A 352 V O L U M E 118
|
N U M B E R 8
|
August 2010 • Environmental Health Perspectives
News
|
Science Selections
An Uneven Path Forward
The History of Methylmercury Toxicity Research
Organic mercury compounds were first described in the 1800s, with
fatal cases of methylmercury poisoning reported in 1865. Early reports
described a distinct set of symptoms of methylmercury toxicity, includ-
ing altered sensation in the face and extremities, tunnel vision, deaf-
ness, loss of coordination, and impaired speech. Nearly a century later,
against a backdrop of widespread environmental contamination, the
clinical picture reappeared, and suspicions of additional harm to human
health had developed. Yet it wasn’t until 2009 that international agree-
ment to control mercury pollution was reached. A historical review
suggests that—as one early commenter observed—the tunnel vision,
forgetfulness, and lack of coordination that symptomize methylmercury
toxicity can also affect the conduct and interpretation of environmental
health research [EHP 118(8):1137–1145; Grandjean et al.].
Methylmercury became commercially important as a crop fungi-
cide around 1914. Worldwide use was accompanied by worker poison-
ings and several large-scale food poisoning incidents. The compound
emerged as an industrial pollutant in the early 1950s around Japan’s
Minamata Bay, where contaminated seafood induced neurologic symp-
toms mirroring those reported in 1865. Epidemiologic evidence from
Minamata, paired with a 1952 report from Sweden, indicated more
severe disease from prenatal and early-life exposures, with symptoms
including mental retardation, seizures, and impaired motor develop-
ment. In the 1960s, advances in analytical technology permitted
chemical analysis of mercury species in environmental samples, result-
ing in the discovery of methylmercury biomagnification in the food
chain and identification of environmental methylation of inorganic
mercury in waterways. Methylmercury had become a worldwide prob-
lem, not simply a local issue.
Defining the scope of the problem, much less acting to address it,
has involved a political, legal, and ethical maze set on an ever-evolving
and still-incomplete scientific foundation. Initially, the inability to iden-
tify mercury species in the environment hampered researchers’ efforts
to link the presence of methylmercury with poisoning symptoms. That
link also was blurred by a time lag of weeks to months between exposure
and initial symptoms as well as slow recognition of the significance of
experimental and wildlife data. Industrial suppression of toxicity data
impaired accurate risk assessment, as did imprecise estimates of expo-
sure, delayed recognition of low-dose effects, and use of adult data only.
Consequently, regulatory safeguards established in the 1960s and
1970s are now known to be inadequate, but improvements have been
deferred in light of scientific uncertainties. For example, although it
remains unknown whether a “safe” threshold exists for prenatal and
early-life exposure to methylmercury, evidence of methylmercury
damage to neurodevelopment has been accumulating since the 1950s.
More research is certainly needed, the authors write, but prevention
and correction of environmental health problems need not and should
not be delayed by a desire for absolute proof.
Julia R. Barrett, MS, ELS, a Madison, WI–based science writer and editor, has written for
EHP since 1996. She is a member of the National Association of Science Writers and the Board of
Editors in the Life Sciences.
Breaking Patterns of Disease
Early-Life Clues May Predict Long-Term Health
Modern diseases often seem to occur in isolation, but many are
now known to emerge from a complex web or pattern of conditions
linked together by certain underlying biological mechanisms and
processes. With the help of large disease databases, medical scientists
have begun to discern how such patterns occur over the course of a
lifetime. A new review focused on developmental immuno toxicology
explores how this integrative perspective might inspire novel strate-
gies for lowering the risk and prevalence of immune-based dis-
eases influenced by environmental stimuli [EHP 118(8):1091–1099;
Dietert et al.].
Many chronic diseases share three common features: 1) early-life
exposures to chemical agents or pathogens, 2) evidence of immune
insult or dysfunction, and 3) the appearance of disease biomarkers in
exposed children although disease itself may not manifest until later
in life. One example of interlinked disease conditions highlighted by
the authors is metabolic syndrome, defined as the co-occurrence of
at least three of five conditions: insulin resistance, obesity, high blood
pressure, elevated triglycerides, and reduced HDL cholesterol.
Immune dysfunction is central to the underlying physiology of
metabolic syndrome, and the authors posit that the seeds of such
dysfunction may be planted in childhood. They describe pre- and
postnatal exposures to environmental risk factors that produce post-
natal lipid dysregulation and immune dysfunction. However, it is
not yet known whether immune dysfunction is an underlying cause
of metabolic syndrome or simply an associated or disease-facilitating
characteristic.
The practical key to preventing metabolic syndrome may lie in
treatments that address overall patterns and their progression, not just
the initial presenting condition. “For those patterns of disease with
immune involvement,” the authors write, “preventing the underlying
immune dysfunction is the single most effective option to minimize
the risk of one or more chronic diseases later in life.” This will require
more information about risk factors for immune dysfunction that
are encountered during development or childhood. Therefore, the
authors also recommend that chemicals and pharmaceuticals be tested
for developmental immunotoxicity end points; currently, safety assess-
ments are based solely on adult exposures.
The authors say patterns of disease can be used to better predict,
prevent, and treat diseases associated with an immune-related pattern
of diseases, and may also serve as the basis for environmental protection
and testing to prevent exposure to developmental immunotoxicants that
may contribute to multiple interconnected diseases. But pattern-based
evaluation, prevention, and treatment will require a shift from the pre-
vailing single-organ approach to disease classification and management.
M. Nathaniel Mead, a science writer living in Durham, NC, has written for EHP since 2002.
?

A
n
n
e
t
t

V
a
u
t
e
c
k
/
i
S
t
o
c
k
p
h
o
t
o

Bringing the Bugs Back In
Environmental Health Research Model
Combines Toxicology and Infectious Disease
Although pathogens are known to modify the effects of toxicants,
U.S. environmental health research currently focuses on phys-
ical agents and chemical toxicants—a focus that limits the field
by ignoring the interaction between pathogens and toxic agents
[EHP 118(8):1165–1172; Feingold et al.]. These authors present a con-
ceptual paradigm that integrates
infectious disease and toxicologic
environmental health research,
promotes cross-disciplinary edu-
cation and communication, and
elucidates a fuller body of environ-
mental health risk factors.
Chemical toxicity often
involves relatively direct effects
of exposures on health outcomes,
but infectious disease transmission
typically is more complex, depend-
ing on factors such as dynamic
environmental and ecologic sys-
tems, patterns of contact among
populations, and host immune
status. But interactions between
pathogens and toxicants are unde-
niable. For instance, hepatitis B
virus and aflatoxin individually
increase the risk of liver cancer, but
combined exposure to both agents
increases risk far more than would
be expected based on effects of the two risk factors in isolation. And in
the case of cervical cancer, although infection with human papilloma-
virus is believed to be necessary for the cancer to occur, smoking may
act as a cofactor and increase the risk the cancer will occur in someone
infected with the virus.
The authors identify multiple points between initial exposure and
clinical disease at which toxicant–pathogen interactions can occur. They
also describe approaches common to both areas of research. Both focus
on upstream interventions to prevent disease by preventing exposure.
Both areas also focus on spatial context (i.e., proximity to toxic or
pathogenic agents) and quantitative
modeling to estimate exposure, and
both use biomarkers to study expo-
sure, susceptibility, and disease.
Fostering collaborations
between researchers in these fields
can lead to a better understanding
of complex exposures and resulting
diseases. “Classic reductionist think-
ing in toxicology focuses on ‘one
toxicant, one outcome’ research,”
the authors write. In contrast,
they conclude, “If basic research
is to increase our ability to predict
the consequences of exposure to
environmental chemicals, we must
embrace nonreductionist thinking
and design experimental models
that emulate human experience.”
Harvey Black of Madison, WI, has written for
EHP since 1994. His work has also appeared
in Environmental Science & Technology,
ChemMatters, and the Milwaukee Journal
Sentinel.
Body of Proof
Biomonitoring Data Reveal Widespread
Bisphenol A Exposures
A review of more than 80 biomonitoring studies from nine nations
suggests exposure to bisphenol A (BPA) is ubiquitous in people
throughout the world [EHP 118(8):1055–1070; Vandenberg et al.].
Moreover, in samples of blood serum, median levels of unconju-
gated (biologically active) BPA were higher than levels predicted by
toxicokinetic models that form the basis of U.S. regulations for the
compound, reaching the range that has been shown to cause adverse
effects in animals.
More than 8 billion pounds of BPA are produced each year,
making it one of the world’s most heavily used chemicals. BPA is used
in baby bottles, drinking bottles, food storage containers, polyvinyl
chloride, stretch films, paper, cardboard, medical equipment, and
the epoxy resins lining most metallic food and beverage cans. BPA
has estrogenic properties, and animal studies have linked low-level
exposure to altered development of the male and female reproductive
tract and brain as well as cancers of the mammary gland and prostate.
The authors analyzed 24 biomonitoring studies involving blood
serum samples from healthy adults, adults with certain diseases, preg-
nant women, and fetuses or fetal tissues. Overall, these studies indicate
exposure to unconjugated BPA is in the range of 0.5–10 ng/mL, with
most studies suggesting an average exposure of 1–3 ng/mL. The latter
concentrations are higher than those shown to cause effects in human
and animal cell cultures.
The only data on BPA levels in children after birth is from studies of
urine samples, most of which measured total (conjugated and unconju-
gated) BPA, but some of which measured unconjugated BPA separately
from conjugated (inactive) BPA. The Centers for Disease Control and
Prevention measured total BPA in urine samples from 314 children aged
6–11 years and 715 adolescents aged 12–19. Compared with adults, the
younger children’s levels were highest, and adolescents were in-between.
Other smaller studies also showed that BPA concentrations were higher in
neonates and young children than in adults.
Some of the studies measuring BPA in human blood were conducted
using the enzyme-linked immunosorbent assay. Although this assay is
considered less specific than the more precise analytical chemistry methods
now favored for measuring BPA, the authors argue these studies are
worthy of inclusion in their review because the concentrations they report
are in line with what have been detected using the newer methods.
The paper also points out “significant deficiencies” in the two studies
that have examined the toxicokinetics of BPA exposure in humans,
which they say have been given undue weight in regulatory decision
making. The authors note we don’t yet know all the potential sources
of exposure to BPA, which makes it impossible to predict toxicokinetics.
Because the biomonitoring findings contradict the toxicokinetic studies,
the authors recommend in a related commentary in the same issue
[EHP 118(8):1051–1054; Vandenberg et al.] that biomonitoring data be
considered in regulatory decision making whenever available rather than
relying only on toxicokinetic models to estimate exposure.
Kellyn S. Betts has written about environmental contaminants, hazards, and technology for
solving environmental problems for publications including EHP and Environmental Science &
Technology for more than a dozen years.
Science Selections
Environmental Health Perspectives • V O L U M E 118
|
N U M B E R 8
|
August 2010 A 353
?

A
n
n
e
t
t

V
a
u
t
e
c
k
/
i
S
t
o
c
k
p
h
o
t
o
Environment
Traditional individual susceptibility factors
Disease
Early
biological
effects,
altered
structure
and function
Interagent
susceptibility
(interaction)
Interagent
susceptibility
(interaction)
Infectious
agents
Carriage,
infectious dose
Infected
cells, agent
replication
Toxicants
Internal dose,
biologically
effective dose
Recovery,
acute disease,
chronic disease,
death
Herd immunity
Immunity
Shedding
Sources,
vectors
Food
Air
Soil
Dust
Water
– +
Pathogen–toxicant inter actions may influence the progression from
exposure to disease at multiple points.
F
e
i
n
g
o
l
d

e
t

a
l
.