Delayed
cerebellar disease and death after accidental
exposure to dimethylmercury
Nierenberg DW et al
Dep Pharmacology and
medicine, Dartmouth-Hitchcock Medical center,
Lebanon, GB
Ingestion of fish or grain contaminated with
methylmercury resulted in epidemics of severe
neurotoxicity and death in Japan in the 1950s
and 1960s' and in Iraq in 1972. The World Health
Organization and other organizations have warned
of the dangers of methylmercury compounds to the
environment and to scientific researchers.
Dimethy1mercury may be even more dangerous than
methylmercury compounds. The physical properties
of dimethylmercury permit transdermal
absorption, and the volatility of this liquid
permits, toxic exposure through inhalation.
Since dimethylmercury is lethal at a dose of
approximately 400 mg of mercury (equivalent to a
few drops, or about 5 mg per kilogram of body
weight), it is supertoxic according to the
rating in a classic toxicology textbook.
We report a case of accidental
dimethylmercury poisoning in a chemist whose
research focused on the biologic toxicity of
heavy metals.Records suggest that she handled
dimethylmercury on only one day, while wearing
latex gloves and working under a ventilated hood
designed to prevent exposure to chemical fumes.
She had delayed but ultimately fatal neurotoxic
effects similar to those caused by methylmercury
compounds. This case illustrates the potent
toxicity of dimethylmercury and the need for
additional safety precautions if it is to be
used in any scientific rescarch.
CASE REPORT
A 48-ycar-old chemistry professor was
admitted to Dartmouth-Hitchcock Medical Center,
in Lebanon, New Hampshire, on January 20, 1997,
with a five-day history of progressive
deterioration in balance, gait, and speech. She
had lost 6.8 kg over a period of two months and
had experienced several brief episodes of
nausea, diarrhea, and abdominal discomfort.
The patient recalled that in August 1996,
while transferring liquid dimethylmercury from a
container to a capillary tube, she spilled
several drops from the tip of the pipette onto
the dorsum of her gloved hand. (A subsequent
review of her dated laboratory notebooks, a
history provided by a coworker, and examination
of the dated materials used in the experiment
later pinpointed the date as August 14, 1996.)
She reported that she had cleaned up the spill
and then removed her protective gloves.
The patient was thin but appeared healthy
and was appropriately concerned about her
neurologic problems. The examination showed
moderate upper-extremity dysmetria, dystaxic
handwriting, a widely based gait, and mild
"scanning speech." The results of routine
laboratory tests were normal. The results of
computed tomography (CT) and magnetic resonance
imaging (MRI) of the head were normal except for
the incidental finding of a probable meningioma,
1 cm in diameter. The cerebrospinal fluid was
clear, with a protein concentration of 42 mg per
deciliter and no cells. Because of the
possibility of methylmercury neurotoxicity,
blood and urine samples were sent for urgent
measurement of mercury content. In view of the
long interval between the date of exposure to
mercury and the onset of neurologic symptoms (
154 days) as well as the rapid progression of
symptoms, other causes of acute cercbellar
dysfunction were considered.
In the ensuing days, the patient noted
tingling in her fingers, brief flashes of light
in both eyes, a soft background noise in both
ears, and progressive difficulty with speech,
walking, hearing, and vision (constricted visual
fields). A preliminary laboratory report
indicated that the whole-blood mercury
concentration was more than 1000 µg per
liter. Chelation therapy with oral succimer (10
mg per kilogram orally every eight hours) was
begun on day 168 after exposure. The next day,
the following laboratory values were reported:
whole-blood mercury, 4000 µg pet liter
(normal range 1 to 8; toxic level, >200);
urinary mercury, 234 µg per liter (normal
range 1 to 5; toxic level >50).
The patients neurologic deterioration
continued, neuropsychiatric testing revealed
marked deficits in all areas. Chelation therapy
was initially successful, with an increase in
urinary excretion of mercury from 257 µg
pet 24 hours (before chelation therapy) to
39,800 µg per 24 hours. Vitamin E was added
to the regimen as a potentially protective
antioxidant.
The patient was transferred to Massachusetts
General Hospital in Boston. Vitamin E and
succimer were continued. An exchange transfusion
reduced the imean whole-blood mercury
concentration from 2230 µg per liter before
the procedure to 1630 µg per liter 2 hours
afterward, but reequilibration resulted in a
concentration of 2070 µg per liter 16 hours
later. The mercury content of bile was 30 to 99
µg per liter. Repeated CT and MRI scans of
the head remained normal, with no evidence of
occipital or cerebellar damage. Audiometry
revealed mild-to-moderate sensorineural hearing
loss. Neuro-ophthalmologic testing revealed
moderately constricted concentric fields, with
no evidence of papilledema. On February 6, 22
days afer the first neurologic symptoms
developed (and 176 days after exposure), the
patient became unresponsive to all visual,
verbal, and light-touch stimuli.
The patient was transferred back to
Dartmouth -Hitchcock Medical Center, and
aggressive general support was continued, along
with 21-day cycles of chelation therapy with
succimer (10 µg per kilogram given orally
every 12 hours). The decline in blood mercury
concentrations over time is shown in Figure 1.
Mercury half-lives (with chelation therapy) were
29 to 37 days. Urinary excretion of mercury
declined rapidly despite ongoing chelation
therapy. Analysis of a long strand of hair
revealed that alter a brief lag, the mercurv
content rose rapidly to almost 1100 µg per
milligram (normal level, <0.26 µg per
milligram potentially toxic level >50 ng per
milligram) and then declined slowly, with a
half-life of 74.6 days.
The patients neurologic status was marked by
periods of spontaneous eye opening, but without
awareness of or any response to visual, sound,
or light-touch stimuli. The Babinski sign was
equivocal, and decerebrate and decorticate
posturing were absent. Painful stimuli resulted
in limb withdrawal. Corneal and pupillary
reflexes were sluggish but present.
Spontaneous yawning, moaning, and limb
movements occurred, with periods of agitation
and crying, requiring large doses of
chlorpromazine and lorazepam. Her condition
appeared to resemble a persistent vegetative
state with spontaneous episodes of agitation and
crying.
Testing of family members, laboratory
coworkers, and laboratory surfaces failed to
reveal any unsuspected mercury spills or other
cases of toxic blood or urinary mercury
concentrations.
We could find only three previously reported
cases of poisoning with dimethylmercury, all of
which were fatal. Equally bleak outcomes have
been reported in patients with severe
methylMercury toxicity. In view of the dismal
prognosis and after more than three months of
aggressive treatment and support, the patient's
advance directives were followed, and she died
peacefully on june 8, 1997, 298 days after
exposure.
At autopsy, dehydration and bronchopnemonia
were noted. The cortex of the cerebral
hemispheres was diffusely thinned, to 3 mm. The
visual cortex around the calcarine fissure was
grossly gliotic, as was the superior surface of
the superior temporal gyri. The cerebellum
showed diffuse atrophy of both vermal and
hemispheric folia. Microscopical study showed
extensive neuronal loss and gliosis bilaterally
within the primary visual and auditory cortices,
with milder loss of neurons and gliosis in the
motor and sensory corticcs. There was widespread
loss of cerebellar granular-cell neurons,
Purkinje cells, and basket-cell neurons, with
evidence of loss of parallel fibers in the
molecular layer. Bergmann gliosis was well
developed and widespread.
An extremely high mercury content was found
in the frontal lobe and visual cortex (average
value, 3.1 µg per gram, or 3100 ppb), livcr
(20.1 µg per gram), and kidney cortex (34.8
µg per gram). The mercury content of the
brain was approximately six times that of whole
blood at the time of death and was much higher
then levels in brain samples obtained at autopsy
from patients not previously exposed to mercury
(2 to 50 ppb).
DISCUSSION
In 1865, two laboratory assistants died
several ,weeks after helping to synthesize
dimethylmercury for the first time. Nearly 100
years later, another laboratory worker died
after synthesizing the compound. He had a rapid
downhill course very similar to that of our
patient, and chelation therapy with
penicillamine was without clinical benefit.
Several conclusions can be drawn from these
case reports, the epidemics of poisoning with
methylmercury compounds, and the information
obtained from this case. First, even an
accidental, brief exposure to dimethylmercury
can be fatal. The data are consistent with a lag
phase after exposure, rapid conversion of
dimethylmercury to methy1mercury, rapid movement
of methylmercury from blood to hair (half-life
of uptake into hair, 5.6 days), and a
first-order decline in the mercury content of
hair (half-life, 74.6 days) that paralleled the
decline in blood mercury. Qualitatively similar
observations have been made in mice exposed to
dimethylmercury through intravenous or
inhilational routes.
In our patient, the rapid, monophasic,
first-order increase in the mercury content of
hair is consistent with either one or several
episocles of exposure to dimethylmercury
beginning on or about August 14, 1996, and is
consistent with the evidence (reports from
coworkers and information from labeled vials and
laboratory notebooks) that a single accidental
exposure to dimethylmercury occurred on August
14. Our findings are also consistent with
earlier reports that methylmercury has a
half-life of about 78 days in humans, that
excretion of methylmercury is first-order in
mice and humans, and that the toxicity of
dimethylmercury is apparently mediated by
methy1mercury metabolites in mice.
Second, disposable latex gloves do not
provide adequate protection against
dimethylmercury. Permeation tests showed that
several types of disposable latex or polyvinyl
chloride gloves (typically, about 0.1 min thick)
had high and maximal rates of permeation by
dimethylmercury within 15 seconds. In contrast,
gloves designed to be chemically resistant are
made of materials specifically selected for
their ability to withstand chemical permeation.
For example, under standard test conditions, no
permeation of a flexible, plastic-laminate glove
(SilverShield) was observed after four hours of
exposure to dimethylmercury. This thin glove can
be wom under a heavyduty outer glove (e.g., one
made of neoprene) for increased protection. Our
patients accidental exposure may have resulted
from both transdermal absorption of the liquid
(given the lack of protection provided by
disposable latex gloves) and inhalation of
vapors (even though the work was conducted under
a fume hood).
Since research in animals suggests that
dimethy1mercury is either promptly exhaled or
converted to methylmercury metabolites that can
bind to tissues we can estimate the body burden
of mercury in our patient. At the time of the
diagnosis, the blood concentration was 4000
µg per liter, which represents about 16.8
mg of mercury in the blood (total volume of
blood, about 4.2 liters) and about 336 mg in the
entire body (since only about 5 percent of an
absorbed dose of methylmercury remains in
blood). Since dimethylmercury has a density of
3.2 g per milliliter, this amount of mercury is
coutained in only 0.11 ml of liquid
dimethylmercury. Since the elimination half-life
in hair was about 75 days and the interval
between exposure and blood studies was just over
150 days, the original body burden of mercury
may have been four times the amount at
diagnosis, or about 1344 mg, requiring
absorption of 0.44 ml of liquid dimethylmercury
(perhaps more if a portion of the absorbed dose
was promptly excreted through exhalation, as
reported in mice exposed to
dimethylmercury).
Third, the interval between exposure and the
onset of neurologic symptoms (154 days) is a
longer latent period than that reported after
oral ingestion of the more common methylmercury
compounds. However, there have been reports of
latent periods lasting for years after the
administration of methylmercury in monkeys. The
reason for this latency is unclear.
Fourth, the brain damage caused by
dimethylmercury in our patient was similar to
that reported previously in patients who died
from exposure to either dimethylmercury or
methylmercury. In all these cases, the damage
involved the cerebral cortex, especially the
calcarine area, with necrosis of neurons and
gliosis. Extensive neuronal death and loss in
the cerebellum was another characteristic
finding. In previous cases, most of the mercury
found in the brain at autopsy was in anorganic
form, which is probably not responsive to
chelation therapy. Research in animals indicates
that dimethylmercury does not enter the brain
until it has been metabolized after several days
to methylmercury, a metabolite capable of
forming covalent bonds with cellular
proteins.
Fifth, the role of chelation therapy in such
cases remains unclear. Succimer has been
recommended as the treatment of first choice for
methylmercury poisoning and other chelators used
in Iraq failed to show a significant clinical
benefit. Dimercaprol may actually be
contraindicated in cases of poisoning with
organic mercury compounds. One study of
chelation therapy in mice exposed to
methylinercury suggested that treatment with
succimer, begun a few days after exposure, is
most effective in reducing brain and blood
mercury levels. Our experience confirms previous
reports that treatment begun long after exposure
to methylmercury, and after serious
neurotoxicity has developed, is of little or no
clinical benefit (even if urinary excretion and
the elimination half-life are improved).
Contact with various forms of mercury is
possible in occupational or other settings. The
american Conference of Governmental Industrial
Hygienists has established "threshold limit
values" and "biological exposure indices" for a
variety of chemicals, including mercury.
Material Safety Data Sheets may be inadequate
sources of information ou how to handle a
particular chemical safely. For example, the
Material Safety Data Sheet for dimethylmercury
states, "Wear appropriate chernical-resistant
gloves," which is simply too vague to provide
adequate guidance for glove sclection. Increased
awareness of personal protection on the part of
scientists and more detailed and specific safety
information from manufacturers could make
research with toxic chemicals safer.
Dimethylmercury appears to be so dangerous
that scientists should use less toxic mercury
compounds whenever possible. Since
dimethylmercury is a "supertoxic" chemical that
can quickly permeate common latex gloves and
form a toxic vapor after a spill, its synthesis,
transportation, and use by scientists should be
kept to a minimum, and it should be handled only
with extreme caution and with the use of
rigorous protective measures.