Too much of a good thing (fish): methylmercury case study.

Introduction

Mercury is an element that occurs naturally in the earth's crust. Over geological time, it has been distributed throughout the environment by natural processes such as volcanic activity: fires; movement of rivers, lakes, and streams; oceanic upwelling; and biological processes. Since the industrial revolution of the 19th century, however, anthropogenic sources have become a significant contributor to the environmental redistribution of mercury and its compounds.

Elemental mercury can combine in the environment with chlorine, sulfur, phosphorus, and other elements to form inorganic compounds. In aquatic microorganisms, inorganic mercury can combine with carbon to form organic mercury compounds, of which methylmercury is the most abundant. In surface waters, methylmercury is rapidly accumulated by aquatic organisms, where it biomagnifies as it ascends the food chain. Carnivorous species of fish at the top of their food chain (e.g., large freshwater pike and marine sharks, swordfish, king mackerel, and tilefish) may have mercury tissue concentrations as much as 10,000 to 100,000 times the concentration in the ambient waters (Callahan et al., 1979; U.S. Environmental Protection Agency [U.S. EPA], 1984; World Health Organization [WHO], 1990, 1991). In humans, methylmercury typically enters the body through the diet, with contaminated fish being the primary source in most cases (Agency for Toxic Substances and Disease Registry [ATSDR], 1999). Studies of large-scale poisoning incidents in Iraq (Cox et al., 1989; Marsh et al., 1981) and Japan (Harada, 1978) have shown that dietary sources highly contaminated with organomercurials can produce severe neurological effects and other health problems.

Epidemics of neurological disorders were reported in Iraq in 1956 and 1960, and again in 1971 and 1972 (Bakir et al., 1973; Jalili & Abbasi, 1961). These cases resulted from consumption of flour made from seed grain treated with ethylmercury p-toluene sulfonanilide. Ataxia, inability to walk, speech difficulties, paraplegia, spasticity, abnormal reflexes, restriction of visual fields, blindness, tremors, paresthesias, insomnia, confusion, hallucinations, and loss of consciousness were reported among affected individuals. In the winter of 1971-1972, more than 6,530 patients required hospitalization after ingestion of contaminated bread prepared from wheat and other cereals treated with a methylmercury fungicide (Bakir et al., 1973). This poisoning incident resulted in 459 deaths, primarily from central-nervous-system damage.

A widespread outbreak of neurological disorders associated with the ingestion of methylmercury-contaminated fish in the Minamata area of Japan was reported by Kutsuna (1968). The neurologic syndrome was characterized by a long list of symptoms, including prickling or tingling sensation in the extremities (paresthesias); impaired peripheral vision, hearing, taste, and smell; slurred speech; unsteadiness of gait and limbs; muscle weakness; irritability; memory loss, depression; and sleeping difficulties (Kutsuna, 1968; Tsubaki & Takahashi, 1986).

In addition to the above studies of acute poisoning episodes, two prospective, longitudinal epidemiological studies have been under way for over a decade. One of these (Grandjean et al., 1997; Grandjean, Weihe, White, & Debes, 1998) has studied the effects of methylmercury intake by pregnant women on their children in the Faroe Islands. Although the Faroese are a fishing culture, the major source of methylmercury exposure for this population is pilot whale meat, which is intermittently consumed (one to two meals per week) as part of the cultural tradition. Children in this study (born in the years 1986 and 1987) were administered a battery of neurologic tests at approximately seven years of age (n = 917). Cord blood and hair samples were collected to evaluate mercury exposure. Geometric mean values for cord blood and hair mercury were 22.9 micrograms per liter ([micro]g/L) and 4.27 micrograms per gram ([micro]g/g, or ppm), respectively (Grandjean et al., 1997). No abnormalities attributable to mercury were found during clinical examinations or neurophysiologic testing. A neuropsychologic test battery also was administered to evaluate possible effects on specific domains of brain function. The neuropsychologic testing indicated mercury-related dysfunction in the domains of language, attention, memory, and visuospatial and motor function (to a lesser extent), which the authors found even when the children of women with maternal-hair mercury concentrations above 10 [micro]g/g (10 ppm) were excluded. This Faroese test population was concurrently exposed to polychlorinated biphenyls (PCBs) and other persistent organic pollutants (POPs), including DDT. Grandjean and co-authors (1997, 1998) did not initially consider these pollutants to be the cause of the observed deficits, but a later publication by these researchers (Grandjean et al., 2001) indicated that PCBs did indeed contribute to the observed results.

The other excellent epidemiological study is the Seychelles Child Development Study (SCDS), in which over 700 mother-infant pairs have, to date, been followed and tested from parturition through nine years of age (Davidson et al., 1997; Myers et al., 2003). In contrast to the Faroese population, the Seychellois regularly consume a high quantity and variety of ocean fish, with 12 fish meals per week constituting a typical methylmercury exposure scenario. The median total mercury concentration in 350 fish sampled from 25 species consumed by the Seychellois was <1 ppm (range, 0.004-0.75 ppm), which is comparable to the mercury concentration in commercially obtainable fish in the United States and many other countries. The children of exposed mothers were evaluated at 6, 19, 29, 66, and 107 months of age with a broad battery of neurobehavioral and neurodevelopmental tests. No adverse effects attributable to methylmercury were found through 66 months of age. The standardized neurobe-havioral test battery used in the 66-month Seychelles study, which was designed to assess multiple developmental domains (Davidson et al., 1998), revealed no evidence of adverse effects attributable to chronic ingestion of low levels of methylmercury in fish (Davidson et al., 1995, 1998). In the 66-month study cohort, the mean maternal-hair level of total mercury during pregnancy was 6.8 ppm (range, 0.5-26.7 ppm; n = 711), and the mean child-hair level at the 66-month testing interval was 6.5 ppm (range, 0.9-25.8 ppm; n = 708).

A recently published study by Myers et al. (2003) reported the results of the testing of the nine-year cohort (n = 643) in the SCDS. Maternal-hair mercury concentrations representing the period of pregnancy averaged 6.9 ppm (SD = 4.5), with 88 of the children tested having been born to mothers with pregnancy-hair mercury concentrations greater than 12 ppm. In this round of testing, recent postnatal methylmercury exposure was included. The mean postnatal-hair mercury concentration was 6.1 ppm (SD = 3.5), the mean age at testing was 107 months, and a total of 21 endpoints were examined. The test battery included both global and domain-specific items, including the Boston Naming Test and other tests reported to have shown an association with methylmercury in other studies (Crump, Kjellstom, Shipp, Silvers, & Stewart, 1998; Grandjean et al., 1997). Neurocognitive, language, memory, motor, perceptual-motor, and behavioral functions all were examined.

Significant associations between prenatal methylmercury exposure and test performance were found for only two of the 21 endpoints examined. On the grooved-pegboard test, there was a significant decrease in performance time for the nondominant hand in males, but not for the dominant hand in males or either hand in females. In addition, there was a significant improvement of the hyperactivity index of the Connor's teacher-rating scale as prenatal methylmercury exposure increased. The biological significance of this effect is uncertain, but would not be considered adverse. Myers and co-authors (2003) provided probability plots of p values showing a distribution that suggests both of the positive outcomes were probably due to chance.

Neither of the two prospective epidemiological studies in the Faroe and Seychelles Islands reported any neurophysiologic signs or symptoms in either the mothers or their children. Thus, the above-mentioned studies of acute, high-level exposure (in Iraq and Japan) and chronic, low-level exposures (in the Faroes and Seychelles) establish intake levels that will result either in clinical signs of toxicity or in no signs of toxicity, respectively, in adults. The area of exposure levels in between, however, is far less clear. While it is generally acknowledged that dietary intake of large amounts of less heavily contaminated seafood over extended periods may also cause signs of mercury intoxication, specific incidents in the peer-reviewed literature have been lacking. The following case report describes a woman who ingested fresh seafood daily for a period of approximately 10 years, and compares biological markers of mercury with reported symptoms.

Case Study

This case study involves an incident of probable methylmercury intoxication resulting from daily ingestion of fish for a prolonged period. The subject, a 53-year-old woman, first contacted the Agency for Toxic Substances and Disease Registry (ATSDR) in 1999 to discuss the results of blood and urine mercury analyses she had recently received, and to obtain assistance in determining the source of the mercury. The information contained in this case study was obtained from copies of laboratory reports and medical records provided by that individual, in addition to extensive telephone conversations in which she provided additional information and a self-reported medical history.

Initial discussion with the woman revealed that she did not work in a profession in which exposure to mercury might reasonably be expected to occur, and she had no hobbies, activities, or medical conditions that might bring her into contact with mercury. The woman did, however, report that she had been eating fish on a daily basis for the past 10 years because of the known nutritional and health benefits it provided. She further noted that she had routinely eaten one or two fish meals each day, at least six days a week, during that period. She also reported that she preferred fresh fish from the market and was particularly fond of swordfish, which she ate about twice a week. She had a preference for ocean fish, but enjoyed freshwater fish as well.

Seven years before contacting ATSDR, and two years after beginning the high-fish diet, the woman had consulted a physician for treatment of erythema (reddened skin). At that time, a hair sample was collected on the basis of the patient's clinical presentation and concern about her high level of fish consumption. Pubic hair was used for the sample, since the patient used a colorant on her scalp hair. Analysis of the sample revealed a hair mercury concentration of 67.8 ppm. (In comparison, average scalp hair mercury concentrations among U.S. adults have been reported to range from 0.47 to 3.8 ppm in various studies [ATSDR, 1999]). She received no pharmacological treatment, but was advised to reduce her fish intake. While she indicated that she did try to cut back somewhat on her fish consumption, she considered the fish to be essential to her health and continued her practice of daily fish consumption.

Several years later, when she began to experience symptoms that included stomatitis (inflammation of the mucous membrane of the mouth), tremors, and ringing in the head and ears, she again sought help from a physician. Because of concern about the earlier hair sample that had been found to contain high mercury levels, blood and urine samples were collected and sent to a laboratory to be analyzed for mercury. No hair sample was collected at that time. Results of the analyses revealed mercury concentrations of 125 [micro]g/L and 24 [micro]g/L for blood and urine, respectively. When the woman was advised of the results of the lab analyses, she was reportedly told that the physician was unable to evaluate or reconcile the apparent discrepancy between the blood and urine values. According to the woman, no specific guidance was offered by the attending physician. At that time, she consulted ATSDR.

At the time of her initial call to ATSDR, the woman was still eating fish six or seven days a week, and often consumed two fish meals each day. The prolonged pattern of high fish intake presented the potential for accumulation of mercury in her body, particularly given the significant daily intake and the comparatively slow excretion half-life of methylmercury, of approximately two months. After a review of the results of the hair, blood, and urine analyses, and after several extensive and substantive discussions with the 53-year-old woman, it appeared obvious that her excessive fish diet was the likely source of the mercury identified in the samples. She was advised to visit an occupational and environmental medicine specialist for proper evaluation of her problem and to substantially reduce her consumption of fish.

Some time after her last contact with ATSDR in 2000, the woman apparently relocated. Repeated attempts in early 2002 to contact or locate her were unsuccessful, so it is unknown whether she sought further medical intervention, as suggested by ATSDR.

Calculated no-observed-adverse-effects level (NOAEL) blood values from the Seychelles and Faroes studies were 61 [micro]g/L and 58 [micro]g/L, respectively. If the calculated NOAEL for the most highly exposed individual in the Seychelles study (25.8 ppm mercury in hair) is used, a NOAEL value of approximately 103 [micro]g/L can be derived based upon that individual alone. In any case, the blood mercury concentration of 125 [micro]g/L and the hair mercury level of 67.8 ppm in the 53-year-old woman reported in this case study are above any reported NOAEL value for human subjects.

Discussion

Among the different forms of mercury (i.e., elemental, inorganic compounds, and organic mercury compounds), methylmercury is the species most often associated with hair samples (Cernichiari, Brewer, et al., 1995; Cernichiari, Toribara, et al., 1995; Clarkson, Small, & Norseth, 1973). Inorganic forms of mercury generally are oxidized to the divalent cationic form ([Hg.sup.++]) relatively rapidly and are either sequestered in other tissues or excreted from the body in the urine. Methylmercury, however, has been shown to be transported intact in the blood to hair follicles, where it can be incorporated into the growing hair shaft and thus be excreted from the body in the hair. This avenue of excretion is believed to be due primarily to the abundance of sulfur, for which mercury has an extremely high affinity and which is present in keratinaceous protein in hair. Clarkson et al. (1973) reported that more than 95 percent of the mercury found incorporated into the hair shaft is usually in the form of methylmercury. (It should be noted that while blood mercury measurements reflect total mercury from all inorganic and organic species, hair mercury is typically assumed to be essentially all methylmercury.)

The background level of mercury in hair in the United States varies by geographical area. Regardless of socioeconomic status, ethnicity, or any variety of other factors, the differences in hair mercury levels seem to depend primarily on differences in fish consumption practices. ATSDR (1999) has compiled the available data on mercury hair concentrations and found that the published studies report mean hair mercury levels for adults ranging from 0.47 ppm (U.S. EPA, 1978a, 1978b) to 3.8 ppm (Airey, 1983a, 1983b), with a maximum value of 15.6 ppm (Fleming et al., 1995). It is noteworthy that the hair mercury level of 15.6 ppm reported in an Everglades, Florida, population is still well below the high hair mercury level of 25.8 reported in the Seychelles (Davidson et al., 1997), at which no effects were reported either in the woman or her offspring.

The mean total mercury levels in whole blood and urine of the general population are approximately 1-8 [micro]g/L and 4-5 [micro]g/L, respectively (Gerhardsson & Brune, 1989; WHO, 1990), and the IUPAC Committee on Toxicology reported an average whole blood mercury level of 2 [micro]g/L in people who do not eat fish (Nordberg et al., 1992). These values are consistent with the values reported by the Centers for Disease Control and Prevention (CDC, 2003) and Schober and co-authors (2003). CDC reported a geometric mean blood mercury concentration of 1.02 [micro]g/L among 1,709 U.S. women providing samples. The 95th percentile value for this population was 7.10 [micro]g/L, indicating that 95 percent of the study population had blood mercury values at or below 7.10 [micro]g/L. Schober and co-authors further broke down the mean value of 1.02 [micro]g/L into groups of women who consumed three or more servings of fish in the 30 days prior to sampling and groups of women who ate no fish during that period. The resultant values were 1.94 [micro]g/L for the fish consumers and 0.51 [micro]g/L for those who had consumed no fish in the 30 days prior to collection of the blood sample. None of the reported blood mercury levels were at or near the NOAELs from the Seychelles (Davidson et al., 1997) and Faroes (Grandjean et al., 1997) studies. In the case of urine mercury concentrations reported by CDC (2003) for that same study population, the 95th percentile urine mercury concentration value was 5.00 [micro]g/L. CDC (2001) has reported the 90th percentile mean hair mercury concentration among 702 women aged 16 to 49 years to be 1.4 ppm.

Over 95 percent of dietary methylmercury is absorbed through the intestine walls (Aberg et al., 1969; Miettinen, Rahola, Hattula, Rissanen, & Tillander, 1971). The fraction of the absorbed dose that is found in the blood is generally considered to be 5 percent of the absorbed dose (Berglund et al., 1971; Sherlock, Hislop, Newton, Topping, & Whittle, 1984; WHO, 1990). Once in the blood, methylmercury is tightly bound (again, ~90-95 percent) to red blood cells while it is transported throughout the body. In the liver, it is conjugated with glutathione and incorporated into the bile, after which it again enters the intestine. As a result of this continuing enterohepatic circulation, methylmercury is primarily excreted in the feces. In addition, a small amount of methylmercury is also incorporated into the hair and excreted in that manner, and demethylation in body tissues results in the further excretion of the ingested methylmercury in the urine as inorganic mercury. Therefore, hair, whole blood, and urine would all be routes of some eventual excretion of mercury in a person chronically exposed to significant amounts of methylmercury through diet. In such a case, the hair and blood would reflect predominantly the parent organomercury compound, while the urine would contain exclusively the inorganic product of in vivo demethylation in lesser amounts proportional to dietary intake of the parent compound. This effect is precisely what was seen in the subject of the case study reported here. If a steady-state blood level of 125 [micro]g/L is assumed--the blood mercury concentration indicated by the previously described laboratory analysis--a daily intake may be derived from the concentration of mercury in the blood according to the following equation from WHO (1990):

C = [f*d]/[b*V] = [[A.sub.D]*[A.sub.B]*d]/[b*V]

Where

C = concentration in blood,

f = fraction of the daily intake taken up by the blood,

d = daily dietary intake,

b = elimination constant,

[A.sub.D] = percent of mercury intake in diet that is absorbed,

[A.sub.B] = percent of the absorbed amount that enters the blood, and

V = volume of blood in the body.

With this equation, a daily mercury intake of 154 [micro]g per day can be estimated for the 53-year-old woman in this case as follows:

C = (0.95 X 0.05 X d)/(0.014 X 4.2)

C = 0.81d

0.125 mg = 0.81d

d = 0.154 mg/day

Under the further assumption of a body weight of 60 kg, this intake would be equivalent to 2.2 [micro]g/kg/day, or seven times the ATSDR chronic oral minimal risk level (MRL) of 0.3 [micro]g/kg/day for methylmercury. No hair sample was taken at the time the blood and urine samples were collected in this case, however, and the hair sample from seven years before suggested that the methylmercury intake may have been even greater at that time. This assessment is supported by the statement from the woman that she had tried to cut back somewhat on her fish intake following the hair analysis.

Therefore, if it is assumed that the concentration of mercury in hair is 250 times the concentration of mercury in blood (Phelps, Clarkson, Kershaw, & Wheatley, 1980), the 67.8 ppm hair mercury level would equate to a blood mercury concentration of 0.271 mg/L. The daily intake might therefore have been as high as 27 [micro]g/day, or 4.5 [micro]g/kg/day--a value 15 times the chronic oral MRL for methylmercury. While the vast preponderance of evidence indicates that there is absolutely no adult health risk associated with intake of methylmercury at levels at or near the MRL for methylmercury, this single case study suggests that chronic dietary methylmercury intake on an order of magnitude or so above the MRL might produce untoward effects on some nonpregnant adults.

Another way of evaluating this exposure is simply to compare the measured blood mercury level of 125 [micro]g/L with known or calculated NOAELs from the published, peerreviewed literature. In deriving a chronic oral minimal risk level (MRL) for methylmercury. ATSDR calculated a blood concentration of 61 [micro]g/L from the mean 15.3 ppm mercury hair concentration of mothers in the highest exposure quintile in the Seychelles study (Davidson et al., 1997) for which no adverse effects were reported in the mothers or their children. Thus, this blood concentration is considered to represent a NOAEL for the Seychellois study cohort. The National Research Council (NRC, 2001) has derived a benchmark dose level (BMDL) of 58 [micro]g/L in blood using the data from the Faroes Island Study (Grandjean et al., 1997). The BMDL was mathematically calculated from the modeled 5 percent response level (benchmark dose, or BMD) on the basis of data from the Faroes cohort. Since the 10 percent response level modeled from experimental data is widely regarded as a NOAEL (Crump, 1995; Crump et al., 1998; Farland and Dourson, 1992), the conservative NRC (2001) BMDL based on the modeled 5 percent response level certainly represents an intake level without effect on the consumer, including pregnant women and their developing fetuses. Since both the Seychelles and Faroes populations have been exposed to presumably constant mercury levels for generations, the respective NOAELs of 61 [micro]g/L and 58 [micro]g/L from these two prospective, longitudinal human epidemiological studies provide a strong indication that these blood levels are without effects in even the most sensitive of human populations (pregnant women and developing fetuses). By comparison, data from the current case study suggest that a mere doubling of the 61 [micro]g/L NOAEL from the Seychelles for a sustained period of years may be associated with adverse health effects in some adult individuals.

The woman in the case study reported here was estimated, on the basis of measured blood and hair mercury levels, to have been ingesting methylmercury at daily levels averaging from 7 to 15 times the MRL for chronic oral exposure to methylmercury. Since the half-life of methylmercury in the body is approximately 60 days (Hursh, Clarkson, Cherian, Vostan, & Mallie, 1976; Rahola, Hattula, Korolainen, & Miettinen, 1973), exceeding the body's ability to excrete the ingested mercury at a rate corresponding to the rate of intake can result in an elevation of methylmercury in the blood and other tissues. This is what is believed to have happened in the case of the 53-year-old high-end fish consumer in this study.

Conclusions

Although empirical evidence suggests that blood mercury levels of 61 [micro]g/L attributable to dietary methylmercury are without adverse effect in sensitive populations, the case study reported here suggests that the slope of the dose-response curve may be rather steep at some point beyond the NOAEL established in the Seychelles. The take-home message to the reader should be twofold: 1) fish is good, and mercury is bad; and 2) while pregnant women or those anticipating becoming pregnant within the next few months would be wise to limit their fish consumption to a couple of cans of tuna per week and to avoid swordfish, shark, king mackerel, and tilefish, other healthy adults need not be so restrictive in their fish intake. In any case, it should be kept in mind that methylmercury can build up in the body over time and result in neurologic--and possibly other--symptoms if fish is eaten daily over a prolonged period of time. Readers are encouraged to visit the Food and Drug Administration Web site for further information regarding fish consumption for the general population. Further studies are needed to determine the safety of chronic consumption of methylmercury at levels between 5 and 15 times the chronic oral MRL of 0.3 [micro]g/kg/day.

Attending physicians and environmental health professionals should be aware that, in the case of suspected methylmercury toxicity, blood and hair are the most appropriate biomarkers of exposure. Urine is of limited value, since only a fraction of the absorbed dose is eventually excreted through the kidneys. In all cases, comparison with normal background blood and hair levels is critical in arriving at a diagnosis of methylmercury toxicity.

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John F. Risher, Ph.D.

Corresponding Author: John F. Risher, Division of Toxicology (E-29), Agency for Toxic Substances and Disease Registry, 1600 Clifton Rd., Atlanta, GA 30333. E-mail: [e-mail].