Correspondence

Death after Exposure to Dimethylmercury

N Engl J Med 1998; 339:1243-1244October 22, 1998

Article

To the Editor:

In the report by Nierenberg et al. (June 4 issue)1 of a tragic case of fatal dimethylmercury toxicity, the patient's history, supported by laboratory records, revealed exposure to the toxin on only one day, with a small spill of several drops onto the dorsum of a latex-gloved hand. It was postulated that toxic tissue levels resulted from transdermal absorption through permeable latex gloves, with possible inhalation despite the use of a fume hood.

There appears to be little doubt regarding the diagnosis; however, we would be interested in more details of the investigation of the possible sources of the toxin. As the accompanying editorial comments, “it remains possible that the patient had unrecognized mercury exposure before the single spill reported.”2 Specifically, we would like to know more about the evaluation of the laboratory by the Occupational Safety and Health Administration after the exposure. More information is needed about the amount of dimethylmercury involved.

Several drops from a pipette is not 0.44 ml, and even if it were, almost complete permeation of the skin would have had to occur, which seems unlikely. Was the skin intact in the area of exposure? How was the possibility of nonaccidental administration of the toxin excluded, given the astounding amount of neurologic damage that occurred from so small a dose? Was there a formal police or medicolegal investigation? Were traces of other toxins or drugs looked for at the time of hospital admission?

Roger W. Byard, M.D.
Richard Couper, F.R.A.C.P.
Women's and Children's Hospital, North Adelaide, SA 5006, Australia

2 References

1. 1

   Nierenberg DW, Nordgren RE, Chang MB, et al. Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med 1998;338:1672-1676
   Full Text | Web of Science | Medline

2. 2

   Kulig K. A tragic reminder about organic mercury. N Engl J Med 1998;338:1692-1694
   Full Text | Web of Science | Medline

To the Editor:

The recent report of the death of a researcher after exposure to dimethylmercury and the companion editorial serve as grim reminders of the dangers associated with exposure to compounds that contain mercury. Mercury cycles through the environment as a consequence of natural and human activity. It is concentrated by predation among aquatic species, reaching the highest levels at the top of the food chain. It causes a variety of effects in humans, primarily through damage to the nervous system.

Although Kulig correctly listed incinerators as a major anthropogenic source of mercury pollution, he stopped short of identifying the specific role of medical-waste incinerators. The Environmental Protection Agency (EPA) ranks medical-waste incinerators as the fourth leading source of mercury contamination of the environment.1 According to the EPA, medical-waste incinerators discharge more mercury into the environment than all manufacturing processes combined.1 Medical-waste incinerators are also a leading source of dioxin production and discharge.2 Although a recent survey of leading hospitals suggests that many are moving away from incineration as a method of disposal, 40 percent still incinerate waste that could be disposed of more safely.2 The maxim “first, do no harm” is the fundamental guiding principle of the practice of medicine. We have an obligation to apply this principle to the disposal of medical waste and to work toward a better solution to the complex problem of medical-waste management.

Alan H. Lockwood, M.D.
State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY 14215

Phillip J. Landrigan, M.D., M.Sc.
Mount Sinai Medical Center, New York, NY 10029-6574

2 References

1. 1

   Office of Air Quality Planning and Standards. Mercury study report to Congress. Washington, D.C.: Environmental Protection Agency, 1997.
   

2. 2

   Environmental Working Group. “Greening” hospitals: an analysis of pollution prevention in America's top hospitals. Washington, D.C.: Environmental Working Group, 1998.
   

To the Editor:

Dimethylmercury is a spontaneously nonreactive, lipophilic mercurial whose physicochemical properties predict what was in fact observed in the only study of its effects in vivo.1 Its rapid metabolic conversion in the liver creates the toxic species methylmercuric ion. If liquid dimethylmercury was in fact the causative agent, and if the fatal toxicity was caused by a single exposure, then the volume coming in contact with the patient's skin should have been something like 10 times that calculated by Nierenberg et al., assuming that dimethylmercury behaves in the same way in humans as Ostlund observed in mice.1 With no evidence to the contrary, it is reasonable to make such an assumption, since the initial distribution of dimethylmercury in vivo should be dictated by its physicochemical properties alone.

Assuming that the patient's death was the result of a single transdermal dose of dimethylmercury, one would expect neurologic symptoms to appear much earlier than five months after exposure. In the two cases of fatal dimethylmercury poisoning in the 1860s,2 both persons were symptomatic shortly after exposure (one died within a few weeks). I can find no data on dimethylmercury toxicity in animal studies: however, single toxic doses of methylmercuric ion given to rats, hamsters, and squirrel monkeys resulted in the appearance of symptoms within a few hours to a few days.3 Humans ingesting methylmercuric ion through multiple exposures (in bread) also manifested toxic effects much sooner than five months,4 as did those consuming pork over a three-month period.5

These points raise questions about the timing, amount, and manner of exposure and the specific mercurial dimethylmercury or methylmercuric ion to which the patient was exposed. Given the circumstances of this case, it is unfortunate that determinations of the presence or absence of methylmercuric ion and inorganic mercury were not made in brain tissues.

David P. Hanlon, Ph.D.
51 E. Wheelock St., Hanover, NH 03755

5 References

1. 1

   Ostlund K. Studies on the metabolism of methyl mercury and dimethyl mercury in mice. Acta Pharmacol Toxicol (Copenh) 1969;27:Suppl 1:1-132
   CrossRef | Medline

2. 2

   Dewhurst F. Edward Franklin and COSHH. Chem Br 1989;25:702-705
   

3. 3

   Hoskins BB, Hupp EW. Methylmercury effects in rat, hamster, and squirrel monkey. Environ Res 1978;15:5-19
   CrossRef | Web of Science | Medline

4. 4

   Bakir F, Damluji SF, Amin-Zaki L, et al. Methylmercury poisoning in Iraq. Science 1973;181:230-241
   CrossRef | Web of Science | Medline

5. 5

   Davis LE, Kornfeld M, Mooney HS, et al. Methylmercury poisoning: long-term clinical, radiological, toxicological, and pathological studies of an affected family. Ann Neurol 1994;35:680-688
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: In response to Drs. Byard and Couper: our patient had worked previously with other mercury compounds, but not with dimethylmercury. Although the content of mercury in her hair before the date of the accident was slightly high (Figure 2 of our report),1 this finding may reflect external contamination of the hair after the accident. Other accidental exposures were not suggested by the patient, laboratory notebooks, hair analysis, or memories of coworkers. Wipe tests and air sampling of the patient's laboratory, office, automobile, and home conducted by a certified industrial-hygiene consultant were remarkable only for elevated airborne mercury levels immediately around the sealed storage can inside the chemical-fume hood. This information, along with the results of the glove-permeation studies, was reviewed by the Occupational Safety and Health Administration. Information from Dartmouth about personal protective equipment for uncommon and highly toxic compounds has been made widely available.2

The patient recalled no skin problems. A comparison of the amount of dimethylmercury purchased with the amount remaining several months after the accident, as well as clinical data, supported the hypothesis of a single exposure through some combination of transdermal absorption and inhalation. Given the density of dimethylmercury (278 mg of mercury per 0.1 ml), just 0.48 ml of dimethylmercury contains 1344 mg of mercury, the net amount that we estimate the patient absorbed.1 By comparison, the minimal lethal dose of methylmercury in an epidemic of mercury poisoning in Iraq was 200 to 312 mg of mercury, and the median lethal dose was 400 to 600 mg.3

Since the patient's history and physical-examination results were consistent with a diagnosis of methylmercury neurotoxicity, and since she had no history of exposure to other drugs or toxins, we did not pursue a “drug screen.” The chief medical examiner of New Hampshire conducted the autopsy. No grounds were found to suspect suicidal or homicidal intent; the case was ruled an accidental death, with no reason for police investigation.

Drs. Lockwood and Landrigan support Dr. Kulig's comment that incinerators (including hospital incinerators) are a major source of mercury contamination of the environment.4,5 Elemental mercury can be a problematic pollutant and workplace contaminant. In addition to limiting the incineration of contaminated medical waste, we urge the minimization or elimination of mercury and use of substitutes whenever possible in the medical workplace.

In response to Dr. Hanlon: we pointed out in our report that some dimethylmercury is exhaled unchanged after intravenous administration to mice or after inhalation.5 By extension, our patient may have initially absorbed more than 1344 mg of mercury, and then lost some through exhalation. On the other hand, there appear to be marked interspecies differences in the kinetics and toxicity of methylmercury chloride.6 In monkeys, the onset of neurotoxicity is later than in rats and hamsters, and delayed, severe neurotoxicity, similar to that seen in our patient, can develop in monkeys. Moreover, slight differences in single toxic doses given to monkeys can produce rapid death, delayed but fatal neurotoxicity, or transient minor neurotoxicity with full recovery.6

In short, there appear to be important but not fully understood interspecies and interpatient differences in the pace and severity of the development of neurotoxicity after exposure to methylmercury or dimethylmercury.

David W. Nierenberg, M.D.
Dartmouth–Hitchcock Medical Center, Lebanon, NH 03756-0001

Michael B. Blayney, Ph.D.
Dartmouth College, Hanover, NH 03755

Thomas W. Clarkson, Ph.D.
University of Rochester School of Medicine, Rochester, NY 14642

6 References

1. 1

   Nierenberg DW, Nordgren RE, Chang MB, et al. Delayed cerebellar disease and death after accidental exposure to dimethylmercury. N Engl J Med 1998;338:1672-1676
   Full Text | Web of Science | Medline

2. 2

   Lewis R. Researchers' deaths inspire actions to improve safety. Scientist 1997;11:1, 4-1, 4
   Web of Science

3. 3

   Bakir F, Damluji SF, Amin-Zaki L, et al. Methylmercury poisoning in Iraq. Science 1973;181:230-241
   CrossRef | Web of Science | Medline

4. 4

   Office of Air Quality Planning and Standards. Mercury study report to Congress. Washington, D.C.: Environmental Protection Agency, 1997.
   

5. 5

   Ostlund K. Studies on the metabolism of methyl mercury and dimethyl mercury in mice. Acta Pharmacol Toxicol (Copenh) 1969;27:Suppl 1:1-132
   CrossRef | Medline

6. 6

   Hoskins BB, Hupp EW. Methylmercury effects in rat, hamster, and squirrel monkey. Environ Res 1978;15:5-19
   CrossRef | Web of Science | Medline

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2. 2

   Ana-Maria Florea, Dietrich Büsselberg. (2006) Occurrence, use and potential toxic effects of metals and metal compounds. BioMetals 19:4, 419-427
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