Mitigating Methylmercury Exposure
Study Confirms Potential of NAC as Antidote and Biomarker
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Researchers have been searching for better
ways to quantify and mitigate exposures to the neurotoxicant
methylmercury (MeHg). Results from a new animal study confirm
that N-acetylcysteine
(NAC), already used to treat acetaminophen overdose, may serve
as a quick-acting antidote for and biomarker of MeHg exposure [EHP 116:26–31;
Aremu et al.].
MeHg is created when elemental mercury
released through the burning of coal, waste incineration, and
other industrial processes is metabolized by aquatic
microorganisms such as anaerobic bacteria. It bioaccumulates
rapidly, with concentrations in some top marine predators
reaching 100,000 times that of surrounding seawater. Fish
consumption is the major source of human exposure. MeHg can
cause irreversible brain damage, and the developing brain is
especially vulnerable to its effects.
Treatments to mitigate MeHg exposure
involve chelation, the administration of compounds that bind
mercury, speeding its elimination from the body and thereby
minimizing its toxicity. Current chelation methods can be
nonspecific, depleting not only MeHg but also minerals required
for normal cell function, such as calcium.
image: Indigo Fish/Shutterstock, Getty Images, Matthew Ray/EHP
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In contrast, chelation treatment with NAC
does not affect levels of essential minerals. NAC, a derivative
of the amino acid L-cysteine and a precursor of the antioxidant
glutathione, is itself a potent antioxidant. NAC can be
delivered intravenously or orally.
In the current study, adult
rats were injected with NAC (1 mmol/kg) 2 hours after being exposed
to
MeHg (0.1 µmol/kg). The treated animals excreted about
5% of their body burden of MeHg within 2 hours, compared with
less
than 0.1% excreted by untreated animals. The response was
transient and dose dependent, with larger doses of NAC
resulting in higher rates of MeHg excretion.
These effects were not
seen in preweaned rats (age 15–19 days) treated with NAC. The researchers
speculate that the transporter systems needed to move the
MeHg–NAC complex through the kidney do not mature until
animals reach adulthood (around 30 days of age). However, oral
NAC treatment in pregnant rats (10 mg/mL in drinking water) did
protect their fetuses, reducing concentrations in the placenta
and the whole fetus by 70–90%. In the dams themselves,
NAC also reduced MeHg concentrations by 70–90% in the
brain, by about 20% in the kidney, and by 60–80% in the
blood and liver.
NAC's short half-life, about 2
hours, may allow it to serve as an accurate real-time biomarker
of MeHg exposure. According to the researchers, such a
quick-acting biomarker could provide critical early warning of
possible acute exposures, where early treatment is critical to
prevent neurological damage. In the current study, MeHg
excretion in animals treated with NAC was proportionate to MeHg
body burden at the time of treatment. In contrast, standard
monitoring techniques, which use hair analysis, can provide
only a history of exposure and cannot guide immediate treatment
for acute exposures. The researchers propose that future studies
test NAC in adult humans as a biomarker of exposure and
a possible treatment for MeHg exposure, especially for pregnant
women whose unborn children are in danger of prenatal MeHg
exposure.
Kris Freeman
Clear Reception
Elucidating the Binding Characteristics of Bisphenol A
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Several studies have
indicated that bisphenol A (BPA), which is widely used in polycarbonate
plastic and epoxy resin manufacturing, can disrupt normal
endocrine function. Given that BPA's estrogen receptor
(ER) binding and interaction are 100–1,000 times weaker
than those of endogenous hormones, researchers have
hypothesized that BPA interacts with nuclear receptors other
than ER. A recent study directly assayed BPA's
interaction with estrogen-related receptor-γ (ERR-γ),
one of a family of "orphan" nuclear receptors—those
for which natural ligands are unknown—and clarified the
structural requirements that enable BPA to bind this receptor [EHP 116:32–38;
Okada et al.].
Earlier research by the same team
demonstrated that BPA strongly binds ERR-γ. The research
also showed that BPA preserves ERR-γ's high constitutive
activity. Receptors with constitutive activity trigger molecular
events in the
absence of a ligand; specific ligands known as inverse agonists
can deactivate these receptors.
The authors emphasize the importance of
this investigation by noting that ERR-γ is
very strongly expressed in the mammalian brain during development
and in the
brain, lung, and other tissues in adults; unpublished results
from this group show the highest expression in the placenta.
It
is possible that BPA's binding ERR-γ could affect
the receptor's role by activating transcription at the
wrong times.
Using tritium-labeled BPA, the researchers
conducted the first saturation binding assay to precisely
characterize how strongly BPA binds ERR-γ. They also ran
competitive binding assays with BPA analogs and other
industrial chemicals, including phenol derivatives, to identify
which structural characteristics of the chemicals are critical
for binding ERR-γ and maintaining its constitutive activity.
They found specific, extremely high binding affinity of BPA for
ERR-γ. BPA analogs
varied in their ability to bind the receptor, and phenol
derivatives were newly discovered to be potential candidates
for ERR-γ–mediated endocrine disruption.
These findings raise the immediate
question of whether reported BPA-related endocrine disruption
might actually be mediated through ERR-γ rather than through
ER. Additionally, the researchers stress the need to determine
the normal physiologic roles of ERR-γ as well as the ways
in which BPA might affect these roles. Given the strong
expression of ERR-γ in the fetal brain and placenta, further
information is especially urgent with regard to outcomes for
newborns.
Julia R. Barrett
Science in the Courtroom
Examining Standards for Litigation-Based Research
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Over the last 20 years,
the term "junk science" has gained increasing use by
defendants in toxic tort litigation as a pejorative phrase to
discredit health effects data that do not meet some standard
for scientific validity—or, some say, that are favorable
to the interests of plaintiffs. Proponents of tort reform have
argued that many large jury verdicts are the unjustified
products of questionable scientific data presented by plaintiff
lawyers to easily swayed jurors. Courts have responded by
raising the bar that scientific evidence must exceed in order
to be admitted as evidence. But has this change produced sound
results? Is there really a distinction between litigation-based
science and other science? In a mini-monograph in this issue,
5
articles examine these questions and others that arise when
examining the juncture of science and litigation [EHP 116:116–147].
Acknowledging that conflicts
of interest are an inherent component of science-based litigation,
authors
Ronald L. Melnick, Kristina A. Thayer, and John R. Bucher of
the NIEHS conclude that public health decisions to allow
exposure to possible carcinogens should not rely "on
untested hypotheses that are promoted to explain away adverse
outcomes." Their article focuses specifically on rodent
carcinogenicity studies and examines how strict attention to
design and evaluation can reduce inaccurate conclusions and
provide data that are useful for evaluating human health risks.
image: Getty Images, Matthew Ray/EHP
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The authors cite early
animal studies on benzene as an example of poor design that failed
to detect
carcinogenic effects, even though epidemiologic studies
demonstrated a causal association between benzene exposure and
leukemia in humans. Those early studies employed too few
animals, insufficient controls, too short a study duration, and
inadequate levels of exposure. In addition, the authors write, "evaluations
that are based on incomplete necropsy or histopathology, do not
combine related tumor effects, fail to
adjust for differences in animal survival, or incorrectly use
historical control data would not be expected to produce
reliable information on chemical carcinogenesis."
Courts, meanwhile,
have also taken steps to reduce the likelihood of "junk science" influencing
juries. Two of the articles in the mini-monograph, the first by
Leslie I. Boden and David Ozonoff of the Boston University
School of Public Health and the other by Sheila Jasanoff of
Harvard University’s Kennedy School of Government,
examine the assertion that science conducted to support
litigation must be held to tougher admissibility standards than
other science. Appeals Court Judge Alex Kosinski made this
claim in 1995 in response to the Supreme Court remand in Daubert v. Merrell-Dow Pharmaceuticals, Inc., deciding that judges were henceforth required
to assume roles as gatekeepers with the responsibility of
culling out unreliable expert evidence. As the authors
describe, many courts following Daubert have held
that research conducted specifically for the purpose of a litigation
is inherently less
reliable than other science.
Boden and Ozonoff re-examine
whether litigation-based science should be treated differently
from
other science offered as evidence in the courtroom. They
conclude that it shouldn’t. Their contentions include an
assertion that cross-examination by attorneys aided by
competent experts, not just journal peer review, also serves
the ends of justice. They further argue that any science is
subject to a variety of biases; for example, they write,
studies funded by pharmaceutical companies or investments by
corporations in research agendas tend to favor their own
economic interest. Finally, the authors argue that tougher
standards for litigation-generated science unfairly burden
plaintiffs.
In her article, Jasanoff agrees that
restrictions placed on litigation-based science following Daubert are
misconceived because the scientific knowledge needed to resolve
legal disputes often arises only in response to litigation.
Rather than assign judges the role of gatekeeper, a more
sensible approach, she writes, would be for judges to assume
the position of referee. In this role, judges would
"focus on the process through which litigation science
is generated rather than on its validity or invalidity. They
would
be in a position to structure agreements among the parties that
would be most conducive to producing relevant and reliable
knowledge."
In a fourth article, Carol J. Henry and
James W. Conrad, Jr., of the American Chemistry Council focus
on the role of federal agencies rather than that of the courts.
They write that the quality of agency scientific research and
testing is already subject to a variety of standards and
practices (e.g., the Federal Information Quality Act, and peer
review and transparency in research practices), and argue that
these standards and practices allow agencies to judge the
quality of work regardless of the reason for which it was
created. They also point out that federal agencies are required
to accept and fairly consider information provided by any
interested person in the course of decision making.
In the last paper, William
R. Freudenburg of the University of California, Santa Barbara,
takes a
critical look at the nature of bias itself, concluding that
scientists oftentimes are not conscious of its influence on
them. Drawing from personal experience, Freudenburg describes
litigation-based research he conducted for a company that never
tried to censor his work and consistently praised him for being
principled and credible. But he subsequently came to realize
that praise for his objectivity actually encouraged him to
interpret his findings in ways that would favor his corporate
sponsors more than if they had tried to tell him what to say.
The problem, he writes, was "the temptation to start
changing my own judgments . . . in response to their repeated
insistence that it was precisely my independent and scientific
credibility that they valued."
The articles in the mini-monograph share a
common thread: when science is used to serve the purposes of
litigation or administrative proceedings, great care is needed
to ensure its proper deployment, and a courtroom judge is
probably not the appropriate person to decide on the
reliability and relevance of scientific evidence. Furthermore,
the perception that bias is inherently bad or avoidable may
itself be biased.
Richard C. Dahl