B7 Mercury

John T. James, Ph.D., and Harold L. Kaplan, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

Physical and Chemical Properties

Elemental mercury is a heavy, silvery-white, slightly volatile liquid at room temperature (Stokinger, 1981; ACGIH, 1986).

Synonym:

Quicksilver

Formula:

Hg

CAS number:

7439-97-6

Atomic weight:

200.6

Boiling point:

356.6°C

Melting point:

-38.9°C

Vapor pressure:

0.0018 torr (25°C)

Solubility:

Insoluble in H2O, soluble in non-polar solvents, vapor soluble in blood than in H2O

Conversion factors at 25°C, 1 atm:

1 ppm = 8.2 mg/m3

1 mg/m3 = 0.12 ppm

Occurrence and Use

Mercury occurs in three chemical forms in the environment: (1) elemental (metallic) mercury (Hg°); (2) inorganic mercurous (Hg++) and mercuric (Hg++) compounds or ions; and (3) organic mercury compounds (Stokinger, 1981). Although this document is concerned with mercury vapor, data on inorganic or organic forms also are included



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--> B7 Mercury John T. James, Ph.D., and Harold L. Kaplan, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch Houston, Texas Physical and Chemical Properties Elemental mercury is a heavy, silvery-white, slightly volatile liquid at room temperature (Stokinger, 1981; ACGIH, 1986). Synonym: Quicksilver Formula: Hg CAS number: 7439-97-6 Atomic weight: 200.6 Boiling point: 356.6°C Melting point: -38.9°C Vapor pressure: 0.0018 torr (25°C) Solubility: Insoluble in H2O, soluble in non-polar solvents, vapor soluble in blood than in H2O Conversion factors at 25°C, 1 atm: 1 ppm = 8.2 mg/m3 1 mg/m3 = 0.12 ppm Occurrence and Use Mercury occurs in three chemical forms in the environment: (1) elemental (metallic) mercury (Hg°); (2) inorganic mercurous (Hg++) and mercuric (Hg++) compounds or ions; and (3) organic mercury compounds (Stokinger, 1981). Although this document is concerned with mercury vapor, data on inorganic or organic forms also are included

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--> when relevant to the toxicity of mercury vapor. The major sources of mercury vapor and compounds of mercury are both natural (degassing of earth's crust, emissions from volcanoes, evaporation of natural bodies of water) and man-made (mining, smelting, refuse incineration, combustion of fossil fuel) (WHO, 1991). Mercury has many diverse uses because of its properties. Liquid elemental mercury is a common component of thermometers, barometers, manometers, and other laboratory and medical measuring instruments (Stokinger, 1981). It is also widely used in electrical devices, including lamps, switches, rectifiers and batteries. The breakage of any of these instruments or devices inside the spacecraft cabin could result in the release and volatilization of liquid mercury and the subsequent exposure of crew members to potentially toxic levels of the vapor. Containment of mercury in such devices is strictly controlled by NASA based on mercury's SMACs and the ability of the air revitalization system to remove mercury vapor from spacecraft air. No method has been developed to monitor mercury vapor in spacecraft air. Recently, there has been much debate over possible health hazards from the inhalation, and ingestion, of elemental mercury released from dental amalgams in the mouth (WHO, 1991). Reported intra-oral vapor concentrations range from 0.003 to 0.029 mg/m3 (Vimy and Lorscheider, 1985). Pharmacokinetics and Metabolism Inhalation of mercury vapor is the most important route of uptake for elemental mercury (WHO, 1991). Human subjects retained approximately 70-80% of inhaled mercury vapor, retention occurring almost entirely in the alveoli (Nielsen-Kudsk, 1965; Hursch et al., 1976). Oxidation of elemental mercury to the mercuric ion is the primary metabolic pathway (Hursch et al., 1976). Mercury accumulates in many tissues, but the most important are the brain and kidneys. Clearance half-times of mercury inhaled by human test subjects vary from 1.7 d for the lungs to 64 d for the kidney region (Hursch et al., 1976). Absorption Experimental results indicated that absorption of mercury vapor by

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--> the skin poses a very minor hazard compared with that by inhalation. In human volunteers exposed via the forearm skin, the rate of uptake by the total body skin was estimated to be 2.2% of that by the lung (Hursch et al., 1989). Approximately one-half of the mercury retained by the skin was shed by desquamation of epidermal cells, and the remainder was slowly released into the body (Hursch et al., 1989). Metabolism and Distribution Mercury vapor rapidly passes from the inspired air in the alveoli into the bloodstream because of its high lipophilicity (Aschner and Aschner, 1990). The dissolved elemental mercury (Hg°) is soon oxidized to mercuric ions (Hg++), partly in red blood cells and partly after diffusion into other tissues of the body (Hursch et al., 1988). This oxidation occurs under the influence of the catalase-hydrogen peroxide complex (Complex I) in mammalian tissues (Nielsen-Kudsk, 1969). Catalase inhibitors, such as ethanol and aminotriazole, inhibit the oxidation reaction, which can change the distribution, retention, and excretion of inhaled mercury vapor (Magos et al., 1974; Hursch et al., 1980; Khayat and Dencker, 1984). Following the inhalation of mercury vapor, mercury quickly accumulates within the brain, but to a much lesser extent than in the kidneys (Magos, 1967). Despite its rapid oxidation by red blood cells, some solubilized vapor persists in the bloodstream sufficiently long to reach and diffuse across the blood-brain barrier into the brain, where it is oxidized by the catalase-hydrogen peroxide system to the divalent mercuric form (Dunn et al., 1978). The mercuric ions, which traverse the blood-brain barrier less freely than elemental mercury, bind to sulfhydryl-containing ligands and are retained within the brain. Because of this greater diffusibility of the vapor, the mercury content in the brains of animals exposed to the vapor was ten times greater than that of animals injected with an equivalent dose of mercuric salts (Berlin et al., 1969). Excretion The principal routes of elimination of inhaled mercury vapor are the

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--> urine and feces; a small portion (7%) of the retained mercury is excreted in the expired air as elemental mercury vapor (Dunn et al., 1981). A small amount of the exhaled vapor is formed by the reduction of divalent mercury produced by the oxidation of the elemental mercury. This reduction occurs both in animals (mice and rats) and humans (Berlin et al., 1969; Sugata and Clarkson, 1979; Dunn et al., 1981). The exhalation of mercury vapor is increased in catalase-deficient mice and by ethanol in mice and humans (Dunn et al., 1981; Ogata et al., 1987). The clearance of inhaled mercury vapor from tissues of the body follows a complicated pattern; biological half-times differ according to the tissue and the time after exposure (WHO, 1991). Tracer studies on human volunteers and animals indicate that, after a short exposure to mercury vapor, the first phase of elimination from blood has a half-time of approximately 2-4 d and accounts for about 90% of the retained mercury (WHO, 1991). This is followed by a second phase with a half-time of 15-30 d. After inhalation by human volunteers of a mixture of stable and radioactive mercury vapor for 1424 min, elimination from the body followed a single exponential process, with an average half-time of 58 d (Hursch et al., 1976). Average half-times for mercury clearance from different parts of the body were the following: lungs, 1.7 d; brain, 21 d; kidneys, 64 d; and chest, 43 d. It is probable that a fraction of the mercury in the brain and the kidneys has a longer biological half-life, particularly when exposures are prolonged (WHO, 1991). Toxicity Summary Acute Toxicity In humans, acute inhalation of mercury vapor might cause irritation and inflammation of the respiratory tract, resulting in tracheo-bronchitis, bronchiolitis, pneumonitis, and various neuropsychiatric reactions or symptoms (Milne et al., 1970; McFarland and Reigel, 1978; WHO, 1991). Accidental exposure of four workers for 2-5 h to mercury vapor at 1.1-2.9 mg/m3 (determined by simulating the exposure conditions) caused minimal discomfort during exposure, but fever, cough, dyspnea, and mild chest tightness developed 4 h later (Milne et al., 1970). In

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--> another accident, exposure of workers for less than 8 h to the vapor at a calculated maximum concentration of 44 mg/m3 caused fever, chills, chest pain, and weakness, and, in some, impaired pulmonary function and evidence of interstitial pneumonitis (McFarland and Reigel, 1978). Various symptoms characteristic of chronic mercurialism developed later, including tremor, nervousness, irritability, lack of ambition, and loss of sexual drive. Animal studies of the acute toxicity of mercury vapor are limited in number and scope and were mostly conducted with high concentrations. In a pharmacokinetic study in which monkeys, rabbits, and rats were exposed to mercury vapor at 1 mg/m3 for 4 h, signs of toxicity (increased irritability, aggressiveness, decreased food intake for 24 h) were observed only in rats (Berlin et al., 1969). An 8-h exposure of a dog at 20 mg/m3 caused dyspnea and weakness; death occurred on the day of exposure (Fraser et al., 1934). In rabbits, a 1-h exposure at 28.8 mg/m3 caused moderate histopathological changes to the kidneys and brain and mild changes to the lungs and heart (Ashe et al., 1953). With 2-, 4-, or 6-h exposures, damage to the kidneys and brain was severe (extensive cellular degeneration and necrosis) and mild-to-moderate in the lungs, liver, colon, and heart. In rats exposed to mercury vapor at 0.55 mg/m3 for 12, 14, or 24 h (four rats per group), it was reported that one animal from each group died with neurological signs. Only small peripheral hemorrhages were found in lung tissues (Møller-Madsen, 1992). These deaths might not have been from mercury since this result is at variance with many other reports (Ernst et al., 1993). Short-Term and Subchronic Toxicity In squirrel monkeys exposed to mercury vapor at 1 and 2 mg/m3, 5 d/w (hours per day not specified), for 6-69 d, no pathological changes were evident in the brain, although some brain structures contained up to 8 ppm of mercury (Berlin, 1976). Exposure of dogs at 15-20 mg/m3, 8 h/d, for 2 or 3 d caused dyspnea, often with cyanosis, extreme weakness or lassitude, occasional vomiting and diarrhea, and death (Fraser et al., 1934). After exposures at 12.5 and 6 mg/m3, these effects were less severe and deaths were delayed. Daily 8-h exposures at 3 and 4.4 mg/m3 for 20-32 d caused gingivitis, loss of appetite, and

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--> diarrhea, without death. In two dogs exposed at 1.9 mg/m3, 8 h/d, for 40 d, no toxic effects were evident except for a transient redness of the gums of one animal (Fraser et al., 1934). In rabbits, repeated exposures at 28.8 mg/m3 for 1, 2, or 4 h for 5 d or for 6 h for 2 or 3 d caused severe damage to the kidneys and brain and less damage to the lungs, liver, colon, and heart (Ashe et al., 1953). After exposures at 6 mg/m3, 7 h/d, 5 d/w, for 1-5 w, tissue damage to the kidneys, brain, heart and lungs was mild-to-moderate and more severe when exposures were 6-11 w. At 0.86 mg/m3, 7 h/d, 5 d/w, for 2-5 w, histopathological changes were generally mild and evident only in the kidneys and brain; for exposures of 6-12 w, changes were moderate in the kidneys and mild in the brain, liver, heart, and lungs. Localized concentrations of mercury in the brain have been studied in rats exposed at up to 0.4 mg/m3, 6 h/d, for 2 w (Ernst et al., 1993). In Wistar rats exposed to mercury vapor at 0.1 mg/m3, 6 h/d, 5 d/w, for 7 w, the mercury content in the kidney was found to be about 50-fold higher than in any other organ (Eide and Wesenberg, 1993). Autoimmune glomerulonephritis and proteinuria were found in Brown-Norway rats exposed to mercury vapor at 1 mg/m3, 24 h/d for 5 w (Hua et al., 1993). A less-exposed group from the same study (5 h/d for 5 w) showed autoimmune glomerulonephritis without proteinuria. Repeated exposure to mercury vapor also causes decrements in operant behavior of the pigeon and the rat. In eight pigeons exposed to mercury vapor at 17 mg/m3, 2 h/d, 5 d/w, response rates (key pecking for food reward) were reduced 50% in one of the eight in the first week, in six of the eight in the fifth week, and in all eight by the fourteenth week (Armstrong et al., 1963). Tremors in the head, neck, and wings appeared during the fifth week of exposure and were the only toxic signs. In rats, exposure to mercury vapor at 17 mg/m3, 2 h/d, 5 d/w, over 30 d decreased shock-avoidance responses and increased escape-response latency time in a conditioned operant test (Beliles et al., 1968). Escape-response latency increased after 15 d of exposure and was 7 times that of controls at 30 d. Tremor and weight loss were evident during the last 5 d. Recovery of operant behavior began at 14 d post-exposure and was almost complete at 45 d. Histopathological changes were not evident in the kidneys, liver, or lungs; but in the brain, two of three rats had lymphocytic cuffing around capillaries of the medulla

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--> oblongata. The same exposure regimen exacerbated shock-induced reflexive fighting behavior of rats and increased spontaneous fighting, requiring termination of the experiment after 18 d (Beliles et al., 1968). Chronic Toxicity In humans, the principal target organs of chronic exposure to mercury vapor are the central nervous system (CNS) and the kidneys. The classic symptoms of chronic inhalation of the vapor include (1) intention tremor; (2) erethism, a neuropsychiatric syndrome that includes irritability, excitability, loss of memory, loss of self-confidence, insomnia, and depression; and (3) gingivitis (Cragle et al., 1984). Less-common effects on the kidneys, including the nephrotic syndrome, proteinuria, and other signs of renal dysfunction, have been attributed to chronic exposure (Kazantzis et al., 1962; Foa et al., 1976; Buchet et al., 1980; Roels et al., 1982; Rosenman et al., 1986). One major study reported no significant signs or symptoms of chronic mercury exposure in 479 workers whose time-weighted average exposures were at or below 0.1 mg/m3, some symptoms (tremor, insomnia, loss of appetite and weight) among 88 workers exposed at 0.110.27 mg/m3, and no evidence of kidney damage or other organ injury (Smith et al., 1970). In a followup study of these and other workers, no correlation was found between adverse health effects in workers and exposure to mercury vapor at levels between 0.05 and 0.1 mg/m3 (McGill et al., 1964; Danzinger and Possick, 1973). Other investigators also reported no cases of classic mercury toxicity or evidence of significant exposure-related abnormalities when average concentrations did not exceed 0.1 mg/m3 (McGill et al., 1964; Danzinger and Possick, 1973). In contrast, other studies attributed various toxic signs, including erethism, tremor, decreased nerve conduction velocity, decreased red-blood-cell cholinesterase, and renal dysfunction, in workers to exposure to mercury vapor below 0.1 mg/m3, or even below 0.05 mg/m3 (Bidstrup et al., 1951; Fawer et al., 1983; Verberk et al., 1986; WHO, 1991). Peak or time-integrated average urinary mercury levels in workers were reported to be associated with neurological dysfunction, increased tremor, impaired psychomotor performance, decreased coordination,

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--> verbal intelligence and memory, renal dysfunction, and other effects (Langolf et al., 1978, 1981; Buchet et al., 1980; Roels et al., 1982; Smith et al., 1983; Rosenman et al., 1986). Based on its review of the literature, the World Health Organization (WHO, 1991) concluded that, at mercury vapor concentrations above 0.08 mg/m3 (corresponding to urinary mercury of 0.1 mg/g creatinine), the probability of developing neurological signs (tremor, erethism) is high. At 0.025-0.08 mg/m3 (corresponding to urinary mercury of 0.030.10 mg/g creatinine), the incidence of certain less severe toxic effects is increased. These subtle effects include impaired psychomotor performance, measurable tremor, impaired nerve conduction velocity, fatigue, irritability, loss of appetite, and possibly proteinuria. Continuous low-level exposure to mercury vapor also occurs as a result of the release of vapor from amalgam fillings in the mouth (WHO, 1991). Several studies have shown a correlation between the number of amalgam fillings or surfaces with mercury content in brain and kidney tissue from human autopsy (WHO, 1991). However, in an epidemiological study of 1024 women, there were no positive correlations between the number of fillings and the symptoms reported (Ahlqwist et al., 1988). In 2 dogs, 18 rabbits, and 25 rats exposed to mercury vapor at 0.1 mg/m3, 7 h/d, 5 d/w, for up to 83 w, there was no histopathology in organs of rats at 72 w, in organs of rabbits and a dog at 83 w, or in kidney biopsy samples from 2 dogs taken at 38 and 48 w (Ashe et al., 1953). Kidney function tests in the 2 dogs at 41 or 43 w and 60 or 83 w also were normal. Mercury vapor at 3 mg/m3, 5 d/w, caused a 50% reduction in shock-avoidance response rate in two of seven rats after 15 w and in avoidance after 41 w and escape rates after 35 w in all seven rats (Kishi et al., 1978). Response rates were normal within 12 w after termination of exposure. No histological changes were evident in the brain, lungs, or liver, but there was a slight degenerative change to the tubular epithelium of the kidneys. Exposure to mercury vapor at 4 mg/m3, 6 h/d, 4 d/w, for 13 w caused occasional tremor and clonus of the fore- and hind-legs of two of six rabbits (Fukuda, 1971). Highest mercury concentrations in brain structures were in the cerebellum, tegmentum, and thalamus.

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--> Genotoxicity and Carcinogenicity An increased incidence of chromosome aberrations was reported in four asymptomatic workers who had been exposed to mercury vapor at 0.15-0.44 mg/m3 and had elevated urinary mercury levels during the preceding year (Popescu et al., 1979). Another study did not find an increase of structural aberrations in peripheral blood lymphocytes in workers exposed to the mercury vapor (Mabille et al., 1984). There are no reports, to our knowledge, that mercury vapor is carcinogenic. An epidemiological study of 2400 workers exposed to mercury vapor for several years did not find excess deaths from diseases or cancers of the brain and CNS, kidneys, liver, or lungs due to mercury vapor exposure (Cragle et al., 1984). Reproductive and Developmental Toxicity The reproductive and developmental toxicities of mercury vapor will be considered together since studies often address both end points. The database consists primarily of epidemiological studies of workers exposed as a result of employment in a factory or as dental professionals and rodent inhalation studies. The potential for developmental toxicity is high because elemental mercury readily crosses the placenta and accumulates in many fetal organs, but at concentrations below those typically found in the mother (Clarkson et al., 1972; Khayat and Dencker, 1982). The reproductive toxicity of mercury has been evaluated in both male and female industrial workers exposed to concentrations that were often incompletely characterized. Female workers (n = 153) in a mercury vapor lamp factory exposed to concentrations mostly below a time-weighted average of 0.05 mg/m3 reported higher rates of menstrual disorders and adverse pregnancy outcomes than unexposed workers did; however, the authors conclude that their findings neither proved nor excluded the possibility that mercury causes adverse effects on reproduction (De Rosis et al., 1985). Male workers (n = 103) from various industrial plants where mercury vapor exposures increased urinary concentrations to 50 µg/g of creatinine (1 µg/g of creatinine in controls)

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--> showed no statistically significant difference in the observed number of offspring compared with a matched control population (Lauwerys et al, 1985). In another study of male workers (n = 247) with exposures to mercury vapor and average urinary concentrations over a 20-y period ranging from 27 to 107 µg/L, there was no association between the father's mercury exposure and decreased fertility, increased malformations in offspring, or childhood illness. Furthermore, the father's mercury exposure was not a significant risk factor for miscarriage after controlling for previous history (Alcser et al., 1989). In a result that seems to contradict this finding, a doubling of the rate of spontaneous abortions was found in the wives of 152 workers with average urinary mercury concentrations above 50 µg/L before pregnancy (Cordier et al,. 1991). A number of studies have focused on potential adverse effects in dental professionals who receive exposure to mercury vapor during amalgam restorations. In a questionnaire study of nearly 60,000 dental workers divided into two groups according to the frequency of amalgam restorations performed, there was no significant increase in the rate of spontaneous abortion or congenital malformations with the presumed increase in exposure to mercury vapor (Brodsky et al, 1985). In contrast, Sikorski et al. (1987) found that the rate of reproductive failures and menstrual cycle disorders in 81 female dental workers was associated with the mercury content of their hair. In a study of over 8000 infants born to dental workers in Sweden, the frequency of perinatal death, low birth weight, and malformations was comparable to the incidence in the general population (Ericson and Kallen, 1989). On the whole, data from worker studies must be considered inconclusive about the potential for mercury vapor to cause reproductive or developmental toxicity at concentrations experienced in occupational settings. Studies in rodents exposed to concentrations well above those experienced by workers have demonstrated mercury vapor's potential for reproductive and developmental toxicity. The estrus cycle was prolonged in rats exposed at 2.5 mg/m3, 6 h/d, 5 d/w for 21 d; however, during the latter weeks of the exposure, CNS signs were observed (Baranski and Szymczyk, 1973). In the same study, offspring of females exposed 3 w before mating and during gestational days 7-20 were reduced in number and all died by the sixth day after birth. In a study reported by abstract only, rats were exposed on gestational days 15-20 or 1-20 to

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--> concentrations of 0.1, 0.5, and 1.0 mg/m3 (Steffek et al., 1987). No effects were seen at 0.1 mg/m3; however, increased resorptions and cranial defects (2 of 84) were found in offspring from the 0.5-mg/m3 group. Relative to the control group, maternal toxicity was evident in the high-exposure group as decreased weight gain (Steffek et al., 1987). Several behavioral effects were found in offspring of dams exposed to mercury vapor for 1 or 3 h/d at 1.8 mg/m3 for 7 d (days 11-14 and 17-20 of gestation) (Danielsson et al., 1993). Interactions with Other Chemicals Catalase inhibitors, such as ethanol and aminotriazole, inhibit the oxidation of elemental mercury to mercuric ion in blood and tissues (Nielsen-Kudsk, 1969; Magos et al., 1974). Pretreatment with ethyl alcohol (rat and marmoset monkey) or aminotriazole (rat) caused decreased mercury retention in most organs and in the whole body, increased blood concentrations of elemental mercury, and increased retention of mercury in most liver and adrenal cells (Khayat and Dencker, 1984). Ingestion of moderate amounts of ethanol by three human volunteers decreased mercury uptake by red blood cells and retention of mercury by the body and increased the rapid phase of vapor expiration and mercury storage in the liver (Hursch et al., 1980).

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--> TABLE 7-2 Exposure Limits Set by Other Organizations Organization Concentration, mg/m3 ACGIH's TLV 0.05, TWA (skin) OSHA's PEL 0.1, TWA (ceiling) NIOSH's REL 0.05, TWA (skin) NIOSH's IDLH 28 NRC's EEGL 0.2, 24 ha NRC's CEGL 0.01, 90 da a NRC, 1984. TLV = threshold limit value. TWA = time-weighted average. PEL = permissible exposure limit. REL = recommended exposure limit. IDLH = immediately dangerous to life and health. EEGL = emergency exposure guidance level. CEGL = continuous exposure guidance level. TABLE 7-3 Spacecraft Maximum Allowable Concentrations Duration ppm mg/m3 Target Toxicity 1 h 0.01 0.08 Respiratory tract 24 h 0.002 0.02 Respiratory tract 7 d 0.001 0.01 CNS, kidney 30 d 0.001 0.01 CNS, kidney 180 d 0.001 0.01 CNS, kidney Rationale for Acceptable Concentrations In setting SMAC values for mercury vapor, the toxic effects on the respiratory tract, the brain and CNS, and the kidney must be considered. Few well-controlled animal studies have been conducted with observations and measurements of toxic end points in adequate numbers of animals and at more than one concentration of vapor. In most reports of human exposures, analytical data are lacking. Guidelines from the Committee on Toxicology have been used to structure the rationale below (NRC, 1992).

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--> Respiratory System Toxicity For single, brief exposures to mercury vapor, it appears that the respiratory system is the most sensitive target organ in human beings (Milne et al., 1970; McFarland and Reigel, 1978). A few hours after exposure, cough, shortness of breath, and tightness of the chest develop, and when clinical evaluations have been conducted, a diffuse pulmonary infiltrate has been found. There are no well-characterized human exposures; however, data from two accidental industrial exposures were used to estimate an acceptable concentration (AC) for the lung. In one accident, nine workers were exposed for about 5 h to a mercury concentration that could have been as much as 40 mg/m3 (McFarland and Reigel, 1978). Even though three of the workers complained of no illness, six had moderate respiratory symptoms like those indicated above. It is possible that human genetic variations in catalase activity and enzymes related to endogenous peroxide supply might affect human responses to inhaled mercury (Clarkson et al., 1980). All six injured workers recovered from respiratory injury; however, in some there were lingering subjective symptoms including fatigue, irritability, and sexual disinterest. Two of the exposed workers had lingering tremors, which never fully disappeared in one subject. In another report of accidental human exposures at 1-3 mg/m3 for 2.5-5 h, similar respiratory symptoms were reported in three-fourths of the exposed workers and one-fourth of the workers reported minimal respiratory symptoms (Milne et al., 1970). Authors of the first study assert that all nine workers had approximately equal exposures to mercury vapor even though there was a wide range in apparent lung injury. An estimate of short-term human exposure limits was made as follows: A LOAEL was estimated from the 13 exposed workers as an exposure of 2 mg/m3 for 5 h. For the 1-h AC to protect the lung, the estimate was 2 mg/m3 x 0.4 (the square root of 13 divided by 10 for the small number of subjects) x 1/10 (LOAEL to NOAEL), or 0.08 mg/m3. For the 24-h AC, the estimate was 2 mg/m3 x 0.4 x 1/10 x 5/24 (Haber's rule), or 0.02 mg/m3. The above estimates of safe mercury concentrations were based on incomplete human data and should not be adopted without comparison with available animal data on lung injury. From short-term exposures

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--> of rabbits at concentrations of 30 mg/m3 for 1-4 h, the degree of histologically detected injury was reported as mild (Ashe et al., 1953). From these data, the 1-h AC to protect the lung was 30 mg/m3 x 1/10 (species extrapolation) x 1/10 (LOAEL to NOAEL), or 0.3 mg/m3. This was about fourfold above the estimate from human data, so the lower 1-h AC of 0.08 mg/m3 was adopted. For the 24-h AC to protect the lung, as estimated from the rabbit data, the value was 30 mg/m3 x 1/10 x 1/10 x 4/24 (Haber's rule), or 0.05 mg/m3. Again, this was above the estimate from human data, so the 24-h AC for the lung of 0.02 mg/m3 was adopted. Nephrotoxicity Data were available for subchronic and chronic exposures of animals to mercury vapor. No more than mild histopathological changes were seen in the kidneys of rabbits exposed at 0.86 mg/m3, 7 h/d, 5 d/w, for up to 4 w, and no histopathological changes were seen in the kidneys of rabbits, rats, and two dogs exposed at 1 mg/m3 for 83 w (Ashe et al., 1953). Applying a species factor of 10 to the long-term NOAEL of 0.1 mg/m3 gave an AC for nephrotoxicity of 0.01 mg/m3 for exposures of 7, 30, and 180 d. Haber's rule was not applied because mercury concentrations in kidneys of exposed rabbits did not increase after the fourth week of exposures (Ashe et al., 1953). Neurotoxicity Animal data for estimating potential neurotoxicity in humans were available from the same study that provided data on nephrotoxicity. Mild histopathological changes in the brains of rabbits resulted from exposure at 0.86 mg/m3, 7 h/d, 5 d/w, for 2-4 w, but no histopathological changes were detected when rabbits, rats, and two dogs were exposed at 0.1 mg/m3 for 83 w (Ashe et al., 1953). In the 83-w study, the tissue concentrations of mercury in the brain were roughly an order of magnitude below the concentrations found in the kidney, but do not conclusively show that mercury is not accumulating in brain tissue. However, the exposures at 0.86 mg/m3 show no increased accumulation

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--> between the fifth and twelfth weeks of exposure, nor does the extent of tissue damage increase (Ashe et al., 1953). Hence, the concentration of 0.1 mg/m3 was considered a NOAEL, and a species factor of 10 was applied, without using Haber's rule, to derive an AC for neurotoxicity of 0.01 mg/m3 for 7-, 30-, and 180-d exposures. A large epidemiological study reported no significant toxic effects below 0.1 mg/m3 in workers chronically exposed to mercury vapor, but there were some complaints of symptoms (Smith et al., 1970). A few much smaller studies suggest occasional complaints, symptoms, or subclinical effects at exposures below 0.1 mg/m3 and even possibly below 0.05 mg/m3 (Bidstrup et al., 1951; Fawer et al., 1983; Verberk et al., 1986). Consequently, 0.1 mg/m3 is considered a LOAEL and a factor of 10 was applied to estimate a human NOAEL. No adjustments to the AC values were necessary for any microgravity-induced physiological changes. Recommendations The most important SMACs for mercury in spacecraft air are the short-term values because this chemical would be removed from the air after release and because a continuous slow-release source is unlikely to be accidentally created. The long-term effects of mercury have been studied thoroughly in occupationally exposed populations; however, the short-term effects in human beings can only be approximated from the few accidental exposures that have occurred. Only one animal study was found on short-term effects of mercury vapor inhalation and it left unanswered several questions important to the setting of short-term SMACs. The time-vs.-concentration relationships need better definition for brief continuous exposures lasting from 1 h to a few days. The relationships need to be defined for each apparent target site in animal models: brain, kidney, liver, colon, heart, and lung. In addition, the mechanism of the damage needs exploration to improve extrapolations from animal models to humans. Because the lung appears to be the target site in humans after acute exposure, future research should be focused on understanding biochemical and microscopic changes in that organ. Appropriate animal models should be selected carefully, with the initial experiments involving exposure of several species.

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--> TABLE 7-4 End Points and Acceptable Concentrations   Uncertainty Factors Acceptable Concentrations, mg/m3 End Point Exposure Data Species and Reference NOAEL Time Species N 1 h 24 h 7 d 30 d 180 d Respiratory tract toxicity At 2 mg/m3, ≈5 h; 9 of 13 moderately severe responses Human, n = 13 (Milne et al., 1970; McFarland and Reigel, 1978) 10 1 or 5 HRa 1 2.5 0.08 0.02 — — —   At 30 mg/m3, 1-4 h; 4 of 4 mild responses Rabbit (Stokinger, 1981; WHO, 1991) 10 1 or 6 HR 10 — 0.3 0.05 — — — Nephrotoxicity NOAEL at 0.1 mg/m3, 7 h/d, 5 d/w, 83 w Dog, rabbit, rat (Ashe et al., 1953) 1 1b 10 — — — 0.01 0.01 0.01 Neurotoxicity NOAEL at 0.1 mg/m3, 7 h/d, 5 d/w, 1-20 y Dog, rabbit, rat (Smith et al., 1970) 1 1c 10 — — — 0.01 0.01 0.01   LOAEL at 0.1 mg/m3, 8 h/d, 5 d/w, 1-20 y Human (Smith et al., 1970) 10 1c 1 — — — — — 0.01 SMAC   0.08 0.02 0.01 0.01 0.01 a HR = Haber's rule. b A time factor was not used because mercury concentrations did not increase in kidneys after 4 w of exposure. c A time factor of 1 for prolonged exposures is supported by mercury concentrations in brains of exposed animals.

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