.) and some studies are excluded on the The horizontal line is the study’s
basis of quality or study design.
statistically significant associations confidence interval (a measure of how
Certain studies are given more weight the results might vary due to chance).
between pesticide exposure and in the meta-analysis. Weighting is The vertical line at 1 represents “no
childhood leukemia. usually related to the sample size in the effect.” If the confidence intervals for
individual studies. individual studies overlap with this
This method can have some limitations. line, it demonstrates that there is no
It usually relies on published studies, statistically significant effect observed.
which may exclude studies that show The diamond represents the summary
negative or insufficient results that are measure of all studies combined.
less likely to be published. Additional
ate Adjunct Professor, Epidemiol- bias can also skew the results if studies
More information: “5 Key Things
ogy/Biostatistics and Epidemiology, are cherry-picked using unsound
University of California-Berkeley, to Know about a Meta-Analysis”
Principal Investigator, Center for methodology for selecting studies.
Scientific American blog post
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Childhood Leukemia
Stephen’s Story
Pesticides
How to read and Pesticide Regulation
EPA and each of the fifty states applicants. Where pesticides may be
other families in the neighborhood register or license pesticides for use in used on food or feed crops, EPA also
meta-analysis?
the US. EPA receives its authority to sets tolerances (maximum pesticide
have regular pesticide applications to register pesticides under the Federal residue levels) for the amount of the
the perimeter of their house and some Insecticide, Fungicide, and Rodenticide pesticide that can legally remain in or
have lawn service, but they do not. Act (FIFRA). States are authorized to on foods. Already-registered pesticides
Find a local Pediatric regulate pesticides under FIFRA and are supposed to undergo periodic
Tricia thought that Stephen’s daycare Environmental Health under state pesticide laws. States may tolerance reassessment and registration
Specialty Unit (PEHSU): place more restrictive requirements on review.
might occasionally use pesticides to A respected network pesticides than EPA. Pesticides must be A recent analysis of EPA practices,
spray for ants and flying insects. of experts in children’s registered both by EPA and the state however, concluded that the
Dr. Baker consulted the pediatrician environmental health. before distribution. government has allowed the majority
at his regional Pediatric Environ- Before registering a new pesticide or of pesticides onto the market without
mental Health Specialty Unit, who Watch: Dr. Catherine new use for a registered pesticide, a public and transparent process and
Metayer discusses EPA is supposed to ensure that the in some cases, without a full set of
confirmed that many studies from insecticides and pesticide, when used according to toxicity tests, using a loophole called
around the world have found herbicides (4:15 mins.) label directions, can be used with a a conditional registration. In fact, as
statistically significant associations reasonable certainty of no harm to many as 65 percent of more than 16,000
human health and without posing pesticides were first approved for the
between pesticide exposure and unreasonable risks to the environment. market using this loophole (NRDC,
childhood leukemia. To do that, EPA is authorized to require 2013).
various scientific studies and tests from
Link to EPA website for more
information on FIFRA

ate Adjunct Professor, Epidemiol-
ogy/Biostatistics and Epidemiology,
University of California-Berkeley,
Principal Investigator, Center for
←
Childhood Leukemia
Stephen’s Story
Occupational Pesticide Exposures
Occupational exposures
Sample prenatal
during pregnancy may environmental health
contribute to childhood history form

for clinicians from
leukemia risk the Consortium
for Reproductive
Dr. Baker asked a few more details Environmental health in
Minority Communities
about the garden center. Tricia said
she worked in the back office while
she was pregnant, up until a few
months before Stephen was born.
Pesticides, solvents, and other
chemicals may cause chromosomal
alterations in parents’ eggs and sperm
cells that increase the risk of their
children developing certain cancers,
or maternal exposure may affect the
child directly while in utero. The largest analysis combining were found for childhood ALL. This
Studies have demonstrated a link between original data from studies (1,329 forest plot of pooled data shows
maternal occupational exposures to cases) around the world found a near individual and summary odds ratios
doubling of risk for AML if mothers for maternal occupational pesticide
pesticides and childhood leukemia. were exposed occupationally to exposure during pregnancy and the
Maternal use of pesticides at home has pesticides during pregnancy OR risk of AML in the offspring, using
also been associated with AML risk. In 1.94 (CI 1.19, 3.18). No associations random effects model.
case studies, maternal exposure to certain Source: Bailey, et al., 2014.
insecticides has been associated with Reproduced with permission.
translocations seen in children with AML.

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Childhood Leukemia
Stephen’s Story
Paternal occupational exposures

around time of conception may
contribute to childhood leukemia risk
Analysis of data (pooled) from studies around the
world, including over 8,000 cases of childhood
leukemia showed a 20% increased risk of ALL
associated with paternal occupational exposure to Key Concept:
pesticides around the time of conception. The risk Take-Home
was about 40% increased in children whose diagnosis Exposures
was at age 5 years or greater and in those with T cell
ALL. This highlights the importance of considering
both critical windows of exposure as well as the
different sub-types of leukemia when possible.
Though “pesticides” includes a wide variety of
different chemicals and these findings do not
implicate specific agents, more than 20 pesticides have
been classified as “possible” or “probable” human
carcinogens by the International Agency for Research
on Cancer (IARC).
Paternal exposures to solvents, paints, and
employment in motor vehicle-related occupations
have also been shown to be associated with
childhood leukemia. Paternal exposures before
conception could result in germ cell damage or
changes in gene expression. Parental exposures
after the child is born may result in exposure to the
family by materials from work being brought home
on clothing.
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Childhood Leukemia
Stephen’s Story
Paternal occupational exposures

around time of conception may
contribute to childhood leukemia risk
Analysis of data (pooled) from studies around the Key concept:
world, including over 8,000 cases of childhood Take-Home Exposures
leukemia showed a 20% increased risk of ALL
associated with paternal occupational exposure to Key Concept:
A “take-home” exposure refers to
pesticides around the time of conception. The risk Take-Home
exposure of a child (or other household
was about 40% increased in children whose diagnosis member) to chemicals, fibers, metals,
Exposures
was at age 5 years or greater and in those with T cell or dusts brought home from a work
site by a parent or from someone else.
ALL. This highlights the importance of considering
Examples of take home exposures have
both critical windows of exposure as well as the included solvents, heavy metals, and
different sub-types of leukemia when possible. pesticides. These can be brought into
If hazardous substances are used by
Though “pesticides” includes a wide variety of the home on family members’ or visitors’
individuals working at home, care
different chemicals and these findings do not clothing or shoes. Workers might also
should be taken to keep the work and
bring home chemicals from work and
implicate specific agents, more than 20 pesticides have living areas separate – and hazardous
use them around the house.
been classified as “possible” or “probable” human materials should be stored and disposed
carcinogens by the International Agency for Research Take home exposures can be prevented of properly.
by actions such as:
on Cancer (IARC). Similarly, hobbies such as painting,
• Changing clothes at work model building, furniture refinishing,
Paternal exposures to solvents, paints, and
• Showering before leaving work and auto repair often involve using
employment in motor vehicle-related occupations solvents. Children and pregnant or
have also been shown to be associated with • Laundering work clothes separately
breastfeeding women and children
childhood leukemia. Paternal exposures before • Removing shoes before entering should avoid these exposures.
conception could result in germ cell damage or the home
changes in gene expression. Parental exposures • Not using chemicals at home that are More information: Pesticide
after the child is born may result in exposure to the meant to be used in the workplace Safety Information from the
family by materials from work being brought home California EPA
on clothing.
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Childhood Leukemia
Stephen’s Story
EXPOSURES TO PAINTS AND SOLVENTS MAY

INCREASE RISKS
David thought back to painting the nursery while
Tricia was pregnant and wondered if using paint or
paint thinners had exposed Stephen to substances
linked to the development of leukemia.
In one study of household use of paints and
solvents, paint was associated with a 65% increase
in ALL risk, and risk was higher with postnatal or
frequent use.* When the analysis was restricted to
the translocation (12;21) the risk increased four-
fold.* Solvents were associated with a two-fold
increased AML risk* (Scelo et al., 2009).
While some previous studies do not identify
increased risks, other studies support these findings
(Freedman et al., 2001; Bailey et al., 2010). In
addition, a number of studies of exposure to
gasoline and traffic exhaust find elevated risks. These
complex exposures include a variety of solvents (see
next section on traffic exposure). Many solvents
are recognized carcinogens. While studies of the
relationship between solvent exposure and childhood
leukemia risk are not as extensive as those examining
tobacco or pesticides, parents may wish to avoid
paint and solvent exposures (when feasible) during
the immediate pre-conception period and pregnancy.
This will also help lower the risk of other adverse
health outcomes associated with the same agents.
*Statistically significant
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Childhood Leukemia
Stephen’s Story
Traffic-related air pollution

may increase childhood
leukemia risk
Living near major roadways results in
exposure to many potential carcinogenic
substances. Estimates place as much as
10% of the U.S. population and as many
as 30-45% of urban residents living near
major roadways.
Studies have suggested that chemicals
and other components of air pollution
may contribute to childhood leukemia.
A recent meta-analysis of seven studies
from Europe and the United States
conducted by the CDC suggests that
living near highly trafficked roadways
after birth increases children’s risk for
leukemia by over 50% (OR 1.53; 95%
CI 1.12, 2.10) (Boothe et al., 2014).
Studies examining exposure to benzene,
one component of air pollution (for
example, living near a gas station),
have suggested an increase in risk for
childhood leukemia. Benzene is recognized
as a cause of leukemia in adults.
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Childhood Leukemia
Stephen’s Story
Early preconception and

prenatal introduction of Preconception and Healthy
Child Development
vitamins and folate reduces
risk of childhood leukemia Prenatal Care and Healthy
Child Development
At their next visit, Dr. Baker asks Tricia
about her pregnancy with Stephen. Like
many other women, she didn’t think
about taking vitamins before or during Folate supplementation
the first two months of the pregnancy, recommendations
especially because she ate a nutritious for women
diet. Otherwise she was very careful to
live a healthy lifestyle while pregnant and
did not smoke or drink. She started on Studies on Folate
prenatal vitamins with folate at her first and Leukemia
prenatal visit at eight weeks gestation.
Folate supplementation has been
associated with reductions in risk for
childhood leukemia, at least for those at
risk for lower folate consumption. Folate
supplementation before conception and
early in pregnancy not only appears to
be protective in the case of leukemia risk,
but also reduces neural tube and other
birth defects, and may reduce the risk of
developing autism. (Schmidt et al., 2012;
Suren et al., 2012)
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Childhood Leukemia
Stephen’s Story
Preconception and Healthy Child Development
Child Development
Preconception care for women
and men is important for lifetime
vitamins and folate reduces health as well as healthy child
development.
Child Development
about her pregnancy with Stephen. Like All women and men can benefit workplace toxicants like lead and
from healthy habits throughout life, pesticides on their clothing, resulting
many other women, she didn’t think whether or not they plan to have a in direct exposures to other family
about taking vitamins before or during Folate supplementation baby one day. These include eating members. (Gerson et al., 1996; Fenske
the first two months of the pregnancy, recommendations healthy food, getting regular exercise, et al., 2013)
especially because she ate a nutritious for women avoiding toxic substances, and Nutritionally, a prospective father’s
reducing excessive stress. diet that is deficient in folate (a “B”
diet. Otherwise she was very careful to
Even prior to conception some specific vitamin) increases the risk of birth
live a healthy lifestyle while pregnant and actions are important for prospective defects in his offspring. (Lambrot et
did not smoke or drink. She started on Studies on Folate parents to take because they can al., 2013). Similarly, maternal folate
prenatal vitamins with folate at her first and Leukemia influence birth outcomes. Maternal supplements in the periconceptual
prenatal visit at eight weeks gestation. exposures to toxic chemicals before period (~ 6 weeks before and after
or around the time of conception can conception) are associated with
Folate supplementation has been adversely affect the quality of eggs decreased risk of having a child
associated with reductions in risk for (ova) and newly-conceived embryos. with an autism spectrum disorder.
childhood leukemia, at least for those at But these exposures can be harmful (Lyall, 2014)
to men’s reproductive health as well. Of course optimal nutrition and
risk for lower folate consumption. Folate For example, a father’s occupational appropriate vitamin and mineral
supplementation before conception and exposure to pesticides has been supplements throughout pregnancy
early in pregnancy not only appears to associated with increased risk of some are also important to help promote
be protective in the case of leukemia risk, childhood cancers and birth defects in optimal fetal development.
but also reduces neural tube and other his offspring. (Roberts et al., 2012).
Parents can also take home from the More information: CDC’s
birth defects, and may reduce the risk of Preconception care for
developing autism. (Schmidt et al., 2012; women and men
Suren et al., 2012)
Image source: Centers for Disease Control
and Prevention, used with permission
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Childhood Leukemia
Stephen’s Story
Prenatal Care for Healthy Development
Child Development
vitamins and folate reduces
Child Development
about her pregnancy with Stephen. Like The fetus can be harmed Positive actions to More information:
many other women, she didn’t think by environmental protect the fetus: • CDC on pregnancy
about taking vitamins before or during exposures including:

Folate supplementation • Avoid smoking or • American Congress
the first two months of the pregnancy, recommendations • Mom’s smoking and drinking, of Obstetrics
second hand smoke, and Gynecology
especially because she ate a nutritious for women
• Mom’s drinking alcohol • Maintain a healthy diet, (ACOG):
diet. Otherwise she was very careful to - Good Health
live a healthy lifestyle while pregnant and and her exposure to other • Supplement with prenatal Before
solvents like those in certain vitamins, including folic Pregnancy (pdf)
did not smoke or drink. She started on Studies on Folate paints, and in products -
Prenatal Nutrition
prenatal vitamins with folate at her first acid, iodine, and vitamin
and Leukemia used in nail salons, - Environmental
prenatal visit at eight weeks gestation. D if maternal serum levels
• Mom’s exposure to lead, are inadequate,
Chemicals
Folate supplementation has been mercury (from some • Royal Congress

associated with reductions in risk for fish and other sources), • Avoid toxicants. of OB/GYN:
pesticides, PCBs (banned - Chemical
childhood leukemia, at least for those at in the US but still found Exposures During
risk for lower folate consumption. Folate in the environment) and Pregnancy
supplementation before conception and certain polybrominated • UCSF: Program
early in pregnancy not only appears to diphenyl ethers (PBDEs – on Reproductive
be protective in the case of leukemia risk, a family of chemicals long- Health and the
Environment
but also reduces neural tube and other used as flame retardants
in foam and furniture),
birth defects, and may reduce the risk of among others.
developing autism. (Schmidt et al., 2012;
Suren et al., 2012) Image source: Centers for Disease Control
and Prevention, used with permission
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Childhood Leukemia
Stephen’s Story
Critical Windows of Exposure Key Concept:

Windows of
to Tobacco Smoke Vulnerability
David smoked before Stephen was born
but quit when his wife found out she Map: Percent
was pregnant. Current Adult
Smokers by State
We know that tobacco smoke could be
affecting the development of the fetus
and the child during pregnancy and
during the early years of life. We also
know that tobacco smoke can affect the
germ cells. Smoking Cessation
Resources:
That means at the time of conception,
or even before conception, tobacco Free Help to Quit
Smoking (Nat’l Cancer
smoke may have an effect. Exposures
Institute)
during multiple time periods may add
Getting Help to Quit
additional risk. Smoking (American
Lung Assoc.)
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Childhood Leukemia
Stephen’s Story
Critical Windows of Exposure Key Concept:

Windows of
Key concept:
David smoked before Stephen was born Windows of Vulnerability
A window of vulnerability is a time Time windows of vulnerability
window(s) during pregnancy or child can be relatively long and extend
Smokers by State
We know that tobacco smoke could be development when the fetus, infant, throughout fetal and infant
affecting the development of the fetus or child is especially susceptible to development, or they can be
particular environmental exposures, relatively short and precise. For
general environmental deprivation, example, thalidomide can cause
during the early years of life. We also suboptimal nutrition, or psychosocial severe limb abnormalities if exposure
know that tobacco smoke can affect the stress. Exposures during these time occurs in the fetus 20-36 days
germ cells. Smoking Cessation windows can disrupt important after conception. Alternatively,
Resources: developmental processes, altering the manifestations of fetal alcohol
Free Help to Quit structural or functional development exposure can vary considerably
or even before conception, tobacco of various organs or physiologic depending on the timing and extent
smoke may have an effect. Exposures systems, with potential lifelong of exposure throughout pregnancy.
Institute)
during multiple time periods may add consequences. .
Getting Help to Quit
Lung Assoc.)
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Childhood Leukemia
Stephen’s Story
Percent Current Adult

Critical Windows of Exposure Key Concept: Smokers by State
Windows of
David smoked before Stephen was born
Smokers by State
We know that tobacco smoke could be
affecting the development of the fetus
during the early years of life. We also
know that tobacco smoke can affect the
germ cells. Smoking Cessation
Resources:
or even before conception, tobacco Free Help to Quit
smoke may have an effect. Exposures
Institute)
during multiple time periods may add
Getting Help to Quit Percent Current Smokers
Lung Assoc.) 9%-12%
12%-16%
Data Source: Centers for Disease Control
and Prevention Behavioral Factor Surveillance
17%-20% System. Smoking Prevalence accessed from
Environmental Public Health Tracking Network:
21%-27% www.cdc.gov/ephtracking. Graphic used with
permission.
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Childhood Leukemia
Stephen’s Story
Exposure to father smoking Paternal smoking Exposure to father smoking before birth combined with postnatal
associated with
before birth combined increased risk of
exposure to SHS result in increased risk for childhood B-cell ALL
with postnatal exposure specific leukemia

subtype
FATHER
smoked
CHILD
exposed
Number
of cases
Number
of controls
OR
(95% CI)
to Second- hand smoke Tobacco Smoke
before birth to passive (n=689) (n=975)
smoking
result in increased risk for and Childhood
AML No No 444 670 Reference
childhood B-cell ALL No Yes 90 127 0.94 (0.69-1.27)
Prenatal and postnatal exposures to Germ Cell
Yes No 44 74 0.90 (0.57-1.41)
environmental tobacco smoke are Formation
Yes Yes 104 88 1.60 (1.07-2.38)*
associated with increased childhood
Watch: For clinicians:
leukemia risk. Paternal smoking, in The odds ratios are derived from logistic regression, adjusted for age, sex,
Dr. Joe Wiemels discusses
particular, prior to conception has race/ethnicity, household income, and maternal smoking.
timing of environmental
*p-value for interaction <0.05
also been linked to increased risk of exposures (2:23 mins.)
childhood acute lymphoblastic leukemia Graphic: Based on Metayer et al.,
(ALL). Father’s smoking before birth 2013, used with permission
combined with second-hand smoke,

from any source, after birth increases
risk for childhood leukemia. This
seems to support the two-hit model
previously discussed.
Studies of maternal smoking are
inconsistent. There could be several Joseph L. Wiemels PhD,
reasons for negative findings including Professor, Division of
maternal under-reporting or fetal loss. Cancer Epidemiology
Differences in how eggs and sperm Leukemia & Lymphoma
Society Scholar in Clinical
are formed may also account for these Research, University of
differences. California-San Francisco
School of Medicine
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Childhood Leukemia
Stephen’s Story
Joint Effect of Paternal Smoking and Early Childhood Exposure to
Exposure to father smoking Paternal smoking Passive Smoking on Risk of Childhood B-cell ALL with Translocation
associated with
before birth combined increased risk of
FATHER
smoked
CHILD
exposed
Number
of cases
Number
of controls
OR
(95% CI)
subtype
before birth to passive (n=130) (n=975)
smoking
No No 82 670 Reference
AML No Yes 12 127 0.69 (0.36-1.32)
childhood B-cell ALL Yes No 8 74 0.85 (0.35-2.03)
Prenatal and postnatal exposures to Germ Cell Yes Yes 26 88 2.08 (1.04-4.16)*
environmental tobacco smoke are Formation
The odds ratios are derived from logistic regression, adjusted for
associated with increased childhood age, sex, race/ethnicity, and household income.
Watch: For clinicians:
leukemia risk. Paternal smoking, in *p-value for interaction =0.01
particular, prior to conception has timing of environmental
also been linked to increased risk of exposures (2:23 mins.) Graphic: Based on Metayer et al., 2013,
used with permission
childhood acute lymphoblastic leukemia
(ALL). Father’s smoking before birth
combined with second-hand smoke, Paternal smoking associated with increased
from any source, after birth increases risk of specific leukemia subtype
risk for childhood leukemia. This This analysis separates the different birth (including preconception and
seems to support the two-hit model time windows before and after birth. prenatal exposure) and when the
child was also exposed after birth.
previously discussed. Exposure to tobacco smoke was
associated with an increased risk only The identified risk is higher when
Studies of maternal smoking are of the translocation (12;21) but not restricted to this specific molecular
inconsistent. There could be several Joseph L. Wiemels PhD, the hyperdiploid subtype. subtype of leukemia.
reasons for negative findings including Professor, Division of Excess risk of childhood B-cell ALL, Fathers who smoked pre-conceptionally
maternal under-reporting or fetal loss. Cancer Epidemiology with the specific translocation can still impact their child’s risk by
Differences in how eggs and sperm Leukemia & Lymphoma not exposing them to passive smoke.
(12;21), is prominently identified
when the father was smoking before
School of Medicine
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Childhood Leukemia
Stephen’s Story
Exposure to father smoking Paternal smoking

Exposure to Tobacco Smoke Increases
associated with
before birth combined increased risk of Risk of Childhood AML
subtype
Childhood AML is very difficult to
study because it only makes up a
Although the numbers in this
analysis are relatively small, this
fraction of all childhood leukemias.
Tobacco smoke contains known
shows a similar pattern as ALL
in that exposure in the home to
AML
carcinogens, and smoking is tobacco smoke doubled the risk of
recognized to cause adult AML (IARC, getting AML for those subtypes that
childhood B-cell ALL 2002). have structural abnormalities like
Prenatal and postnatal exposures to Germ Cell One recent study found that a child’s translocation, deletion, or inversion
Formation (OR = 2.76;95% CI 1.01-7.58) (Metayer
environmental tobacco smoke are passive exposure to tobacco smoke
et al. 2013).
associated with increased childhood in the home is associated with a 40%
Watch: For clinicians: higher risk of AML (OR = 1.41).
leukemia risk. Paternal smoking, in
particular, prior to conception has timing of environmental
also been linked to increased risk of exposures (2:23 mins.)
childhood acute lymphoblastic leukemia
(ALL). Father’s smoking before birth
combined with second-hand smoke,
from any source, after birth increases
risk for childhood leukemia. This
seems to support the two-hit model
previously discussed.
Studies of maternal smoking are
inconsistent. There could be several Joseph L. Wiemels PhD,
reasons for negative findings including Professor, Division of
maternal under-reporting or fetal loss. Cancer Epidemiology
Differences in how eggs and sperm Leukemia & Lymphoma
School of Medicine
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Childhood Leukemia
Stephen’s Story
Doctor – is any one risk

factor the identifiable cause
of Stephen’s leukemia?
Ecological
Toward the end of their clinic visit, Tricia Approach to
and David were visibly distressed about Disease
all of the potential factors that could
have contributed to their son’s leukemia.
Dr. Baker told Tricia and David that
they cannot blame themselves for their
son’s disease. He explained, for example,
that studies examining the link between
pesticide exposures and leukemia involve
Watch: Dr. Gary Dahl
fairly large groups of people and cannot discusses the clinic visit
be used to establish the cause of disease (3:08 mins.)
in an individual. He pointed out that
most children exposed to pesticides do
not get leukemia and in most cases
there is no clear explanation for the
cause of a specific child’s leukemia.
He added, that due to health concerns
about exposures to environmental
toxicants, it would be a good idea “Playschool.”
for everyone to minimize their by Susan Macfarlane,
exposures to them. About this painting, with words of the
artist in italics >
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Childhood Leukemia
Stephen’s Story
Some Children are at Key Concept:

Epigenetics
Higher Risk
A few months after Stephen began
treatment, Tricia and David start
chatting with a customer, Lynn, while
she is purchasing plants at their garden
center. Tricia recognizes Lynn’s daughter
Ava in the shopping cart because she
used to be in Stephen’s child care.
Ava has Down syndrome. Lynn asks
about Stephen, who is napping nearby. Family History
Tricia explains about Stephen’s illness. and Childhood
Lynn mentions that their pediatrician Leukemia
told her that kids with Down syndrome
are at higher risk for leukemia (10-20-
Genetic conditions with
fold higher risk). Fortunately, fewer increased incidence of ALL:

than one percent of children with Down
syndrome get childhood leukemia.
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Childhood Leukemia
Stephen’s Story
Key concept:
Epigenetics
Some Children are at Key Concept:
Cancer is an epigenetic disease as much
Epigenetics
Higher Risk as it is a genetic disease; fully 10% of the
leukemia genome is epigenetically altered
compared to normal blood cells. Some
A few months after Stephen began of these alterations may be a result of
treatment, Tricia and David start adaptations to our environment very early
chatting with a customer, Lynn, while in our development. Such adaptations
may be appropriate at the time, but have
she is purchasing plants at their garden consequences later for disease risk. Such
center. Tricia recognizes Lynn’s daughter an idea was well explained in the Barker Watch: Dr. Mark Miller discusses
Hypothesis (developmental origins of
Ava in the shopping cart because she health and disease), now known to have epigenetics (1:45 mins)
used to be in Stephen’s child care. epigenetic mechanisms.
What is Epigenetics?
Ava has Down syndrome. Lynn asks The genetic code, or DNA sequence, is
about Stephen, who is napping nearby. Family History
exactly the same in each body cell. We
Tricia explains about Stephen’s illness. and Childhood
need some way, however, to express our
genes in a correct manner for each cell
Lynn mentions that their pediatrician Leukemia type, be it blood, bone, muscle, brain,
told her that kids with Down syndrome etc. Early in development, our genes
are encoded with a set of distinguishing
are at higher risk for leukemia (10-20- marks on top of genes, or epigenetic
fold higher risk). Fortunately, fewer marks, that influence gene expression.
than one percent of children with Down Epigenetic marks are important to all
stages of all cell types, to keep each
syndrome get childhood leukemia. Watch: Dr. Mark Miller discusses cell organized within our whole
the Barker hypothesis (1:40 min.) human organism.
Exposures to environmental chemicals,
As the extent to which epigenetic infections, and diet can result in the
mechanisms play a role in cancer turning of genes on or off. For instance,
become better understood, we will in a high pollution environment, our
also better understand the influence bodies can turn on detoxification
of environmental variables on these enzymes. In a low folic acid environ-
mechanisms. This remains a highly active ment, the body can adjust to retain
research field. more folate within our cells.
Mark Miller MD MPH, Director, Children’s

Environmental Health Program, Office of .
Environmental Health Hazard Assessment,
California EPA; Director, UCSF Pediatric
Environmental Health Specialty Unit
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Childhood Leukemia
Stephen’s Story
Home exposures via dust Watch: Dr. Todd

How do we come in contact with
After Stephen’s diagnosis, his parents Whitehead on chemical
flame-retardant chemicals?
were approached by researchers and exposures from house
asked to participate in a study to analyze dust (1:56 mins.)
their household’s dust. Stephen’s parents
wondered what could possibly be in the
house dust that would give researchers
clues as to what may cause childhood
leukemia. The researchers were very
clear that the study is designed to learn
about the possible causes of leukemia
and would not be able to pinpoint a 1) Flame retardants

specific cause of Stephen’s leukemia. are not bound
Todd Whitehead PhD, to foam.
The researchers explained that they were post-doctoral fellow,
going to analyze the dust for polychlori- School of Public Health,
nated biphenyls (PCBs) and structurally- University of California-
Berkeley
similar polybrominated diphenyl ethers 2) They off-gas
(PBDEs), classes of chemicals that can from foam and
settle into dust.
remain in the environment for long pe- PCBs in house dust.
riods of time. PCBs had many industrial 3) Dust is ingested
through hand-to-
and commercial applications, including mouth contact.
electrical equipment and building materi- PBDEs in house dust.
als. PBDEs are used as flame retardants in
plastics, textiles, and furniture.
Find out more:
These chemicals can migrate from Green Science Policy
consumer products and collect in house Institute - California’s
dust. Because children crawl on the floor policy and consumer
resources
and put their hands in their mouth, they
may be exposed to higher amounts of
chemicals commonly found in house dust
than adults.
←
Childhood Leukemia
Stephen’s Story
Infections as a Protective Factor Watch: Dr. Joe Wiemels

discusses theories about
infection and leukemia
Stephen attended preschool before he rates (3:55 mins.)
started chemotherapy.
One day, Tricia and David ran into
parents at the grocery store whose
children also attended Stephen’s
preschool. They mentioned that their
daughter had just gotten over a cold.
Tricia thought it seemed like she was
always hearing about someone getting
sick in that school, but it was one of
the larger preschools. She started to worry
about whether something was going
around at school that could have made
Stephen sick.
Stephen got several serious infections as Infection and
a young child and they emailed Dr. Baker leukemia risk
about whether this could be related to their
son’s leukemia.
Dr. Baker responded that going to a large Infection-related
pre-school could actually be protective damage leading
against childhood cancer, but that children to leukemia
with leukemia report more frequent severe
infections throughout their childhood
before diagnosis, perhaps indicating an
altered or more severe immune system
response to common infections.
←
Childhood Leukemia
Stephen’s Story

Stephen attended preschool before he rates (3:55 mins.) Immune System Modulation:
Exposure to Common Childhood Infections May Modulate the
One day, Tricia and David ran into Immune System and Reduce Leukemia Risk
parents at the grocery store whose One meta-analysis of 14 studies Another study used month of birth,
children also attended Stephen’s (shown below) indicates that day-care timing of birth in relation to cold and
preschool. They mentioned that their attendance is associated with a reduced flu season, and birth order as markers of
risk of ALL (OR = 0.76) (Urayama et al., exposure to infections. They found an
daughter had just gotten over a cold. 2010). Day-care was used as a surrogate increased risk of developing leukemia in
Tricia thought it seemed like she was measure of exposure to common children born in the spring and summer
always hearing about someone getting infections early in life. This reduced risk and who experience cold and flu season
supports the hypothesis that common at 9-12 months old (OR = 1.44) (Marcotte
sick in that school, but it was one of infections can be protective against et al., 2014). This may indicate that
the larger preschools. She started to worry exaggerated responses by the immune early mild infections could be protective
about whether something was going system that may be implicated in against leukemia.
childhood leukemia.
around at school that could have made
Stephen sick.
Stephen got several serious infections as Infection and
a young child and they emailed Dr. Baker leukemia risk
about whether this could be related to their
son’s leukemia.
with leukemia report more frequent severe Urayama et al, 2010.
infections throughout their childhood Graphic used with permission.

←
Childhood Leukemia
Stephen’s Story

Stephen attended preschool before he rates (3:55 mins.) Infection-related damage leading to leukemia
Exposure to a variety of infections specific enzyme, APOBEC, which has a
One day, Tricia and David ran into followed by an appropriate immune role in protecting our cells from viruses.
parents at the grocery store whose response is a healthy part of growing APOBEC enzyme can attack and mutate
up, and seems to decrease leukemia invading viruses causing clusters of
children also attended Stephen’s risk. However, recent advances in DNA specific mutations in the viruses, but this
preschool. They mentioned that their sequencing technology have revealed activity can result in collateral damage
daughter had just gotten over a cold. a mechanism by which strong immune to our own genetic code. Finding these
response to infections may induce mutation “signatures” in leukemia
Tricia thought it seemed like she was specific damage leading to leukemia. reveals a link between epidemiologic
always hearing about someone getting Researchers have now determined evidence that strong infections can
sick in that school, but it was one of the detailed genetic code of the trigger leukemia, and the mutations
the larger preschools. She started to worry entire genome of cancer cells from within leukemia cells themselves. We
many patients. Childhood leukemia know that leukemia results from both
about whether something was going cells have among the lowest level prenatal and postnatal genetic events
around at school that could have made of mutations compared to all other (the “two hit” hypothesis), and infection
Stephen sick. cancer types, which is not surprising in this regard represents a cause for the
since there is very little time in a second, postnatal hit. Prevention of this
Stephen got several serious infections as Infection and child’s brief life prior to diagnosis to second “hit” by modifying our responses
a young child and they emailed Dr. Baker accumulate mutations. Interestingly, to infections may lead to prevention
leukemia risk
point mutations in leukemia cells appear strategies for leukemia.
about whether this could be related to their to be predominantly produced by a
son’s leukemia.
with leukemia report more frequent severe
infections throughout their childhood
←
Childhood Leukemia
Stephen’s Story
Cancer Clusters Find out more:

Community Health
One day while waiting in the hospital for Studies and
Stephen’s treatment, Tricia and David Environmental
meet a military family who recently Contamination
moved to the area. The family tells
them about a study they learned of that
Read the Cancer
showed possible clusters of leukemia Clusters Fact Sheet
near a military base in Fallon, Nevada. from the National
A cancer cluster occurs when a greater Cancer Institute
than expected number of cancer
cases arise among people in a defined
geographic area over some time. Due
to the nature of the disease and the
time it takes for cancers to develop,
investigations to determine if a cancer
cluster exists and what might be the
potential cause are very challenging.
Most investigations of a suspected
possible cluster are not fruitful,
meaning no cause is identified and
the clustering of cases turns out to Watch: View video of
be random. Steve Francis’ presentation,
“Could infection contribute A cancer cluster occurs when a greater
to a possible leukemia than expected number of cancer
cluster in Fallon?” cases arise among people in a defined
(Long - 23:07 mins) geographic area over time.
←
Childhood Leukemia
Stephen’s Story
Ionizing radiation (including

X-ray and CT scan) exposure The
Electromagnetic
and childhood leukemia Spectrum
Along with the few infections that
Stephen had as a baby, he caught Non-ionizing
pneumonia when he was six months old. Radiation
This required a trip to the doctor and a
few chest x-rays.
Exposure to ionizing radiation from National Cancer
Institute - Radiation
nuclear accidents, x-rays, or radiation
Risks and Pediatric
therapy has been associated with Computed
increased risk of childhood leukemia. Tomography (CT)
Multiple studies have consistently
shown in utero exposures to ionizing
radiation increase the risk of leukemia by
approximately 40% (Buffler et al., 2005).
CT-scans are of particular concern for
children because children are considerably
more sensitive to radiation than adults,
they have a longer life expectancy resulting
in a larger window of opportunity for
expressing radiation damage, and doses
are cumulative over a lifetime. CT-scans
have not been extensively studied for links “Radiotherapy”
to leukemia, but their use has substantially by Susan Macfarlane,
increased in recent years and they often About the painting with the
result in higher radiation exposures than words of the artist in italics >
X-rays (Linet et al., 2009). More >
←
Childhood Leukemia
Stephen’s Story
Ionizing radiation (including

X-ray and CT scan) exposure The
1634
Electromagnetic
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
and childhood leukemia Spectrum 4

(continued) 3.5
Odds ratios and 95% CIs

However, if the imaging test is necessary Non-ionizing 3
and clinically justified, then the parents Radiation
2.5
can be reassured that the benefits
will outweigh the long-term cancer 2
risks. In recent years, radiologists and National Cancer
1.5
Institute - Radiation
technicians in many hospitals have
Risks and Pediatric 1
undertaken steps to reduce the exposure Computed
0.5
from x-rays and CT scans while Tomography (CT) Chest only Broken bone only Skull only Other only Chest and any Any type but
maintaining the necessary quality of other type chest
the image (Lambert et al., 2014). Many Type of X-ray Exposure
clinicians are considering whether a Figure 3 ORs and 95%One CIsstudy’s
for ever X-ray exposure, by region
patient evaluation involving radiation results suggest elevated risks ofof theassociated
ALL body exposed
with for the following, mutual
combinations of exposure:
chest(i)X-rays
chestonly
only; (ii) broken
(OR=1.36, 95% bone only; (iii)
CI 0.99–1.89) andskull
chest only;
X-rays(iv) ‘other’ only; (v) multiple
exposure is truly necessary, or if the exposed, including chest and (vi)with
combined multiple
other regions exposed,(OR=1.94,
regions exposed not including
95% CIchest.
1.13– The estimates are for ever ex
information of interest can be acquired for numbers of X-rays, 3.34),
e.g. ‘chest only’that
indicating includes
risk ofall subjects
exposure who
may received
differ at least
by region of one chest X-ray and no oth
X-rays body exposed.
in some other way.
Bartley et al, 2010. Graphic used with permission.
Although having anyclose exposure •

window x to X-rays (e.g. one or
Discussion
more X-ray) was not associated with increase in risk
of ALL (OR ¼ 1.21, 95% CI 0.96–1.51), children who In the current analysis, we found an
had ever received three or more X-rays at any body between exposure to 53 X-rays and AL
“Radiotherapy”
region had a 1.85-fold elevated risk of ALL (95% CI association between B-cell ALL and ever
by Susan Macfarlane, Using an additive model, number of X
1.22–2.79). An increased
reproducedOR was
with observed for B-cell
permission.
ALL subjects who About
had the
received onetheor more X-rays
painting with
associated with ALL. Although history
(OR ¼ 1.40, 95% CIwords of the artist
1.06–1.86) in italics
but not >for T-cell ALL X-rays was associated with elevated risk
subjects (OR ¼ 0.54, 95% CI 0.28–1.70). The disparity univariate analyses, this association dimin
in point estimates and range of CIs suggests a difference accounting for number of X-rays. We did n
in the influence of X-ray exposure by immunopheno- associations between post-natal X-rays an
←
Childhood Leukemia
Stephen’s Story
social support
Dr. Baker emphasizes to Tricia and David
Hope Labs
the importance of Stephen continuing his
chemotherapy medications throughout Commonweal Cancer
the duration of recommended treatment. Help Program
Stephen will undergo an intensive
therapy period that ranges from 6-9
months, requiring frequent visits to Dr. Find out more about
Baker’s office or the hospital. After this support groups,
community links:
time, Stephen will receive maintenance
CureSearch for
chemotherapy where he visits the Children’s Cancer
oncologist approximately once a month,
Cancer.Net
but the frequency of these visits will
The Leukemia &
depend on how well Stephen tolerates his
Lymphoma
medications. Society (LLS)
A month into Stephen’s therapy his
parents joined a support group for
parents of kids with leukemia and
learned about different resources.
Studies indicate that social support can
improve the quality of life in pediatric
cancer patients. These benefits can
include reduced anxiety and post-
traumatic stress among childhood
cancer survivors. More adaptive coping
strategies were also observed with Watch: Dr. Gary Dahl on
family and social support. chemotherapy compliance
(1:30 mins.)
←
Childhood Leukemia
Stephen’s Story
After learning about the risks of chemical

substances in the environment, Stephen’s
parents are taking steps to reduce
exposures to their family and their Integrated Pest
community. Management
The nursery that they own will be
transitioning to an all organic business
model, and they are working with other
local businesses like the town’s golf course
to partner together and use Integrated
Pest Management (IPM). They have also
become active in the local school board to
help Stephen’s preschool switch to IPM.
Tricia and David are considering having
another child after Stephen completes
chemotherapy and is in full remission.
They are relieved that the risk of
leukemia for siblings remains low
After researching the possible causes
of Stephen’s disease and becoming
more knowledgeable about how many
environmental factors impact health,
they will take extra precautions to
promote a healthy pregnancy. Tricia
will be taking folate supplements before
conception and during the pregnancy.
She also plans to avoid the various
environmental exposures that she has
learned about to the extent possible.
←
Childhood Leukemia
Stephen’s Story
After learning about the risks of chemical

substances in the environment, Stephen’s Integrated Pest Management:
parents are taking steps to reduce Reducing Use of Pesticides
exposures to their family and their Integrated Pest in Homes, Schools and
community. Management Other Buildings
The nursery that they own will be
transitioning to an all organic business Integrated pest management (IPM) is an
approach to pest control that begins with
model, and they are working with other avoiding the use of pesticides at all unless
local businesses like the town’s golf course absolutely necessary. Many non- pesticide
techniques can help to keep unwanted
to partner together and use Integrated pests, like insects and rodents, from your
Pest Management (IPM). They have also home, lawn and garden, as well as public
become active in the local school board to buildings and spaces.
help Stephen’s preschool switch to IPM. If pesticides must be employed,

preference is given to the least toxic
Tricia and David are considering having alternatives. According to the EPA, IPM
is “an effective and environmentally
another child after Stephen completes sensitive approach to pest management
chemotherapy and is in full remission. that relies on a combination of common-
They are relieved that the risk of sense practices. IPM programs use current,
comprehensive information on the life
leukemia for siblings remains low cycles of pests and their interaction
with the environment. This information, More Resources:
After researching the possible causes in combination with available pest
of Stephen’s disease and becoming control methods, is used to manage pest
Pesticides: EPA - Integrated Pest
Management
more knowledgeable about how many damage by the most economical means,
and with the least possible hazard to Bio-Integral Resource Center (BIRC)
environmental factors impact health, people, property, and the environment. Pesticide Action Network (PANNA)
they will take extra precautions to The IPM approach can be applied to
both agricultural and non- agricultural University of California – Pesticide
promote a healthy pregnancy. Tricia settings, such as the home, garden, and Application Equipment
will be taking folate supplements before workplace.” IPM in Early Care and Education
conception and during the pregnancy.
She also plans to avoid the various
environmental exposures that she has
Drawing courtesy of the Bio-Integral
learned about to the extent possible. Resource Center. Artist Diane Kuhn.
←
Childhood Leukemia
Stephen’s Story
When Tricia, David, and Stephen joined

the rest of the family at this year’s
reunion, they were cautiously optimistic
about the future.
Stephen was responding well to
chemotherapy and the family had found
comfort in their local cancer support
group and advocacy efforts to bring
about change in their Connecticut town.
David tells the family about how far
cancer treatments have progressed
in recent years and that Stephen has
approximately a 90% chance of being
free of cancer in 5 years. They were all
still concerned about the possibility of
a relapse but have grown stronger as a
family and as a community.
←
Childhood Leukemia
Stephen’s Story
Summing Up Viewing health and disease as a result of the

complex ecology of modern life reveals many key
Several common themes arise in Stephen’s story that are similar to others
in A Story of Health. These include the importance of critical windows
leverage points in which preventive actions may
of susceptibility, the consideration of sub-groups within a disease, the reduce disease incidence and improve health
multiple risk factors, and the interaction of underlying genetics with
the chemical, social and other environments. We are also reminded that
population studies can illuminate underlying risk factors of disease (and
therefore possible preventive actions), but generally cannot answer the
specific question, “what caused this illness in this child?”
Like other chronic diseases that have been increasing in recent years,
childhood leukemia is complex. Although there is no consensus
amongst experts about its causes, except in a small percentage of cases,
evidence implicating a variety of risk factors continues to accumulate.
For example, considerable evidence from multiple studies around the
world implicates exposures to tobacco smoke, pesticides, radiation, and
traffic-related air pollution. The evidence of protective effects of peri-
conception folate supplementation and early exposures in daycare also
has substantial support.
Other associations that we have discussed in Stephen’s story (e.g., PCBs
and PBDEs) have been examined in only one or two studies and highlight
the need for further investigation.
Though it may seem daunting, viewing health and disease as a result of Population studies can
the complex ecology of modern life reveals many key leverage points illuminate underlying risk
in which preventive actions may reduce disease incidence and improve
health. Several of these are merely reinforcing current recommendations factors of disease (and
from medical societies and other expert practice guidance. therefore possible preventive
Many of the risk factors associated with childhood leukemia are also actions), but generally
risk factors for other diseases discussed in A Story of Health. People cannot answer the specific
will benefit in a variety of ways from avoiding unnecessary exposures question, “what caused this
to tobacco smoke, pesticides, and other environmental concerns. illness in this child?”
Continue to Final Thoughts >
←
A Stor y of Health Help Page Reunion Asthma Cancer Learning/ Diabetes Infertility Cognitive References Go Back
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, continued
Childhood Leukemia Case Metayer C, Milne E, Dockerty Radiation Trends

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SF, Kosary CL, et al., (eds). SEER
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A systematic review and meta-
ije/dyq162.
Cancer Statistics Review, 1975-
Boice JD Jr, Miller RW. Childhood 2011, National Cancer Institute.
Developmental analysis of childhood leukemia
and parental occupational pes-
and adult cancer after intrauterine Bethesda, MD, July 2014.
exposure to ionizing radiation.
Disabilities ticide exposure. Environ Health
Perspect 2009:117:1505-1513.
Teratology 1999:59(4):227-33. Ward E, DeSantis C, Robbins A,
Kohler B, Jemal A. Childhood and
___________ Prenatal/Preconception Care,
ILLUSTRATION Buffler, P.A., M.L. Kwan, P. Reyn-
olds, and K.Y. Urayama. 2005.
Adolescent Cancer Statistics, 2014.
CA Cancer J Clin. 2014 Mar-
Nutrition, Folic Acid IN PROGRESS Environmental and genetic risk Apr;64(2):83-103
Diabetes ACOG Practice Bulletin No. 44 factors for childhood leukemia: Non-ionizing Radiation Slusky DA, Does M, Metayer C,
Neural Tube Defects. American appraising the evidence. Cancer Mezei G, Selvin S, Buffler PA.
___________ College of Obstetricians and Investigation 23 (1):60-75. Ahlbom A, Day N, Feychting M, et Potential role of selection bias in
Gynecologists. Obstet Gynecol al. A pooled analysis of magnetic the association between childhood
Infertility 2003;102 (1):203-213.
Chokkalingam AP, Bartley K,
Wiemels JL, et al. Haplotypes of
fields and childhood leukaemia. Br leukemia and residential magnetic
J Cancer, 83 (2000), pp. 692–698. fields exposure: A population-
___________ ACOG FAQ: Nutrition During DNA repair and cell cycle control
genes, X-ray exposure, and risk Chen G, Xu Z. Global protein ex- based assessment. Cancer Epide-
Pregnancy. 2013 miology 2014: 38: 307-313.
pression in response to extremely
Cognitive Decline Bailey HD, Miller M, Langridge
of childhood acute lymphoblastic
leukemia. Cancer Causes Control low frequency magnetic fields. Wertheimer N, Leeper E. Electri-
A, de Klerk NH, van Bockxmeer 2011:22(12):1721-1730 Adv Exp Med Biol. 2013; 990: cal wiring configurations and
FM, Attia J, Scott RJ, Armstrong 107-110. childhood cancer. Am J Epidemiol
BK, Milne E. Maternal dietary Schmidt RJ, Tancredi DJ, Ozonoff Doll R, Wakeford R. Risk of child- 1979: 109:273-284.
intake of folate and vitamins B6 S, et al. Maternal periconceptional hood cancer from fetal irradiation. Greenland S, Sheppard AR, Kaune
and B12 during pregnancy and the folic acid intake and risk of autism Br J Radiol 1997:70:130-139. WT, Poole C, Kelsh MA. A pooled Social Support
risk of childhood acute lympho- spectrum disorders and devel- analysis of magnetic fields, wire
opmental delay in the CHARGE Infante-Rivard C, Mathonnet G, codes, and childhood leukemia Kazak AE, Barakat LP, Meeske
blastic leukemia. Nutr Cancer. Sinnett D. Risk of childhood leu-
(Childhood Autism Risks from Childhood Leukemia-EMF Study K, Christakis D, Meadows AT,
2012;64(7):1122-30 kemia associated with diagnostic
Genetics and Environment) case- Group. Epidemiology, 11 (2000), Casey R, Penati B, Stuber ML.
Lambrot R, Xu C, Saint-Phar S, control study. Am J Clin Nutr irradiation and polymorphisms in pp. 624–634 Posttraumatic stress, family func-
Chountalos G, Cohen T, Paquet 2012;96:80–9. DNA repair genes. Environ Health tioning, and social support in
M. Suderman M, Hallett M, and Perspect 2000:108(6):495-8. IARC. Non-Ionizing Radiation, survivors of childhood leukemia
Kimmins S. Low paternal dietary Surén P, Roth C, Bresnahan M, Part 1: Static and Extremely Low- and their mothers and fathers.
Haugen M, Hornig M, Hirtz D, Lie Linet M, Kim K, Rajaraman P. Frequency (ELF) Electric and J Consult Clin Psychol. 1997
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born-Kjennerud T, Schjølberg S, medical radiation and cancer risk: the Evaluation of Carcinogenic
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←
Learning/Developmental Disabilities Amelia’s Story *
Amelia is a 13-year-old who

lives with her parents Darrell
and Gloria in a small town
in Louisiana.
She enjoys being with her friends,
riding her bike, playing soccer,
listening to music, and helping out
at the restaurant where her mother
is the bookkeeper.
Amelia likes school, although she
has difficulty learning and is More information
on learning and
occasionally socially awkward. developmental
Like one in six young people disabilities
definitions
in America, Amelia has a and US trends
developmental disability.
(* a fictional case)
←
Learning/Developmental Disabilities Amelia’s Story
Specific Developmental Disabilities in
Amelia is a 13-year-old who U.S. Childrens Aged -17 Years*
lives with her parents Darrell
and Gloria in a small town
in Louisiana.
She enjoys being with her friends,
riding her bike, playing soccer,
listening to music, and helping out
at the restaurant where her mother
is the bookkeeper.
Amelia likes school, although she Link: Developmental
Disabilities Increasing
has difficulty learning and is More information in US
occasionally socially awkward. on learning and
developmental
Like one in six young people disabilities
in America, Amelia has a definitions
and US trends Developmental Disabilities Definitions and US Trends
developmental disability. Developmental disabilities (DD) are a identified as early as possible in order to
diverse group of conditions that are provide the necessary therapies, interventions,
neurologically based and result in physical and education that will help the child reach
and/or mental impairments that affect his or her full potential.
function and performance in many ways. As can be seen from the table above, there
People with DD may have difficulty with has been an alarming increase in the rate of
physical activities such as walking or ma- most DD conditions that indicate a serious
nipulating objects, difficulties with speech, public health challenge requiring urgent
language, communication, interaction, and attention. Not all children are affected equally,
socialization, as well as difficulties with learn- for example, boys are more likely than girls
ing and cognitive skills that may affect their to have autism and ADHD (Ekanayake et al.,
ability to live and work independently. 2014), and poor children who are insured with
Developmental disabilities begin anytime Medicaid are also more likely to have ADHD,
during development up to 22 years of age and learning disabilities and intellectual disabilities
usually last throughout a person’s lifetime. It than their more affluent peers who have
is very important that any disabilities are private insurance. (Rubin et al., 2012)
*Centers for Disease Control and Prevention,

National Center for Health Statistics, NHS, 1997-2008.
˄ Statistically significant trend over four time periods
(1997-1999, 2000-2002, 2003-2005, 2006-2008).
←
A single variable, such as birth Multiple Contributors to Developmental Disabilities
trauma or prenatal exposure to Developmental disabilities like Amelia’s
alcohol, may sometimes be the can result from interactions among
genetic inheritance and combinations
cause of a developmental disability. of a number of different environmental
variables from preconception
More commonly, however, multiple throughout development.
risk factors combine to alter brain radiation
development and/or function in
a variety of ways, resulting in a
developmental disability. toxicants
Developmental disorders are nutrition
generally better conceptualized as
heterogeneous (different) conditions
arising from interactions among
genetic and environmental factors. social
(See “More” below for in-depth environment
information.)
infectious
More on environmental and agents
genetic contributors to
developmental disabilities perinatal
genetics events

(such as preterm
birth, hypoxia)
←
A single variable, such as birth Environmental and Genetic general population. They may include
Contributors to Developmental environmental influences within the
trauma or prenatal exposure to Disabilities home or other shared experiences such
as having mutual friends or teachers.
alcohol, may sometimes be the While environmental chemicals like Non-shared environmental influences for
lead or organophosphate pesticides
cause of a developmental disability. are toxic to everyone, certain inherited
twins who live in the same home could
be a head injury, another kind of unique
genes can influence the response of
More commonly, however, multiple particular individuals and increase their
traumatic event, exposure to a physical
or toxic chemical substance, or some
risk factors combine to alter brain susceptibility to cognitive and behavioral kind of abuse to which the other twin
problems after exposures. was not similarly exposed.
development and or function in
Environmental factors Twin studies of children with ADHD
a variety of ways, resulting in a generally find a relatively high
reported to be
developmental disability. associated with ADHD*
genetic correlation with symptoms
of inattention, hyperactivity, and
Developmental disorders are impulsivity in children with ADHD.
For example, some genes affect the (Thapar, 2012) But even in identical
generally better conceptualized as metabolism of organophosphate twins who are more likely to have
pesticides (such as the paraoxonase gene) similar symptoms than fraternal
heterogeneous (different) conditions while others may have modest effects on twins, the concordance is not 100%,
arising from interactions among lead absorption and metabolism (such suggesting that non-inherited factors
as the vitamin D receptor and delta- also contribute.
genetic and environmental factors. aminolevulinic acid dehydratase genes).
In comparison, inherited genetic
(See “More” below for in-depth Twin Studies predisposition to reading and math
Family and twin studies help in problems in children with learning
information.) estimating the extent to which the disabilities appears to be considerably
origins of various developmental less. (Willcutt et al., 2010)
More on environmental and disabilities can be attributed to genetic Autism spectrum disorder has historically
genetic contributors to inheritance or the shared and unshared been thought to result primarily from
developmental disabilities environments. Twins share the same genetic susceptibility, but recent twin studies
uterine environment and usually, but show that shared environmental factors
not always, share the same home contribute at least 50% of autism risk.
environment after birth. (Hallmayer, 2011; Sandin, 2014)
Shared environmental influences These observations are reminders of
are those that are more common the importance of gene-environment
among individuals within a family interactions in individuals with and
than in unrelated individuals in the without particular genetic susceptibility.
*Thapar A, Cooper M, Jeffries R, Stergiakouli E.

What causes attention deficit hyperactivity disorder?
Arch Dis Child. 2012;97:260–265
←
Developmental Milestones More information

Amelia’s developmental disability on Developmental
was not particularly noticeable at Milestones >
a young age. Her developmental
milestones had been only slightly Checklists for Parents:
delayed compared to her peers, CDC’s Developmental
Milestones by specific age
and she also seemed to be some-
what inattentive, but otherwise
progressed reasonably well.
In addition, the subtle expression
of her delays and difficulties was
missed by her parents, who were
distracted after her baby brother
David was born.
Watch: How early

recognition of
developmental disabilities
can assist parents and
providers.
Learning and
math disabilities
and IQ
←
Amelia’s parents, Darrell and Gloria, first
became somewhat concerned that she might
be having difficulty with school work when
she was in the second grade. She seemed
to be having trouble paying attention and
finishing tasks like her homework. Watch: Dr. Mark Miller
describes the benefits
They decided, though, that she was just of an enriched social
going through some normal adjustments environment and the
at school and at home. Because they way it influences brain
were both working long hours at their structure and function.
jobs, taking care of a new baby, and
struggling with finances, they did not
seek help for Amelia at that time as
her difficulties did not seem to be
very serious.
Both parents did make sure they
spent time with her to help her
read and comfort her when she
seemed frustrated.
Mark Miller MD MPH, Director,
The beneficial effects of an Children’s Environmental
Health Program, Office of
enriched social environment
Environmental Health Hazard
For these and other reasons, her parents Director, UCSF Pediatric
put off addressing Amelia’s problem until Environmental Health
Specialty Unit
a parent-teacher meeting in the third
grade, where they learned more about the
difficulty Amelia was having in school.
They realized they needed to take action.
←
Evaluation of Learning Disabilities

Amelia’s parents met with the school
psychologist, Mr. Richards, who did
an evaluation to determine Amelia’s
education needs. He also offered to refer
them to a medical setting to see if the
family wanted to pursue further diagnosis.
When they asked, he referred them to a
center in a large city where she could be
further evaluated.
Evaluation – What does it mean?
The medical setting was somewhat Find out more about

intimidating at first, but the people at the Evaluations
center made them feel at ease. They were
introduced to Dr. Bradley, a developmental
pediatrician, who said she would be
conducting a number of screening
procedures with Amelia.
After the screening, Dr. Bradley met with
Amelia and her parents. She explained
that Amelia’s challenges were somewhat
difficult to categorize as she had several
that cut across syndromes they might
have heard of, such as ADHD.
She explained that Amelia’s reading and
comprehension difficulties qualified as a
learning disability. However, Amelia also
exhibited inattention during the testing but
not sufficiently for a diagnosis of ADHD.
←
Capacities/
Capacities/Behaviors vs. Syndromes Behaviors
OVERLAPPING SYNDROMES Cognitive and behavioral But there is often considerable
capacities and behaviors overlap among syndromes.
Learning and behavioral
such as word comprehension, For example, many children
disorders often overlap memory, attention, or impul- with a diagnosis of ADHD also
with other categories. sivity can be evaluated using have a learning disability.
For example: validated age-appropriate Variability in the clinical ex-
diagnostic tests. pression of neurodevelopmen-
Among children with
Sometimes multiple capacities tal disorders creates challenges
ADHD: and behaviors are bundled for diagnostic categorization Testing
• 10-30% also have together into defined clini- and demonstrates the com-
cal syndromes, such as ADHD plexity of their origins.
learning disabilities;
or autism spectrum disor-
• 30-50% also have ders, for purposes of classi-
fication and deciding among Clinical Diagnosis
language disability;
possible interventions.
• 30-80% have other
Dr. Bradley said she thought Amelia Asperger’s
behavior disorders. Learning
would do well with some extra help at Disability ADHD Syndrome
ADHD is also frequently Autism
school along with making other healthy
associated with autism
living choices. spectrum disorder,
obsessive compulsive

disorder, tic disorders, and
Developmental Screening Tools intellectual disabilities.
for Clinicians:
Developmental Screening in
Early Childhood Systems,
American Academy of Pediatrics Developmental Syndromes
(AAP)
Developmental and Behavioral
Screening Initiative,
Administration for Children &
Families (ACF)
Learning ADHD Autism spectrum disorder

Disability
←
Amelia’s parents, Darrell and Gloria,

asked Dr. Bradley what could have caused
Amelia’s learning disability, and Dr. Preconception and Healthy
Bradley was interested in exploring that Child Development
as well.
Dr. Bradley suggested that there is often
a genetic predisposition and added that if Prenatal Care and Healthy
Amelia had been born prematurely, or had Child Development
a low birth weight, either could be a risk
factor for her developmental disability.
Gloria told her that Amelia was a little Folate supplementation
underweight when she was born, but no recommendations
one seemed very concerned about it at for women
the time. Dr. Bradley also mentioned that
smoking or drinking during pregnancy
could increase the risk. Gloria told her A Rationale for
that her husband had smoked during her Thyroid Screening
pregnancy, although when Amelia was
born he had quit with help from their local
medical clinic.
For Clinicians: Prenatal
Finally, Dr. Bradley told them about the environmental health history
risk to brain development from exposures form, PEHSU Region 5
early in life to other toxic chemicals and
substances, such as lead, mercury, and
diesel fumes from trucks and cars.
←
Preconception and Healthy
Images: Centers for Disease Control

asked Dr. Bradley what could have caused Child Development
Preconception care for women
Bradley was interested in exploring that and men is important for
and Prevention
Child Development
lifetime health as well as
as well. healthy child development.
All women and men can benefit from Recent studies also show periconceptual
a genetic predisposition and added that if Prenatal Care and Healthy healthy habits throughout life, whether or folate supplements associated with a
Amelia had been born prematurely, or had Child Development not they plan to have a baby one day. These significantly decreased risk of having a child
a low birth weight, either could be a risk include eating healthy food, getting regular with an autism specturm disorder. (Schmidt
exercise, avoiding toxic substances, and et al, 2012; Suren et al, 2013; Lyall, 2104)
factor for her developmental disability. reducing excessive stress. Schmidt et al. also found greater risk
Gloria told her that Amelia was a little Folate supplementation Some specific actions are also important reduction with daily folate > 0.6 mg
underweight when she was born, but no recommendations for prospective parents to take even prior when either the mother or child had
to conception because they can influence specific higher risk polymorphisms in
birth outcomes. MTHFR genes. The MTHFR gene
the time. Dr. Bradley also mentioned that Maternal exposures to toxic chemicals provides instructions for making
smoking or drinking during pregnancy before or around the time of conception methylenetetrahydrofolate reductase, a
could increase the risk. Gloria told her can adversely affect the quality of eggs More information: CDC’s
A Rationale for
(ova) and newly-conceived embryos. But Preconception care for
that her husband had smoked during her Thyroid Screening these exposures can be harmful to men’s women and men
pregnancy, although when Amelia was reproductive health as well. For example, a
father’s occupational exposure to pesticides rate limiting enzyme in the methyl cycle.
born he had quit with help from their local Some genetic variants of the enzyme result
has been associated with increased risk of
medical clinic. some childhood cancers and birth defects in altered or inactivated enzyme function.
For Clinicians: Prenatal in his offspring. (Roberts et al., 2012). Altered enzyme activity can interfere with
Finally, Dr. Bradley told them about the environmental health history its ability to help process folate, a key
risk to brain development from exposures Parents can also take home from the
form, PEHSU Region 5 nutrient for neurodevelopment. Some
workplace toxicants like lead and
early in life to other toxic chemicals and pesticides on their clothing, resulting in
variants have been associated with increased
risk for developing neural tube defects and
substances, such as lead, mercury, and direct exposures to other family members.
other neurologic disorders. About 60% of
diesel fumes from trucks and cars. (Gerson et al., 1996; Fenske et al., 2013)
the US population have at least one risk-
Nutritionally, a prospective father’s diet that conferring MTHFR gene.
is deficient in folate (a “B” vitamin) increases
Of course optimal nutrition and
the risk of birth defects in his offspring.
appropriate vitamin and mineral
(Lambrot et al., 2013). Similarly, maternal
supplements throughout pregnancy are
folate supplements in the periconceptual
also important to help promote optimal
period (the time period around conception)
fetal development.
help reduce the risk of birth defects
←
Prenatal Care for Healthy Development
Images: Centers for Disease Control

as well.
and Prevention
a low birth weight, either could be a risk The fetus can be harmed Actions to help protect More information:
factor for her developmental disability. by environmental the fetus: • CDC on pregnancy
Gloria told her that Amelia was a little exposures including:

Folate supplementation • Avoid smoking or • American Congress
underweight when she was born, but no recommendations • Mom’s smoking and drinking, of Obstetrics
second hand smoke, and Gynecology
• Mom’s drinking alcohol, • Maintain a healthy diet, (ACOG):
the time. Dr. Bradley also mentioned that - Good Health
and her exposure to other • Supplement with prenatal Before
smoking or drinking during pregnancy
solvents like those in certain vitamins, including folic Pregnancy (pdf)
could increase the risk. Gloria told her A Rationale for paints and in products -
Prenatal Nutrition
that her husband had smoked during her Thyroid Screening acid, iodine, and vitamin
used in nail salons, - Environmental
D if maternal serum levels
pregnancy, although when Amelia was • Mom’s exposure to lead, Chemicals
are inadequate,
born he had quit with help from their local mercury (from some • Royal College
medical clinic. fish and other sources), • Avoid toxicants. of OB/GYN:
For Clinicians: Prenatal pesticides, PCBs (banned - Chemical
Finally, Dr. Bradley told them about the environmental health history in the US but still found Exposures During
risk to brain development from exposures form, PEHSU Region 5 in the environment), and Pregnancy
early in life to other toxic chemicals and certain polybrominated • UCSF: Program
substances, such as lead, mercury, and diphenyl ethers (PBDEs – on Reproductive
diesel fumes from trucks and cars. a family of chemicals long- Health and the
Environment
used as flame retardants
in foam and furniture),
among others.
←
Prenatal Healthy care
Amelia’s learning disability, and Dr. A Rationale for Thyroid Screening
Before or During Pregnancy
Bradley was interested in exploring that Child Development Thyroid System
Adequate levels of thyroid hormone are
as well. necessary for normal brain development.
During the first trimester of pregnancy,
Dr. Bradley suggested that there is often before onset of fetal thyroid hormone
a genetic predisposition and added that if Prenatal Care and Healthy production, an adequate supply of
Amelia had been born prematurely, or had Child Development maternal thyroid hormone is essential.
Recent studies show that even modest
a low birth weight, either could be a risk reduction in maternal TH, as in subclinical
factor for her developmental disability. hypothyroidism (moderately elevated
TSH and normal or low-normal T4 levels)
Gloria told her that Amelia was a little Folate supplementation or low-normal free T4 levels (below the
image credit: Wikimedia commons

underweight when she was born, but no recommendations 5th or 10th percentiles) with or without
elevated TSH, is associated with suboptimal
neurodevelopment (Haddow, 1999;
the time. Dr. Bradley also mentioned that Pop et al., 1999; LaFranchi, 2005)
smoking or drinking during pregnancy According to the CDC, about 30% of
women of reproductive age in the US
could increase the risk. Gloria told her A Rationale for have insufficient iodine intake. Iodine is
that her husband had smoked during her Thyroid Screening an essential element in the production of
pregnancy, although when Amelia was thyroid hormones. The American Congress
of Obstetricians and Gynecologists (ACOG)
born he had quit with help from their local recommends that all prenatal vitamins
Thyroid disruption
medical clinic. contain at least 150 micrograms iodine, but
technical diagram
For Clinicians: Prenatal many vitamins do not contain this amount.
Finally, Dr. Bradley told them about the environmental health history A number of environmental chemicals can disrupt thyroid hormone levels and
risk to brain development from exposures form, PEHSU Region 5 function through a variety of mechanisms. (Pearce & Braverman, 2009)
early in life to other toxic chemicals and Opinions about the value of universal screening for maternal thyroid status during
substances, such as lead, mercury, and pregnancy differ between the Endocrine Society and American Thyroid Association.
Nevertheless, experts generally agree that clinicians should attempt to identify women
diesel fumes from trucks and cars. at risk for inadequate thyroid hormone and undertake corrective measures.
←
Prenatal Healthy care
Amelia’s learning disability, and Dr. A Rationale for Thyroid Screening
Before or During Pregnancy
as well.
a low birth weight, either could be a risk
factor for her developmental disability.
Gloria told her that Amelia was a little Folate supplementation
underweight when she was born, but no recommendations
the time. Dr. Bradley also mentioned that Thyroid disruption
smoking or drinking during pregnancy Environmental chemicals can interact
could increase the risk. Gloria told her A Rationale for with the thyroid system in a variety of
that her husband had smoked during her Thyroid Screening ways, including altering TH synthesis,
carrier-protein binding, metabolism, and
pregnancy, although when Amelia was excretion, and interfering with thyroid
born he had quit with help from their local receptor binding and gene expression
(see diagram).
medical clinic. Pearce & Braverman, 2009,
graphic used with permission
For Clinicians: Prenatal Since individuals are regularly exposed to more than
Finally, Dr. Bradley told them about the environmental health history one of these agents, risk assessments should consider
risk to brain development from exposures form, PEHSU Region 5
cumulative exposures when assessing the safety of a
single chemical. (Science and Decisions: Advancing Risk
early in life to other toxic chemicals and Assessment. Natl. Research Council.) Unfortunately this is
substances, such as lead, mercury, and not yet routine practice.
diesel fumes from trucks and cars. Clinicians should be aware of the many variables that can
influence the thyroid hormone status of patients, and
strongly consider assessing thyroid hormone status in
women of reproductive age and women who are pregnant.
←
Brain development Timeline of major events in brain development
Brain development begins soon after

conception and continues throughout Developmental Phase
adolescence into adulthood. It is Prenatal
Early Early
Birth Infancy Childhood Childhood Adolescence Adolescence
Emerging
Adulthood
characterized by a critical sequence of Gestation (weeks)
events that helps to determine brain 4 8 12 16 20 24 28 32
structure and function. Each of these

processes is subject to disruption by Find out more: Neurulation
Neuronal
Cellular events in
exposure to various environmental agents. neurodevelopment
Proliferation
Neuronal
Inadequate nutrition and adverse social Differentiation
circumstances can also impair these Neuronal

Migration
developmental processes. Synapse
Formation
Even brief disruptions during critical Programmed
Cell Death
periods of early brain development can
Synaptic
have significant downstream effects with Pruning
long-lasting consequences. Myelination
The clinical manifestation of disruption Timeline of major events in brain development.

from neurodevelopmental toxicants or Source: Preventing Mental, Emotional and Behavioral Disorders Among Young People: Progress and
Possibilities. Mary Ellen O’Connell, Thomas Boat, and Kenneth E. Warner, Eds. Natl Academies Press,
other stressors depends on the nature of Washington, DC. 2009. Graphic used with permission.
Fig5-2.eps
the agent as well as the size, timing, and broadside
duration of exposure.
←
Brain development
Experience-dependent synapse formation
The pattern of formation of nerve
connections (synapses) in thebeneficial effects. Together, these findings provide
cerebral cortex
“Core Concepts in the
is characterized by rapid proliferation and and continuously
an instructive growing body of
Science of Early Childhood
over-production of synapses,knowledge
followed byabouta both successfulHarvard
Development” and ineffective
phase of synapse elimination (pruning) that Univ. Center for the
investments.
reduces the number of synapses to more Developing Child
adult-like levels. For the first time, researchers are now able to
This process is prominent inpresent a unified
the first years framework that can guide priori-
tiessome
of life, although it extends to for science-based
degree early childhood policies and
into adolescence. However,practices
differentthat
brainare grounded in a combination of
regions with different functions develop neuroscience,
cutting-edge on developmental-behav-
different time courses.
ioral research, and program evaluation. Drawing
on the best and most widely accepted evidence
from all of these fields of study, we can confident-
ly articulate the following findings.
Early experiences determine whether a
child’s developing brain architecture provides a
strong or weak foundation for all future learn- Graphic: “A Science-Based Framework for Early Childhood
Policy” Center on the Developing Child, Harvard University
ing, behavior, and health. The brain is composed ofReproduced
billionswithofpermission.
highly integrated sets of neural
circuits (i.e., connections among brain cells) that are “wired” under the interactive influences of
genetics, environment, and experience. Genes determine when circuits are formed, but a child’s
experiences shape how that formation unfolds. Children develop in an environment of relation-
ships that begins within their family, extends into their community, and is affected by broader so-
cial and economic resources. From early infancy, they naturally reach out for interaction through
such behaviors as babbling, making facial expressions, and uttering words, and they develop best
when caring adults respond in warm, individualized, and stimulating ways. In contrast, when the
←
Dr. Bradley discussed some of the ways

that Gloria and Darrell could help Amelia
with her learning problems and discussed
Healthy eating habits
eligibility that would allow support for
Amelia to attend special programs.
She encouraged them by saying that it was
never too late to focus on habits to promote Effect modifiers:
health for the whole family, like healthy iron deficiency, poverty,
eating, exercise, avoiding toxic chemicals, lead exposure.
and trying to deal positively with stress.
She referred them back to Mr. Richards at
the school to discuss developing a school
program tailored to Amelia’s needs. Resources to help parents:
Learning Disabilities
She gave them some booklets and
Association
brochures. Amelia’s parents thought Dr.
Bradley was helpful but left feeling a little
overwhelmed.
Amelia was worried because she figured
there was extra school work in her future.
Watch: Dr. Mark Miller

describes how lead
and stress affect brain
functioning, and the
benefits of an enriched
environment. (4 min.)
Healthy Eating Plate graphic copyright © 2011 Harvard University www.hsph.harvard.edu/nutritionsource/

healthy-eating-plate. Used with permission. For more information about The Healthy Eating Plate, please see
The Nutrition Source, Department of Nutrition, Harvard School of Public Health, www.thenutritionsource.org
and Harvard Health Publications, www.health.harvard.edu.
←
Effect modifiers – Iron deficiency, poverty, lead exposure
Dr. Bradley discussed some of the ways
Although Amelia has generally had common and is a risk factor for
that Gloria and Darrell could help Amelia impaired cognitive development. Iron-
good nutrition throughout her life,
with her learning problems and discussed many children and families are not supplemented formula, however, can
Healthy eating habits
eligibility that would allow support for able to access nutritious food for adversely impact brain development
Amelia to attend special programs. many reasons. in infants whose iron stores are
already adequate as evidenced by
She encouraged them by saying that it was For example, nutritious food may not high hemoglobin levels (Lozoff et al.,
never too late to focus on habits to promote be available or affordable, resulting 2012). Poverty also adversely impacts
Effect modifiers:
in “food insecurity.” According to the brain growth and development.
health for the whole family, like healthy iron deficiency, poverty,
USDA, about 20% of US households The neurotoxicant lead is also a
eating, exercise, avoiding toxic chemicals, lead exposure.
with children suffer from food- well-recognized cause of impaired
and trying to deal positively with stress. insecurity. In half of those, only adults neurodevelopment with adverse
She referred them back to Mr. Richards at were food-insecure (perhaps because impacts on cognition, behavior, and
the adults go hungry while giving food attention. Lead exposure, dietary iron
the school to discuss developing a school deficiency, and lower socioeconomic
to their children), while in half both
program tailored to Amelia’s needs. Resources to help parents:
children and adults were food-insecure. status often co-occur, and their impacts
Learning Disabilities may be more than additive.
She gave them some booklets and Nutritional deficiencies can have
Association For example, the consequences of
brochures. Amelia’s parents thought Dr. significant adverse impacts on
lead exposure can be accentuated by
Bradley was helpful but left feeling a little child development, including
iron deficiency because lead uptake
overwhelmed. neurodevelopment. All nutrients
from the intestine and lead deposition
are necessary for optimal brain
Amelia was worried because she figured in the brain increase. (Hubbs-Tait et
development and growth, but some
al., 2005, Weiss et al., 2006) Similarly,
there was extra school work in her future. are more important than others. They while stressful life events can worsen
include protein, iron, zinc, iodine, negative impacts of poverty, nurturing
selenium, folate, vitamin A, choline, caregiving can help to mitigate them.
Watch: Dr. Mark Miller and polyunsaturated fatty acids.
describes how lead These are examples of effect
Dietary iron deficiency with or modification.
and stress affect brain without associated anemia is quite
functioning, and the
benefits of an enriched
environment. (4 min.)
←
economic costs
Developmental disabilities affect
individuals, families, and communities
and have staggering economic costs. • ADHD doubles health care costs
for children, comparable to costs
Effects can include: for children with asthma.
• academic difficulties, • Total annual cost-of-illness for
• employment problems, a child with ADHD in the US
(includes health-, education-,
• financial stress, behavior-related costs):
• emotional stress, $12,005-$17,458/yr.
• substance abuse,
• Estimated costs of neuro-
• lawbreaking , and even behavioral disorders attributable
• suicide. to environmental pollutants
in the US:
$18.3 billion/yr.
(CDC, National Center on Birth

Defects and Developmental
Disabilities – ADHD Data and
Statistics; Trasande & Liu, 2011)
←
Toxicants and Health

Gloria decided to look online to learn
more about environmental chemicals
that can contribute to learning and 2002 Rankings: Major Chemical Releases or Waste
developmental disabilities. Generation in Louisiana*
She began to think of the many ways
that her family might have been exposed
to lead, mercury, pesticides, endocrine
disruptors, solvents, air pollution and
other substances that she read about.
Chemicals and neurodevelopmental Link: Scorecard:
health effects – an overview. Get an in-depth
pollution report for
It was not difficult. Before Amelia was your county, covering
born her parents lived in Baton Rouge, air, water, chemicals,
Louisiana where Gloria worked at a and more.
petrochemical factory. At the factory she
had noticed the smell of solvents nearly
every day. The smells from the factory See how this state ranks on other chemical release and waste management attributes tracked by Scorecard
Link: California
were more bothersome when Gloria was Proposition 65 - Graphic used with permission.
dealing with morning sickness. chemicals known

Gloria and Darrell moved to their current to cause cancer or
reproductive toxicity
home just as Gloria was beginning her
second trimester of pregnancy.
←
Toxicants and Health Chemicals and neurodevelopmental effects: an overview

Gloria decided to look online to learn Long-lasting, adverse neurodevelopmental Grandjean provides an updated list of 213
more about environmental chemicals (brain and central nervous sysytem) industrial chemicals known to be toxic to
that can contribute to learning and impacts of prenatal, infant, and/or the nervous system in adults. Many of
childhood exposures to lead, alcohol, these chemicals are present not only in the
developmental disabilities. and methylmercury are well known. workplace but also in consumer products
They demonstrate the vulnerability of and the general environment, resulting in
She began to think of the many ways the developing brain to neurotoxicant exposure to the general population.
that her family might have been exposed exposures at levels that have fewer Unfortunately, most of these chemicals
to lead, mercury, pesticides, endocrine and less severe effects in adults. In have not undergone developmental
recent years, the list of environmental
disruptors, solvents, air pollution and chemicals that can adversely impact brain
neurotoxicity testing in laboratory
animals, nor have their impacts been
other substances that she read about. development at environmentally relevant examined in epidemiologic studies of
levels of exposure has grown rapidly. It
Chemicals and neurodevelopmental Link: Scorecard: developing children. As a result, our
includes additional metals (e.g., arsenic,
Get an in-depth ability to estimate the contribution of
health effects – an overview. manganese), various solvents, some environmental chemicals to adverse brain
pollution report for pesticides, and a range of persistent,
It was not difficult. Before Amelia was your county, covering organic compounds that contaminate the
development and function is limited.
Nonetheless, enough is known from
born her parents lived in Baton Rouge, air, water, chemicals, general food supply, among others. studies of limited numbers of chemicals to
Louisiana where Gloria worked at a and more. In a recent book, Only One Chance: How justify more routine neurodevelopmental
Environmental Pollution Impairs Brain testing of chemicals to which the general
petrochemical factory. At the factory she Development—and How to Protect the population is likely to be exposed.
had noticed the smell of solvents nearly Brains of the Next Generation, Dr. Philippe
every day. The smells from the factory
Link: California
were more bothersome when Gloria was Proposition 65 - Grandjean P, Landrigan P. Neurobehavioural
dealing with morning sickness. chemicals known effects of developmental toxicity Lancet
Gloria and Darrell moved to their current to cause cancer or Neurol. 2014 March;(13):330-338.
reproductive toxicity
home just as Gloria was beginning her
second trimester of pregnancy.
←
Toxicants and Health - Air

Pollution
When Darrell and Gloria moved from
Baton Rouge to a smaller town in
Louisiana, they chose their new home
because of its affordability. The house
was a nice size for the growing family,
but it was on a busy street, where many
trucks passed on their way to factories in
surrounding towns.
Soon after the family moved to their new
home, Gloria and Darrell undertook Air pollution, family
some remodeling. Darrell was very busy stress and nutrition -
with his new job, and Gloria (who was synergistic effects on
pregnant with Amelia) did most of the brain development.
painting and had new carpet installed.
It was not until many years after moving
that Gloria learned that air pollution from
traffic emissions can have adverse effects
on child development. She also learned that
remodeling projects can involve exposures
to chemicals that can harm a developing
child’s brain.
←
Toxicants and Health - Air Air pollution and neurodevelopment – additional impacts
Pollution of family stress and sub-optimal nutrition
When Darrell and Gloria moved from Exposure to higher levels of human infant neurodevelopment
Baton Rouge to a smaller town in indoor and outdoor air pollution have not been studied. However, a
during pregnancy has an study in mice (Maternal Stress and
Louisiana, they chose their new home adverse impact on infant mental Effects of Prenatal Air Pollution
because of its affordability. The house development (Bayley Scales of on Offspring Mental Health
was a nice size for the growing family, Infant Development) (Guxens et al., Outcomes in Mice; Bolton, et al.)
but it was on a busy street, where many 2012; Friere et al., 2010; Perera et “hypothesized that the addition
al., 2006). In one study, the effect of maternal stress to the impact
trucks passed on their way to factories in was greater among children whose of prenatal air pollution exposure
surrounding towns. mothers reported low intakes would act synergistically in off-
of fruits and vegetables during spring to impair mental health
Soon after the family moved to their new pregnancy, suggesting a role for outcomes, compared with the
home, Gloria and Darrell undertook Air pollution, family
oxidative stress and beneficial effects of either exposure alone.”
some remodeling. Darrell was very busy effects of antioxidants. (Guxens It concluded “that maternal
stress and nutrition - et al., 2012)
with his new job, and Gloria (who was synergistic effects on stress during late gestation
Studies have also identified a increases the susceptibility of
pregnant with Amelia) did most of the brain development.
significantly increased risk of offspring—particularly males—
painting and had new carpet installed. autism spectrum disorder in to the deleterious [negative]
children exposed to higher levels of effects of prenatal air pollutant
It was not until many years after moving air pollution, mostly from traffic- exposure, which may be due to a
that Gloria learned that air pollution from related sources, during gestation synergism of these factors acting
traffic emissions can have adverse effects and early life. (Becerra, 2013; Volk, on innate immune recognition
2013; Roberts, 2013; Volk, 2014) genes and downstream
on child development. She also learned that neuroinflammatory cascades
Except for tobacco smoke, the
remodeling projects can involve exposures interactive effects of other kinds of within the developing brain.”
to chemicals that can harm a developing air pollution and maternal stress on
child’s brain.
←
Toxicants and Health - Pesticides

Gloria recalled that they had the new
house sprayed for pests after receiving
promotional materials in the mail soon
after Amelia was born. Although they do
not use pesticides in their home or outside
any longer, their neighbors regularly spray
their lawns with pesticides. She later
learned that pesticides, some of which
are neurotoxic and can impair brain
development, are widely used.
Gloria also thought about Darrell’s job as
a carpenter and how he works with a lot Prevention Strategies:
of chemicals. Integrated Pest
Management
She was amazed at how many exposures
to toxic chemicals her family had
experienced that she had never thought
about before!
←
Graphic: Bio-integral Resource Center, reproduced with permission.

Toxicants and Health - Pesticides
Integrated Pest Management:
Gloria recalled that they had the new
Reducing Use of Pesticides
house sprayed for pests after receiving
in Homes, Schools and
promotional materials in the mail soon Other Buildings
after Amelia was born. Although they do
not use pesticides in their home or outside Integrated pest management (IPM) is an
any longer, their neighbors regularly spray approach to pest control that begins with
their lawns with pesticides. She later avoiding the use of pesticides at all unless
absolutely necessary. Many non-pesticide
learned that pesticides, some of which techniques can help to keep unwanted
are neurotoxic and can impair brain pests, like insects and rodents, from your
home, lawn and garden, as well as public
development, are widely used. buildings and spaces.
Gloria also thought about Darrell’s job as If pesticides must be employed,
a carpenter and how he works with a lot Prevention Strategies: preference is given to the least toxic
people, property, and the environment.
Integrated Pest alternatives. According to the EPA, IPM
of chemicals. is “an effective and environmentally
The IPM approach can be applied to
Management both agricultural and non-agricultural
sensitive approach to pest management
She was amazed at how many exposures that relies on a combination of common-
settings, such as the home, garden, and
to toxic chemicals her family had sense practices. IPM programs use current,
workplace.”
experienced that she had never thought comprehensive information on the life More Resources:
cycles of pests and their interaction
about before! with the environment. This information, Pesticides: EPA - Integrated Pest
in combination with available pest Management
control methods, is used to manage pest
Bio-Integral Resource Center (BIRC)
damage by the most economical means,
and with the least possible hazard to Pesticide Action Network (PANNA)
Drawing courtesy of the Bio-Integral

Resource Center, artist Diane Kuhn
←
Toxicants and HealtH - Mercury

Amelia liked to go fishing with her father,
who was an avid fisherman. For several
years they had enjoyed catching and eating
a variety of fish from the local lake.
Gloria remembered Darrell coming home
from fishing one day and telling her about
a posted fish advisory, warning fisherman
not to eat the fish due to contamination
from mercury.
The advisory included a state web site
where Gloria was able to learn more. She
Link: EPA fish advisories
read that mercury, like lead, is a heavy
metal that disrupts brain development.
Illustration © Stephen Burdick Design

Photos from EPA: http://
She also read about the health benefits water.epa.gov/scitech/
swguidance/fishshellfish/
of eating uncontaminated fish and about fishadvisories/index.cfm,
used with permission.
nutritious fish with low contaminant levels
available in local supermarkets.
Link: Pediatric
Gloria searched for an alternative place Environmental Health
where Darrell and Amelia could continue Toolkit animation on
to enjoy fishing and from which the family mercury in fish and
could also eat the fish they caught. She children’s health
found a nearby river where the fish were
not contaminated. Amelia was happy that
she and her dad could still fish together.
←
Toxicants and HealtH - Lead

Finally, Gloria thought about the older
houses they had lived in and the lead Link: CDC: Primary
prevention of lead
paint problems. They had been careful to exposure
remove the paint properly, but maybe they
had not removed it all.
Lead removal from gasoline and other
products – a public health success story
Luckily, she didn’t have to worry about

Where is the Lead?
lead in gasoline anymore. She read about
• Formerly used in house
how that was a public health success story paint, gasoline, water
and how it had reduced blood lead levels pipes, solder in food cans.
in children. • Currently found in
imported pottery, some
Lead - developmental effects cosmetics, some traditional
(indigenous or folk)
medicine, older water
Pediatric Environmental Health pipes, older house paint,
Toolkit animation on lead exposure some types of industrial
and children’s health paint, aviation fuel, car
batteries, and bullets.
• Most common sources of
exposures: older paint,
dust, and water pipes.
←
Toxicants and HealtH - lead Lead removal – a public health success story
Finally, Gloria thought about the older This graph shows declining mean when we prioritize a problem, and address
houses they had lived in and the lead Link: CDC: Primary blood lead levels in US toddlers it upstream with policy actions, rather than
prevention of lead from 16 to 1.5 microgms/dL since the expecting to solve the problem through
paint problems. They had been careful to exposure 1970s, corresponding to public health individual behavior changes. In this case,
remove the paint properly, but maybe they interventions removing lead from various some products were reformulated and lead
products, including paint and gasoline. was completely eliminated rather than
had not removed it all. relying exclusively on attempts to control
This is an important public health success
story. It is an example of what we can do exposures from lead-containing materials.
Lead removal from gasoline and other
Luckily, she didn’t have to worry about

Where is the Lead? Mean blood lead levels in toddlers in the US
lead in gasoline anymore. She read about
• Formerly used in house population 1976-2008
how that was a public health success story paint, gasoline, water lead paint
and how it had reduced blood lead levels pipes, solder in food cans; 18
mean blood lead levels in US toddlers (microgms/dL)

ban 1976
in children. • Currently found in can solder phase
16 out begins 1978
imported pottery, some
Lead - developmental effects cosmetics, some traditional 14 unleaded gasoline
(indigenous or folk) introduced 1979
medicine, older water 12
Pediatric Environmental Health pipes, older house paint,
Toolkit animation on lead exposure some types of industrial 10 lead & copper
paint, aviation fuel, car rule 1991
and children’s health 8
batteries, and bullets; can solder
ends 1992
• Most common sources of 6
exposures: older paint, leaded gas
ends 1996
dust, and water pipes. 4 2.7
2.0
1.5
2
0 ‘74 ‘76 ‘78 ‘80 ‘82 ‘84 ‘86 ‘88 ‘90 ‘92 ‘94 ‘96 ‘98 ‘00 ‘02 ‘06 ‘08
Today elevated blood lead levels remain a problem for a significant number
of children, particularly in older housing and urban environments, but the
population-wide exposures resulting from air releases have been substantially
reduced by removal of lead from gasoline and other products.
←
Toxicants and HealtH - lead Cognitive and Behavioral Traits Associated with Lead
Finally, Gloria thought about the older

houses they had lived in and the lead Link: CDC: Primary
prevention of lead Traits that Tend to Increase Traits that Tend to Decrease
paint problems. They had been careful to exposure • Hyperactivity • Executive function
remove the paint properly, but maybe they
• Impulsivity • Attention/vigilance
had not removed it all.
• Distractibility • Social skills
Lead removal from gasoline and other • Conduct problems • Fine motor skills
• Difficulty with instructions • Visual motor coordination
Luckily, she didn’t have to worry about • Aggressiveness • Academic skills (reading, math,
Where is the Lead? spelling, pattern recognition,
lead in gasoline anymore. She read about • Antisocial behaviors
and word recognition)
• Formerly used in house
how that was a public health success story paint, gasoline, water • Getting off-task
and how it had reduced blood lead levels pipes, solder in food cans;
in children. • Currently found in Hearing may be impacted even at very low levels. In
imported pottery, some adolescents, >2mcg/dl compared to <1mcg/dl lead levels
Lead - developmental effects cosmetics, some traditional are associated with twice the rate of15dB high frequency
(indigenous or folk)
hearing loss. High frequency hearing loss may reduce the
medicine, older water
pipes, older house paint,
ability to understand speech and thus may impact many of
Pediatric Environmental Health
some types of industrial the traits noted above.
Toolkit animation on lead exposure
and children’s health paint, aviation fuel, car
batteries, and bullets;
• Most common sources of
exposures: older paint,
dust, and water pipes.
←
Toxicants and HealtH

Gloria also wondered about other More information:
chemicals that she was exposed to when
Benefits of early childhood
she was pregnant with Amelia, including education and policies:
second-hand tobacco smoke and solvents
• Benefits of early
at the factory where she worked before childhood education
they moved. • Early childhood policy
Amelia had thrived in her daycare.
Preventing/reducing toxic
She seemed happy there and learned chemical exposures in child
some of the basic skills she needed for care settings:
kindergarten. Amelia’s daycare was a • Eco-Healthy Child Care
good choice, but Gloria thought about • Integrated pest
hazardous chemicals Amelia might have management curriculum
been exposed to when she was there. and Green cleaning
toolkit
These include formaldehyde emitted
from certain furnishings and
building materials like cabinets,
hazardous chemicals in
carpeting, phthalates in flexible
plastic toys and vinyl flooring,
bleach and other cleaning
solutions, and air pollutants
from indoor natural gas
combustion.
Watch: Watch Dr. Mark
Miller describes the
benefits of early
childhood education
(1.42 min.)
←
Toxicants and community HealtH

Gloria and Darrell became worried that
there might not be much they could do Key Concept:
Environmental Justice
about reducing the family’s ongoing
exposures to hazardous
chemicals.
Gloria decided to call up a
friend who was involved in
the community to see if she
knew more about community
exposures to toxic chemicals.
Her friend told her there was a
local group called “Clean and Watch: Representative
Green” that was working on reducing Donna Christensen from
the U.S. Virgin islands
the use of chemicals in their town and speak about EJ from a
other issues relating to the environment. physician’s perspective.
(2.47 min.)
She said they had received information
from other communities
facing similar issues.
Gloria heard the term
“environmental justice”
for the first time.
Watch: Peggy Shepard of

WE ACT for Environmental
Justice addresses “sacrifice
zones” at TEDxHarlem
(8 min.)
←
Key Concept:
Toxicants and community HealtH Environmental Justice
The modern “environmental justice” or low income and communities of color in
Gloria and Darrell became worried that “EJ” movement emerged in 1982 as a the United States, further catalyzing the
there might not be much they could do Key Concept:
result of demonstrations by the resi- national movement for environmental
Environmental Justice
about reducing the family’s ongoing dents of Warren County, North Carolina justice. Robert D. Bullard, author of
against the dumping of contaminated Dumping in Dixie, was a leader in this
exposures to hazardous wastes in their community. Hundreds in movement.
chemicals. this predominantly According to African American
black, lower income
Gloria decided to call up a community lay their
Voices in Congress, the origins of
friend who was involved in the EJ movement may be traced
bodies across the even further back to the Civil
the community to see if she road and were ar- Rights Movement of the 1960s.
knew more about community rested in protest of “Low income communities of
the trucks’ delivery of color emerged as strong activists
exposures to toxic chemicals. PCB (polychlorinated against what they viewed as
Her friend told her there was a biphenyls) contami- environmental attacks on their
nated waste to a new civil rights.”
local group called “Clean and Watch: Representative dump. Their actions
Green” that was working on reducing Donna Christensen from sparked national at- The U.S. Environmental
the U.S. Virgin islands tention to the issue of Protection Agency defines
the use of chemicals in their town and speak about EJ from a Environmental Justice as “the fair
race, class, and toxic
other issues relating to the environment. physician’s perspective. exposures and a movement of treatment and meaningful involvement
(2.47 min.)
She said they had received information solidarity among civil rights and of all people regardless of race, color,
national origin, or income with respect
from other communities environmental activists.
to the development, implementation,
facing similar issues. The United Church of Christ’s and enforcement of environmental
Commission for Racial Justice landmark laws, regulations, and policies.”
Gloria heard the term 1987 publication, Toxic Wastes and Race
“environmental justice” in the United States: A National Report
on the Racial and Social Economic
for the first time. Characteristics of Communities of
Find out more: Toxic Wastes and Race at
Hazardous Waste Sites, identified a
Twenty: 1987-2007 (pdf)
national pattern of hazardous waste
landfills disproportionately located in Read the latest goals for the EPA’s
national EJ program, “Plan EJ 2014”
“Dumping in Dixie”
Watch: Peggy Shepard of photo by Jenny Labalme, Browse maps: Interactive Global Atlas
used with permission.
WE ACT for Environmental of Environmental Justice
Justice addresses “sacrifice
zones” at TEDxHarlem
(8 min.)
←
Toxicants and community HealtH

Gloria started attending meetings of
Clean and Green.
Chemical
She learned a lot about the many sources regulations
of pollution in the community, in the air,
in the water, and on land.
The group had information about
environmental contamination and Community
Health Studies
community health studies. They were
working with scientists from a nearby
university who were considering doing a
health study, as there seemed to be higher
than expected levels locally of several
diseases, including cancer, and concerns
that there were excessive numbers of
children being born with birth defects.
←
Toxicants and community HealtH Chemical Regulations

Federal regulatory laws addressing
Gloria started attending meetings of chemicals have evolved over decades,
although some have been more
Clean and Green. effective than others. The Environmental
Chemical
Protection Agency (EPA) is authorized
She learned a lot about the many sources regulations
to regulate pesticides under the Federal
of pollution in the community, in the air, Insecticide, Fungicide and Rodenticide
in the water, and on land. Act (FIFRA); other industrial chemicals consumer products and the general
under the Toxic Substances Control Act environment. Studies of human blood,
The group had information about (TSCA); air pollutants under the Clean urine, hair, or other tissues show that
Air Act; and water pollutants under
the Safe Drinking Water and the Clean
exposures to hundreds of these chemicals
Health Studies are widespread in the general population.
community health studies. They were Water Acts. Pharmaceuticals, chemicals Several versions of legislation to reform
working with scientists from a nearby in food, and cosmetics are under the TSCA have been introduced in Congress in
regulatory authority of the Food and Drug
university who were considering doing a Administration (FDA).
the past several years, but none has been
adopted. Some states have enacted laws
health study, as there seemed to be higher Over 80,000 chemicals are currently in intended to restrict, phase out, or label
than expected levels locally of several the TSCA inventory. Among its many certain hazardous chemicals. They include
weaknesses, when TSCA was first passed in California’s Proposition 65, which requires
diseases, including cancer, and concerns 1976, tens of thousands of chemicals on the warning labels on products containing
that there were excessive numbers of market were grandfathered and remain chemicals known to cause cancer or
children being born with birth defects. in use today with very limited safety data. reproductive disorders, and also prohibits
Moreover, chemical manufacturers are discharge of these chemicals into drinking
not required to evaluate the safety of water sources. Washington state has
new chemicals before notifying the US adopted a plan to phase out of commerce
EPA of their intent to manufacture and certain persistent, bioaccumulative, toxic
market them. And the EPA has very limited chemicals. California has also enacted a
authority to require pre-market safety green chemistry law that will slowly
testing. As a result, thousands of chemicals require safer alternatives for a few
known to be harmful or for which safety chemicals in consumer products.
data are largely missing are present in
Links for more info:

Safer Chemicals
Healthy Families
EPA: Laws and
Executive Orders
←
Toxicants and community HealtH Community Health Studies and the Environment
Citizens concerned about pollution in
Gloria started attending meetings of their community, or about apparent
Clean and Green. high levels of diseases like cancer,
Chemical sometimes turn to scientists and health
She learned a lot about the many sources regulations experts to ask them to study their town
of pollution in the community, in the air, to see if there are connections between
in the water, and on land. pollution and their health. These studies
are difficult and expensive, and citizens
The group had information about are often disappointed in the results.
community health studies. They were Health Studies Find out why with these
two resources. From Exposure to Illness:
working with scientists from a nearby Community Health Studies and
Health Studies Guide: Environmental Contamination
university who were considering doing a Boston University Superfund
health study, as there seemed to be higher Research Project The Environmental Health Investigations
Branch, California Department of Public Health
than expected levels locally of several A guide for making informed decisions,
written to assist community groups and Created as a means to share the experience
diseases, including cancer, and concerns individuals who think that some form and perspective of public health staff dedicated
that there were excessive numbers of of environmental health investigation to studying links between environmental
exposure to chemicals and health effects in
children being born with birth defects. or health study may be useful or
California communities.
necessary in their community.

←
The next time Amelia went to her new

family practice for a checkup, Gloria
told them about Amelia’s diagnosis of a
learning disability.
Her nurse practitioner, Robert, suggested Benefits of spending
some things to do that could help Amelia. time in green space or
natural surroundings
They included making sure she got enough on cognition and
exercise, adequate sleep, healthy and general health.
nutritious foods, and encouragement to
spend time outdoors in green space or
natural surroundings, such as in the park,
because that could help her with her
attention and focus.
Link: Animation on
“Healthy Food and
Exercise” –
UCSF Pediatric
Environmental Health
Specialty Unit.
←
Amelia’s parents both became involved in

the community group. Over the years they
had some major successes, including getting
the truck route that used to go by their
house changed to a less residential area.
They knew that would promote the health
of their entire family and community.
The education plan that the school, the
developmental pediatrician, and Amelia’s
parents put together included learning
strategies for reading and math that
Amelia found helpful.
Amelia still struggles to some extent
with particular tasks in school and can
sometimes become frustrated in social
situations, but she knows she has the
support of her family and friends and that
means a lot.
Her parents know they are doing
everything they can to improve the
health of their family.
←
Throughout the pages of Amelia’s story A wide range of

we’ve seen a wide range of interacting interacting factors
factors across her lifespan that may have across Amelia’s
increased her risk for developmental lifespan may
disabilities. increase the risk
These include exposure to toxic for developmental
chemicals and community stressors, disabilities
diet, socioeconomics, genetics, and
gene-environment interactions.
We have also seen factors that can
increase resilience and enhance healthy
development, such as parental love and
attention, childhood enrichment activities,
and early childhood education.
Although Amelia’s story is fictional, Children
children throughout our country
throughout our
face a similar range of issues and
circumstances. Developmental disabilities
country face a
are widespread. It is critical that we
similar range of
consider the multiple environmental exposures and
influences associated with increased risks consequences.
of developmental disabilities, and their
long term consequences for children It is critical that we consider the multiple
like Amelia, when we design prevention environmental influences associated with
strategies and treatments to address them. increased risks of developmental disabilities,
Continue to Final Thoughts > and their long term consequences for
children like Amelia, when we design
prevention strategies and treatments.
←
Some Final Thoughts

Resources
Common themes We have linked to many Additional resources to help
useful resources in each story prevent disease and promote health:
Although the fictional narratives relevant to a wide range Portal to Science Resources:
in A Story of Health describe of audiences, including Hundreds of additional
clinicians. To quickly access
the lives of people with different resources on specific topics in
resources on environmental
health including organizations,
diseases, common themes each story, use the Bookmarks publications, videos and more.
resonate. They include: toolbar on the left (which
you can open or close), or Pediatric Environmental Health
• Important environmental influences • Common themes return to the Help page for Toolkit: Materials for health care
come from the natural, chemical, food, in stories more details on other providers and patients in English
eBook features. and Spanish.
built, and social environments. • Additional Resources
Out of Harm’s Way: Preventing
• Although there are exceptions, most • Register for Toxic Threats to Child
diseases as well as good health are the Continuing Development: Fact Sheets in
Education Credits English and Spanish.
result of complex interactions among
Approaches to Healthy Living:
multiple environmental influences and A 4-page guide on how to avoid
genetics. toxicants, eat healthier, reduce
stress.
• Early-life experiences, particularly
Healthy Aging: The Way Forward:
during critical windows of development, We’d love to hear An ecological approach to policy
can have profound beneficial or from you. Give us your level interventions for healthy
detrimental lifelong effects, even feedback on A Story aging across the lifespan.
into elder years. of Health. Click here!
• Preventing disease and promoting health Continuing Education

require actions and commitments from Register for Continuing Education
the individual, family, community and (CE) credits for A Story of Health
society, as they are all interconnected. for a variety of health professions.
Free credits are offered by the
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Prevention/Agency for Toxic environmental health offered by
Substances and Disease Registry the CDC/ATSDR is the Pediatric
at this link. Environmental Health Toolkit
online course.
←
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Exercise in Children With ADHD: international conference on health LaFranchi SH, Haddow JE, Hol-
A Systematic Review. J Atten environmental risk factors for ability to environmental pollut- lowell JG.Is thyroid inadequacy
and design. Stockholm, Sweden: autism spectrum disorders. Int J ants. Environ Health Perspect
Disord. 2014 Mar (epub) Svensj Byggtjanst; 2001:49-59 during gestation a risk factor for
Epidemiol 2014;43(2):443-464 2006;114(10):1479-1485 adverse pregnancy and develop-
Lozoff B, Castillo M, Clark K, Preterm birth, low birth mental outcomes? Thyroid. 2005
Smith J. Iron-fortified vs low- weight and mental health Jan;15(1):60-71
iron infant formula: develop- Mitka M. Even mild iodine
mental outcome at 10 years. Singh G, Kenney M, Ghandour
R, et al. Mental health outcomes deficiency during gestation may
Arch Pediatr Adolesc Med. 2012 impair brain function in children.
Mar;166(3):208-215 in US children and adolescents
born prematurely or with low birth JAMA 2013 Jun 19;309(23)2428
weight. Depress Res Treat. 2013;
2013:570743
←
Diabetes
Marcela’s Story
Xerorro te comnimo el idipis Officipsae que in por

as pedis ipsam Proviti uta nemporum quos ad doloris si dol-
lam asit explit experna tintisquo vel maiorepudis ut lab ium
que sit faceatur alitae pori que nectur aut fuga. rerum alibus
aut ulpa cus et am re sequi occupta, inciat volor sitatiis re,
veliberovit es dunt, nulparis sim dolentu rescipis molut que
remolup tatur.
Basic information: Health professionals: References:
(to come) (to come) (to come)
←
Infertility
Toshio & Reiko’s Story
Mil mint hitae siti ut repellam doloris si dollam asit

explit experna tintisquo vel maiorepudis ut lab ium que sit
faceatur alitae pori que nectur aut fuga. Xerorro te comni-
mo el idipis rerum alibus aut ulpa cus et am re sequi occupta
proviti uta nemporum quos ad eosamentiam, officipsae que
in por as pedis ipsam inciat volor sitatiis re, veliberovit es
dunt, nulparis sim dolentu rescipis molut que remolup tatur.
←
Cognitive Decline
Donald’s Story
Officipsae que in por as pedis ipsam Proviti uta

nemporum quos ad doloris si dollam asit explit experna
tintisquo vel maiorepudis ut lab ium que sit faceatur alitae
pori que nectur aut fuga. Xerorro te comnimo el idipis re-
rum alibus aut ulpa cus et am re sequi occupta, inciat volor
sitatiis re, veliberovit es dunt, nulparis sim dolentu rescipis
molut que remolup tatur.

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A Story

Contributing Authors Reviewers

References and Citations: Certain

This is a story about health.

built and natural

come from the natural, built,

© Stephen Burdick Design

The ecological framework can include community society

are complex and variable. They exert timing of

© Stephen Burdick Design

The ecological health

Following are stories of people like you and

Infertility Learning and

Introduction Our Stories

These stories are not meant to

A Family Reunion Six Stories

This page is your portal to

Health professionals can

Introduction Free Continuing Education

Information on free continuing education Review these

(Asthma) > Continuing education available

Asthma: Brett’s Story (a fictional case)

Basic information: Health professionals: Asthma resources and

Asthma: Brett’s Story (a fictional case)

Asthma Information for Health

Asthma: A Multifactorial Disease

Brett’s mother sometimes wonders what

In general, asthma is a multifactorial disease

John Balmes MD, Professor and Division

Asthma: A Multifactorial Disease

Int J Epidemiol. 1985; 14(1):32-38. 1973; 2(3):219-220.

Asthma: A Multifactorial Disease

Asthmagens: Risk factors for the development of asthma

There are hundreds of substances

Asthmagens: Risk factors for the development of asthma

There are hundreds of substances Asthma in the Workplace and Elsewhere

Asthmagens: Risk factors for the development of asthma

Some early life environmental risk factors

Asthma: Prenatal and Early Life Exposures

Karen also thinks about what her doctors

Asthma: Prenatal and Early Life Exposures

In someone like Brett who already has Potential Asthma Triggers

© Stephen Burdick Design

Asthma: Effects on the Lungs and Immune System

Brett’s doctor told him that the

© Stephen Burdick Design

Asthma and Lung Development

The lung is susceptible to many influences

Reference: Kajekar R. Environmental factors

Asthma and Lung Development

The lung is susceptible to many influences

dular phase (6–16 weeks of gestation

During the embryonic period primary dramatic increase in surface area.

Asthma and Lung Development

Stages of Lung Development

survival, with most continuing postna- alveolarization, the primitive alveoli

During the embryonic period primary dramatic increase in surface area.

Graphic reproduced with permission.

Asthma and Lung Development

Environmental exposures at critical developmental

Reference: Plopper CG, Smiley-Jewell SM, Miller LA,

Asthma and Lung Development

Environmental exposures at critical developmental