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TOXICITY SUMMARY FOR MERCURY


http://tarasun.hsr.ornl.gov/tox/profiles/mercury.doc

ACKNOWLEDGMENTS

        The toxicity information included in this summary was researched and compiled by Robert Young, Ph.D., who is a member of the Chemical Hazard Evaluation Group in the Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory

EXECUTIVE SUMMAR

      Mercury is a naturally occurring element existing in multiple forms and in various oxidation states. It is used in a wide variety of products and processes. In the environment, mercury may undergo transformations among its various forms and among its oxidation states. Exposure to mercury may occur in both occupational and environmental settings, the latter primarily involving dietary exposure (ATSDR 1989). 

      Absorption, distribution, metabolism, and excretion of mercury is dependent upon its form and oxidation state (ATSDR 1989, Goyer 1991). Organic mercurials are more readily absorbed than are inorganic forms. An oxidation-reduction cycle is involved in the metabolism of mercury and mercury compounds by both animals and humans (ATSDR 1989). The urine and feces are primary excretory routes. The elimination half-life is 35 to 90 days for elemental mercury and mercury vapor and about 40 days for inorganic salts (Goyer 1991).

Ingestion of mercury metal is usually without effect (Goldwater 1972). Ingestion of inorganic salts may cause severe gastrointestinal irritation, renal failure, and death with acute lethal doses in humans ranging from 1 to 4 g (ATSDR 1989). Mercuric (divalent) salts are usually more toxic than are mercurous (monovalent) salts (Goyer 1991). Mercury is also known to induce hypersensitivity reactions such as contact dermatitis and acrodynia (pink disease) (Mathesson et al. 1980). Inhalation of mercury vapor may cause irritation of the respiratory tract, renal disorders, central nervous system effects characterized by neurobehavioral changes, peripheral nervous system toxicity, renal toxicity (immunologic glomerular disease), and death (ATSDR 1989).

      Toxicity resulting from subchronic and chronic exposure to mercury and mercury compounds usually involves the kidneys and/or nervous system, the specific target and effect being dependent on the form of mercury (ATSDR 1989). Organic mercury, especially methyl mercury, rapidly enters the central nervous system resulting in behavioral and neuromotor disorders (ATSDR 1989, Goyer 1991). The developing central nervous system is especially sensitive to this effect, as documented by the epidemiologic studies in Japan and Iraq where ingestion of methyl mercuryBcontaminated food resulted in severe toxicity and death in adults and severe central nervous system effects in infants (Bakir et al. 1973, Amin-Zaki et al. 1974, Harada 1978, Marsh et al. 1987). Blood mercury levels of <10 μg/dL and 300 μg/dL corresponded to mild effects and death, respectively (Bakir et al. 1973). Teratogenic effects due to organic or inorganic mercury exposure do not appear to be well documented for humans or animals, although some evidence exists for mercury-induced menstrual cycle disturbances and spontaneous abortions (Derobert and Tara 1950, Amin-Zaki et al. 1974, ATSDR 1989).

A subchronic and chronic oral RfD of 0.0001 mg/kg/day for methyl mercury is based on a benchmark dose of 1.1 μg/kg/day relative to neurologic developmental abnormalities in human infants (EPA 1995, 1996). A subchronic and chronic oral RfD of 0.0003 mg/kg/day for mercuric chloride is based on immunologic glomerulonephritis (EPA 1996). A Lowest Observed Adverse Effect Level (LOAEL) of 0.63 mg Hg/kg/day for mercuric chloride was identified (EPA 1987). No Observed Adverse Effect Levels (NOAELs) were not available for oral exposure to inorganic mercury or methyl mercury. A subchronic and chronic inhalation RfC of 0.0003 mg Hg/m3 for inorganic mercury (EPA 1995, 1996) is based on neurological disorders (increased frequency of intention tremors) following long-term occupational exposure to mercury vapor (Fawer et al. 1983). The LOAELs for subchronic and chronic inhalation exposures to inorganic mercury are 0.32 and 0.03 mg Hg/m3, respectively. NOAELs were unavailable. An inhalation RfC for methyl mercury has not been determined.

      No data were available regarding the carcinogenicity of mercury in humans or animals. EPA has placed inorganic mercury in weight-of-evidence classification D, not classifiable as to human carcinogenicity (EPA 1996). Weight-of-evidence classifications of C (possible human carcinogen) have been assigned to mercuric chloride and methyl mercury by EPA (1996) based upon limited evidence of carcinogenicity in rodents. No slope factors have been calculated.

1. INTRODUCTION

      Mercury (Hg) is a naturally occurring element that may exist in elemental, inorganic, or organic forms and in various oxidation states. Mercury is used in a wide variety of products and processes, including pressure sensitive devices (thermometers, barometers), electrical apparatus (wiring, switches, batteries), paints, pharmaceuticals, and in the production of various chemicals (ATSDR 1989). The oxidation state and chemical form of mercury are important in determining its toxicity, with mercurous salts (monovalent mercury) being less toxic than mercuric salts (divalent mercury). Organic mercurials such as methyl mercury are highly toxic. In the environment, mercury may undergo transformations among the various oxidation states and chemical forms. Both environmental and occupational exposure are relevant to mercury and its compounds, although environmental exposure is unimportant for mercury vapor. Mercury intake from occupational exposure is of greater significance than that from environmental exposure. Environmental exposure to mercury may involve dietary intake (especially from fish) and possibly from dental amalgams, the latter source being controversial (ATSDR 1989, Langworth et al. 1991).

2. METABOLISM AND DISTRIBUTION

2.1 ABSORPTION

      Generally, organic mercurials are absorbed much more rapidly than are inorganic forms. However, approximately 80% of mercury vapor is absorbed following inhalation exposure. Data on the inhalation absorption of organic mercury are limited and inconclusive. Metallic mercury and mercurous salts (e.g., Hg2Cl2) are poorly absorbed (<0.10%) following oral exposure (Friberg and Nordberg, 1973). Absorption of mercuric chloride by adult mice was reported to be only 1 to 2% (Clarkson 1971) but 1-week-old mice absorbed 38% of the orally administered compound. Gastrointestinal absorption of inorganic salts of mercury from food is <15% for mice and about 7% for humans (Goyer 1991). Organic mercury compounds (methyl- and phenylmercury) have been shown to be readily absorbed (>80%) by humans and animals following oral exposure (ATSDR 1989, Goyer 1991). 

 

2.2 DISTRIBUTION

      Being lipid soluble, mercury vapor readily enters the red blood cells and the central nervous system following inhalation exposure. The kidneys will exhibit the greatest concentration of mercury following exposure to inorganic mercury salts. Organic mercury is readily distributed throughout the body but tends to concentrate in the brain and kidneys (ATSDR 1989, Goyer 1991). Mercury is known to bind to microsomal and mitochondrial enzymes resulting in cell injury and death. Mercury in renal cells localizes in lysosomes (Madsen and Christensen 1978). Following 23-month exposure, neither inorganic nor organic mercury levels were increased in hair and urine of female workers exposed to mercury vapor concentrations of <0.02 mg Hg/m3 (Ishihara and Urushiyama 1994). However, the concentrations of inorganic as well as organic mercury were increased in the plasma and organic mercury levels were increased in erythrocytes. Petersson et al. (1991) administered 203Hg-labeled methyl mercury intraperitoneally to rabbits twice weekly for nine weeks. After one week of treatment, the highest concentration of 203Hg was detected in the fur with substantially lower levels being found in the kidney, liver, brain, muscle, and blood. Inorganic mercury levels in the liver of the rabbits increased with time after cessation of treatment. A report by Dutczak et al. (1991) providing data for guinea pigs, hamsters, and a macaque monkey indicate that extensive absorption of methyl mercury occurs in the gall bladder. Subsequent biliary-hepatic cycling of the compound may contribute to the long biologic half-life of methyl mercury. Yoshida et al. (1991) reported that substantial concentrations of metallothionein-associated mercury were found in the kidneys and livers of neonate guinea pigs exposed to mercury vapor for 120 minutes on the day of birth. Metallothionein synthesis increased in the liver but not in the kidneys. Animal data indicate that all forms of mercury cross the placenta and that mercury levels may be 2-fold greater than in maternal levels with fetal red blood cells containing mercury levels 30% higher than maternal red blood cells (Goyer 1991). The placenta provides no barrier for methyl mercury thereby allowing easy access to the developing brain and development of subsequent neurological disorders characteristic of fetal exposure to methyl mercury (Rice et al. 1996)

2.3 METABOLISM

      Mercury is not destroyed by metabolism but rather converted to different forms and oxidation states. The metabolism of mercury and mercury compounds appears to be similar for animals and humans (ATSDR 1989) and involves an oxidation-reduction cycle. Inhaled mercury vapor is rapidly oxidized to the divalent form in red blood cells (Halbach and Clarkson 1978). Oxidation of elemental mercury also occurs in the lungs of humans and animals (Magos et al. 1973, Hursh et al. 1980), and some evidence suggests hepatic-mediated oxidation (Magos et al. 1978). Animal studies have provided some data suggesting that the divalent inorganic mercury cation may be further reduced to elemental mercury (Clarkson and Rothstein 1964, Dunn et al. 1981). Organic mercury compounds are also converted to divalent mercury by cleavage of the carbon-mercury bond (Goyer 1991) with subsequent metabolism occurring via the oxidation reduction cycle. Aryl mercury compounds (e.g., phenylmercury) undergo this conversion more readily than do the short-chain (methyl) mercury compounds. No evidence of demethylation of methyl mercury by the brain of rabbits was noted following parenteral administration of the compound (Petersson et al. 1991). 

2.4 EXCRETION

      The urine and feces are the primary routes for the excretion of inorganic mercury by humans (ATSDR 1989). Following brief exposure of humans to inorganic mercury, urinary excretion accounts for 13% of the total body burden, whereas this value increases to 58% for long-term exposure. For inorganic mercury, the urinary levels do not parallel blood levels (ATSDR 1989). Henderson et al. (1974) identified three forms of mercury in the urine of occupationally-exposed individuals: elemental mercury, a reducible mercuric-cysteine complex, and a large complex in which the mercury can only be released following organic destruction. The data available for elemental mercury and mercury vapor indicate half-times for these forms to be 35 to 90 days (Goyer 1991). The biologic half-time for inorganic mercury salts is about 40 days.

      Fecal elimination is an important excretory route following exposure to organic mercury compounds (Norseth and Clarkson 1970). However, Petersson et al. (1991), using 203Hg-labeled methyl mercury administered intraperitoneally to rabbits twice weekly for nine weeks, showed that 12 weeks after cessation of treatment 54% of administered dose had been excreted in the urine and only 5% had been excreted in the feces. 

      The elimination of organic mercury compounds generally follows first-order kinetics with whole body clearance times and blood clearance times being longer than for inorganic mercury. The biologic half-time for methyl mercury is about 70 days. Some evidence suggests that females tend to excrete organic mercury faster than males (Aberg et al. 1969, Miettinen 1973). Additional excretory routes include saliva, bile, and sweat (ATSDR 1989).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

3.1.1.1 Human

      Generally, any form of mercury in high acute doses may cause tissue damage resulting from the ability of mercury to denature proteins, thereby disrupting cellular processes (WHO 1976). However, oral exposure to mercury metal is usually without serious effects. A dose of 200 g caused no adverse health effects in a 2-year-old child, and unspecified large amounts were without effect in adults (Goldwater 1972). 

      Ingestion of inorganic salts of mercury such as mercury bichloride (corrosive sublimate) may cause gastrointestinal disorders including pain, vomiting, diarrhea and hemorrhage, and renal failure resulting in death. Additional effects of acute mercury poisoning include shock and cardiovascular collapse (WHO 1976). Acute lethal doses in humans range from 1 to 4 g (10 to 42 mg Hg/kg for a 70 kg adult) for inorganic mercuric salts (ATSDR 1989)

      A hypersensitivity reaction to mercurous compounds such as mercurous chloride (calomel) is characterized by vasodilation, hyperkeratosis, and hypersecretion of the sweat glands. Children exhibiting this condition, also known as acrodynia or pink disease, may also develop fever, a pink‑colored rash, swelling of the spleen and lymph nodes, and hyperkeratosis and swelling of the fingers (Matheson et al. 1980, Goyer 1991).

      The effects of acute exposure to organic mercury compounds are not well documented. However, exposure to organomercurials are known to contribute to the body burden of mercury and have resulted in serious developmental and neurological effects as reported in the following sections.

3.1.1.2 Animal

      The acute toxicity of inorganic mercury in animals is similar to that observed in humans (ATSDR 1989). Neurological effects and death have been reported for various animal species receiving inorganic mercury orally (ATSDR 1989). The LD50 values in animals for elemental mercury range from 10 to 40 mg/kg (WHO 1976). A comparison of oral LD50 values for mercury salts in various rodent species is shown in Table 1. 

                  Table 1. Comparison of oral LD50 values for mercury compounds in rodent species

Mercury Compound

Species

LD50 (mg/kg)

Mercurous chloride (Hg2Cl2)

Rat

Mouse

166

1500

Mercuric cyanide (Hg(CN)2)

Rat

Mouse

25

33

Mercurous sulfate (Hg2SO4)

Rat

Mouse

205

152

Mercuric sulfate (HgSO4)

Rat

Mouse

57

25

Source: Adapted from Von Burg (1995)

3.1.2 Subchronic Toxicity

3.1.2.1 Human

      The effects of subchronic exposure to mercury and mercury compounds are likely to be similar to those of chronic exposure if the exposure level and body burden of mercury is increased (see Sect. 3.1.3.1.). Renal toxicity and neurological effects would be the most typical effects associated with subchronic exposure. 

      In Iraq, mor than 6000 individuals were hospitalized and 459 individuals died as a result of consuming bread prepared with flour made from wheat and barley treated with a methylmercurial fungicide (Bakir et al. 1973). Methyl mercury concentration in the wheat flour ranged from 4.8 to 14.6 μg/g (mean=9.1 μg/g). The clinical symptoms included paresthesia, visual disorders, dysarthria, and deafness. The most severe cases resulted in coma and death due to central nervous system failure. Based on data obtained during this incident, a dose-response relationship between blood mercury levels (<10 μg/dL to 500 μg/dL), and frequency and severity of symptoms showed that mild symptoms occurred at the lower blood mercury levels and that deaths occurred at levels >300 μg/dL.

3.1.2.2 Animal

      Oral exposure to inorganic mercury has produced neurological, immunological, and systemic effects in rodents exposed for periods of 1 to 11 weeks. The NOAEL for these studies was 0.42 mg/kg/day, and the LOAEL was 0.8 mg/kg/day (ATSDR 1989).

      Evidence for a systemic autoimmune response involving the kidneys was reported by Bernaudin et al. (1981) for rats given mercuric chloride (3000 μg/kg/week) orally for up to 60 days. Druet et al. (1978) noted renal immunologic insufficiencies in Brown Norway rats given subcutaneous injections of mercuric chloride (100 μg/kg) for 8 to 12 weeks. Andres (1984) also reported autoimmune glomerulonephritis in brown Norway rats administered mercuric chloride (3 mg/kg) by gavage twice weekly for 60 days.

      In a 110-day exposure of mice to mercuric chloride (1 or 3 mg/kg/day) only decreased body weight gain was noted (Ganser and Kirschner 1985).

      Behavioral and pathological effects were reported for cats receiving methyl mercury at doses of 0.01 mg/kg/day for 11 months or 0.45 mg/kg/day for 83 days, and for rats receiving the compound at 0.6 to 2.4 mg/kg/day for 8 weeks or 1 mg/kg/day for 11 weeks (USAF 1990). Systemic, neurological, and developmental effects resulting from subchronic, oral exposure to organic mercury have been reported for various species of rodents (ATSDR 1989). Necrosis and degeneration of brain tissue were reported for rabbits exposed to metallic mercury vapor (0.86 mg/m3) for 12 weeks (Ashe et al. 1953).

3.1.3 Chronic Toxicity

3.1.3.1 Human

      Chronic oral exposure to mercury or mercury compounds may affect the central nervous system, gastrointestinal tract, and the kidneys; the renal effect, in part, involving an immunologically‑mediated response (ATSDR 1989). Davis et al. (1974) reported dementia, colitis, and renal failure in two women chronically (6 and 25 years) ingesting a mercurous chlorideBcontaining laxative. Generally, little information is available regarding the toxicity of inorganic mercury following chronic oral exposure.

      Exposure to organic mercury causes central nervous system effects, especially in the fetus and neonate (Marsh et al. 1987). Although any exposure to organic mercury compounds will contribute to the body burden of mercury, exposure during pregnancy or the postnatal period has the most significant consequences as discussed in Sect. 3.1.4.

3.1.3.2 Animals

      Chronic oral exposure (2 years) of rats to inorganic mercury produces glomerulonephritis (Fitzhugh et al. 1950). 

      Neurological as well as other systemic toxic effects have resulted following chronic oral exposure of animals to organic mercury compounds (ATSDR 1989). Neurotoxic effects indicative of central nervous system involvement have been reported for mice and rats orally administered organic mercury compounds (usually methyl mercury) for several weeks to over a year (ATSDR 1989). Glomerulonephrotic changes were observed in rats fed phenylmercuric acetate for 2 years (Fitzhugh et al. 1950). Monkeys orally exposed to methyl mercury for 1000 days at doses adjusted to maintain a blood mercury level of 100 to 400 μg/mL exhibited reduced sensitivity to visual stimulation, somesthetic impairment, and incoordination (Evans et al. 1977). 

3.1.4 Developmental and Reproductive Toxicity

3.1.4.1 Human

      No information was available regarding developmental/reproductive toxicity of inorganic mercury in humans following oral exposure. 

      The developmental toxicity of organic mercury is best exemplified by the epidemic poisonings by methyl mercury in Iraq and Minamata and Niigata, Japan. Although no evidence of teratogenicity was observed, Amin-Zaki et al. (1974) found other severe developmental effects (impaired motor and mental function, hearing loss, and blindness) in infants of mothers exposed via contaminated grain during the Iraqi epidemic. The most severely affected infants had mercury blood levels ranging from 319 to 422 μg Hg/dL. It is also important to note that a 45% mortality rate was reported for pregnant women with signs of mercury poisoning versus a 7% mortality rate for the general population. In Minamata and Niigata, Japan, methyl mercury poisoning resulted from the ingestion of fish that had accumulated methyl mercury and other mercury compounds resulting from contaminated surface waters (WHO 1976). Based upon analyses of the Minimata and Iraqi data, it was concluded that a 5% risk of minimal effect in offspring may be associated with a peak maternal hair mercury level of 10 to 20 ppm (WHO 1990). Harada (1978) reported that at about 6 months of age 13 of the 220 infants prenatally exposed to methyl mercury during the Minamata Bay incident showed signs of mercury poisoning characterized by instability of the neck, convulsions, and severe neurological and mental impairment. Choi et al. (1978) reported abnormal cytoarchitecture of the brain in infants prenatally exposed to methyl mercury. No other significant anatomical defects have been reported.

      Marsh et al. (1987) provided an analysis of the Iraqi epidemiologic data by summarizing clinical neurological signs of toxicity and mercury burden in hair samples of 81 mother and child pairs. Mercury concentrations of 1 to 674 ppm were detected and were correlated with clinical signs. The Seafood Safety Committee (Seafood Safety 1991) tabulated the data from the Iraqi incident and established five dose groups and incidence rates for neurological effects. The effect categories included delayed onset of walking, delayed onset of talking, mental symptoms, seizures, neurological scores above 3, and neurological scores above 4 (neurological scores were determined by various clinical evaluations). 

3.1.4.2 Animal

      Only limited information was available regarding the developmental toxicity of inorganic mercury. Gale (1974) reported an increase in fetal resorptions in hamsters receiving a single oral dose of mercuric chloride (31.4 mg Hg/kg). This study also identified a dose of 15.7 mg Hg/kg as a NOAEL for hamsters based on the absence of developmental toxicity.

      A 100% incidence of neonatal deaths and failure of dams to deliver was reported for rats receiving dietary methylmercuric chloride equivalent to 5 mg Hg/kg/day (Khera and Tabacova 1973). The investigators reported no maternal toxicity.

      Ultrastructural changes in the nervous system of mice exposed in utero to methylmercuric hydroxide (up to 10 mg Hg/kg/day) were reported by Hughes and Annau (1976). A dose of 3 mg Hg/kg/day produced significant behavioral changes in the mice. Ultrastructural changes in the nervous system have also been reported for rats prenatally exposed to methylmercuric chloride (4 mg Hg/kg/day) (Chang et al. 1977).

      Exposure of rats to methyl mercury in the drinking water (0.25 to 0.50 mg Hg/kg/day) from 1 month prior to mating to the end of gestation resulted in ultrastructural changes in the livers of the fetuses (Fowler and Woods 1977).

      In their study using monkeys exposed from birth to 3 or 4 years of age (Sect. 3.1.3.1), Rice and Gilbert (1982) noted that the young, developing monkeys were especially vulnerable to the toxic effects of methyl mercury on visual function as demonstrated by the low dose at which these effects occurred.

      Pregnant monkeys (Macaca fascicularis) given methyl mercury in apple juice (50 or 90 μg methyl mercury/kg/day resulting in blood mercury levels of 1.0"0.13 ppm or 2.0"0.33 ppm, respectively) exhibited a decrease in pregnancy rate and increased abortion rate for mercury blood levels above 1 ppm (Mottet et al. 1985).

      The effects of methyl mercury chloride on postnatal development of rats was studied by Sakamoto et al. (1993). Adverse effects on weight gain and development of motor function were observed in rats given the mercury compound orally for 10 days starting on postnatal days 1, 14, or 35. Effects varied with the postnatal period of exposure as well as with dose; most effects were observed at the 10 mg/kg/day dose but some were noted at doses as low as 2.6 mg/kg/day.

3.1.5 Reference Dose

3.1.5.1 Subchronic

Elemental mercury:

      ORAL RfDs                                  Not available

 

Mercuric chloride:

      ORAL RfDs:                                   3E-4 mg/kg/day (EPA 1995)

      UNCERTAINTY FACTOR:           1000

      NOAEL:                                         Not available

      LOAEL:                                         0.633 mg Hg/kg/day

 

      CONFIDENCE:

      Study:                  Not applicable

      Data base:           High

      RfD:                    High

 

      PRINCIPAL STUDY: EPA 1987 analysis of data base

 

      COMMENTS: The RfD for mercuric chloride is based upon a consensus that the most sensitive mercuric chloride-induced adverse effect is autoimmune glomerulonephritis, the Brown Norway rat is a an appropriate test species, and oral absorption of divalent mercury is 7% and absorption from subcutaneous exposure is 100%. The RfD is based upon data from various studies including Bernaudin et al. (1981), Druet et al. (1978), and Andres (1984). The RfD is based upon back-calculation from the Drinking Water Equivalent Level (DWEL) of 0.010 mg/L (RfD = [0.010 mg/L H 2 L/day]/70 kg = 0.0003 mg/kg/day).

Methyl mercury:

      ORAL RfDs                                  1E-4 mg/kg/day (EPA 1995)

      UNCERTAINTY FACTOR:           10

      MODIFYING FACTOR:                1

 

      A benchmark dose approach rather than the traditional NOAEL/uncertainty factor method was used to derive the RfD for methyl mercury

 

      CONFIDENCE:

      Study:                  Medium

      Data base:           Medium

      RfD:                    Medium

     

      PRINCIPAL STUDY: Marsh et al. 1987, Seafood Safety 1991.

      COMMENTS: RfD is based on a benchmark exposure of 11 ppm in maternal hair. This is equivalent to maternal blood levels of 44 μg/L and a body burden of 69 μg or a daily intake of 1.1 μg/kg/day. Hair-to-blood mercury concentration ratio of 250:1 was used for calculations (see EPA 1996 for details).

3.1.5.2 Chronic

Elemental mercury:

      ORAL RfDc                                  Not available

 

Mercuric chloride:

      ORAL RfD:                                    3E-4 mg/kg/day (EPA 1996)

      UNCERTAINTY FACTOR:           1000

      NOAEL:                                         Not available

      LOAEL:                                         0.633 mg Hg/kg/day

 

      CONFIDENCE:

      Study:                                             Not applicable

      Data base:                                      High

      RfD:                                               High

 

      PRINCIPAL STUDY: EPA 1987 analysis of data base

      COMMENTS: The RfD for mercuric chloride is based upon a consensus that the most sensitive mercuric chloride-induced adverse effect is autoimmune glomerulonephritis, the Brown Norway rat is a an appropriate test species, and oral absorption of divalent mercury is 7% and absorption from subcutaneous exposure is 100%. The RfD is based upon data from various studies including Bernaudin et al. (1981), Druet et al. (1978), and Andres (1984). The RfD is based upon back-calculation from the DWEL of 0.010 mg/L (RfD = [0.010 mg/L H 2 L/day]/70 kg=0.0003 mg/kg/day). The derivation of this RfD is complex; for more detailed information, the reader is referred to EPA (1996).

 

Methyl mercury:

      ORAL RfDc                                  1E-4 mg/kg/day (EPA 1996)

      UNCERTAINTY FACTOR:           10

      MODIFYING FACTOR:                1

      For derivation of this RfD, a benchmark dose approach was used rather than the traditional NOAEL/uncertainty factor. Therefore, neither a NOAEL nor a LOAEL were required.

      CONFIDENCE:

      Study:                  Medium

      Data base:           Medium

      RfD:                    Medium

 

      VERIFICATION DATE: 11/23/94 (EPA 1995)

      PRINCIPAL STUDY: Marsh et al. 1987, Seafood Safety 1991.

      COMMENTS: RfD is based on a benchmark exposure of 11 ppm in maternal hair. This is equivalent to maternal blood levels of 44 μg/L and a body burden of 69 μg or a daily intake of 1.1 μg/kg/day. Hair-to-blood mercury concentration ratio of 250:1 was used for calculations. The methodologies and analyses employed in the derivation of this RfD are extensive; for additional details, the reader is referred to EPA (1996).

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

3.2.1.1 Human

      Inhalation of mercury vapor may result in corrosive bronchitis, interstitial pneumonitis, and death (Goyer 1991). Systemic effects following inhalation exposure may include shock, renal disorders, and central nervous system effects characterized by lethargy and neurobehavioral effects (insomnia, loss of memory, excitability, etc.). Occupational exposure to metallic mercury vapor at concentrations of 1.1 to 44 mg/m3 for 4 to 8 hours produced chest pains, dyspnea, cough, hemoptysis, impairment of pulmonary function, and interstitial pneumonitis (ATSDR 1989). Acute effects of inorganic mercury poisoning may be accompanied by a metallic taste, sore gums, and excessive salivation. 

      A case report cited an incident wherein four adults were acutely exposed to mercury vapor resulting from the smelting of dental amalgams (Taueg et al. 1991). Initial signs of toxicity included nausea, diarrhea, dyspnea, and chest pains. Despite chelation therapy, all four patients died 11 to 24 days after initial exposure. Mercury concentrations in the house were as high as 912 μg/m3 at or within 11 to 188 days after the exposure, and postmortem blood mercury levels ranged from 58 to 369 μg/L. Historically, the triad of increased excitability, tremors, and gingivitis has been recognized as characteristic for mercury poisoning (Goyer 1991).

3.2.1.2 Animal

      Death resulting from severe pulmonary edema has been reported for mice, guinea pigs, and rats following inhalation exposure to mercury vapor (Christensen et al. 1937). Similarly, inhalation exposure of rabbits to mercury vapor at a concentration of 1 to 1.1 mg/m3 for 1 to 30 hours resulted in death (Ashe et al. 1953). This same study also showed that 30-hour exposure of rabbits to mercury vapor at a concentration of 28.8 mg/m3 caused extensive necrosis of the lungs. Data are lacking regarding the effects of inhalation exposure of animals to organic mercury compounds (ATSDR 1989). 

3.2.2 Subchronic Toxicity

3.2.2.1 Human

      Subchronic inhalation exposure to mercury vapor will result in effects similar to those for acute exposure and will vary depending on exposure severity and duration. Sax and Lewis (1989) reported a lowest toxic exposure level of 0.15 mg/m3 for human females exposed to mercury vapor for 46 days. Sexton et al. (1976) reported tremors (especially in activities requiring fine control), insomnia, and nervousness resulting from 7 to 25 weeks of exposure to mercury vapor.

      Langolf et al. (1978) noted that short-term exposure to high levels of mercury appears to induce greater neurological effects than does long-term exposure to lower mercury levels.

      Exposure of humans to diethylmercury at vapor concentrations of 1 to 1.1 mg/m3 for 4 to 5 months resulted in death, the cause of which was not determined (Hill 1943). Data are lacking regarding inhalation exposure to methyl mercury.

      Exposure of female workers to mercury vapor (<0.02 mg Hg/m3, 8 hrs/day, 44 hrs/week) for 23 months did not produce any signs or symptoms of toxicity (Ishihara and Urushiyama 1994).

3.2.2.2 Animal

      The effects of subchronic inhalation exposure to mercury or mercury compounds is dependent on the exposure concentration and the specific form of mercury. Low levels of exposure will generally affect the kidney and central nervous system while high-level exposure will target the respiratory, cardiovascular, and gastrointestinal systems as described in Sect. 3.1. Exposure of rabbits to mercury vapor (0.86 to 6.0 mg/m3) for 2 to 12 weeks resulted in marked degeneration and necrosis of the heart (Ashe et al. 1953). Subchronic inhalation exposure of rats and rabbits to mercury has also produced neurobehavioral changes (ATSDR 1989). Evidence for a systemic autoimmune response was reported by Bernaudin et al. (1981) for rats inhaling vapors of mercuric chloride or methyl mercuric chloride 4 hours/day for 60 days. The kidney, lungs, and spleen were identified as target organs. Druet et al. (1978) noted renal immunologic insufficiencies in Brown Norway rats given subcutaneous injections of mercuric chloride (100 μg/kg) for 8 to 12 weeks. 

3.2.3 Chronic Toxicity

3.2.3.1 Human

      Chronic exposure to low levels of mercury vapor may induce immunologic glomerular disease (Goyer 1991). A number of studies have been conducted with individuals occupationally exposed to inorganic mercury compounds (mercuric oxides, mercurial chlorides, mercuric nitrate) and have been reviewed by the USAF (1990). Briefly, neuropsychological symptoms (insomnia, fatigue, headaches, etc.) and renal effects that correlated with blood mercury levels were reported for those exposed $ 2 years. The emotional and psychological disturbances often referred to as the AMad Hatter Syndrome@ has been attributed to inhalation of the dust or vapors of mercuric nitrate used in the making of felt hats (Clarkson 1989).

      Central nervous system effects including fatigue, tremors, and gingivitis have been reported for chronic exposures to mercury vapor (Goyer 1991). As exposure increases, the frequency and magnitude of muscle tremors increase and are accompanied by personality and behavioral changes (memory loss, excitability, depression, and hallucinations). 

      Low-level chronic exposures to mercury may affect the peripheral nervous system resulting in polyneuropathies (reduced sensory and motor nerve function) and neuropsychological effects (visual alterations, sensory loss, stress) (ATSDR 1989); these effects correlate to tissue levels of 20 to 40 μg/g. Neuropsychological effects were also reported by Smith et al. (1970) for occupational exposure to mercury levels of > 0.1 mg/m3. Mercury concentrations below this value did not appear to cause observable effects. Kishi et al. (1993) reported that neurobehavioral and motor function effects persisted in ex-mercury miners more than 10 years after cessation of exposure.

      Several reports regarding occupational exposure of chloralkali workers to mercury vapor are available. Fawer et al. (1983) reported an increase in the frequency of intention tremors of workers exposed to mercury vapor (time-weighted-average [TWA] of 0.026 mg/m3) over an average of 26 years. Piikivi and Tolonen (1989) found alterations in EEGs in workers exposed to mercury vapor for an average of 15.6 years. Piikivi and Hanninen (1989) reported adverse change in subjective measures of memory disturbance and sleep disorders in workers occupationally exposed for an average of 13.7 years. Subjectively and objectively determined alterations in autonomic function (pulse rate, blood pressure autonomic reflexes) were reported for workers exposed to mercury vapor for an average of 15.6 years. Neurobehavioral effects (motor speed, visual scanning, visuomotor coordination and concentration, visual memory, visuomotor coordination speed) were affected in individuals occupationally exposed to TWA concentrations of 0.014 mg/m3 (Ngim et al. 1992). Workers exposed to mercury vapor concentrations of 0.033 mg/m3 (range 0.005 to 0.19 mg/m3) for at least two years exhibited significantly poorer performance on neurobehavioral tests than did unexposed control subjects (Liang et al. 1993).

      Inhalation exposure to alkyl mercury compounds may occur during the manufacture or use of alkylmercury fungicides. The effects reported for these compounds include paresthesia of the extremities, mouth and lips, constriction of the visual field, deafness, motor incoordination and compromised reflex function. In severe cases, loss of speech and mental deterioration may occur (McComish et al. 1988).

      Endocrine function of the pituitary, thyroid, testes, and adrenal glands was studied in chloralkali workers exposed to mercury vapor for an average of 10 years (Bårregard et al., 1994). With the exception of inhibition of deiodination of T4 to T3, no significant effects were detected in the endocrine functions studied.

      Mercury vapor from dental amalgams has been identified as a major source of exposure to inorganic mercury in the general population (WHO 1991). An average mercury dose from dental amalgams has been estimated to be only 4 to 5 μg (Halbach 1995).

3.2.3.2 Animal

      Chronic inhalation exposure (72 to 83 weeks) of rats, rabbits, and dogs to metallic mercury vapor (0.01 mg/m3) did not produce histological evidence of renal toxicity (Ashe et al. 1953). Additional information on the chronic inhalation toxicity of inorganic mercury in animals was not available.

      Information regarding the toxicity of organic mercury following chronic exposure of animals was not available.

3.2.4 Developmental and Reproductive Toxicity

3.2.4.1 Humans

      Evidence suggests that chronic exposure of women to metallic mercury vapor may increase the frequency of menstrual disturbances and spontaneous abortions (Derobert and Tara 1950, ATSDR 1989). Mishonova et al. (1980) reported an increased frequency of pregnancy complications for women occupationally exposed to metallic mercury vapor.

      No data were available regarding the developmental/reproductive toxicity potential of inhaled organic mercury compounds.

3.2.4.2 Animal

      Steffek et al. (1987) showed that exposure of pregnant rats to metallic mercury vapor at concentrations of 0.5 mg/m3 on gestational days 10 to 15 caused an increase in resorptions and congenital defects in the offspring.

      Prolonging the estrus cycle of rats exposed to metallic mercury vapor at concentrations of 2.6 mg/m3, 6 hours/day for 21 days was reported by Baranski and Szmczyk (1973). This same study also showed that gestational exposure of rats to metallic mercury vapor (2.5 mg/m3) resulted in a decrease in the number of living fetuses and increased pup mortality.

3.2.5 Reference Concentration

3.2.5.1 Subchronic

Elemental mercury:

      INHALATION RfCs:                      0.0003 mg Hg/m3 (EPA 1995)

      UNCERTAINTY FACTOR:           30

      MODIFYING FACTOR:                None

      NOAEL:                                         None

      LOAEL:                                         0.009 mg Hg/m3

 

      PRINCIPAL STUDY: Fawer et al., 1983, Piikivi and Tolonen (1989), Piikivi and Hanninen (1989), Piikivi (1989), Ngim et al. (1992), Liang et al. (1993).

 

Mercuric chloride:

      INHALATION RfCs:                      pending (EPA 1996)

 

Methyl mercury:                                    Not available.

 

3.2.5.2 Chronic

 

Elemental mercury:

      INHALATION RfC:                       0.0003 mg Hg/m3 (EPA 1996)

      UNCERTAINTY FACTOR:           30

      MODIFYING FACTOR:                None

      NOAEL:                                         None

      LOAEL:                                         0.009 mg Hg/m3 (based upon an 8-hr TWA, occupational exposure)

 

      CONFIDENCE:

      Study:                  Medium

      Data base:           Medium

      RfC:                    Medium

 

      VERIFICATION DATE: 04/19/90 (EPA 1996)

 

      PRINCIPAL STUDIES: Fawer et al. (1983), Piikivi and Tolonen (1989), Piikivi and Hanninen (1989), Piikivi (1989), Ngim et al. (1992), Liang et al. (1993).

 

      COMMENTS: The RfC is based upon occupational exposures and slight subjective and objective evidence of autonomic dysfunction.

 

Mercuric chloride:

      INHALATION RfC:                       Pending (EPA 1996)

 

      COMMENTS: RfC is not yet verified but the review panel is in concordance with the data.

 

Methyl mercury:

      INHALATION RfC:                       Not available

 

 

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

      Dermal contact with organic or inorganic mercury compounds may cause dermatitis especially in hypersensitive individuals (USAF 1990). Renal effects have been reported following dermal exposure to organic mercurials, and neurological effects have been reported for dermal exposure to inorganic mercury (ATSDR 1989). No data are available for other routes of exposure.

3.3.2 Subchronic Toxicity

      No information was available regarding the subchronic toxicity of mercury by other routes of exposure.

3.3.3 Chronic Toxicity

      No information was available regarding the chronic toxicity of mercury by other routes of exposure.

3.3.4. Developmental Toxicity

      No information was available regarding developmental toxicity of mercury by other routes of exposure.

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

3.4.1.1 Primary target(s) 

1.   Central nervous system and kidneys: Both the central nervous system and kidneys are affected by inorganic mercury. The toxic effects may occur with acute, subchronic, or chronic exposure depending on the exposure level and the resulting body burden of mercury. Animal data suggest that the renal effects may be immunologically mediated. The central nervous system, especially during prenatal and postnatal development, is the primary target organ for methyl mercury.

3.4.1.2 Other target(s) 

1.   Cardiovascular system: acute exposure to mercury has caused cardiovascular collapse and some effects associated with acrodynia involve cardiovascular responses.

2.   Immune system: As noted in Sect. 3.4.1.1, animal data suggest that the nephrotoxic effects of mercury may be, in part, the result of mercury-induced immunological effects.

3.   Skin: Skin rashes and hyperkeratosis are involved in acrodynia, a response to mercurous chloride (calomel).

3.4.2 Inhalation Exposures

3.4.2.1 Primary target(s) 

1.   Central nervous system and peripheral nervous system: The critical target organs for inhalation exposure to elemental mercury vapor are the central nervous system and the peripheral nervous system. 

2.   Kidney: Inorganic mercury salts will primarily affect the kidneys.

      Definitive data were unavailable regarding the target organ for inhalation exposure to organic mercury compounds but, as for oral exposure, it is likely that the central nervous system would be the primary target organ. 

3.4.2.2 Other target(s) 

1.   Respiratory system: Exposure to high concentrations of metallic mercury vapor may cause irritation of the respiratory system.

2.   Cardiovascular system: Exposure to high concentrations of metallic mercury vapor may also affect the cardiovascular system.

3.   Gastrointestinal tract: Exposure to high concentrations of metallic mercury vapor may also affect the gastrointestinal systems, probably as a result of swallowing mercury that has been removed from the airways by the mucociliary escalator. 

 

4. CARCINOGENICITY

4.1 ORAL EXPOSURE

4.1.1 Human

      Definitive data regarding the potential carcinogenicity of mercury and mercury compounds in humans were unavailable. Several studies were available but all were of poor design, lacked adequate methodologic descriptions, and provided no definitive evidence of carcinogenicity

4.1.2 Animal

      Definitive data regarding the potential carcinogenicity of mercury and mercury compounds in animals was limited to dietary exposure studies in mice and rats.

      In an NTP study (1993), F344 rats (60/sex/group) were administered mercuric chloride by gavage at doses of 0, 2.5, or 5 mg/kg (equivalent to 0, 1.9, and 3.7 mg/kg/day), 5 days/week for 104 weeks. Squamous cell papillomas of the forestomach (males and females) and the incidence of thyroid follicular cell carcinomas exhibited statistically significant dose-related positive trends. However, NTP noted that the high dose exceeded the maximum-tolerated-dose (MTD), the forestomach tumors did not progress to malignancy, and the thyroid carcinomas are usually seen in conjunction with increased hyperplasia and adenomas neither of which were observed.

      NTP (1993) also conducted studies on B6C3F1 mice using a similar exposure protocol and doses of 0, 5, or 10 mg/kg. A statistically significant, positive, dose-related trend was shown for the combined incidences of renal tubular adenomas and adenocarcinomas (0/50, 0/50, 3/49). An EPA analysis of the data showed that the renal tubular adenoma/adenocarcinoma combined incidence in the high-dose mice was significantly elevated relative to historical controls.

      Hirano et al. (1986) gave dietary methylmercuric chloride to groups of 60 male and female ICR mice for 104 weeks. Dietary concentrations were 0, 0.4, 2, or 10 ppm (equivalent to 0, 0.03, 0.15, or 0.73 mg/kg for males, and 0, 0.02, 0.11, or 0.6 mg/kg/day for females). The incidence of renal epithelial tumors was significantly increased in high-dose males. An increase in non-neoplastic lesions in the kidneys indicated that a the MTD was exceeded. 

      Groups of 60 male and 60 female B6C3F1 mice were given dietary methylmercuric chloride (0, 0.4, 2, or 10 ppm equivalent to 0, 0.03, 0.14, and 0.69 mg/kg/day for males and 0, 0.03, 0.13 and 0.60 mg/kg/day for females) for 104 weeks (Mitsumori et al., 1990). The incidences of renal tubule focal hyperplasia, renal epithelial carcinomas, renal adenomas, and various non-neoplastic lesions were significantly greater in high-dose males. High mortality in the high-dose males indicated that the MTD was exceeded.

      No increases in tumor incidences were observed in male or female Sprague-Dawley rats given dietary methylmercuric chloride (0.4, 2, or 10 ppm equivalent to 0.014, 0.964, and 0.34 mg/kg/day) for up to 130 weeks (Mitsumori et al. 1983, 1984).

      Munro et al. (1980) also reported no increases in tumor incidences for Wistar rats given dietary methylmercury (2, 10, 50, or 250 μg/kg/day) for 26 months.

4.2 INHALATION EXPOSURE

4.2.1 Human

      Definitive data regarding the potential carcinogenicity of mercury and mercury compounds in humans were unavailable. An equivocal study by Janicki et al. (1987) reported an association between exposure to mercury-containing fungicides and leukemia.

4.2.2 Animal

      Definitive data regarding the potential carcinogenicity of mercury and mercury compounds in humans were unavailable.

4.3 OTHER ROUTES OF EXPOSURE

      No information was available regarding the potential carcinogenicity of mercury or mercury compounds by other routes of exposure.

4.4 EPA WEIGHT-OF-EVIDENCE 

Elemental mercury:

      Classification:       DCNot classifiable as to human carcinogenicity

      Basis:                  Inadequate human and animal data (EPA 1996)

 

Mercuric chloride:

      Classification:       CCPossible human carcinogen (EPA 1996)

      Basis:                  Inadequate data in humans and limited evidence of carcinogenicity in animals (increased incidences of focal papillary hyperplasia and squamous cell papillomas in the forestomach and thyroid follicular cell adenomas and carcinomas in male rats). The relevance of forestomach papillomas is equivocal in assessing cancer risk in humans because there was no evidence that the lesions progressed to malignancy. The thyroid tumors observed in rats are also questionable regarding a human carcinogenic response because these tumors are generally considered to be secondary to hyperplasia; an effect not observed in the high-dose rats.

Methyl mercury:

      Classification:       CCPossible human carcinogen (EPA 1996).

      Basis:                  Inadequate data in humans and limited evidence of carcinogenicity in animals (increased incidences of renal adenomas, adenocarcinomas, and carcinomas in male ICR and B6C3F1 mice exposed to dietary methylmercuric chloride for 104 weeks.

4.5 CARCINOGENICITY SLOPE FACTOR

      The available data do not allow for a quantitative assessment. Therefore, no slope factors have been calculated.

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