Methyl mercury reference dose: response to Schoen.

Mercury symptoms have been documented in the literature from many different exposures: from the "blue pill" used in the treatment of syphilis (Hirschhorn et al. 2001), to the mercurials used in teething powders causing acrodynia (or pink disease) (Dinehart et al. 1988), the mercury nitrate in hatters (O'Carroll et al. 1995), methyl mercury in fish in Japan (Fukuda et al. 1999; Harada 1995), and methy mercury-tainted seed grain in Iraq (Bakir et al. 1973). Goldsmiths, tinsmiths, mirror makers, and miners also had symptoms caused by occupational exposure to mercury vapor (Ramazzini 1983). Recently, contact lens solutions containing ethyl mercury (thimerosal) caused blepharoconjunctivitis and punctate keratitis in many contact lens wearers. As a result, thimerosal was removed from the solutions (Campbell et al. 1992).

It is clear that the side effects of mercury at lower exposure levels vary between individuals. This was evident in acrodynia, a debilitating and sometimes deadly condition of infants and children. Although the disease was recognized as early as 1890, the cause--multiple forms of mercury compounds--was not confirmed until after 1948. It was later thought to be a type of "hypersensitivity reaction" because some children with the same exposure were not noticeably affected (Dinehart et al. 1988).

The variation of effects seen when comparing the Seychelles (Myers et al. 1995 2003) and Faroese (Grandjean et al. 1998) cohorts may be simply because of genetic differences. It is possible that an isolated population exposed to mercury for generations could, by natural selection, tolerate higher amounts of mercury.

Recent articles have shown an association with increased myocardial infarction and death from myocardial infarction with mercury levels close to the current reference dose (RfD) set by the U.S. Environmental Protection Agency (EPA) (Guallar et al. 2002; Rissanen et al. 2000; Salonen et al. 1995, 2000). Other researchers have identified an accumulation in the hearts of those with idiopathic dilated cardiomyopathy thousands of times higher than even the surrounding tissues of the same individual (Frustaci et al. 1999). Induction of cardiomyopathy in laboratory rats with mercury exposure has also been demonstrated (Bachmaier et al. 1999; Ilback et al. 1996, 2000; South et al. 2001).

In a recent article on carotid atherosclerosis, Salonen et al. (2000) concluded that of 20 risk factors, mercury had the best predictive value for intimal wall thickness and was associated with progression of carotid atherosclerosis. Cerebral arteriosclerosis was seen in infants suffering from Minamata disease (Harada 1995).

A correlation between mercury and autoimmune phenomena is of tremendous concern. Mercury-induced autoimmunity is one of the few animal models in which administration of a chemical induces a specific loss of tolerance to self-antigens. Auto-antibodies elicited include antiglomerular basement membrane, anti-single-stranded DNA, anti-double-stranded DNA, antithyroglobulin, antiphospholipid, and anticollagen I and II (Bagenstose et al. 1999; Bernier et al. 1995; Bigazzi 1994; Nielsen and Hultman 2002; Stejskal et al. 1999; Stejskal and Stejskal 1999; Via et al. 2003).

Although Minamata disease sufferers were thought to have extremely high mercury levels in hair, other studies in Japan looked at lower-end chronic methyl mercury exposures. Subjective complaints analyzed in a population living in a methyl mercury--polluted area showed an increase of symptoms after several years of exposure and had atypical and subclinical features unlike those of "classic Minamata." Exposed individuals reported higher prevalence of many complaints than the internal and external controls. Symptoms that were statistically significant are as follows: muscle stiffness, dysesthesia, hand tremor, dizziness, loss of pain sensation, muscle cramps, upper arm muscular atrophy, arthralgia, lumbago, leg tremor, tinnitus, muscular atrophy, chest pain, palpitations, fatigue, visual dimness, and staggering. Symptoms with statistical significance for men only were difficulty with urination and thirst. Those with statistical significance only in women were muscular weakness, urine incontinence, forgetfulness, and insomnia (Fokuda et al. 1999).

Adverse affects after low-level methyl mercury exposure were reported recently in the area of neuropsychiatric functioning in adults (Yokoo et al. 2003).

The U.S. EPA's RfD was defined in the Mercury Study Report to Congress as the amount of methyl mercury that, when ingested over a lifetime, is anticipated to cause no adverse health effects to humans, including those in sensitive populations (U.S. EPA 1997). The dose is 0.1 [micro]g/kg body weight/day and corresponds to a blood level of 4-5 [micro]g/L or a hair level of 1.0 [micro]g/g. The benchmark dose lower limit is the intake of methyl mercury associated with the lower bound on a 95% confidence interval of a dose producing a 5% prevalence of adverse effects (in addition to a background effect of 5% adverse effects) (U.S. EPA 1997). The benchmark dose lower limit calculated using the Faroese study, which used fetal exposure outcomes, was 58 [micro]g/L [National Research Council (NRC) 2000]. The NRC, through review of a vast amount of literature, concluded that the U.S. EPA's RfD was justified and recommended application of an uncertainty factor of at least 10 in setting the U.S. EPA's RfD for methyl mercury (NRC 2000).

A benchmark dose for cardiac and autoimmune disease has not been identified and could be lower than that set for fetal exposures.

The best advice is still to consume no more mercury than the RfD set by the U.S. EPA to avoid accumulation over a lifetime. Education for consumers and health-care professionals can result in lower mercury levels, despite high fish consumption.

The author declares she has no competing financial interests.

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Jane Hightower

California Pacific Medical Center 

San Francisco, California 

E-mail: [e-mail]