EPA/6007R-92/199
June 1994
Summary Review of Health Effects
Associated with Mercuric Chloride:
Health Issue Assessment
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
Printed on Recycled Paper
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental Protection
Agency policy and approved for publication. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
ii
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TABLE OF CONTENTS
Page
LIST OF TABLES
LIST OF FIGURES
PREFACE
AUTHORS, CONTRIBUTORS, AND REVIEWERS
1. SUMMARY AND CONCLUSIONS
2. INTRODUCTION
3. AIR QUALITY AND ENVIROJMMENTAL FATE .....
3.1 SOURCES
3.1.1 Natural Occurrence
3.1.2 Anthropogenic Sources
3.2 DISTRIBUTION AND FATE
3.3 AMBIENT LEVELS
3.3.1 Exposure .
4. PHARMACOKINETICS
4.1 ABSORPTION
4.2 RETENTION AND DISTRIBUTION
4.3 EXCRETION
5. MUTAGENICITY AND CARCINOGENICITY
5.1 MUTAGENICITY
5.1.1 Prokaryotic Organisms
5.1.2 Eukaryotic Organisms
5.1.3 Whole Animal Assays
5.1.4 Summary
5.2 CARCINOGENICITY
6. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
6.1 IN VITRO STUDIES
6.2 INJECTION STUDIES
6.3 ORAL EXPOSURE STUDIES '......
6.4 INHALATION EXPOSURE STUDIES
6.5 HUMANS
6.6 SUMMARY
7. OTHER TOXIC EFFECTS
7.1 ACUTE TOXICITY
7.2 SUBCHRONIC AND CHRONIC TOXICITY
v
vi
vii.
ix
1-1
2-1
3-1
3-1
3-1
3-1
3-3
3-5
3-7
4-1
4-1
4-2
4-7
5-1
5-1
5-1
5-1
5-5
5-6
5-8
6-1
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6-2
6-5
6-7
6-7
6-7
7-1
7-1
7-3
111
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TABLE OF CONTENTS (cont'd)
7.2.1 Health Effects
7.2.2 Pathology of Immunological Effects
7.3 BIOCHEMICAL EFFECTS
8. U.S. ENVIRONMENTAL PROTECTION AGENCY CANCER
AND NONCANCER ASSESSMENTS
8.1 CARCENOGENICITY
8.2 DRINKING WATER EQUIVALENT LEVEL
8.3 MAXIMUM CONTAMINANT LEVEL GOAL
8.4 MAXIMUM CONTAMINANT LEVEL
8.5 ORAL REFERENCE DOSE
8.6 INHALATION REFERENCE CONCENTRATION
9. REFERENCES
Page
7-3
7-5
7-7
8-1
8-1
8-1
8-3
8-3
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8-3
9-1
IV
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LIST OF TABLES
Number
1-1 Summary of Official Standards for Airborne Mercury
1-2 Estimated Average Daily Intake and Retention of Elemental
Mercury and Mercury Compounds in the General Population
Not Occupationally Exposed to Mercury
1-3 Summary of Effects of Mercuric Chloride on Mammals or
Mammalian Cells
2-1 Physical and Chemical Properties of Mercuric Chloride . .
2-2 Comparison of Mercury Demand Within U.S. Mercuric
Chloride User Industries in 1989 and 1991 ..........
3-1 Estimated 1990 Nationwide Mercury Emissions for
Selected Source Categories
5-1 In Vitro Genotoxicity of Inorganic Mercury
5-2 In Vivo Genotoxicity of Inorganic Mercury
1-3
1-4
1-7
2-4
2-6
3-2
5-2
5-3
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Number
4-1
LIST OF FIGURES
Relationships between individual daily levels of mercury
in air on hopcalite filters by personal sampler and those
in blood samples taken at lie end of the work shift or
those in urine samples collected the following morning .
4-10
VI
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PREFACE
The Office of Health and Environmental Assessment has prepared this health assessment
to serve as a source document for use by the Office of Air Quality Planning and Standards to
support their information needs on the health effects of mercuric chloride, which is listed as a
hazardous air pollutant in the Clean Air Act Amendments of 1990.
In the development of this assessment document, the scientific literature through August
1993 has been inventoried, key studies have been evaluated, and summary/conclusions have
been prepared so that the chemical's toxicity and related characteristics are qualitatively
identified. Observed effect levels and other measures of dose-response relationships are
discussed, where appropriate, so that the nature of the adverse health responses is placed in
perspective with observed environmental levels.
Information regarding sources, emissions, ambient air concentrations, and public
exposure has been included only to give the reader a preliminary indication of the potential
presence of this substance in the ambient air. Although the available information is presented
as accurately as possible, it is acknowledged to be limited and dependent in some instances on
assumption rather than specific data. Appropriate information regarding sources, emissions,
and ambient air concentrations is needed to provide additional information for drawing
regulatory conclusions regarding the extent and significance of public exposure to this
substance.
VII
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
The original author of this document was Kathleen M. Thiessen, Ph.D., Chemical
Effects Information Branch, Information Research and Analysis Division, Oak Ridge National
Laboratory, P.O. Box X, Oak Ridge, Tennessee 32381. It was updated by the current U.S.
Environmental Protection Agency (EPA) project manager (Dr. Gift), principally to include
new (1989 through 1993) studies.
The EPA project manager for this document was David E. Weil, Ph.D. (through 1989),
and is currently Jeffrey S. Gift, Ph.D., Environmental Criteria and Assessment Office, Office
of Health and Environmental Assessment, MD-52, Research Triangle Park, NC 27711.
Peer Reviewers
Earlier drafts of this document were reviewed by the following individuals:*
Dr. Michael Bolger
Food and Drug Administration
Washington, DC
Dr. Robert Gosselin
Dartmouth Medical School
Hanover, NH
Dr. Robert Goyer
National Institute of Environmental
Health Sciences
Research Triangle Park, NC
Dr. Jeffrey Robinson
DeWitt, NY
*Peer reviewers were selected on the basis of their recognized expertise and contribution to the
scientific literature on mercuric chloride.
IX
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1. SUMMARY AND CONCLUSIONS
Mercuric chloride (HgCl2) is one. of the more important inorganic mercury (Hg)
compounds. A white crystal or powder at room temperature, HgCl2 has been widely used in
medicine, agriculture, and chemistry. Although most agricultural and pharmaceutical uses of
mercury compounds have been discontinued in the United States in recent years, HgCl2 is
still used as a disinfectant or pesticide. It is also a useful catalyst or reagent in various
chemical reactions.
The chemistry of HgCl2 must be considered in the.context of mercury chemistry in
general, as the various species of mercury (Hg°, Hg2+, Hg22+, and organic mercury) are
interchangeable in environmental or biological situations. In other words, mercury entering
an environmental system in one form (e.g;, Hg2+ in HgCl2) may be changed, in that system,
into a different form (e.g., CH3HgCl) with a different level or type of toxicity. A significant
feature of mercury chemistry in general (including HgCy is the strong affinity of mercury
for sulfur and sulfhydryl groups. The binding or complexing of mercury to .sulfhydryl groups
of enzymes and other proteins is of central importance in many of the biochemical effects of
mercury compounds.
Specific figures for the production, use, and emission of HgCl2 are not available.
Figures are available for total mercury use and emission by various types of industries in the
United States, and, from the figures given for those industries that are known to use HgCl2,
an estimate of 138 metric tons was obtained for 1991 use of HgCl2. Mercuric chloride may
be released into the atmosphere from natural sources (e.g., geothermal activity) and
anthropogenic sources (e.g., fossil fuel combustion, municipal waste incineration, or
industries using HgCy. An estimate of 332 metric tons/year was obtained for combined
Hg° and HgCl2 atmospheric emissions in 1990 in the United States from anthropogenic
sources.
Mercury, particularly elemental mercury vapors, can be transported great distances in
the atmosphere and, when reentrainment is considered, has an effective residence time of up
to 3 years. The major route of mercury removal from the atmosphere is probably rainfall.
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Divalent mercury may be transformed into elemental or organic mercury in the air, water,
and soil.
Total atmospheric mercury levels vary with the degree of industrialization and proximity
to various natural and anthropogenic point sources. Estimated average background levels at
3,900 sites indicate that total atmospheric mercury is 1 to 2 ng Hg/m3 in rural areas and
10 to 20 ng/m3 in urban areas. Little specific information is available on the background
concentration of HgCl2 in the air, although HgCl2 may account for 1 to 25% of the total
atmospheric mercury, depending on the location.
Approximately 20,000 people in the United States are exposed to HgCl2 through
occupational use of the compound. The Occupational Safety and Health Administration
(OSHA) recommends an exposure ceiling of 0.1 mg Hg/m3 air for aryl and inorganic
mercury, and the American Conference of Governmental Industrial Hygienists (ACGIH)
o
recommends a time-weighted average (TWA) exposure of 0.1 mg Hg/mr for aryl and
inorganic mercury. Exposure of a working adult to 0.1 mg Hg/m3 as HgCl2 would mean a
maximum inhalation of 1.35 mg HgCl2/day (1.0 mg Hg/day), assuming a breathing rate of
10 m3/work shift with 1 shift/day and no additional exposures. Assuming an average
breathing rate of 20 m3/day and a background level of 10 ng Hg/m3 in an urban area, a
nonoccupationally exposed adult could inhale 200 ng Hg/day, including up to 52 ng HgCl2
(38 ng Hg or 19% of the total mercury). Exposure to mercury also occurs through inhalation
of elemental mercury released from dental amalgam restorations and ingestion of inorganic
mercury through corrosion of amalgam material into saliva (essentially, no mercury is
absorbed following ingestion of elemental mercury). The estimated average intake of
inorganic mercury (principally HgCl^ for an adult from air, food, water, and dental
amalgam restorations is between 3,900 and 24,600 ng Hg/day (3.9 to 24.6 ^g Hg/day); the
absorbed dose of inorganic mercury is between 300 and 2,500 ng Hg/day (0.3 to 2.5 fig,
Hg/day). Summaries of official standards for airborne mercury and estimated human intake
of various forms of mercury are given in Tables 1-1 and 1-2, respectively. Other potential
sources of nonoccupational human exposure to inorganic mercury compounds include skin
ointments, surgical antiseptics, and accidental poisoning.
1-2,
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TABLE 1-1. SUMMARY OF OFFICIAL STANDARDS FOR AIRBORNE MERCURY
Standard
Source
Federal standard
(OSHA)
0.10 mg Hg/m3, ceilinga, aryl and inorganic mercury
0.01 mg Hg/m3, TWA, organic mercury
0.03 mg Hg/m3, ceiling, STEL, alkyl mercury
A
A
A
ACGIH
fj
0.05 mg Hg/m , TWA, mercury vapor, all forms
except alkyl mercury
0.01 mg Hg/m3, TWA, alkyl mercury
0.03 mg Hg/m3, STEL, alkyl mercury
0.10 mg Hg/m3, TWA, aryl and inorganic mercury
B
B
B
B
'Given as 1 mg Hg/10 m3 in the cited publication.
Abbreviations:
ACGIH = American Conference of Governmental Industrial Hygienists.
OSHA = Occupational Safety and Health Administration.
STEL = Short-term exposure limit (15 min).
TWA = Time-weighted average (8 h).
Sources:
A = Code of Federal Regulations (1992).
B = American Conference of Governmental Industrial Hygienists (1992).
Little specific information is available on the absorption of inhaled HgCl2; the estimate
generally used is 80%, although 40% absorption has been estimated in dogs. Less than 20%
of ingested HgCl2 is absorbed from the gastrointestinal tract, and 7% is the estimate used by
both the U.S. Environmental Protection Agency (EPA) and the World Health Organization
(WHO). Some HgCl2 also may be absorbed through the skin, but the major route of human
exposure to HgCl2 is via the gastrointestinal tract.
The distribution of mercury compounds in the body and within organs is dependent on
the dose and type of mercury received, the time elapsed since the dose was received, and the
metabolic parameters of binding and reaction. Most divalent mercury is concentrated in the
kidneys. Divalent mercury does not readily cross either the placenta! or blood-brain barriers,
and relatively little mercury accumulates in the brain following exposure to divalent mercury
as compared with exposure to elemental or organic mercury.
Total body burden of mercury has been estimated to be 13 mg, or 0.19 mg/kg (wet
weight) for a 70-kg man. People from urban populations have been found to contain
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fc
,
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statistically higher levels of mercury than people from rural populations. The normal upper
limit for blood mercury levels is 10 to 30 jwg Hg/L blood. The highest mercury
concentrations in the body are generally found in the kidneys. Normal kidney levels of
mercury are usually below 2.8 mg Hg/kg. The normal upper limit for mercury in urine is
25 to 30 /*g Hg/L; urinary mercury levels are more closely related to blood levels than to
kidney levels. The half-life of inorganic mercury in the human body is between 1 and 2 mo,
although for certain organs, particularly the kidneys and brain, the retention times are
somewhat longer. The major route of removal of inorganic mercury is via the urine,
although the feces are also important.
Mercuric chloride is mutagenic in various experimental systems;' however, cytotoxicity
usually occurs at HgCl2 levels sufficient to produce mutations or chromosome aberrations.
Mercuric chloride does damage DNA, producing both single-strand breaks and DNA-DNA
cross-links. Mercuric chloride inhibits spindle polymerization resulting in numerical
chromosome aberrations (aneuploidy). No epidemiological studies are available that assess
the potential carcinogenicity of HgCl2. The only adequate carcinogenicity study of HgQ2 is
a 2-year study of rats and mice that were administered HgCl2 by gavage. The forestomach of
male rats exposed to 2.5 and 5 mg/kg/day, 5 days/week after 15 mo developed basal cell
hyperplasia, which became extensive after 2 years. Focal papillary hyperplasia and squamous
cell papillomas of the forestomach also were noted at 2 years. The National Toxicology
Program (NTP) also reported an increased incidence of thyroid follicular cell adenomas and
carcinomas in male rats, which may have been related to HgCl2 exposure. Squamous cell
papillomas also were observed in high-dose group female rats. The NTP reported "some
evidence" of carcinogenic activity in male rats and "equivocal evidence of carcinogenic
activity" in female rats related to administration of HgQ2. The incidence of forestomach
neoplasms in male and female mice were within the range of historical controls and could not
be regarded as evidence of carcinogenic activity. However, NTP noted "equivocal evidence
of carcinogenic activity" in male mice based on the occurrences of two renal tubule adenomas
and one renal tubule adenocarcinoma. The EPA considered the relevant information for
HgCl2 and other mercuric salts and has assigned inorganic mercury a preliminary "C"
classification, Which means that inorganic mercury is considered a "possible human
carcinogen". This classification is considered preliminary because it has not yet been posted
1-5
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on the EPA Integrated Risk Information System (IRIS) database. The study of male rats
provides the principal evidence for a carcinogenic effect from HgCl2 exposure. However,
high mortality in male rats from severe renal disease suggests that the potential toxicity of
HgCl2 may pose a greater hazard than its potential carcinogenicity.
Oral HgCl2 exposures in the range of 1 to 4 mg/kg can affect various aspects of
reproduction and development in experimental animals. Reported effects include delayed
ovtilation, decreased male fertility, and inhibited development of embryos. The compound is
highly toxic to embryos, especially before the development of the placenta. Divalent mercury
does not readily cross the placenta, although it does accumulate in the placenta. The
disruption in placental function and ensuing embryotoxicity caused by both in vivo and
in vitro exposure to HgCl2 provide sufficient evidence that this agent is a developmental
toxicant in experimental animals. No specific evidence is available concerning reproductive
or developmental effects of HgCl2 in humans.
Most cases of acute toxicity from HgCl2 in humans have been reported following oral
ingestion of the compound. Toxic effects include corrosive action on the gastrointestinal
tract, followed by renal failure due to necrosis of the proximal tubular epithelium. The mean
lethal oral dose for an adult is 1 to 4 g, which corresponds to a blood concentration of about
15 mg Hg/L. The lowest kidney mercury concentration reported for a fatal case of mercury
poisoning is 16 mg/kg wet weight.
The most important result of chronic oral exposure to HgCl2 alone is kidney damage,
either by necrosis of the proximal tubule or by an autoimmune reaction. A specific form of
mercury hypersensitivity called acrodynia or pink disease is occasionally found in children.
A genetic component is involved in autoimmune responses to mercury, at least in
experimental animals. Neurotoxicity is also a potential risk following chronic exposure to
divalent mercury, especially in cases of exposure to mixtures of mercury species.
The binding of divalent mercury to sulfhydryl groups and other biological ligands is
responsible for most of the biochemical effects of HgCl2. Mercuric chloride has been found
to inactivate many enzymes, induce other enzymes, inhibit polymerization of microtubules,
affect membrane permeability, and alter many aspects of cellular and subcellular metabolism.
Many of the adverse effects of divalent mercury probably occur as a result of general
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metabolic disruption and toxicity to cells and tissues. A summary of some dose-effect
relationships of HgCl9 in mammalian systems is given in Table 1-3.
TABLE 1-3. SUMMARY OF EFFECTS OF MERCURIC CHLORIDE (HgCl2) ON
MAMMALS OR MAMMALIAN CELLS
Population Studied
Dose (HgClj)
Effect
Source
Humans
General population
Acute oral dose, > 0.5 g mean,
1 to 4 g
Lethal
G
Children
Dose not certain; usually
associated with chronic Hg
exposure and with urine Hg
levels >50 /tg Hg/L
Acrodynia in about 1 in A,C
500 (hypersensitive reaction?)
Lymphocytes,
in vitro
108 /ig/L (0.4
270 /ig/L (1 jiM)
1.4 mg/L (5
2.7 mg/L (10
Increased sister chromatid L
exchange O,P
No effect (C-mitosis or
chromosome aberrations)
Chromosome aberrations
C-mitosis
P
O
Animals. Inhalation Studies
Mice
Pregnant females
0.23 mg/m3, aerosol (no
MMAD given) 4 h/day on
Gestation Days 9-12
Chromosome aberrations
(structural and numerical),
retarded growth, and skeletal
abnormalities in embryos
M
Brown Norway rat
Male and female
200 to 240 /ig/kg/week, aerosol,
2 mo (estimate of minimum
air concentration is 1 mg HgCl2/m3,
1 h/day, 4 days/week for 2 mo)
Autoimmune disease
B
Animals. Other In Vivo Studies
F344 rat
Male
2.5 mg/kg/day, 5 days/week,
104 weeks, gavage
Increased mortality,
chronic nephropathy,
forestomach hyperplasia, and
squamous cell papillomas
F344 rat
Male and female
5.0 mg/kg/day, 5 days/week,
104 weeks, gavage
Increased mortality, 5
forestomach hyperplasia,
squamous cell papillomas, and
nasal mucosa inflammation
B6C3F1 mice
Male and female
5.0 mg/kg/day, 5 days/week,
104 weeks, gavage
Nephropathy
Brown Norway rat
Male and female
60 /ug/kg/week, intratracheal
instillation, 2 mo
No effect on kidney
B
Brown Norway rat
Male and female
110 /ig/kg/week, intratracheal
instillation, 2 mo
Autoimmune disease
B
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TABLE 1-3 (cont'd). SUMMARY OF EFFECTS OF MERCURIC CHLORIDE (HgCl2)
ON MAMMALS OR MAMMALIAN CELLS
Population Studied
Dose
Effect
Source
Animal. Other In Vivo Studies (cont'd)
Brown Norway rat
Female
2.00 mg/kg/week, im, 39 weeks Autoimmune disease
Brown Norway rat
Male and female
3.00 mg/kg/week, oral,
2 mo
Autoimmune disease
B
Mouse embryos
< 1.35 mg/kg, iv dose to mother
1.35 mg/kg, iv dose to mother
No effect
Embryotoxicity in vivo
H
Syrian hamster
Female
8.6 mg/kg, sc, single dose
3 to 4 mg/kg/day, sc,
during estrous cycle
Chromosome aberrations
(bone marrow cells)
Delayed or reduced ovulation
Q, U
Mice
Male
Rats
Male
1.35 mg/kg, ip, smgle dose
0.025 /ig/kg/day, oral,
12 mo
No dominant lethals
No dominant lethals
K
N,R
0.25 jig/kg/day, oral
12 mo
Dominant lethals
Aairnals. In Vitro Studies
Chinese hamster
CHO cells
Rat embryos
270 /tg/L (1 pM)
<2.7mg/L(<10/tM)
2.7 mg/L (10 jtM)
270 /tg/L (1 /*M)
Slows cell growth
Inhibition of DNA
repair and replication
Chromosomal aberrations
DNA damage, cell death
CNS abnormalities
F
D,E
T
D,E
I
Sources:
A = Berlin (1986).
B = Bemaudin et al. (1981).
C = Bilderback and Anderson (1975).
D = Cantoni and Costa (1983).
E = Christie et al. (1986).
F « Costa et al. (1982).
G = Gosselin et al. (1984).
H = Kajiwara and Inouye (1986a).
I = Kitchin et al. (1984).
J = Knoflach et al. (1986).
K - Lee and Dixon (1975).
L = Morimoto et al. (1982).
M = Selypes et al. (1984).
N = Vasil'eva et al. (1982).
O = Verschaeve et al. (1984).
P = Verschaeve et al. (1985).
Q = Watanabe et al. (1982).
R = Zasukhina et al. (1983).
S = National Toxicology Program (1993).
T = Howard et al. (1991).
U = Mattison et al. (1983).
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The literature contains two studies on the effects of inhalation exposure to HgCl2 on
experimental animals. Bernaudin et al. (1981) studied autoimmune disease in rats induced by
intratracheal installation (60 to 750 ^g/kg/week) for 2 mo and aerosol administration of
5 mL of a 1% HgCl2 solution 1 h/day, 4 days/week for 2 mo. The aerosol exposure
resulted in a retention of 50 to 60 ^g HgCl2/kg/h. Assuming a rat hourly breathing rate of
0.044 m3/kg/h (U.S. Environmental Protection Agency, 1988b), the air concentration in the
chamber is estimated to have been at least 1,140 fig HgCl2/m3, (50 fig/kg/h •*• 0.044
m3/kg/h = 1,140 jug/m3) or roughly 1 mg HgCl2/m3. Evidence of autoimmune disease was
noted for all but the lowest intratracheal exposure (60 /tg HgCl2/kg/week). Selypes et al.
(1984) found embryotoxic effects in rats exposed to aerosols of 230 ftg HgCl2/m3 for 4 h/day
for 4 days during pregnancy.
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2. INTRODUCTION
This report is intended to provide a brief review of the available information on the
potential health effects associated with exposure to mercuric chloride (HgCy. The major
interest is in potential health effects on the general public from exposure to ambient airborne
concentrations of HgCl2. Sources, distribution, fate, and ambient levels of mercuric chloride
are reviewed. Data concerning the pharmacoMnetics, mutagenicity, carcinogenicity,
teratogenicity, and acute and chronic toxicity of HgCl2 are discussed. Mercuric chloride,
elemental mercury (Hg), and the numerous other mercury compounds are closely interrelated
in terms of their chemistry, their environmental distribution and impact, and their health
effects. The distribution and potential health effects of HgCl2 therefore must be considered
within the broader context of mercury and mercury compounds in general, with particular
attention given to information dealing specifically with HgCl2.
Mercury is not a particularly abundant element, constituting about 2.7 x 10"6 percent of
the earth's crust and ranking 74th in abundance of all the elements (Goldwater and Clarkson,
1972). It is found in a number of different minerals (Nriagu, 1979a, lists 24 principal
minerals), although only one, cinnabar (HgS), is of great commercial importance. Most of
the world's supply of mercury comes from mines in Spain, Yugoslavia, Italy, the Soviet
Union, China, Mexico, and the United States (Nriagu, 1979a). United States mercury
reserves are located primarily in California and Nevada (SRI International, 1983; Nriagu,
1979a).
Elemental mercury is the only metal that exists as a liquid at room temperatures
(melting point -38.9 °C, boiling point 356.6 °C; Berlin, 1986), and it is quite volatile, as
are many of its compounds (Singer and Nowak, 1981). Mercury in inorganic compounds
exists in one of two oxidation states, +1 (mercurous, Hg22+) or +2 (mercuric, Hg2+).
Organic mercury compounds contain only the +2 form, bound covalently as either R-Hg+ or
R-Hg-R1, where R and R' are organic moieties. Mercuric chloride, Hg22+, and Hg2+ can
all be found in an aqueous solution containing mercury; the representation at equilibrium of
each oxidation state is determined by the redox potential of the solution and the presence of
compounds that form complexes with the ions (Berlin, 1986).
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One distinguishing characteristic of mercury chemistry in general is the tendency of
mercury to form covalent rather than ionic bonds (Andren and Nriagu, 1979). Halide salts
such as HgCl2 do not ionize readily, and Hg-C bonds (in organic mercury compounds) are
stable. Another important chemical feature is that elemental mercury can be readily oxidized
to Hg22+ and Hg2+ in some environmental or biological situations, and in others, Hg2+ is
reduced to Hg22+ or free Hg° (U.S. Environmental Protection Agency, 1984a). In the
presence of sulfhydryl groups, Hg22+ undergoes disproportionation to Hg° plus Hg2+
(Berlin, 1986). Certain microbial systems also produce methyl mercury (monomethyl
mercury, CH3Hg+) compounds from Hg2+ (U.S. Environmental Protection Agency, 1984a).
Methyl mercury is probably the most toxic to humans of any of the mercury compounds.
The significance of these reactions is that mercury may enter the environment or a given
system in one form (e.g., Hg2+ in HgCLj), but, once there, it may be changed into a
different form (e.g., CH3HgCl) having a different potency or type of toxicity. A third major
characteristic of mercury chemistry is the affinity of mercury and many mercury compounds
for sulfur and sulfhydryl groups. The term "mercaptan" was first used by Zeise in 1834 to
describe a particular sulfur-containing compound having a strong affinity for mercury
(Goldwater, 1972); "mercaptan" or "mercapto" is now used for any thiol or sulfhydryl group,
and "mercaptide" for a metallic salt of a mercaptan. Most of the biochemical effects of
mercury or mercury compounds are caused by the binding of the mercury to sulfhydryl
groups on various proteins (Berlin, 1986; Goldwater, 1972).
Mercuric chloride, also known as corrosive sublimate, traditionally, has been one of the
most important of the many inorganic mercury compounds for use in medicine, agriculture,
and chemistry. Existing as white crystals or powder at room temperature, it is one of two
chloride salts of mercury; the other is mercurous chloride (Hg2Cl2), or calomel. Mercurous
chloride, like most mercurous salts, is nearly insoluble in water (0.002 g/L), and probably
for that reason has a very low toxicity compared to HgCl2 (solubility in water, 71.5 g/L at
25 °C; Singer and Nowak, 1981). Mercuric chloride is essentially a covalent molecule
(Carty and Malone, 1979; MacGregor and Clarkson, 1974). Up to 1,000 °C, gaseous HgCl2
consists of linear monomers (Cl-Hg-Cl) (Carty and Malone, 1979). The predominant species
in aqueous solution is undissociated HgCl2 (Carty and Malone, 1979; Brodersen, 1977),
although three other complexes of divalent mercury with chloride ions also exist, including
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HgCl+, HgCl3-, and HgCl42- (Berlin, 1986; MacGregor and Clarkson, 1974). The serum
concentrations of HgCl2, HgCl3", and HgCl42" are almost equal at normal serum chloride ion
concentrations (MacGregor and Clarkson, 1974; see also Carty and Malone, 1979).
In contrast to some other mercuric compounds, HgCl2 is not a good source of free Hg2+ in
solution (Carty and Malone, 1979).
The vapor pressure of HgCl2 is 0.1 mm Hg at 100 °C and 3 mm Hg at 150 °C, and it
sublimes at about 300 °C (Singer and Nowak, 1981). The vapor pressure of HgCl2 is less
than or nearly equal to that of elemental mercury at temperatures below approximately
180 °C; above 180 °C, HgCl2 has a higher vapor pressure than does mercury (compare
values for mercury and HgCl2 in Weast et al., 1986; Singer and Nowak, 1981; Hayes, 1982;
and Anonymous, 1978). Mercuric chloride vapor has a high density (9.8 g/cm3) and
dissipates slowly (Singer and Nowak, 1981). Some important chemical and physical
properties of HgCl2 are summarized in Table 2-1.
The major uses for mercury (all forms) include electric lighting, wiring devices and
switches, batteries, chlor-alkali production, paint manufacture, chemical and allied
production, measuring and control equipment, dental equipment and supplies, and laboratory
uses. Of these, the principal uses for mercuric chloride include batteries (as raw material in
the manufacture of dry-cell batteries), paint (as a preservative agent), and chemical and allied
product production (e.g., as a catalyst in organic synthesis or in the preparation of other
mercury compounds). From 1989 to 1991, however, there was significant change in the
overall demand for mercury among these industries (see Table 2-2). The most dramatic
change occurred in the paint industry where demand dropped from 211 tons in 1989 to 7 tons
in 1991. Prior to 1991, much larger amounts of mercury were used in paint to preserve the
paint film from mildew after the paint is applied to a surface. As of May 1991, all
registrations for mercury biocides used in paints were canceled voluntarily by the registrants,
thus causing a drastic decrease in the use of mercury in paint (U.S. Environmental Protection
Agency, 1993b).
Prior to the late 1980s, most primary batteries and some storage batteries contained
mercury in the form of mercuric oxide (HgO), zinc amalgam (Zn-Hg), mercuric chloride
, or mercurous chloride (Rg2Cl^). As indicated in Table 2-2, from 1989 to 1991,
2-3
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Property
TABLE 2-1. PHYSICAL AND CHEMICAL PROPERTIES OF
MERCURIC CHLORIDE
Source
Code Numbers:
CAS Registry Number: 7487-94-7
RTECS Number: NIOSH/OV9100000
NCI-C60173; UN 1624; TL 898
MEDLARS H (HSDB) (1987)
MEDLARS H (RTECS) (1986)
Keith and Walters (1985)
Chemical Name:
Mercuric chloride; mercury (II)
chloride
Weast et al. (1986)
Windholz et al. (1983)
Common Synonyms:
Mercuric bichloride; mercury bichloride;
mercury chloride [HgClJ; mercury
dichloride; mercury perchloride;
dichloromercury; bichloride of mercury;
perchloride of mercury; corrosive mercury
chloride; corrosive sublimate; fungchex;
MC; calochlor
MEDLARS H (HSDB) (1987)
MEDLARS H (RTECS) (1986)
Weast et al. (1986)
Keith and Walters (1985)
Windholz et al. (1983)
Weiss (1980)
Chemical Formula: Cl2Hg (HgClj)
Molecular Weight:
Composition, wt %:
Physical State:
Melting Point:
Boiling Point:
Heat of Fusion:
Refractive Index:
Specific Gravity:
Vapor Density:
Solubility:3
Water (0 °C)
(20 °C)
(25 °C)
(100 °C)
Alcohol (25 °C)
Ether
Dissociation Constants:
Partition Coefficients:
Diethyl ether
Oils
271.50
Cl, 26.12
Hg, 73.88
Crystals or white granules or powder
276 °C
302 °C
15.3 cal/g
1.859
5.44 (25 °C)
4.44 (280 °C)
9.8 g/cm3
36 g/L
69 g/L
71.5 g/L
480 g/L
330 g/L
250 g/L
pKi - 6.74
pK2 = 6.48
log P = -0.58
log P = -0.46
Weast et al. (1986)
Windholz et al. (1983)
Windholz et al. (1983)
Windholz et al. (1983)
Weast et al. (1986)
Weast et al. (1986)
Weast etal. (1986)'
Weast et al. (1986)
Weast et al. (1986)
Stokinger (1981)
Singer and Nowak (1981)
Weast et al. (1986)
Windholz et al. (1983)
Hayes (1982)'
Singer and Nowak (1981)
Stokinger (1981)
Webb (1966)
Hansch and Leo (1979)
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TABLE 2-1 (cont'd). PHYSICAL AND CHEMICAL PROPERTIES OF
MERCURIC CHLORIDE
Property
Source
Vapor Pressure:11
1.4 X 10'4 mm Hg at 35 °C (solid)
0.1 mm Hg at 100 °C (solid)
1.0 mm Hg at 136.2 °C (solid)
3 mm Hg at 150 °C (solid)
10 mm Hg at 180.2 °C (solid)
40 mm Hg at 212.5 °C (solid)
100 mm Hg at 237 °C (solid)
400 mm Hg at 275.5 °C (solid)
760 mm Hg at 304 °C
Hayes (1982)
Singer and Nowak (1981)
Weast et al. (1986)
Singer and Nowak (1981)
Weast et al. (1986)
Weast et al. (1986)
Weast et al. (1986)
Weast et al. (1986)
Weast et al. (1986)
Odor:
None
Weiss (1980)
Taste:
Metallic
Hayes (1982)
Biological Oxygen
Demand:
None
Weiss (1980)
Softness Parameter
(Chemical Reactivity):
0.064 (Hg2*)
Christie and Costa (1983)
Reactivity:
Does not react with water or with other common materials, stable
during transport. Not flammable, but heat from fire may cause
formation of toxic fumes of HgCl2. Unstable in the presence of
alkalis, decomposed to metallic mercury by sunlight in the
presence of organic matter. Readily reduced to mercurous
chloride or elemental mercury. Coagulates albumin. With
NaOH, produces yellow precipitate. Hg2+ can form stable
complexes or covalent bonds with organic compounds, including
cellular macromolecules.
Christie and Costa (1983)
Windholz et al. (1983)
Hayes (1982)
Weiss (1980)
*HgCl2 is also soluble in acetic acid, pyridine, acetone, formic acid, benzene, glycerol, ethyl acetate, and carbon
disulficle.
bln general, for HgCl2 at temperatures between 0 and 235 °C, log V° = 13.28 - (4541/T) - (0.65)(log T)
— 0.00113 T, where V° is the vapor pressure in mm Hg and T is the absolute temperature and equal to
273.1 + t (°C).
the use of mercury in battery production decreased 69%, and further reductions were
expected in 1992 and 1993 (U.S. Environmental Protection Agency, 1993a).
The figures in Table 2-2 for U.S. consumption of mercury for "other chemical and
allied products" includes catalysts for plastics and miscellaneous catalysts. This entire
category was reported to have consumed 20 tons of mercury in 1991, which represents about
4% of the total mercury consumed in the United States (U.S. Environmental Protection
Agency, 1993a). Mercuric chloride is used as a catalyst in the production of vinyl chloride
2-5
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TABLE 2-2. COMPARISON OF MERCURY DEMAND WITHIN U.S. MERCURIC
CHLORIDE USER INDUSTRIES IN 1989 AND 1991
Industry
Battery
Paint
Other chemical and allied products
Total demand
Mercury Demand,
1989
250 (275)
192(211)
40 (44)
482 (530)
Mg (tons)
1991
78 (86)
6(7)
18 (20)
102(113)
Source: U.S. Environmental Protection Agency (1993a).
(U.S. Environmental Protection Agency, 1993a). Most of the vinyl chloride produced in the
United States (approximately 97.5%), however, is produced via the oxychlorination of
ethylene, a process that does not involve mercuric chloride (SRI International, 1991).
Agricultural use of a number of mercury compounds was suspended by the United
States in 1970 (specifically alkyl mercury compounds used as seed disinfectants and certain
other mercury-based fungicides or slimicides; SRI International, 1983; Singer and Nowak,
1981). Essentially all agricultural use of mercury compounds in the United States was
prohibited in 1972 (Singer and Nowak, 1981), as was pharmaceutical use in 1973 (SRI
International, 1983).
In the United States in 1991, a total of 102 metric tons of mercury (22% of the total
mercury consumption; equivalent to 138 metric tons of pure HgCl2) was used in the
production of chemical and allied products, in battery manufacture, and in paints. This
figure includes most, if not all, of the HgCl2 used in the United States, but it also includes
various other mercury compounds used for these purposes and must therefore be considered a
very rough upper limit for total HgCl2 consumption. Total mercury consumption in U.S.
industries that consume this and other forms of mercury is estimated to have been 520 tons in
1991 (U.S. Environmental Protection Agency, 1993a). The general trend for consumption of
all forms of mercury is downward as efforts are made to decrease mercury emissions, recycle
mercury by-products, and replace mercury compounds and processes involving mercury with
less hazardous substances and processes (U.S. Environmental Protection Agency, 1993a,b).
Although specific figures for the consumption of HgCl2 in the United States are not available,
2-6
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all indicators point to a decline in HgCl2 use over the past several years, concurrent with the
decreased consumption of total mercury.
The OSHA has established a federal occupational exposure standard for mercury of
*3 *3
0.1 mg Hg/m air (1 mg/10 m ) as a ceiling concentration not to be exceeded at any time
during an 8-h shift (Code of Federal Regulations, 1992; official standards for airborne
mercury are summarized in Table 1-1). For organic mercury, a time-weighted-average or
_____ O "3
TWA of 0.01 mg/nr was established, with a short-term exposure limit of 0.03 mg/m . The
American Conference of Governmental Industrial Hygienists (1992) recommended a threshold
limit value (TLV) of 0.05 mg/m3 (TWA) for mercury vapor (all forms except alkyl mercury,
which has a TWA of 0.01 mg/m3 -and a short-term exposure limit of 0.03 mg/m3). For aryl
and inorganic mercury compounds only, a TWA of 0.1 mg/m3 is permitted, although there
may be little or no margin of safety at this level (American Conference of Governmental
Industrial Hygienists, 1992). Occupational standards in other countries are comparable to the
«
United States (e.g., Czechoslovakia and Sweden, 0.05 mg Hg/m [American Conference of
Governmental Industrial Hygienists, 1992]). Although the standards of most countries do not
distinguish between mercury and mercury compounds (e.g., HgCl^, Poland has set a
separate limit of 0.01 mg/m3 for elemental mercury and 0.05 mg/m3 for compounds
(American Conference of Governmental Industrial Hygienists, 1992).
A number of books and review articles are available on the health and environmental
effects of mercury and mercury compounds in general (World Health Organization, 1976,
1990, 1991; Berlin, 1986; U.S. Environmental Protection Agency, 1984a,b, 1985a,b;
Nriagu, 1979b; National Research Council, 1978; Miller and Clarkson, 1973; National
Institute for Occupational Safety and Health, 1973; D'ltri, 1972; Friberg and Vostal, 1972;
Goldwater, 1972; Hartung and Dinman, 1972; International Atomic Energy Agency, 1972).
The occurrences of mercury poisoning in Japan, Iran, and New Mexico provide especially
graphic examples of the hazardous potential of mercury in environmental situations. These
events resulted from mercury contamination of water and of seed-grain accidentally used for
food. The present report, within the limits of available information, details the effects on
human health that can be expected from exposure to HgCl2. Whenever possible, these health
effects of HgCl2 have been correlated with exposure to ambient, airborne concentrations;
2-7
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much of the available data, however, concerns occupational concentrations or oral and
in vitro routes of exposures for experimental animals.
2-8
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3. AIR QUALITY AND ENVIRONMENTAL FATE
3.1 SOURCES
3.1.1 Natural Occurrence
One of the largest sources of airborne mercury is the natural degassing of the earth's
crust, particularly in regions with mercury-rich soils or mineral deposits (World Health
Organization, 1991; Matheson, 1979). Geothermal activity such as volcanoes and hot springs
also contributes mercury to the air (Nriagu, 1989.; Lindqvist and Rodhe, 1985). Natural
emissions of mercury in Hawaii include both gaseous and particulate mercury, and the
gaseous mercury includes both Hg° and Hg2+ (Siegel and Siegel, 1979). The anionic species
accompanying Hg2+ is dependent on regional availability; in Hawaii, HgCl2 and Hg° are the
two biologically significant natural geothermal forms of gaseous mercury. Both mercury
vapor (Hg°) and organic mercury compounds are released to the atmosphere from soils; the
amount varies with soil type and location (Grant et al., 1991; Siegel and Siegel, 1979;
Rogers, 1978). The mercury vapor may be from either accumulated elemental mercury or
the reduction of inorganic mercury compounds by organic matter or organisms. Increased
levels of mercury, as either mercury vapor or organic mercury, are found in the air over soils
to which HgCl2 or other inorganic mercury compounds have been added experimentally
(Matheson, 1979; Rogers, 1978; Johnson and Braman, 1974). Recent estimates indicate that
total natural emissions of mercury are of the order of 2,500 metric tons/year (Nriagu, 1989).
3.1.2 Anthropogenic Sources
Mercury from anthropogenic sources was thought at one time to account for just 25 to
30% of the annual atmospheric mercury worldwide (Matheson, 1979; Miller and Buchanan,
1979; Watson, 1979). Current estimates, however, indicate that anthropogenic sources of
mercury may be responsible for 30 to 75% of the total yearly input to the atmosphere from
all sources, or between 2,000 and 4,500 metric tons/year (Lindqvist et al., 1991; Fitzgerald,
1994). Increasing anthropogenic activities may account for increases in global atmospheric
mercury during the past few decades (Slemr and Langer, 1992). Mercury emissions to the
3-1
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atmosphere are estimated at 332 metric tons/year in the continental United States (U.S.
Environmental Protection Agency 1993a,b). Table 3-1 illustrates the relative contributions of
the most prominent sources to total atmospheric emission of Hg° and HgCl2 in the United
States.
TABLE 3-1. ESTIMATED 1990 NATIONWIDE MERCURY EMISSIONS
FOR SELECTED SOURCE CATEGORIES
Source Category
Mercury Emissions
(tons/year)
Mercury and Mercury Compound Production
Secondary mercury production
Major Uses of Mercury
Chlor-alkali production
Battery manufacture1*
Electrical uses
Combustion Sources
Coal combustion
Oil combustion
Natural gas combustion
Municipal waste combustion"
Sewage sludge combustion
Medical waste combustion*
Wood combustion
Miscellaneous Manufacturing Processes
Portland cement production
Lime manufacturing
Carbon black production
By-product coke production
Primary lead smelting
Primary copper smelting
Petroleum refining
Oil shale restoring
Geothermal power plants
Other Miscellaneous Sources
Mercury catalysts
Dental alloys
Mobile sources
Crematories
Paint
6.3
10.2
0.1
9.9
122.0
14.9
0
63.8
1.8
64.7
0.3
6.2
0.7
0.2
NA
9.0
NA
NA
0
1.4
0
0.6
5.0
0.4
14.6
Total
332.0
"Industries for which a significant fraction of emissions is expected to be HgCl2.
Source: U.S. Environmental Protection Agency (1993a).
3-2
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Anthropogenic sources of atmospheric mercury include mining and smelting operations
(both of mercury and of several other metals); production and consumption of mercury-
containing goods such as paint and batteries; production processes that involve mercury, such
as chlor-alkali production; and the burning of fossil fuels, which contain varying amounts of
mercury. The largest sources of anthropogenic mercury discharges to the environment are
generally point-source emissions such as the burning of fossil fuels (particularly coal) and
refuse incineration. The mercury emitted from the coal combustion process is thought to be
primarily mercury vapor and mercuric oxide (Lindqvist et al., 1991). Metzger and Braun
(1987) and Collins and Cole (1990) have reported that the majority of the mercury emitted
from municipal solid waste incineration (80 to 90%) is in the form of HgC^, with some
mercurous chloride also present. Reduced emissions of mercury are expected as this industry
makes use of spray dryer scrubber, high-efficiency particulate-control devices equipped with
charcoal filters (Rothstein et al., 1991; Lindqvist et al., 1991).
3.2 DISTRIBUTION AND FATE
Simulations of the global mercury cycle have generally shown the atmosphere to be the
primary vehicle for the distribution of mercury at the surface of the earth (Fitzgerald and
Clarkson, 1991; National Research Council, 1978; Lindqvist and Rodhe, 1985). Using
estimated emission factors for different source categories, the overall distribution for
anthropogenic emissions within North America has been calculated to be 81% Hg°, 17%
Hg2+, and 2% particulate mercury (Bloxam and Petersen, 1990). These estimates have been
used to model the long-range transport, transformation, and deposition of mercury (Bloxam
et al., 1991). Mercury emitted from incinerators or power plants as Hg2+ is readily
scavenged and dry deposited. Theoretically, HgCl2 and other mercuric mercury compounds
also may be reduced to mercury in the atmosphere (Schroeder et al., 1990); however, no
experimental studies of such reactions have been performed under conditions relevant to the
atmosphere. Given the low observed values of air Hg2+ and particulate mercury
concentrations, model runs have been performed assuming no net gas-phase chemistry (i.e.,
reduction reactions are assumed to nearly balance oxidation reactions) (Bloxam et al., 1991).
Elemental mercury can be transported great distances in the atmosphere, as is evident from
3-3
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the detection of elevated mercury levels in fish from areas far from any known mercury
sources (Tomlinson and McLean, 1976, cited in Miller and Buchanan, 1979; Fitzgerald and
Watras, 1989; Wiener et al., 1990; see also World Health Organization, 1976).
Atmospheric mercury may be deposited to and revolatilized from both land and water
many times, therefore effectively being recycled. The effective residence time for mercury
vapor in continental air has been estimated to be up to 3 years if this recycling is taken into
account (World Health Organization, 1991; Miller and Buchanan, 1979). Other estimates for
atmospheric residence time, that do not necessarily allow for recycling, range from 5.5 to
90 days (Andren and Nriagu, 1979; Miller and Buchanan, 1979; National Research Council,
1978). Mercuric chloride is probably recycled proportionately less than total mercury
because at least some of the HgQ2 deposited on the land or in water is transformed to Hg° or
organic mercury. This would result in a shorter effective atmospheric residence time for
HgCl2 than for total mercury.
Precipitation is thought to be a major route for removal of mercury from the air.
However, dry deposition of Hg° and Hg2+ does occur to a lesser extent. Recent studies
suggest there is a measurable dry deposition rate of mercury to forests (Lindberg et al., 1991,
1992), which increases in the summer («0.03 cm s"1) and decreases in the winter
(-0.001 cm s'1).
Both inorganic and organic forms of mercury are subject to conversion in the
environment (particularly in water or soil) by either chemical and physical or biologically
mediated processes (World Health Organization, 1990). Ionic mercury (Hg2+) can be
formed in the environment by oxidation of metallic mercury vapor (Hg°) or by the
breakdown of various organic mercury compounds. The ionic mercury, depending on local
conditions such as the presence of certain bacteria, can be reduced to elemental mercury,
form complexes and chelates with organic materials, or be converted to methyl mercury and
other organic mercury compounds. Aqueous Hg(OH)2 is reduced when irradiated with
simulated sunlight; however, HgCl2 is stable under these conditions (Munthe and McElroy,
1992).
These conversion reactions can have a significant effect on the distribution of mercury
species, particularly on the local level. Perhaps, the most important of these processes is the
methylation of inorganic mercury by bacteria in aquatic sediments. Methyl mercury
3-4
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compounds, which are probably the most toxic forms of mercury to man, accumulate in fish
in mercury-polluted waters, no matter what the actual mercury species might be (U.S.
Environmental Protection Agency, 1979; World Health Organization, 1990). The ratio of the
methyl mercury concentration in fish tissue to the concentration of inorganic mercury in
water is usually between 10,000 and 100,000 to one (World Health Organization, 1991).
Divalent inorganic mercury (e.g., in HgCy will not necessarily remain as divalent inorganic
mercury, but may be transformed in the environment to elemental or organic mercury,
including methyl mercury compounds.
3.3 AMBIENT LEVELS
Atmospheric mercury levels over nonmineralized (i.e., non-ore-bearing) rural areas
range from < 0.005 to 2 ng/m3 (mean, 0.15 ng/m3) particulate mercury and 1 to 10 ng/m3
(mean, 4.0 ng/m3) total volatile mercury (Grant et al., 1991; Schroeder, 1982; Matheson,
1979; National Research Council, 1978). Total gaseous mercury over the Atlantic Ocean
(7 to 54° N) ranged from 1 to 2.6 ng/m3 (mean, 1.763 ng/m3) in October 1977 to 1.41 to
3.41 ng/m3 (mean, 2.247 ng/m3) in October 1990 (Slemr and Langer, 1992), reflecting an
increase of about 1.46 + 0.17%/year. Total mercury levels (particulate + volatile) in
ore-bearing terrestrial areas range from 7 to 20 /-eg/m3 and in volcanic areas from 20 to
37 ptg/m3 (Schroeder, 1982; National Research Council, 1978). Particulate mercury levels in
urban areas range from <0.01 to 220 ng/m3 (mean, 2.4 ng/m3) and volatile mercury levels
from 0.5 to 50 ng/m3 (mean, 7.0 ng/m3). In areas around industrial point sources such as
chlor-alkali plants, thermometer factories, smelters, and mercury mines, total atmospheric
mercury levels up to 5 mg/m3 have been observed (Schroeder, 1982; National Research
Council, 1978). Mercury levels in the air are affected by local variations in mercury
emanations from land or water, distance above ground, wind speed and direction (e.g., from
the direction of a mercury emission source), and ambient temperature. The average or
background concentration of total atmospheric mercury in regions away from point sources
has been estimated to be 1 to 2 ng Hg/m3 air in rural areas (U.S. Environmental Protection
Agency, 1984a) and up to 10 ng/m3 (U.S. Environmental Protection Agency, I984a) or
3-5
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20 ng/m3 (Berlin, 1986) in urban areas. Mean atmospheric mercury concentrations for large
cities in the United States ranged from 10 to 170 ng/m3 (Gerstner and Huff, 1977).
The principal mercury species reported to occur in the atmosphere are elemental
mercury vapor (Hg°), mercuric chloride vapor (HgQ2) and possibly some other volatile
inorganic compounds, organomercury compounds such as methyl mercuric chloride
(CH3HgCl) and dimethyl mercury [(CH3)2Hg], and particulate mercury of unknown chemical
species (Schroeder, 1982). Only a few studies have attempted to distinguish various chemical
forms of mercury in the atmosphere, and most available measurements of atmospheric
mercury content are of particulate mercury alone, mercury vapor or volatile mercury
(of whatever chemical species) alone, or total mercury (particulate + vapor).
The atmospheric mercury in one urban area (Tampa, PL) was found to include, on the
average, 49% Hg°, 25% mercuric halides (including but not limited to HgCl2), 21%
monomethyl mercury compounds, 4% particulate mercury, and 1% dimethyl mercury
(Johnson and Braman, 1974; Matheson, 1979; National Research Council, 1978). The
concentration of mercury as Hg2+ varied from 0 to 220 ng Hg/m3 air, and from 0 to 75% of
total atmospheric mercury (Johnson and Braman, 1974). Due to the age of these reports, the
state-of-the-art at the time, the strong potential for contamination of samples during transport,
and artifacts in sampling media, these data should be viewed cautiously.
As part of more recent work aimed at developing analytical methods for the
determination of mercury species in the atmosphere, Schroeder and Jackson (1985, 1987)
determined gaseous and particulate-phase levels of mercury at four locations (urban and rural
sites influenced by various potential sources of mercury including a coal-fired power plant,
waste incineration operations, and a battery manufacturing plant) in and around Toronto,
Canada, over a 3-week period during the fall of 1981. Using a Barringer mercury monitor,
they determined that elemental mercury comprised 75 to 96%, and mercuric chloride
accounted for just 0 to 3% of total vapor-phase mercury at the four sites. Particulate
mercury accounted for just 0.4 to 3.3% of the total atmospheric mercury at the four sites.
Levels of airborne HgCl2 from 0 to 2.4 ng Hg/m3 were measured. Total mercury levels
varied from 3 to 114 ng/m3. -
In short, atmospheric mercury levels, both of total mercury and of inorganic mercury,
may vary considerably with the degree of industrialization and the proximity to various
3-6
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natural and anthropogenic point sources of mercury. The amount of inorganic mercury
present is probably not a constant fraction of the total amount of mercury. If one assumes
that the total mercury concentration in an urban area is 10 ng/m3 and that an average of 19%
of the mercury is inorganic mercury (Hg2+; U.S. Environmental Protection Agency, 1984a),
o
an estimate of 1.9 ng/m for the average ambient concentration of inorganic mercury is
obtained. If all of the inorganic mercury were HgCl2, this would correspond to an ambient
A
level of 2.6 ng HgCl2/m air. The data of Schroeder and Jackson (1987) suggest that the
actual proportion of airborne mercury present as HgCl2 may actually be considerably lower
(<3%). Information on indoor (nonoccupational) concentrations of mercury or HgCl2 was
not available.
3.3.1 Exposure
Most available studies (and many of the analytical techniques used) fail to distinguish
between various forms of mercury, or at best distinguish only between organic and inorganic
mercury. For this reason, information on exposure to HgQ2 cannot always be separated
from available information on exposure to total mercury or to total inorganic mercury.
However, because of the known interconversions of mercury species in the environment and
the rarity of exposure to a single mercury compound, information on exposure to total
mercury and to the general types of mercury must also be considered in assessing actual or
potential health effects of HgCl2 on humans.
In 1985, the NIOSH estimated that 20,293 people (including 10,062 women) were
exposed to HgCl2 from occupational use of the compound (MEDLARS II, HSDB, 1987).
The NIOSH also estimated that 51,024 people were potentially exposed to HgCl2 through
actual use of HgCl2 (25%), use of trade name products known to contain HgCl2 (1%), or use
of certain types of products that may contain HgCl2 (74%; MEDLARS II, HSDB, 1987).
It is not known what products were involved or whether this figure included people with
occupational exposure to HgCl2. Based on assumptions of an inhalation volume of
10 m3/working day and exposure to mercury at the OSHA limit of 0.1 mg/m3, the maximum
expected inhalation of mercury by an occupationally exposed adult is 1.0 mg of mercury
3-7
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(as elemental or inorganic mercury) in a working day. If all the mercury were in the form of
HgCl2, this would mean a maximum inhalation of 1.35 mg HgCl2/day.
Although local concentrations of mercury and HgQ2 may be very high in some
industrialized areas (up to 5 mg/m3), the general public probably encounters a maximum of
10 to 20 ng total Hg/m3 air in urban areas and as little as 1 to 2 ng/m3 in rural areas (see
Section 3.3). To assess human inhalation exposure to mercury, it would be necessary to
know concentrations in microenvironments, including indoors and relate this to activity
patterns. However, this information is not available. The World Health Organization (1990)
estimates an average daily intake of inorganic mercury by air of 2 ng/day. Total intake of
atmospheric mercury will be considerably higher near point sources, but the proportion of
HgCl2 and therefore the amount of HgCl2 inhaled will depend on the specific type of point
source.
The general public also is exposed to mercury and mercury compounds in drinking
water and food (U.S. Environmental Protection Agency, 1984a, 1985b). The average human
intake of mercury from drinking water has been estimated to be 50 ng/day; this figure is
based on an average mercury concentration in noncontaminated drinking water of 25 ng/L
and a daily water intake of 2 L for an adult (U.S. Environmental Protection Agency, 1984a).
Most of this mercury is thought to be inorganic mercury (Hg2+), although as much as 30%
may be methyl mercury (U.S. Environmental Protection Agency, 1984a).
Food (seafood, in particular, in the case of organic mercury) may be the major source
of mercury for people who are not occupationally exposed to it. The average adult ingests
3,200 ng (3.2 jwg) inorganic and organic Hg/day in their diet (Grant et al., 1991). Grant
et al. (1991) estimate that recreational fishermen may consume as much as 70 /xg/day total
mercury in fish (7jiig as inorganic and 63 jug as methyl mercury) and populations (e.g.,
Native Americans) that rely on fish as their principal food source may consume about
216 jug/day total mercury in fish (21.6 ^g as inorganic and 194.4 \i% as methyl mercury).
Due to the predominant source of mercury in these subpopulations (i.e., freshwater fish from
acidified ponds and lakes), inorganic mercury content is likely less than 10%, and methyl
mercury content is likely to approach 90% of the total mercury (Grant et al., 1991). When
gastrointestinal absorption rates of inorganic and methyl mercury are considered (7 and 90%,
3-8
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respectively), the average adult is found to retain more methyl mercury from food than
inorganic mercury (see Table 1-2).
Another source of exposure to mercury, principally elemental mercury, is dental
amalgam fillings. Amalgams used for dental restorations generally contain approximately
50% mercury at the time of mixing with various silver alloys. The release of elemental
mercury vapor from dental amalgams has been known for over a half a century (World
Health Organization, 1991; Clarkson et al., 1988). Exposure to inorganic mercury, can occur
through corrosion of the amalgam material into saliva or ingestion of amalgam particles
abraded from restored surfaces (U.S. Public Health Service, 1992; Eley and Cox, 1988;
Brune, 1986). -Several reviews document the difficulties associated with making accurate
estimations of the amount of each mercury species released and the resultant mercury uptake
by the human body (Olsson and Bergman, 1992; U.S. Public Health Service, 1992; World
Health Organization, 1991; Berglund, 1990; Clarkson et al., 1988). Factors that influence
the release of mercury include bruxism (i.e., teeth grinding), chewing, number of amalgams,
and the use of sealants. Estimates of daily mercury absorption from dental amalgam
restorations range from 1.2 to 29 ^g for mercury vapor and 0 to 2 jig for inorganic mercury
(U.S. Public Health Service, 1992; Olsson and Bergman, 1992; World Health Organization,
1990).
Ranges of estimates from recent EPA, WHO, and U.S. Public Health Service
documents for daily intake and retention of total mercury and mercury compounds by the
general population (not occupationally exposed) are depicted in Table 1-2. These estimates
indicate that the hypothetical adult would have an estimated total daily intake of between
5.7 and 63 ^g Hg/day, including 3.9 to 24.6 /zg Hg/day as inorganic mercury, 1.5 to
36 /^g/day as Hg°, and 0.3 to 2.4 jug/day as methyl mercury. The estimated amount of
mercury absorbed will be considerably less: 0.26 to 1.7 ng Hg as inorganic mercury, 1.2 to
29 /tg Hg°, and 0.3 to 2.3 /Ltg organic mercury, for a total of 1.8 to 33 /tg Hg absorbed/day.
If all of the inorganic mercury is assumed to be HgCl2, this amounts to an estimated intake
of between 5.3 and 33 /*g HgCl2/day for an adult; the amount of absorbed HgCl2 is between
0.4 and 2.3 /*g HgCl2/day. For a 70 kg adult, the estimated total absorbed dose of inorganic
mercury would be 4 to 24 ng Hg/kg/day, or 6 to 33 ng HgCl2/kg/day if all the inorganic
mercury were in the form of HgCl2.
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Some people also are exposed to HgCl2 or other mercury compounds through the use of
various skin ointments (Bourgeois et al., 1986; Dyall-Smith and Scurry, 1990) and soaps
(Lauwreys et al., 1987). United States Food and Drug Administration regulations limit the
concentration in bleaching creams to 0.2% (Burge and Winkelmann, 1970). Peritoneal
lavage with HgCl2 solutions (0.1 to 0.2%) has been used in some types of cancer surgery in
an effort to prevent recurrence of the cancer (Gelister et al., 1985; Laundy et al., 1984;
Umpleby and Williamson, 1984; Dick, 1983; Elliott and Dale, 1983; Lai et al., 1983).
Several cases of mercury poisoning (including several fatalities) have resulted from this
practice; for this reason and because HgCl2 is not the most effective agent for killing cancer
cells, this use of HgCl2 has been discontinued (Gelister et al., 1985; Laundy et al., 1984;
Dick, 1983; Elliott and Dale, 1983; Lai et al., 1983). Accidental ingestion of HgCl2 does
occur occasionally, however, and can be fatal (Giunta et al., 1983; Stack et al., 1983;
Samuels et al., 1982; Winek et al., 1981).
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4. PHARMACOKINETICS
4.1 ABSORPTION
Specific information on the absorption of inhaled inorganic mercury compounds such as
HgQ2 is lacking, although absorption of approximately 40% is estimated in dogs (Clarkson,
1989). The EPA assumed a retention factor of 0.8 (80%) for all forms of nonparticulate
mercury (elemental mercury vapor, inorganic ionic mercury, and methyl mercury
compounds) in estimating mercury dosages from inhalation (U.S. Environmental Protection
Agency, 1984a). Inhalation of suspended dusts or aerosols of inorganic mercury compounds
can also occur (most likely in an occupational setting), and deposition and absorption of
mercury is then dependent primarily on the size of the particles and the solubility of the
compounds involved (Chang, 1980; Gerstner and Huff, 1977).
Absorption of mercuric compounds from the mammalian gastrointestinal tract is
generally less than 20% and may be as low as 2%, depending at least in part on the solubility
of particular compounds (Berlin, 1986; Sin et al., 1983; Chang, 1980; Gerstner and Huff,
1977; Clarkson, 1972, 1973). Up to 15% of mercury administered as protein-bound
mercuric nitrate was retained by human volunteers (Chang, 1980; Clarkson, 1972). The EPA
has used estimates of 10% (U.S. Environmental Protection Agency, 1984a) and 7% (U.S.
Environmental Protection Agency, 1988a) absorption of inorganic mercury from water or
food sources. These estimates were based on studies that may not have accounted adequately
for possible rapid excretion of absorbed mercury during the experimental period. Nielsen
(1992) has estimated an absorption rate of 20% from whole body retention data obtained
from mice given single oral doses at two different dose levels. Regardless of the absorption
rate assumed, food provides most of the inorganic mercury absorbed by a typical
nonoccupationally exposed person. Gastrointestinal absorption of HgCl2 in rats is dependent
on pH (increased absorption with increased pH) and on the region of the gastrointestinal tract
involved, and it seems to be correlated with binding to an unknown protein (Endo et al.,
1984, 1986). Absorption of HgCl2 may be increased at high doses due to its corrosive action
on the gastrointestinal tract (Berlin, 1986; Gerstner and Huff, 1977). Increased absorption of
inorganic mercury compounds and other heavy metals from the gastrointestinal tract has also
4-1
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been observed in suckling animals, including nonhuman primates, but similar data are not
available for humans (Berlin, 1986; Lok, 1983; Webb, 1983; Walsh, 1982; Jugo, 1979).
Absorption of HgCl2 or other mercuric compounds across the skin has also been
demonstrated (Baranowska-Dutkiewicz, 1982; Chang, 1980; Gerstner and Huff, 1977; Burge
and Winkelman, 1970). Available information from animal studies indicates that up to 6 or'
8% of HgCl2 may be absorbed (Berlin, 1986; Chang, 1980), and the rate of absorption is
related to concentration and inversely related to time (Baranowska-Dutkiewicz, 1982). Skin
exposure to mercury compounds may occur with solutions, ointments, and suspended dusts or
aerosols, but, especially for the latter source, the relative importance of skin exposure versus
inhalation has not been established.
The major route of exposure to elemental mercury is inhalation of the vapor, of which
about 70 to 80% may be absorbed (Berlin, 1986; Cherian et al., 1978, Gerstner and Huff,
1977). Although elemental mercury can be absorbed through the skin (Winship, 1985), this
is probably a far less important route of exposure than is inhalation (Berlin, 1986; Gerstner
and Huff, 1977). Essentially, no mercury is absorbed from the gastrointestinal tract
following ingestion of elemental mercury unless soluble oxides or sulfides are formed
(Winship, 1985). Mercurous (Hg22+) compounds are generally less soluble than mercuric
compounds and are therefore less likely to be absorbed by the body (Gerstner and Huff,
1977). In some cases, they may be oxidized to form soluble and therefore more absorbable
compounds (Winship, 1985). The major route of exposure to organic mercury, particularly
methyl mercury compounds, is through absorption from food (especially fish); between
90 and 100% of ingested methyl mercury and 80 to 100% of organic mercury compounds in
general are absorbed from the gastrointestinal tract (U.S. Environmental Protection Agency,
1984a; Chang, 1980; Clarkson, 1973). About 80% of inhaled organic mercury and 6% of
methyl mercury applied to skin may also be absorbed (Berlin, 1986; Chang, 1980).
4.2 RETENTION AND DISTRIBUTION
Mercuric chloride does not dissociate readily in aqueous solution (Carty and Malone,
1979). However, on entering the bloodstream, the mercuric ions may enter reversible
complexes with ligands other than Cl", such as the sulfhydryl groups of proteins (Carty and
4-2
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Malone, 1979; Gerstner and Huff, 1977). Essentially no free or ultrafilterable mercury is
found in the blood. Most of the ions are bound either to albumin or other protein fractions
of the plasma (Winship, 1985; Gerstner and Huff, 1977) or to the membranes and proteins
(such as hemoglobin) of the erythrocytes (Berlin, 1986; Gerstner and Huff, 1977).
The ratio of erythrocyte mercury to plasma mercury in man is between 1 to 1 and 1 to
2.5 several hours after parenteral, oral, or inhalation exposure to inorganic mercury
compounds or elemental mercury (Berlin, 1986; Chang, 1980; Gerstner and Huff, 1977;
MacGregor and Clarkson, 1974; Clarkson, 1972), although immediately following inhalation
of elemental mercury, it may be as high as 40 to 1 (Cherian et al., 1978). The
corresponding distribution of mercury in humans exposed to organic mercury compounds may
be 10 or 20 to 1, and in some mammalian species it may be as high as 300 to 1 (Chang,
1980; Gerstner and Huff, 1977; MacGregor and Clarkson, 1974; Clarkson, 1972). This
difference in distribution may be related to differing abilities of organic mercury and the
mercuric ion to form stable complexes in the plasma (MacGregor and Clarkson, 1974). The
clinical significance of the different distribution of mercury types in the blood is that it
permits diagnosis of the type of mercury to which an. individual has been exposed, although
because of such factors as the biotransformation of mercury in the body, the accuracy of
diagnosis may decrease with time following exposure (Gerstner and Huff, 1977). Short-chain
alkyl mercury compounds such as methyl- or ethylmercury are very stable in the body,
whereas long-chain compounds may be metabolized over time to the mercuric ion; the
mercury distribution in the blood therefore may shift from a distribution characteristic of
organic mercury compounds to one more suggestive of inorganic compounds. Elemental
mercury and monovalent mercury are also oxidized to the mercuric ion in the bloodstream
(Berlin, 1986; Chang, 1980; Gerstner and Huff, 1977). The ratio of erythrocyte to plasma
mercury concentration, together with blood levels of mercury, can be used to calculate the
body burden of short-chain alkyl mercury compounds but not that of mercury from inorganic
or long-chain organic compounds (Gerstner and Huff, 1977).
The distribution of divalent mercury in the body and within organs varies with species,
strain, route of exposure, dose, and time following exposure. In general, most of the
divalent mercury in the body is concentrated in the proximal convoluted tubules of the
kidneys and to a lesser extent in the liver (Nielsen and Andersen, 1990; Berlin, 1986;
4-3
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Winship, 1985; Gerstner and Huff, 1977; MacGregor and Clarkson, 1974). However,
Bernaudin et al. (1981) observed effects (granular fixation patterns) normally observed in the
kidneys of rats exposed by other routes in the lungs and spleens of rats exposed
intratracheally to HgCl2 for 2 mo. At the lowest dose tested, these effects were observed in
the lungs and spleens, but not in the kidneys, suggesting that the kidneys may not be the
preferential site of deposition following inhalation exposure. Within a day, after 5 days of
subcutaneous exposures to 1.4 mg HgCl2/kg/day, mean kidney levels of mercury
(micrograms per grams of tissue) in five rats were 78 times higher. However, Nielsen and
Andersen (1990) found that the relative deposition (percentage of residual body burden) of
mercury in the liver, stomach, and spleen 14 days after a single ip injection of HgCl2 tended
to increase with increasing doses (ranging from 13.6 to 1,360 /tg HgCl2/kg) in two strains of
mice, but tended to decrease with increasing dose in kidneys, lungs, and brain. Therefore,
whereas the kidney remained the major depot besides the carcass, the ratio between the
mercury burden in the kidneys and liver ranged from 4.4 at the low dose to 1.7 at the high
dose. Following gavage dosing, the combined relative deposition in kidneys and liver is not
markedly different (Nielsen and Andersen, 1989, 1990), but, in one mouse strain, the
kidneys to liver ratio was 2.5 at a dose of 0.27 mg HgCl2/kg and 0.8 at a dose of 27 mg
HgCl2/kg. Therefore, within several hours after parenteral administration of inorganic
mercury, kidney mercury levels may be as much as 300 times greater than blood levels, and
the kidneys retain mercury longer than other tissues (Clarkson, 1972). The liver contains the
next highest concentration of inorganic mercury, and mercury may also accumulate in the
mucous membranes of the intestinal tract and the epithelium of the skin, the spleen, and
certain tissues in the testes and the brain (Berlin, 1986).
In contrast to mercury vapor and methyl mercury compounds, divalent mercury does
not readily cross either the blood-brain or placenta! barriers, although some divalent mercury
does accumulate in the placenta, fetal membranes, and amniotic fluid, as well as the frontal
and basal cerebral regions of the brain (Berlin, 1986; Winship, 1985). Brain mercury levels
following a single injection of divalent mercury may be approximately 10 times as high as
blood levels, but are still substantially lower than brain levels found following injection or
inhalation of mercury vapor or organic mercury (Clarkson, 1972; see also Ogata et al., 1985;
Chang, 1980; Berlin et al., 1969). Intraperitoheal injection of HgCl2 results in an uneven
4-4
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distribution of mercury within the different anatomical structures of the brain. At the cellular
level, the largest accumulation of mercury was seen in the spinal cord neurons.
UltrastructuraUy, mercury deposits were located exclusively in lysosomes (Schionning and
Moller-Madsen, 1991; Moller-Madsen, 1990). The same pattern of mercury central nervous
system distribution occurs following oral administration (Moller-Madsen, 1990).
Experiments in rats and mice have shown that intramuscular injection of inorganic mercury
results in retrograde axonal transport and accumulation of Hg2H" in motor neurons (Arvidson,
1990).
The half-life of inorganic mercury in the human body is between 1 and 2 mo, although
for certain organs, particularly the kidneys and brain, the retention times are somewhat longer
(Berlin, 1986; Cherian et al., 1978; Gerstner and Huff, 1977; Clarkson, 1972). The kidney
is considered the critical target organ in cases of oral and parenteral exposure (especially
acute exposure) to inorganic mercury; for exposure to elemental mercury, alkyl-mercury
components such as methyl mercury, mixtures of mercury species, or chronic low doses of
inorganic mercury, the nervous system is the critical target organ (Berlin, 1986; Jugo, 1979;
Chang, 1980). Due to the lack of pulmonary toxicity studies, the importance of the lung as a
target organ is unknown.
In rats" exposed to 2 to 3 subcutaneous doses of HgCl2, 70 to 84% of the mercury found
in the kidney was bound to metallothionein, a low molecular weight cytoplasmic protein rich
in sulfhydryl groups (Piotrowski et al., 1974). Studies with HgCl2 indicate that mercuric
mercury, like other divalent cations such as cadmium, zinc, and copper, can induce the
synthesis of metaUothionein (Lee et al., 1983; Piotrowski et al., 1974). However, unlike
cadmium, mercuric mercury appears to induce metallothionein production in kidney cells
without impacting synthesis of metallothionein in the liver (Piotrowski et al., 1974).
The transport and distribution of inorganic mercury are different in suckling animals
than in adult animals; considerably more mercury (13- to 19-fold) is accumulated in the liver
and brain of the suckling animal than in the adult, presumably because the kidneys bind the
mercury less well in the young animal (Jugo, 1979). This could be due, in part, to an
elevated store of hepatic metallothionein (Daston et al., 1984). Hepatic metallothonein
concentration has been reported to be 8- to 20-fold higher in prenatal rats than in postweaning
animals (Bell, 1980; Wong and Klaassen, 1980). Although renal damage is generally of
4-5
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much greater concern in acute exposures, nervous system damage does occur from inorganic
mercury poisoning; therefore, it seems likely that very young children might be at a much
greater risk for nervous system toxicity from inorganic mercury exposure than are adults,
even though specific data are not available for humans (Jugo, 1979).
Although high blood levels of mercury among members of a population generally
indicate high exposure of the population, individual exposure to or body burden of inorganic
mercury cannot necessarily be estimated from blood or urine concentrations (Gerstner and
Huff, 1977). In particular, mercury concentrations in target organs such as the kidneys and
nervous system cannot be calculated from blood levels. Blood mercury levels in normal
individuals having no known occupational or other specific source of exposure vary
considerably and are not correlated with age, sex, or body weight (Gerstner and Huff, 1977).
Reported values in these individuals range from 5 to 100 /xg Hg/L (Stokinger, 1981). The
upper limit of "normal" is currently considered to be 30 jug Hg/L blood (0.03 mg/L), based
on a study of 812 blood samples from 15 countries (Goldwater, 1972; see also Stokinger,
1981; Gerstner and Huff, 1977; 95% of the samples had mercury levels less than 30 /tg/L).
Gerstner and Huff (1977) suggest that a level of 10 jwg/L is an acceptable upper limit for
healthy populations.
Schroeder (1971) lists a blood mercury level of 5 /*g/L (0.005 mg/L) for'a 70-kg
reference man. This man also has kidney, brain, lung, and liver mercury concentrations of
2.81, 1.0, 0.58, and 0.3 mg/kg wet weight, respectively, and a total body burden of
approximately 13 mg Hg (about 0.19 mg/kg wet weight). Joselow et al. (1967) found an
average of 2.75 mg Hg/kg wet weight in kidney tissue (maximum, 26.3 mg/kg) from
39 autopsies of humans with no known mercury exposure. Liver concentrations averaged
0.30 mg/kg and brain 0.10 mg/kg (maximum, 0.9 and 0.6 mg/kg, respectively), and tissue
mercury levels did not appear to be related to age. In an analysis of tissue samples from
113 human autopsies, Mottet and Body (1974) found that 70% of the bodies contained total
mercury burdens of less than 0.25 mg/kg wet weight, and only 6% had levels higher than
0.75 mg/kg. The most variable tissue was the kidney, which had an average mercury burden
of approximately 0.75 mg/kg wet weight (29% of the samples were higher than this); liver
and lung contained 0.25 mg/kg on the average, and cerebellum approximately 0.13 mg/kg.
People from urban populations contained a statistically higher level of mercury than did
4-6
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people from rural populations, but no correlation was found between tissue mercury levels
and age (range, 26 weeks of gestation to 88 years).
Several additional studies of mercury levels in human tissues were reviewed by Mottet
and Body (1974) and Goldwater (1972). Although tissue mercury levels vary among studies
(probably due to differences in analytical techniques), in all cases, the highest mercury
concentrations in the body were found in the kidneys. These data suggest that average body
burdens of mercury are 10 to 100 times higher than the concentrations in blood; mercury
concentrations are higher in the kidneys than in other tissues and are approximately 3 to
10 times higher than total body mercury concentrations. It should be noted that these values
(for blood and tissues) are for total mercury and do not distinguish between inorganic and
organic mercury.
The mercury content of hair can sometimes aid in estimation of body burden and may
be used to trace the history of a person's exposure to methyl mercury (Kobayashi et al.,
1988; Gerstner and Huff, 1977). Mercury is bound firmly to the keratin in hair, and the
structure of hair is such that neither loss of mercury from hair nor contamination from
external mercury sources is a significant concern (Gerstner and Huff, 1977). The fairly
uniform growth rate of hair (0.75 to 1.35 cm/mo, depending on the individual) and the fact
that formation of new material occurs only at one end permit estimation of approximate dates
and amounts of mercury exposure. Concentrations of mercury in hair are generally 250 to
300 times higher than blood concentrations. Mean values for mercury in hair are usually in
the range of 1 to 5 mg/kg, although some reported values have been as high as 25.0 mg/kg
(mean for a group) and 100 mg/kg (individual sample; Gerstner and Huff, 1977). These
values again are for concentrations of total mercury, both inorganic and organic.
4.3 EXCRETION
Divalent mercury can be excreted by several routes, including urine, feces (via bile,
saliva, and gastric and intestinal secretions), sweat, milk, tears, and exhaled air, although
most of it is removed from the body via the urine and feces (Berlin, 1986; Winship, 1985;
Gerstner and Huff, 1977). Little information is available on levels of mercury in milk, tears,
sweat, or expired air. Sweating has been used since at least the 18th century as a means of
4-7
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lowering the body burden of mercury in cases of chronic mercury poisoning, and its use for
that purpose has been suggested again in recent years (Stopford, 1979). A small amount of
divalent mercury may be reduced in the body to mercury vapor, which then may be exhaled
from the lungs, but this is not considered a significant route of mercury removal (Berlin,
1986; Ogata et al., 1987). The amount of mercury (Hg°) vapor exhaled by mice following
treatment with HgCl2 was greater when the mice also received ethanol (Dunn et al., 1981),
indicating an ethanol-sensitive reduction pathway for ionic mercury (Hg+ +) in the body.
Mercury in the breast milk of women exposed to methyl mercury compounds was
correlated with blood levels, averaging approximately 5% of simultaneous concentrations in
maternal whole blood (World Health Organization, 1976). Inorganic mercury accounted for
80% of the mercury in one study and 40% in another, with the rest being methyl mercury.
Suckling infants with no other mercury exposure accumulated mercury at levels in excess of
1.0 mg/L in their blood (World Health Organization, 1976).
Mercury is excreted into the intestinal tract by the liver through the bile and also by the
mucous membranes of the small intestines and colon (Berlin, 1986); the latter probably
involves active transport across the membranes (Gerstner and Huff, 1977). Mercury also
enters the digestive tract via the saliva. Few details are known about fecal excretion of
mercury. The potential for recirculation of salivary and biliary mercury must be considered,
and the use of a polythiol resin to reduce resorption of mercury from the intestines has been
suggested, at least for cases of methyl mercury poisoning (see Chang, 1980). Salivary
mercury levels are closely correlated with mercury concentrations in blood, but not in urine,
and are sometimes used to monitor occupational exposure to mercury (Stokinger, 1981;
Stopford, 1979; Goldwater, 1972). Mercury was not detected in the saliva of unexposed
people by a method having a sensitivity of 5 /xg/L (Stokinger, 1981; Goldwater, 1972),
although salivary mercury levels in workers known to have had mercury exposure ranged
from 10 to 155 /zg/L (Goldwater, 1972).
Most excretion of inorganic mercury occurs via the kidneys, and a greater proportion of
the mercury dose is excreted in the urine than in the feces with an increase in total dose
(Berlin, 1986; Chang, 1980). Approximately 60 to 75% of absorbed mercury is excreted as
sulfhydryl mercury compounds, primarily with cysteine or N-acetylcysteine, and essentially
no free inorganic mercury is found in the urine (Winship, 1985; Hultman et al., 1985).
4-8
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Urinary excretion involves active tubular transport and also passive glomerular filtration
(Gerstner and Huff, 1977; Berlin, 1986; Chang, 1980), although glomerular filtration is
probably not a major pathway of excretion (Cherian et al., 1978). Excretion of mercury via
urine is more closely correlated to blood levels than to the mercury burden of the kidney
itself (Berlin, 1986).
The normal upper limit of mercury in the urine is approximately 25 to 30 /*g/L (Berlin,
1986; Winship, 1985); concentrations up to 100 jug/L or more have been found in urine
samples from people with no known mercury exposure, but levels above 50 jiig/L are rare
(Jacobs et al., 1964). In a study described by Jacobs et al. (1964) and Goldwater (1972 [this
is the same study with some additional data]), 95% of urine samples had mercury
concentrations less than 20 ^ig/L (96% were below 25 jwg/L); the highest value was
221 ftg/L, whereas approximately 80% contained no detectable mercury (<0.5 /xg/L). The
study included a total of 13107 samples from 15 countries, including 434 samples-from the
United States. Mercury concentrations in the U.S. samples ranged from 0.0 to 221.0 jwg/L,
with 344 samples (79%) having mercury levels below the limit of detection. Urinary
mercury excretion in children is normally less than 10 jug/L (Berlin, 1986).
Mercury levels in urine are used in monitoring exposure to mercury, although urinary
concentrations vary considerably and are not always good indicators of the body burden of
mercury (Winship, 1985; Gerstner and Huff, 1977). Good correlation, at least on a
population level, does exist between the concentration of mercury vapor in the air and the
mercury concentrations in both blood and urine (Winship, 1985; Gerstner and Huff, 1977;
Jacobs et al., 1964). On an individual level, mercury levels in the urine of exposed people
may fluctuate widely (as much as 3- to 10-fold) during the course of a day and from day to
day (Jacobs et al., 1964). Some people with no symptoms of mercury toxicity may excrete
large amounts of mercury in their urine (up to 3.0 mg Hg/L or more), whereas other people
with urinary mercury levels below 0.3 mg/L may show definite signs of mercury poisoning.
There seems to be no level of urinary mercury above which symptoms of poisoning may be
expected and below which symptoms will not occur. There is also no evidence for a
correlation between urinary mercury levels and duration of exposure to mercury, nor does
there appear to be any justification for correcting urinary concentrations for the specific
gravity of the sample (Jacobs et al., 1964). Urinary mercury levels in cases of acute
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ingestion of mercury salts can give an indication of the amount of mercury intake, and
urinary levels can also be used to monitor the effectiveness of therapeutic measures (e.g., an
increased urinary mercury level would indicate that a given therapy was aiding mercury
removal from the body) (Gerstner and Huff, 1977).
Because mercury levels in urine are variable, due to factors such as differences in urine
flow from person to person, recent efforts have focused on normalization of mercury to urine
creatinine levels. Where personal samplers have been used, the ratio between urinary
*5
mercury expressed as /xg Hg/g creatinine and air (|«g/m ) has been between
1 and 2 (Figure 4-1 A) (Roels et al., 1987; World Health Organization, 1991). Reels et al.
(1987) reported a regression equation, where a urine mercury level of 50 /ttg/g creatinine
(observed after exposure to 40 jwg Hg/m3) is correlated to a blood mercury level of 16 /*g/L
(Figure 4-1B).
100
1
•3?
1
I
80
60
40
O)
20
JL
JL
JL
20 40 60 80 100
Hg-Airfrg/n?)
B
£ 5
I4
I,
n-40
r-0.86
p< 0.001
00°0
\ I I
20 40 60 80
Hg-Airdig/ni3)
100
Figure 4-1. Relationships between individual daily levels of mercury in air on hopcalite
filters by personal sampler and (A) those in blood samples taken at the end
of the work shift (1400 hours) or (B) those in urine samples collected the
following morning (0900 hours).
Source: Roels et al. (1987).
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5. MUTAGENICITY AND CARCEVOGENICITY
5.1 MUTAGENICITY
The genetic effects of mercury and mercury compounds have been reviewed by Leonard
et al. (1983), Kazantzis and Lilly (1986), and more recently by the Agency for Toxic
Substances and Disease Registry (1993). As is indicated in Tables 5-1 and 5-2, the induction
of primary DNA in mammalian and bacterial cells and weak mutagenesis in mammalian cells
suggest that inorganic mercury compounds have some genotoxic potential.
5.1.1 Prokaryotic Organisms
Mercury compounds have exhibited little mutagenic activity in most bacterial assay
systems. Mercuric chloride failed to produce a mutagenic response hi plate incorporation
assays using several Salmonella tester strains (Wong, 1988; Arlauskas et al., 1985; Marzin
and Phi, 1985). One of these experiments specifically showed that HgCl2 does not cause
AT •> GC base pair substitution (Marzin and Phi, 1985). Fluctuation assays in both
Escherichia coli and Salmonella were also negative for HgCl2-induced mutagenic activity
(Arlauskas et al., 1985). Treatment of a lysogenic E. coli strain with HgCl2 failed to induce
lambda prophage, a response that would have indicated forward mutation or DNA damage
sufficient for the induction of a cellular compensatory mechanism known as the "SOS"
system (Rossman et al., 1984). On the other hand, Kanematsu et al. (1980) found that
HgCl2 did cause some DNA damage as indicated by marginal inhibition of growth in
recombination-repair-deficient Bacillus subtilis cells at an HgCl2 concentration of 1.4 mg
Hg/L (0.05 M). Methyl mercuric chloride caused significantly greater inhibition of growth at
a concentration of 0.14 mg Hg/L (0.005 M).
5.1.2 Eukaryotic Organisms
A major effect of mercury on the genetic material in eukaryotic systems is the inhibition
of the formation of the mitotic (or meiotic) spindle, an effect known as C-mitosis
(or C-meiosis) after the similar effect of colchicine (Verschaeve et al., 1985; Watanabe
5-1
-------
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5-3
-------
et al., 1982; Galloway and Ivett, 1986). A much more gradual dose-response effect is seen,
with mercury compounds than with colchicine, such that at low doses of mercury the mitotic
block is incomplete (Ramel, 1972); this situation can result in varying degrees of aneuploidy
as well as polyploidy. The lowest dose of HgCl2 that caused C-mitosis was 2.7 mg/L
(Verschaeve et al., 1985). The inhibition of the mitotic spindle formation is thought to be
caused by binding of the mercury to sulfhydryl groups hi the proteins of the spindle fibers
(Andersen et al., 1983; Leonard et al., 1983), although interaction of mercury with other
proteins and enzymes such as RNA polymerase I may also be involved (Verschaeve et al.,
1985).
Other reported effects of mercury compounds on the genetic material of eukaryotes
include breakage of DNA; induction of point mutations, dominant lethal mutations, sister
chromatid exchanges, and chromosomal aberrations; inhibition of the activity of nucleolus-
organizing regions; and decreases in DNA synthesis (Howard et al., 1991; Zasukhina et -al.,
1983; Cantoni and Costa, 1983; Cantoni et al., 1982, 1984a,b; Christie etal., 1984, 1986;
Verschaeve et al., 1983; Morimoto et al., 1982).
Verschaeve et al. (1985) found a statistically significant increase in chromosomal
aberrations in human lymphocytes treated in vitro with HgCl2 at concentrations as low as
1.4 mg/L (5 j«M) in the culture medium, and Howard et al. (1991) reported an' increase in
the percentage of chromosomal aberrations in Chinese hamster ovary cells treated in vitro
with 0.27 mg HgCl2/L (1 ^M). However, Umeda and Nishimura (1979), Nishimura and
Umeda (1978), and Paton and Allison (1972) reported no increase in chromosomal
aberrations in human lymphocytes or other mammalian cells treated in vitro with HgCl2.
Concentrations of HgCl2 in the latter studies ranged from less than 8.1 /ig/L (0.03 pM; Paton
and Allison, 1972) to 2.7 to 17.3 mg/L (10 to 64 /xM; Umeda and Nishimura, 1979; the
highest dose in this study was cytotoxic).
A concentration of 3.2 mg/L HgCl2 (corresponding to 50% inhibition of cell growth)
did not increase the number of sister chromatid exchanges (SCEs) in Chinese hamster Don
cells (derived from lung cells of a Chinese hamster named Donald; Hsu, 1979), nor did
mercuric acetate or mercuric iodide at doses also corresponding to 50% cell inhibition (Ohno
et al., 1982). Mercuric chloride at media concentrations up to 2.7 mg/L (10 fiM) did not
increase the SCE frequency in PSSSDj (lymphoid neoplasm-derived) mouse cells or Chinese
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hamster ovary (CHO) cells (Howard et al., 1991), but did increase the frequency in some
cultures of human lymphocytes (Andersen, 1983). On the other hand, Morimoto et al.
(1982) found significant increases in SCE frequency in human lymphocytes treated in vitro at
concentrations as low as 0.108 mg/L (0.4 fjM), which was about five times the concentration
of methyl mercuric chloride required to produce the same effect. Addition of sodium selenite
(Na2SeO3), able by itself to damage DNA, to the medium at a molar ratio (selenite:mercury)
of 1:1 prevented the induction of SCEs by HgCl2 (a ratio of 1:2 was required to counteract
methyl mercuric chloride). The mechanism of this phenomenon has not been described, but
it may involve a complex of glutathione with both metals, effectively preventing damage to
the DNA by either one (Morimoto et al., 1982).
Mercuric chloride in concentrations of 2.7 /*g/L (10 jttM) or higher also caused a
decrease in the molecular weight of the DNA of intact CHO cells (Robison et al., 1982) and
of nucleoids (isolated nuclear preparations) from CHO cells (Robison et al., 1984). This
decrease is attributable to single-strand breaks in the DNA, rather than double-strand breaks,
and it is not an artifact of the experimental techniques used (Cantoni et al., 1984a).
Following treatment with HgCl2, DNA-DNA cross-links, but not DNA-protein cross-links,
are found (Christie et al., 1984; Cantoni and Costa, 1983); the Hg2+ ion binds to the DNA,
replacing hydrogen in the complementary binding of thymidine to adenine (Cantoni et al.,
1984b).
Mercuric chloride was mutagenic in L5178Y mouse lymphoma cells, inducing 1.4 to
3.5 times the control frequency of mutations when present in the culture medium at
concentrations of 2 to 8 mg/L (Oberly et al., 1982). Metabolic activation with a rat liver
S9 fraction was required to obtain the maximum response.
5.1.3 Whole Animal Assays
Male rats orally exposed daily to HgCl2 (0.25 or 2.5 /*g/kg body weight) for 12 mo
exhibited about a fourfold increase in the frequency of dominant lethal mutations in their
offspring (Zasukhina et al., 1983; Vasil'eva et al., 1982); no increase was seen at a dose of
0.025 jug/kg (2.5 X 10"5 mg/kg). No evidence of dominant lethal effects was found
following treatment of male mice with 1.35 mg/kg HgCl2 (1 mg Hg2+/kg body weight,
single intraperitoneal dose; Lee and Dixon, 1975).
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Both structural and numerical chromosomal aberrations were found in the cells of mouse
embryos when the mothers were exposed during pregnancy to aerosols (no mass median
aerodynamic diameter given) of HgCl2 (0.23 or 2.1 mg/m3, 4 h daily for 4 days on Gestation
Days 9 through 12) (Selypes et al., 1984). Chromosomal aberrations also have been reported
in the peripheral blood lymphocytes of humans with occupational exposure to mercury
compounds, including HgCl2 (Popescu et al., 1979). The subjects of the Popescu et al. study
were exposed either to mercury vapor or to mixed mercury compounds; HgCl2 was a minor
component of the mixture, and the observed chromosomal aberrations were not necessarily
attributable to exposure to HgCl2 (Popescu et al., 1979). No increased frequency of
chromosomal aberrations was found in the bone marrow or spermatogonia of mice injected
intraperitoneally with 2 to 6 mg/kg body weight of HgCl2 (Poma et al., 1982, 1981).
The incidence of structural, but not numerical, chromosomal aberrations was slightly
increased in bone marrow cells of female Syrian (golden) hamsters injected subcutaneously
with HgCl2 at doses of 6.4 or 12.8 mg Hg/kg body weight and examined 5 days later
(Watanabe et al., 1982). Serum mercury concentrations for animals receiving the higher dose
averaged 5.84 mg/L. Similar doses of methyl mercuric chloride (6.4 or 12.8 mg Hg/kg)
caused some increase in numerical anomalies (particularly polyploidy) as well as structural
aberrations; the average serum mercury concentration was 1.06 mg/L. Even at the higher
dose of HgCl2, no increase in structural or numerical aberrations was seen in metaphase II
oocytes in the hamsters at either the first or second estrus following treatment. Mercury
concentrations in the ovaries following the higher dose of HgCl2 averaged 4.37 mg/kg at the
first estrus and 6.86 mg/kg at the second. Corresponding ovarian mercury concentrations for
hamsters receiving 12.8 mg/kg methyl mercuric chloride were 18.04 and 10.52 mg/kg at the
first and second estrus, respectively, and some increase in numerical aberrations in metaphase
II oocytes was found in these hamsters (Mailhes et al., 1986; Watanabe et al., 1982).
5.1.4 Summary
Several conclusions can be drawn from the studies described thus far. Mercuric
chloride does not appear to be a potent mutagen. The mutagenic responses of eukaryotes to
mercury compounds are generally less than the corresponding responses to certain other
metals (e.g., cadmium or chromium) or to other known mutagenic agents (e.g., ethyl
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methanesulfonate; Oberly et al., 1982), and inorganic mercury compounds usually have less
of an effect than organic mercury compounds (Morimoto et al., 1982; Ramel, 1972). The
occurrence of mutations (as opposed to chromosome aberrations or SCEs) may require some
aspect of eukaryotic metabolism. This is suggested by the absence of increased mutations in
bacterial assays (Arlauskas et al., 1985; Marzin and Phi, 1985; Rossman et al., 1984) and the
requirement for a rat liver S9 fraction in the mouse lymphoma assay (Oberly et al., 1982).
In vivo studies show that low chronic doses of HgCl2 can cause an increase in dominant
lethal mutations in rats (Zasukhina et al., 1983; Vasil'eva et al., 1982), but much higher,
single doses did not cause a similar effect in mice (Lee and Dixon, 1975). The finding in
some experiments of a moderate increase in the frequency of chromosomal aberrations or
SCEs indicates that HgCl2 does do some damage to genetic material in vivo (Watanabe et al.,
1982). Chromosomal aberrations were not found in spermatogonia or oocytes of animals
receiving 4.4 (male mice) or 12.8 (female hamsters) mg Hg/kg as HgCl2 (6 and 17.3 mg
HgCl2/kg) (Poma et al., 1981; Watanabe et al., 1982).
In the one reported experiment involving inhalation of HgCl2, exposure of pregnant
mice to 0.23 and 2.1 mg/m3 resulted in genetic damage (structural and numerical
chromosomal aberrations) to the embryos (Selypes et al., 1984). Although this study
provides a clear indication that inhaled HgCl2 can cause genetic damage and developmental
effects (see Chapter 6), it did not characterize exposure adequately (e.g., particle size was not
given), report the number of animals in any group, employ tests of statistical significance, or
demonstrate a clear lowest-observed-adverse-effect level (LOAEL).
In vitro exposures at concentrations as low as 0.1 mg/L (Morimoto et al., 1982) also
showed chromosomal effects, although other studies found no chromosomal aberrations at
in vitro HgCl2 concentrations as high as 17 mg/L (Umeda and Nishimura, 1979). In many
of the in vitro experiments, however, cytotoxicity became a problem at or even below the
concentrations of HgCl2 at which chromosomal aberrations or other genetic effects were seen
(e.g., Ohno et al., 1982; Umeda and Nishimura, 1979; Cantoni et al., 1984a; Kasschau and
Meyn, 1981; Umeda et al., 1969). Some species or cell-type differences also may be
involved in the differing responses seen. It should also be mentioned, with respect to in vitro
work, that the concentration of HgCl2 added to the medium is not necessarily the
concentration that the cells are effectively exposed to. Other components in the medium such
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as amino acids or reduced glutathione may bind Hg2+, thereby making it unavailable to the
cells (Cantoni et al., 1986; Gosta et al., 1982; Christie et al., 1984; Verschaeve et al.,
1985). .
Although HgCl2 is not a potent mutagen or inducer of chromosome aberrations of
SCEs, some work has demonstrated that HgCl2 is capable of .damaging DMA and inhibiting
DNA synthesis. Both in vitro and in vivo studies have shown that mercuric chloride can
induce single-strand breaks in the DNA of rat- and mouse-embryo fibroblast cells; the effect
is proportional to the dose, although cells from different species and strains may differ in
their sensitivity to HgCl2 and in their ability to repair the damage (Zasukhina et al., 1983;
Vasil'eva et al., 1982).
5.2 CARCINOGENICITY
Mercuric chloride at a concentration of 13.5 mg/L (0.05 mM) enhances viral
transformation in hamster embryo cells (Heck and Costa, 1982a; Casto et al., 1979), and
HgCl2 is weakly mutagenic in several experimental systems (see discussion in Section 5.1).
Many chemicals, including some metals, are both mutagenic and carcinogenic (see Kazantzis
and Lilly, 1986; Heck and Costa, 1982b); however, especially for metals, mutagenicity and
carcinogenicity are not always correlated, and Heck and Costa (1982b) emphasize that each
metal and even each metal compound must be considered separately. Robison et al. (1984)
suggest that, in contrast to some other metal compounds such as nickel chloride, HgCl2 may
be too cytotoxic to be a strong carcinogen.
There are very few epidemiological studies or animal bioassays available on the
potential carcinogenicity of mercury or mercury compounds (Winship, 1985; U.S.
Environmental Protection Agency, 1984a,b; Andersen, 1983; Vainio and Sorsa, 1981;
Shroeder and Mitchner, 1975; Fitzugh et al., 1950). The only long-term toxicity or
carcinogenicity study of HgCl2 is a 2-year study of F344/N rats and B6C3Fj mice
administered HgCl2 by gavage (National Toxicology Program, 1993). Groups of 60 rats of
each sex were administered 0, 2.5, or 5 mg/kg HgCl2 in deionized water (dose volume
5 mL/kg) 5 days/week for 103 to 104 weeks. Groups of 60 mice of each sex were given 0,
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5, or 10 mg/kg HgCl2 in deionized water (dose volume 10 mL/kg) on the same schedule as
the rats.
Survival was significantly (p < 0.001) lower after 24 mo in male rats at 2.5 and
5 mg/kg (10/50 and 5/50, respectively) than controls (26/50). During the second year of the
study, body weight gains of males at 2.5 and 5 mg/kg were 91 and 85% of controls,
respectively, and body weight gains of female rats at 2.5 and 5 mg/kg were 90 and 86% of
controls, respectively. At study termination, nephropathy had occurred in almost all male
and female rats including controls, but the number of males with severity considered to be
"marked" was much greater at 2.5 and 5 mg/kg (29/50 at both doses) than in controls (6/50).
After 15 mo, the forestomach of male rats in both exposure groups developed basal cell
hyperplasia, which became extensive after 2 years.. Focal papillary hyperplasia and squamous
cell papillomas of the forestomach were observed in the high-dose male rats at 2 years.
Squamous cell carcinomas were not observed, and it is not known if the squamous cell
papillomas found had the potential to progress to carcinomas. There was no evidence that the
papillomas were proceeding to malignancy. Subsequently, for male rats, the NTP reported
"some evidence", rather than "clear evidence", of carcinogenic activity related to
administration of HgCl2. The NTP also reported an increased incidence of thyroid follicular
cell adenomas and carcinomas in male rats that may have been related to HgCl2 exposure.
Squamous cell papillomas of the forestomach were also observed in high-dose group females.
These lesions have occurred in 0/265 female historical controls at the NTP, however, because
only two squamous cell papillomas were found, the data were considered to represent
"equivocal evidence of carcinogenic activity" in female rats.
Survival of male mice was not affected by the administration of mercuric chloride;
however, survival of high-dose females was slightly lower than controls (31/60 compared to
41/60 in controls; p = 0.051). Body weight gain was not affected. Female mice exhibited a
significant increase in the incidence of nephropathy (21/49 in controls, 43/50 at 5 mg/kg, and
42/50 at 10 mg/kg). Nephropathy was observed in 80 to 90% of the males in all groups.
Both males and females exhibited significant (p < .0.001) increases in the average severity
scores for nephropathy (1.08 in control males, 1.74 in males at 5 mg/kg, and 2.51 in males
at 10 mg/kg; 0.47 in control females, 1.02 in females at 5 mg/kg, and 1.24 in females at
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10 mg/kg). Renal tubule hyperplasia was observed in 2/49 high-dose males compared to
1/50 controls.
Renal tubule adenomas or adenocarcinomas occurred in 3/49 high-dose male mice
compared to 0/50 controls. The historical incidence of renal tubule adenomas or
adenocarcinomas in males dosed by gavage was 0/205. Although the incidence of these
tumors was not significantly increased, a statistically significant trend (p = 0.032) for
increased incidence with increased dose was observed. Thus, the NTP noted equivocal
evidence of carcinogenic activity in male mice based on the occurrences of two renal tubule
adenomas and one renal tubuie adenocarcinoma.
The NTP study of male rats provides the principle evidence for a carcinogenic effect
from HgCl2 exposure. However, the high mortality in male rats from severe renal disease
during the last 15 weeks of the study suggests that the potential nephrotoxicity of HgCl2 (see
Section 7.2) may pose a greater hazard than its potential carcinogenicity (National Toxicology
Program, 1993).
A 2-year feeding study in rats (20 or 24/sex/group; strain not specified) was conducted
in which rats were administered mercuric acetate in the diet at doses of 0, 0.5, 2.5, 10, 40,
and 160 ppm (0, 0.2, 0.1, 0.4, 1.7, and 6.9 mg Hg/kg/day) (Fitzhugh et ali, 1950).
Survival was not adversely affected in the study. An increase in kidney weight and renal
tubular lesions was observed at 40 and 160 ppm. No effects were reported regarding
carcinogenicity. However, this study was not intended as a carcinogenicity assay, the number
of animals per dose was rather small, histopathological analyses were conducted on only 50%
of the animals (complete histopathological analyses conducted on only 31 % of the animals
examined), and no quantitation of results or statistical analyses were performed.
Mercuric chloride was negative in a carcinogenicity study using white Swiss mice
(Schroeder and Mitchener, 1975). Groups of mice (54/sex/group) were exposed until death
to mercuric chloride in drinking water at 5 ppm Hg (0.95 mg Hg/kg/day). After dying, mice
were weighed and dissected; gross tumors were detected; and some sections were made of
heart, lung, liver, kidney, and spleen for microscopic examination. Mercuric chloride was
nontoxic in the study. No effects were seen on the formation of tumors. This study is
limited because complete histological examinations were not performed.
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6. REPRODUCTIVE AND DEVELOPMENTAL
TOXICITY
In both humans and experimental animals, mercury and its compounds may affect
development and maturation of the female reproductive system; alter the function of the
hypothalamus, pituitary, or reproductive organs; decrease ovulation and implantation;
decrease male fertility; and cause teratogenic effects (Lee, 1983; Mattison et al., 1983;
Shepard, 1983; Koos and Longo, 1976). The effects of inorganic mercury (Hg2+
compounds) and organic mercury (especially methyl mercury) are different in many cases,
probably reflecting both different mechanisms of action and differences in rates of absorption
and clearance by specific tissues (Mueller et al., 1985; Leonard et al., 1983; Lee, 1983).
In general, HgCl2 is not as well absorbed, particularly following oral exposures, and causes
less severe reproductive and developmental effects than does methyl mercury.
6.1 IN VITRO STUDIES
Cultured mouse embryos in the preimplantation stages were inhibited at various stages
of development by 4.0 mg Hg/L HgCl2 (20 /*M), and mitotic arrest occurred at 10.0 mg
Hg/L (50 jJiM) (Katayama and Matsumoto, 1985; Katayama et al., 1984; Matsumoto et al.,
1984). Mercuric chloride at 1.4 mg Hg/L (5 juM) caused a decrease in protein synthesis
(Katayama et al., 1984). Methyl mercuric chloride was approximately 200 times as toxic as
HgCl2 in terms of inhibiting embryonic cell proliferation and 20 to 50 times as toxic with
respect to the inhibition of protein synthesis (Katayama et al., 1984). The difference in
toxicity of the two mercury compounds was attributed to the different rates of penetration of
the compounds into the embryonic cells and their different distributions within the cells
(Matsumoto et al., 1984).
Mueller et al. (1985) also reported embryotoxicity of HgCl2 to preimplantation mouse
embryos in vitro, with 2.7 mg Hg/kg (10 /nM) essentially inhibiting all growth. They also
found that HgCl2 enhanced the effects of x-irradiation on morphologic development and on
cell proliferation. The growth of rat embryos (removed on Day 10.5 of gestation and
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cultured for 48 h in vitro) was inhibited at a Hgd2 concentration of 1.1 mg Hg/L (4 /*M),
and extreme growth retardation was observed at 2.7 mg Hg/L (10 jwM) (Kitchin et al., 1984).
Developmental abnormalities, primarily of the central nervous system, were observed at
concentrations of HgCl2 as low as 0.27 mg Hg/L (1 /*M); in comparison with methyl
mercuric chloride, higher concentrations of HgCl2 were required to cause either abnormal
embryos or embryolethality. Addition of reduced glutathione to the culture medium reduced
the effects of HgCl2 on the embryos (Kitchin et al., 1984).
6.2 INJECTION STUDIES
Administration of mercury salts during organogenesis can produce defects in the
urogenital tract of experimental animals, probably as a result of general toxicity rather than of
specific action on that system (Mattison et al., 1983). Renal effects were observed in the
offspring of rats treated with a 1 mg/kg sc injection of mercuric chloride during the last
8 gestational days of pregnancy (Bernard et al., 1992). Mercury enters the hypothalamus and
the anterior pituitary in animals treated with HgCl2 and may have an effect there, probably
on the control of ovulation (Thorlacius-Ussing et al., 1986, 1985; Mattison et al., 1983).
In one study, the amount of mercury in the anterior pituitary of rats was dependent on the
route and level of exposure and on the time since the last exposure (Thorlacius-Ussing et al.,
1985).
Rats receiving 3 to 4 mg HgCl2/kg daily by ip injection had considerably higher
amounts of mercury deposited in the anterior pituitary than did rats receiving 9 mg HgCl2/kg
via drinking water, reflecting the low absorption rate of inorganic mercury compounds from
the gastrointestinal tract. Pituitary levels of mercury declined with time after treatment,
although mercury deposits were still evident 4 mo after cessation of treatment (Thorlacius-
Ussing etal., 1985).
Delayed or reduced ovulation following treatment with HgCl2 has been observed in
Syrian hamsters receiving ip injections of 2 to 3 mg Hg/kg body weight (3 to 4 mg
HgCl2/kg) daily during the estrous cycle or a one-time ip injection of up to 12.8 mg Hg/kg
as HgCl2 (Mattison et al., 1983; Watanabe et al., 1982) and in rats receiving daily doses
(by oral gavage) of 16 mg Hg/kg as HgCl2 (Pritchard et al., 1982b). In the hamsters
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receiving acute doses of mercury, the effect of HgCl2 on ovulation was greater than the effect
of an equivalent dose of methyl mercuric chloride (12.8 mg Hg/kg), although the ovarian
mercury concentration was higher following treatment with methyl mercury (18.04 and
10.52 mg Hg/kg at the first and second estrus, respectively, following treatment) than
following treatment with HgC^ (4.37 and 6.86 mg Hg/kg, respectively) (Watanabe et al.,
1982). This difference could be attributed either to a greater toxicity to the ovaries of HgCl2
than of methyl mercury or to a greater systemic effect of HgCl2 (i.e., on the hypothalamus or
pituitary) (Watanabe et al., 1982).
Both HgCl2 and methyl mercury administered by one ip injection at a concentration of
1 mg/kg caused decreased fertility in male mice, attributed to inhibition of DNA synthesis in
spermatogonial cells and possibly also to inhibition.of various essential enzymes (Lee, 1983;
Lee and Dixon, 1975). Mercuric chloride had a lesser antifertility effect than methyl
mercury, was deposited more slowly in the testes, and was more slowly eliminated from the
testes. Mercuric chloride also had its greatest effect over a different time interval
posttreatment than methyl mercury, indicating different effects of the two mercury
compounds on the various stages of spermatogenesis. Both compounds affected
spermatogonial cells and premeibtic spermatocytes, but HgCl2 did not affect early spermatids
(Lee, 1983; Lee and Dixon, 1975). Inhibition of spermatogenesis may be caused by
reduction of testosterone synthesis (Chowdhury et al., 1985). Recent in vivo investigations
have also noted marked decreases in sperm mobility following HgCl2 and methyl mercury
exposure to rats (Chowdhury et al., 1989). Decreased sperm mobility has been attributed to
a defect in mitochondria! energy production or a defect in chemomechanical energy
transduction (Ernst et al., 1991).
Genetic or cytogenetic effects on the germ cells (e.g., chromosomal aberrations,
dominant lethal mutations, aneuploidy) have not been reported in most cases following
treatment of experimental mammals with HgCl2 (Lee, 1983; Leonard et al., 1983; Mattison
et al., 1983; Watanabe et al., 1982; Poma et al., 1981; Lee and Dixon, 1975; see discussion
in Section 5.1).
Both HgCl2 and methyl mercuric chloride are toxic to mouse, embryos in vivo (Kajiwara
and Inouye, 1986a,b, 1992). Although intravenous injections (to the mother, on Day 0 of
gestation) of either compound at up to doses of 1.0 mg Hg/kg maternal body weight caused
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no significant effect on embryos examined at 3.5 days gestation, the percentage of abnormal
embryos was proportional to the dose of HgQ2 above 1.0 mg Hg/kg, and almost 100% of
the embryos were abnormal at a HgCl2 dose of 2.5 mg Hg/kg (Kajiwara and Inouye, 1986a).
Both mercury compounds were toxic at all stages of early embryonic development (i.e., there
was no specific stage of arrest), but at later developmental stages there appeared to be some
difference in response to the two chemicals (Kajiwara and Inouye, 1986b). A significant
decline in body weight, corresponding to mercury dose, also was noted for the dams treated
with HgCl2, but not for those treated with methyl mercuric chloride. The correlation
between the percentage of abnormal embryos and decrease in maternal weight suggests that
embryotoxicity may be related to maternal toxicity for Hgd2, and that some other
mechanism may be involved in methyl mercuric chloride toxicity (Kajiwara and Inouye,
1986a).
Gale and Perm (1971) found that mercuric acetate is embryotoxic under similar
conditions. They injected pregnant golden hamsters (6 to 19 per group) intravenously with
0, 2, 3, or 4 mg mercuric acetate per kg (0, 1.3, 1.9, or 2.5 mg Hg/kg, respectively) on
Gestation Day 8. Maternal animals were sacrificed on Gestation Day 12 or 14.
A significantly increased incidence of resorptions was observed at all doses. In addition,
increased incidences of retarded and edematous fetuses were observed at all doses (statistical
significance not reported).
Gale (1974) compared the embryotoxicity of mercuric acetate in pregnant golden
hamsters (3 to 23 per group) when administered by different routes. The data for oral
exposure is presented in Section 6.3. Subcutaneous administration of 0, 4, 8, 20, 35, or
50 mg mercuric acetate per kg (0, 2.5, 5, 13, 22, or 32 mg Hg/kg, respectively) on
Gestation Day 8 resulted in a significant decrease in the percentage of normal embryos and a
significant increase in the percentage of small embryos at 4 mg mercuric acetate per kg.
At 8 mg mercuric acetate per kg, significant increases in resorptions and abnormal, retarded,
edematous, and malformed fetuses were observed. Intraperitoneal administration of 0, 2,
4, or 8 mg mercuric acetate (0, 1.3, 2.5, or 5 mg Hg/kg, respectively) on Gestation Day 8
resulted in significant increases in the percentage of resorptions and abnormal, small, and
edematous fetuses at 2 mg mercuric acetate per kg. Intravenous administration of 0 or 4 mg
mercuric acetate per kg (0 or 2.5 mg Hg/kg) on Gestation Day 8 resulted in significant
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increases in resorptions and abnormal, small, retarded, edematous, and malformed fetuses at
4 mg mercuric acetate per kg. Comparison of the extent of the developmental toxicity
demonstrated that the efficacy for developmental toxicity was as follows: intraperitoneal >
intravenous > subcutaneous > oral.
A high rate of embryotoxicity was observed in hamsters following subcutaneous
injection of pregnant females with 9.4 mg Hg/kg as mercuric acetate (15 mg/kg mercuric
acetate) on Day 8 of gestation and examined on Days 12 or 15 (Gale, 1981). Adverse effects
included embryonic death and both external and internal abnormalities, especially edema and
cardiac abnormalities; significant variation in embryotoxicity was observed between several
strains of hamsters, indicating that the genotype of an individual is important in the
interaction with the teratogenic agent.
Kavlock et al. (1993) injected pregnant Sprague-Dawley rats (6 to 25 per group)
subcutaneously with 0, 1, 2, 3, or 4 mg mercuric chloride per kg (0, 0.7, 1.5, 2.2, or
3.0 mg Hg/kg, respectively) on Gestation Day 7, 9, 11, or 13. On Gestation Day 21, rats
were sacrificed. No increase in malformations was observed in fetuses from mercuric
chloride-treated dams. Exposure on Gestation Day 7 resulted in a significant decrease in fetal
weight and an increase in the number of supernumerary ribs (significance not reported) at
3 mg mercuric chloride per kg. Exposure on Gestation Day 9 resulted in significantly
decreased live fetuses per litter and increased resorptions at 4 mg mercuric chloride per kg.
Exposure on Gestation Day 11 or 13 resulted in no significant differences in fetal parameters.
6.3 ORAL EXPOSURE STUDIES
A group of abstracts by Pritchard et al. (1982a,b) and McAnulty et al. (1982) report on
a series of investigations into the potential for oral exposures to inorganic mercury to cause
reproductive and developmental effects. They reported no decrease in litter size or viability
from oral doses (exposure protocol not given) of 4, 8, or 16 mg HgCl2/kg administered daily
from Day 15 postcoitum until Day 25 postpartum. No marked adverse effects on
development or behavior of the offspring were reported, but the weight of 1-day-old offspring
was reduced at 8 mg HgCl2/kg/day, and subsequent weight gain of offspring in all HgCl2-
treated groups was reduced. Dosages up to 16 mg HgCl2/kg/day were reported to have had
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no adverse effects on morphogenesis, but, at 24 mg HgCl2/kg/day, delayed ossification and a
range of major malformations were observed in a small number (not specified) of fetuses
(McAnulty et al., 1982). These results Pritchard et al. (1982b) reported no reproductive
effects (i.e., effects upon fertility, conception, survival in utero) in female rats exposed
(duration of exposure not specified) before mating and during gestation to as much as 12 mg
HgCl2/kg/day. At doses of 16 mg HgCl2/kg/day and higher, they reported marked weight
reduction in the dams, irregular or abolished oestrous cycles, and high preimplantation losses.
An overview of these abstracts is provided as qualitative evidence of reproductive and
developmental effects from HgCl2 exposure. Although these data provide some indication of
the low potency of inorganic mercury relative to organic mercury (McAnulty et al., 1982),
they should not be relied on for a quantitative assessment due to the limited reporting of
experimental detail and the lack of supportive statistics.
Gale (1974) administered 0, 4, 8, 25, 35, 50, 75, or 100 mg mercuric acetate per kg
(0, 2.5, 5, 16, 22, 32, 47, or 63 mg Hg/kg, respectively) to pregnant golden hamsters
(10 per dose except controls; 3 controls were used) by gavage in distilled water on Gestation
Day 8. The pregnant animals were sacrificed on Gestation Day 12 or 14, and the uterine
contents were examined. A statistically significant increase in the incidence of abnormal
fetuses (combined incidence of small, retarded, edematous, and malformed fetuses) was
observed at 25 mg mercuric acetate per kg. Statistically significant increases in the
percentage of resorbed fetuses was observed at 35 mg mercuric acetate per kg and, in the
percentages of small, retarded, and edematous fetuses, were observed at 50 mg mercuric
acetate per kg. No treatment-related effects were observed on the fetuses at 8 mg mercuric
acetate per kg.
Rizzo and Furst (1972) administered 2 mg Hg as mercuric oxide (approximately
7 mg Hg/kg) to pregnant Long-Evans rats (five per group) by gavage in peanut oil on
Gestation Day 5, 12, or 19 in a pilot study. On Gestation Day 20 or 21, the rats were
sacrificed, and the uterine contents were examined. Rats administered mercury on Gestation
Day 5 had a higher percentage of fetuses with growth retardation and inhibition of eye
formation (statistical significance not reported). Similar increases in these effects were not
observed after administration on Gestation Day 12 or 19.
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6.4 INHALATION EXPOSURE STUDIES
Selypes et al. (1984) reported an increase in both dominant lethal mutations and
chromosomal aberrations in embryonic cells following inhalation exposure of pregnant mice
to aerosols of HgCl2 (0.17 and 1.6 mg Hg/m3 [0.23 and 2.1 mg HgCl2/m3, respectively],
4 h daily during pregnancy). They also reported both decreased fetal weight and some
skeletal abnormalities in offspring. However, this study was difficult to interpret because it
did not characterize exposure completely (e.g., particle size was not given), report the
number of animals in any group, or employ any tests of statistical significance; and it did not
demonstrate a clear LOAEL.
6.5 HUMANS
There is no available epidemiological evidence concerning reproductive effects of
mercury in humans (Sager et al., 1986). Only one report is available concerning potential
effects of divalent mercury on human fetuses. Afonso and De Alvarez (1960; cited in Koos
and Longo, 1976) describe the case of a pregnant woman who ingested 2.5 g HgCl2 in an
attempt to induce abortion. She developed inorganic mercury poisoning, including acute
renal failure. She did abort the infant, which appeared grossly normal, but it is not clear
whether the abortion was induced by the HgCl2, the general toxicity of the HgCl2 to the
woman, or from the procedures used to treat the poisoning (Koos and Longo, 1976):
No epidemiological studies are available concerning developmental effects of HgCl2 on
humans, nor are any specific developmental abnormalities known to be associated with human
exposure to HgCl2.
6.6 SUMMARY
Several conclusions can be made from the results of the studies described thus far.
Divalent mercury, and specifically HgQ2, has definite adverse reproductive effects on
experimental animals at certain exposure levels. Both ovulation and spermatogenesis can be
delayed or reduced (Sager et al., 1986; Lee, 1983; Mattison et al., 1983; Pritchard et al.,
1982b; Watanabe et al., 1982; Lee and Dixon, 1975). Mercuric chloride is toxic to embryos
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of various stages both in vitro and in vivo (Kajiwara and Inouye, 1986a,b; Katayama and
Matsumoto, 1985; Mueller et al., 1985; Katayama et al., 1984; Kitchin et al., 1984;
Matsumoto et al., 1984; Selypes et al., 1984; McAnulty et al., 1982; Pritchard et al., 19825;
Gale, 1981). Adverse effects on embryos have been observed at in vitro HgCl2
concentrations as low as 0.3 mg Hg/L (1 /nM) after single in vivo intravenous injection doses
to mouse dams above 1.0 mg Hg/kg (Kajiwara and Inouye, 1986a) and following repeated
oral doses to rat dams above 12 mg HgCl2 kg/day (Pritchard et al., 1982b). Decreased
maternal weight and other signs of maternal toxicity were reported in some of the studies, as
was decreased fetal or neonatal weight (Kajiwara and Inouye, 1986a; Selypes et al., 1984;
McAnulty et al., 1982; Pritchard et al., 1982b; see also Magos and Webb, 1983).
Treatment by HgCl2 injection during early to midgestation appeared to have a greater
effect than treatment during late gestation (Pritchard et al., 1982a), although there are not yet
enough available studies with which to make an adequate comparison. Two types of evidence
*»
support this idea, however. One is the finding by Kajiwara and Inouye (1986a) that mercury
concentrations in the female reproductive tract decline only slightly with time after injection
of the animal with HgCl2, 'indicating that early embryos in this study were potentially
exposed to mercury through the whole preimplantation period. The second type of evidence
is the finding that the mercuric ion is poorly transported across the placenta (much less so
than either metallic mercury or methyl mercury), but rather is concentrated in the placenta
(see Ogata and Meguro, 1986; Sager et al., 1986; Khayat and Dencker, 1982; Clarkson
et al., 1972). Ogata and Meguro (1986) reported ratios of mercury concentration of 0.420,
0.015, and 0.006 for placenta/maternal blood, fetus/placenta, and fetus/maternal blood,
respectively, for pregnant mice injected with HgCl2 on Day 18 of gestation. In other words,
the placenta contained almost half the concentration of mercury that was found in maternal
blood, and fetuses contained 0.6% of the maternal blood mercury concentration. Several
authors report inhibition of placental transfer of nutrients by divalent mercury (e.g., Shoaf
et al., 1986; Danielsson et al., 1984; Goodman et al., 1983; Miller and Holliday, 1982), and
Sager et al. (1986) have suggested that mercury accumulation in the placenta compromises
the development of the fetuses.
In summary, the experimental animal studies cited in this section indicate that HgCl2
can affect essentially all aspects of reproduction and development. The disruption in
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placental function and ensuing embryotoxicfty caused by both in vivo and in vitro exposure to
HgCl2 provide sufficient evidence to consider this agent as a developmental toxicant in
experimental animals and a likely developmental toxicant in humans. However, there is
insufficient information to develop an exposure-response assessment for laboratory animals or
humans for either the oral or inhalation routes of exposure.
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7. OTHER TOXIC EFFECTS
7.1 ACUTE TOXICITY
Most reported cases of acute HgCl2 poisoning occur by oral ingestion of the salt
(Winship, 1985; Gerstner and Huff, 1977; Goldwater, 1972; Worth et al., 1984; Giunta
et al., 1983; Newton et al., 1983; Stack et al., 1983; Samuels et al., 1982; Winek et al.,
1981; Chugh et al., 1978), although systemic poisoning may occur from absorption through
the skin (Winship, 1985; Gosselin et al., 1984). Skin contact with HgCl2 may also cause
skin irritation and dermatitis, and contact with the eyes may cause ulceration of the
conjunctiva and cornea (Gosselin et al., 1984).
The critical organs for cases of acute ingestion of high doses of HgCl2 are the
gastrointestinal tract and the kidneys. The salt, or a concentrated solution of the salt, has a
corrosive effect on the mucous membranes of the digestive tract (Berlin, 1986; Winship,
1985; Gosselin et al., 1984; Gerstner and Huff, 1977). Injury to the mouth, esophagus, and
stomach is almost instantaneous and causes severe pain (Gosselin et al., 1984; Gerstner and
Huff, 1977). The action of the salt causes extensive precipitation of proteins, and symptoms
of poisoning include tissue necrosis, ashen discoloration of the exposed skin, a metallic taste,
and a sense of oral and pharyngeal constriction (Berlin, 1986; Hayes, 1982; Gerstner and
Huff, 1977). Vomiting usually ensues within a few minutes. If the HgCl2 is permitted to
reach the lower gastrointestinal tract, the result is a severe, bloody diarrhea with necrosis of
the intestinal mucosa (Berlin, 1986; Winship, 1985; Hayes, 1982). In some cases, death
from circulatory collapse may occur within a few hours. In patients who survive the
gastrointestinal damage, renal failure generally occurs within 24 h; the major damage is
necrosis of the proximal tubular epithelium, although glomerular damage may also occur
(Berlin, 1986; Winship, 1985). Anuria and uremia follow, and without treatment death will
occur within a few days (Berlin, 1986; Gosselin et al., 1984). Similar results will occur
following poisoning with any ionizable mercuric compound; the anion seems not to be a
major factor (Gerstner and Huff, 1977).
Oral doses as low as 0.5 g of HgCl2 have proved fatal, although the mean lethal dose in
adults is probably 1 to 4 g (Gosselin et al., 1984). The lethal concentration of mercury in
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the blood is 15 mg/L (Worth et al., 1984; Winek et al., 1981), as compared with normal
values of up to 10 j«g/L (Gerstner and Huff, 1977; see Section 4.2). With adequate and
timely treatment, patients with initial blood mercury levels as high as 1.2, 1.9, and 4.5 mg/L
have recovered completely (Newton et al., 1983; Stack et al., 1983; Samuels et al., 1982).
Following poisoning with mercuric salts, mercury levels in the kidney of 10 to 70 mg/kg
have been reported (Berlin, 1986), in contrast to normal values of <0.1 to 3 mg/kg (see also
Section 4.2). The lowest kidney mercury concentration reported for a fatal case of divalent
mercury poisoning is 16 mg/kg wet weight, measured at death, 6 days after the mercury
intake (Suzuki, 1979).
Acute poisoning also" has been reported in surgical patients following irrigation of the
wound with a solution of HgCl2 (0.1 to 0.2%) in an effort to kill remaining cancer cells
(Gelister et al., 1985; Laundy et al., 1984; Dick, 1983; Elliott and Dale, 1983; Lai et al.,
1983). Renal failure was the major derangement noted, although circulatory collapse,
vomiting, bloody diarrhea, nausea, abdominal pain, and a metallic taste in the mouth also
have been reported (Laundy et al., 1984; Lai et al., 1983). Recovery often occurs, with the
help of hemodialysis, but several fatalities from this treatment have been reported (see
Laundy et al., 1984; Dick, 1983). Other chemicals are available that are at least as effective
as HgCl2 in destroying stray cancer cells (Umpleby and Williamson, 1984), and it has been
suggested that HgCl2 should no longer be used for this purpose because of the high risk of
renal failure and death (Gelister et al., 1985; Laundy et al., 1984; Dick, 1983; Elliott and
Dale, 1983; Lai et al., 1983).
The kidneys of newborn and suckling rats are less sensitive to inorganic mercury
toxicity than are the kidneys of adult rats, possibly because a smaller proportion of the dose
reaches the kidneys in the young animals (Daston et al., 1983, 1984, 1986; Jugo, 1979).
The difference in toxicity with age ultimately may be caused by differences in metallothionein
levels (see Section 4.2). Mercuric chloride was administered by subcutaneous injection in
these experiments. For young animals ingesting HgQ2 orally, the decreased sensitivity may
be offset somewhat by a greater gastrointestinal absorption of mercury (see Section 4.1).
No comparable data are available concerning acute nephrotoxicity of HgCl2 in newborn
humans.
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Despite much laboratory research, the pathogenesis of acute renal failure is not well
understood. Studies in rats injected once with 3.5 mg HgCl2/kg suggest that tubular
obstruction and back-leak of tubular fluid is the primary pathogenic mechanism in HgCl2-
induced acute renal failure and that hemodynamic factors such as a decrease in the glomerular
permeability coefficient may be secondary (Conger and Falk, 1986). However, the relative
contributions of these various factors during the different phases of acute renal failure is a
matter of considerable controversy. Contrary to some theories, the renin-angiotensin system
does not seem to be an important factor (Conger and Falk, 1986; Daston et al., 1983;
De Rougemont et al., 1982), and, despite some pharmacologic evidence that adenosine
mediates the observed hemodynamic changes, a recent bioassay to delineate the role of renal
adenosine system in HgCl2-induced renal failure provides no support for this hypothesis
(Rossi et al., 1990). The underlying mechanisms may involve effects of Hg2+ on essential
enzymes, membrane transport processes, and mitochondria! function resulting in necrosis of
cells, particularly in the proximal tubular region (see for instance Ansari et al., 1990, 1991;
Rossi et al., 1990; Bulger, 1986; Nicholson et al., 1985; Schwertz et al., 1985; Weinberg
et al., 1982a,b; Trifillis et al., 1981). In vitro exposure of human erythrocyte to HgCl2
causes a considerable decline in glutathione content (Bansal et al., 1992), and glutathione
depletion markedly alters the effects of HgCl2 on rat renal function (Ansari et al., 1991;
Guillermina et al., 1989). Mercuric chloride also enhances the rate of superoxide
dismutation, leading to increased production of hydrogen peroxide (H2O2), which may
contribute to its oxidative tissue damaging properties (Miller et al., 1991; Woods et al.,
1990a,b). Recent findings suggest that cytosolic calcium (Ca2+) deregulation may play a
role in HgCl2 toxicity (Smith et al., 1991).
7.2 SUBCHRONIC AND CHRONIC TOXICITY
7.2.1 Health Effects
Chronic exposure to mercuric compounds such as HgCl2 without concurrent exposure to
metallic mercury vapor is considered rare (Berlin, 1986). Chronic exposure to calomel
(mercurous chloride) or to mercury-containing skin ointments also is found (Dyall-Smith and
Scurry, 1990; Berlin, 1986; Winship, 1985).
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The major effect of chronic exposure to low levels of divalent mercury is kidney
damage; other symptoms in humans may include increased salivation, inflammation in the
gums, and black lines on the teeth (World Health Organization, 1991; Berlin, 1986). Renal
damage from chronic exposure to HgCl2 administered by gavage, subcutaneously or
intramuscularly has been observed in experimental work with mice, rats, and rabbits (Dieter
et al., 1992; National Toxicology Program, 1993; Andres and Brentjens, 1984; Enestrom
and Hultman, 1984; Madsen and Maunsbach, 1981). Bernaudin et al. (1981) identified
similar renal damage following repeated mercuric chloride intratracheal and aerosol exposures
to rats (see Section 8.6). Two types of renal damage have been observed in animals and
humans: (1) glomerular injury caused by an autoimmune reaction against the glomerular
tissue, and (2) tubular damage caused by necrosis in the proximal tubule (World Health
Organization, 1991; Berlin, 1986). Immune responses to inorganic mercury also are involved
in erythema and contact dermatitis following application of mercury compounds to the skin
(Berlin, 1986; Stokinger, 1981). Similar immune responses were also noted in the lungs and
spleens of rats intratracheally exposed to mercuric chloride (Bernandin et al., 1981).
Children between 4 mo and 4 years of age may develop a syndrome known as
acrodynia or pink disease following chronic exposure to low levels of any of a number of
mercurial compounds (Berlin, 1986; Bilderback and Anderson, 1975). This disease is
characterized by generalized body rash, pink coloring of the extremities, listlessness and
irritability, excessive perspiration and thirst, depressed appetite, and severe pain (Gosselin
et al., 1984; Bilderback and Anderson, 1975). Increased levels of mercury (usually
> 50 /xg/L) are found in the urine. Acrodynia is thought to be a special form of mercury
hypersensitivity, as only a fraction of chronically exposed children (perhaps 1 in 500) develop
the disease (Berlin, 1986; Winship, 1985; Bilderback and Anderson, 1975).
Mercury is a potent neurotoxin, and chronic exposure to methyl mercury compounds or
metallic mercury vapor in particular can cause severe damage to the human central nervous
system. Divalent mercury does not as readily pass the blood-brain barrier (see Section 4.2),
and its major effect in humans is on the kidneys. Ultrastructural alterations of brain cortex
have been observed in rats following intraperitoneal administration of a single dose (6 mg/kg
body weight) of mercuric chloride (Gajkowska et al., 1992). Behavioral effects have been
reported in animals following exposure to divalent mercury (Evans et al., 1975); neurological
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effects due to divalent mercury alone are probably possible in humans as well, but are likely
to be of less importance than renal effects. Chronic HgCl2 exposure in animals has also been
associated with systemic toxicity, poor appetite, decreased respiratory function, cardiovascular
effects, endocrinopathy, and skin conditions (National Toxicology Program, 1993; Agrawal
and Chansouria, 1989; Carmignani et al., 1983; McAnulty et al., 1982; Pritchard et al.,
1982b; Roberts et al., 1982).
7.2.2 Pathology of Immunological Effects
During the last two decades, great attention has been paid to effects of inorganic
mercury on the immune system. The most sensitive adverse effect caused by mercuric
mercury is the formation of mercuric-mercury-induced autoimmune glomeralonephritis,
particularly in the Brown Norway strain of rats. However, it is important to note that in at
least one other strain (Lewis rats) immunosuppression is observed (World Health
Organization, 1991). An autoimmunological origin of glomerular nephritis following
mercury exposure is well documented, however, in the Brown Norway strain of rat (Andres,
1984; Fukatsu et al., 1987; Knoflach et al., 1986; Druet et al., 1982a; Bernaudin et al.,
1981) and can occur at doses too low to cause toxic lesions such as renal tubular necrosis
(Knoflach et al., 1986). Brown Norway rats injected with low intravenous doses of HgCl2
have been shown to develop a variety of autoimmune abnormalities, including
lymphoreticular proliferation as indicated by spleen and lymph node enlargement, increased
production of nonspecific IgE, and development of circulating antibodies to the glomerular
basement membrane (Dubey et al., 1993; Esnault et al., 1992; Druet et al., 1978, 1982a).
Autoimmune disease of the kidney has been reported in the Brown Norway rat following
sc injection of 150 /j.g HgCl2/kg/week (Druet et al., 1978), gavage administration of
1,500 jtig HgCl2/kg/week (Knoflach et al., 1986) and 3,000 /xg HgCl2/kg/week (Bernaudin
et al., 1981), intratracheal installation of 110 to 750 /*g HgCl2/kg/week (Bernaudin et al.,
o
1981), or inhalation of an aerosol air concentration estimated at 1 mg HgQ2/nr (see
Chapters 1 and 8) for 1 h/day, 4 days/week for 2 mo (reported lung retention was 50 to
60 jug HgCl2/kg/h). No immunologic response to the kidney was seen following intratracheal
installation of 60 jug HgCl2/kg/week (Bemandin et al., 1981).
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This autoimmune response is not observed in other inbred strains of rats, indicating that
a genetic component is involved in susceptibility (Druet et al., 1982b). Several genes appear
to be involved, including genes linked to the histocompatibility complex (Druet et al., 1982b;
Sapin et al., 1982); however, the specifics of genetic control of HgCl2-induced autoimmunity
appears to be quite different between the animal species and strains (Saegusa et al. 1991).
The genotype of the host immune system seems to be more important than the genotype of
the kidney (Druet et al., 1983).
This autoimmune disease is characterized by the production of autoantibodies to renal
and extrarenal basement membranes. These antibodies are found deposited along the
glomerular basement membrane in a linear pattern. After 3 to 4 weeks, a typical
membranous glomerulopathy with granular, subepithelial immunoglobulin G (IgG) deposits is
observed. The majority of rats develop proteinuria, which progresses in some animals to
nephrotic syndrome (World Health Organization, 1991). The disease is transient, and rats
that do not die recover. The fine mechanism of action at the cellular level remains to be
fully elucidated. It is known that mercuric chloride induces a polyclonal activation of B cells
in Brown Norway rats (Pelletier et al., 1988a). T cells are required for this activation, as
Brown Norway rats depleted of T cells are resistant (Pelletier et al., 1987a). T cells from
Brown Norway rats injected with mercuric chloride are able to transfer autoimmune
manifestations to normal Brown Norway recipients and Brown Norway rats depleted of
T cells (Pelletier et al., 1988b).
Different effects of HgCl2 on the immune system have been observed in other rat
strains and in mice. Decreased hemolytic complement activity has been observed in
intravenously exposed Wister rats (Asahara and Mochizuki, 1981). Induction of antinuclear
antibodies has been described in several other strains of rats and mice (Goter Robinson,et al.,
1984, 1986; Hultman and Enestrom, 1992; Kubicka-Muranyi et al., 1993). In sharp contrast
to Brown Norway rats, Lewis rats are genetically resistant to induction of autoimmunity via
injection of HgCl2. For this reason, HgCl2-induced immune dysregulation in the rat is being
used as a model to study the effects of an immunotoxic agent on different target cells (Dubey
et al., 1993; Pelletier et al., 1987b). Recent studies have demonstrated a dose-related
decrease in human lymphocyte (T and B cell) and monocyte viability and function (Shenker
et al., 1992a,b, 1993a).
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7.3 BIOCHEMICAL EFFECTS
Investigators have known for many years that the mercuric ion interacts readily with
sulfhydryl (SH) groups both on proteins and on small molecules such as glutathione
(MacGregor and Clarkson, 1974). Recent studies, however, provide evidence that the impact
of mercury on GSH levels may play an important role in the aforementioned cytotoxicity
associated with low-level mercury exposure (Shenker et al., 1993b; van der Meide et al.,
1993). Shenker et al. (1992a,b) found that mercury inhibited in vitro activation of T-cells
only in the presence of monocytes, and that, of the cells they examined, monocytes were the
most sensitive to the cytotoxic effects of mercury. Because monocytes are known to play a
role in regulating lymphocyte GSH levels, these investigators also determined the relation
between this mercury-induced cytotoxicity and GSH levels (Shenker et al., 1993b). They
found that sensitivity of human lymphocytes to the toxic effects of mercury is related to the
endogenous levels of GSH. They also determined that, at low concentrations, mercury
decreases the GSH concentration of lymphocytes and monocytes. Thus, because GSH
provides the major source of reducing equivalents in the cell, a decrease in the level of this
intermediate and subsequent alterations in the thiol redox could, at least in part, account for
the aforementioned cellular changes associated with low-level mercury exposure.
Mercury also may form complexes with various other ligands in biological systems,
including the nitrogen bases of DNA (Cantoni et al., 1984b; see Section 5.1). The specific
ligand (SH or non-SH) that combines with the mercuric ion is highly dependent on the
biological situation, including such factors as the ability of the mercuric ion to reach a certain
intracellular site and the availability and accessibility of specific ligand sites (MacGregor and
Clarkson, 1974). Many of the physiological effects of mercury probably are attributable to
the effects of its binding to and subsequent altering of various macromolecules, including but
not limited to SH-containing enzymes.
' Mercuric chloride has been shown to inhibit a number of enzymes either in vitro or
in vivo, including (but not limited to) lactate dehydrogenase, glutamic-oxaloacetic transferase,
carbonic anhydrase, adenosine triphosphatase, acetylcholinesterase, ribonuclease, lipase,
thyroid peroxidase, urease, hexokinase, .alkaline phosphatase, glucose-6-phosphatase, and
Na+/K+-ATPase (Nishida et al., 1990; Magour et al., 1987; Magour, 1986; Mehra and
Kanwar, 1986; Lai and Barrow, 1984; Christensen et al., 1982). Other enzymes, such as
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acid phosphatase or alkaline phosphatase in certain tissues (Mehra and Kanwar, 1986) and
renal UDP glucuronyl transferase (Tan et al., 1990) may be induced by HgCl2. Inhibition or
induction of enzymes in vivo is tissue and enzyme specific, and may vary with the duration
of exposure, level of maturity or sex of the individual (Dieter et al., 1992; Mehra and
Kanwar, 1986; Bartolome et al., 1984). For example, urinary levels of alkaline phosphatase
and gamnia-glutamyl transferase were higher in both male and female rats at 4 mo, higher
only in female rats at 6 mo, and no different from controls in either sex after 2 years of
gavage exposures (5 days/week) to HgCl2 (Dieter et al., 1992).
Mercuric chloride induces biosynthesis of metallothionein in experimental animals,
especially in the kidneys, and the binding of the mercuric ion to metallothionein is involved
in the accumulation of mercury in the kidney (Berlin, 1986; Chmielnicka et al., 1983;
Piotrowski et al., 1974). Urinary metallothionein levels also increase following exposure to
mercury (Lee et al., 1983). The increase in kidney metallothionein does not occur in the
presence of selenium (Chmielnicka et al., 1986); selenium appears to have an antagonistic
effect on the acute toxicity of HgCl2, diminishing the affinity of Hg for the kidney and
increasing the whole-body retention of mercury (Christensen et al., 1991; Chmielnicka et al.,
1986). Other metals such as zinc, tellurium, and copper also may be involved in the
metabolism of Hg or Hg2+ in the mammalian body, and vice versa (e.g., Chmielnicka et al.,
1983, 1986; FuMno et al., 1986; Khayat and Dencker, 1984). Muto et al. (1991) observed
increased copper levels in the livers and kidneys of rats 24 h after injection with 1 mg
HgCl2/kg. Selenium, zinc, and tellurium seem to decrease the toxicity of inorganic mercury,
possibly by mechanisms involving glutathione complexes (see Fukino et al., 1986; Morimoto
etal., 1982; Naganumaet al., 1982).
Other biochemical effects of HgCl2 include inhibition of the polymerization of
microtubules (De Saint-Georges et al., 1984), altered release of neurotransmitter substances
(McKay et al., 1986a,b), changes in calcium homeostasis (McKay et al., 1986b; Shier and
DuBourdieu, 1983), induction of phospholipid hydrolysis and prostaglandin synthesis (Shier
and DuBourdieu, 1983), inhibition of vasopressin release (Clifton et al. 1986), inhibition of
glucose metabolizing enzymes (Dieter et al., 1983), initiation of peroxidation in erythrocytes
(Ribarov et al., 1983, 1984), and alterations in the complement system (Asahara and
Mochizuki, 1981). Mercuric chloride also causes structural and functional damage to
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biological membranes, resulting in altered permeability of cells at an in vitro exposure
concentration of 10~5 M (Walum and Marchner, 1983) or altered mitochondria! function in
rats as a result of subcutaneous injection of 5 mg HgCl2/kg (Weinberg et al., 1982a,b).
In short, a large number of cellular and subcellular systems or functions are adversely
affected by the presence of HgCl2 or the mercuric ion. Many of the pathogenic effects of
HgCl2 probably occur as a result of general disruption of cellular metabolism causing general
toxicity to cells, tissues, or entire organisms (see Section 5.1 and Chapter 6).
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8. U.S. ENVIRONMENTAL PROTECTION AGENCY
CANCER AND NONCANCER ASSESSMENTS
8.1 CARCINOGENICITY
On January 13, 1988, EPA's Carcinogen Risk Assessment Verification Exercise
(CRAVE) Work Group assigned inorganic mercury a "D" classification ("not classifiable as
to human carcinogenicity"). The results of a chronic, gavage exposure carcinogenicity study
recently were finalized by NTP (National Toxicology Program, 1993). On March 3, 1994,
EPA's CRAVE Work Group reassigned inorganic mercury a "C" classification, which means
that inorganic mercury is a "possible human carcinogen". This reclassification should be
considered preliminary until it is officially posted on the EPA Integrated Risk Information
System (IRIS) database. It is based on evidence of carcinogenicity in rats and mice following
gavage exposures (National Toxicology Program, 1993) (see Section 5.2). No human data
are available. No quantitative cancer risk assessment has been performed for inorganic
mercury.
8.2 DRINKING WATER EQUIVALENT LEVEL
On October, 26 and 27, 1987, a panel of mercury experts met at a Peer Review
Workshop on mercury issues in Cincinnati, OH, and reviewed outstanding issues concerning
the health effects and dose-response assessment of inorganic mercury (U.S. Environmental
Protection Agency, 1988a). Drinking Water Equivalent Level (DWEL) values were derived
for several individual studies, including Druet et al. (1978). In this study, Brown-Norway
rats were exposed to mercuric chloride via subcutaneous injection, 3 times/week for 8 weeks.
The dose levels were 0, 100, 250, 500, 1,000, and 2,000 /ttg/kg, and there were 6 to
20 animals/groups. An additional group of animals received 50 /tg/kg for 12 weeks.
Proteinuria occurred at doses £100 /tg/kg (LOAEL); the proteinuria was considered a highly
deleterious effect, as if frequently let to hypoalbuminemia and even death. A DWEL of
7.0 /ig/L was calcuated.
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In a 60-day study conducted by Bernaudin et al. (1981), Brown-Norway rats (5/dose
groups) were force-fed 0 or 3,000 /ig/kg/week mercuric chloride. At the end of the 60 days,
there were no histological abnormalities in the kidneys of treated animals. Using
immunofluorescence, however, IgG deposition was evidence in all of the treated rats, and
weak proteinuria was noted in 3/5 dosed animals. Based on the LOAEL of
3,000 /ig/kg/week, the EPA derived a DWEL of 11 fig/L. Similar results were obtained by
Andres and Brentjens (1984). Brown-Norway rats were exposed to 3,000 /ng/kg mercuric
chloride via gavage 2 times/week for 60 days. After 60 days, the kidneys of all treated
animals appeared normal histologically and there no proteinuria was reported in any treated
animals, but IgG deposition in the renal'glomeruli was demonstrated using
immunofluorescence in Brown-Norway rats. Based on the LOAEL of 3,000 jug/kg, a DWEL
of 22 jfg/L was deterimed.
Some of the consensus conclusions and recommendations that resulted from this
workshop are presented below.
The most sensitive adverse effect for mercury risk assessment is formation
of mercuric-mercury-induced autoimmune glomerulonephritis. The
production and deposition of immunoglobulin G (IgG) antibodies to the
glomerular basement membrane can be considered the first step in the
formation of this mercuric-mereury-induced autoimmune glomerulonephritis. ,
The Brown Norway rat should be used for mercury risk assessment. The
Brown Norway rat is a good test species for the study of autoimmune
glomerulonephritis. The Brown Norway rat is not unique in this regard
(this effect has also been observed in rabbits).
The Brown Norway rat is a good surrogate for the study of mercury-induced
kidney change in sensitive humans. For this reason, the uncertainty factor
used to calculate criteria and health advisories (based on risk assessments
using the Brown Norway rat) should be reduced by 10-fold.
A drinking water equivalent level (DWEL) of 0.010 mg/L was
recommended based on the weight of evidence from the studies using Brown
Norway rats and limited human tissue data.
Thus, three studies using the Brown Norway rat as the test strain, Druet et al. (1978),
Bernaudin et al. (1981), and Andres and Brentjens (1984), were chosen from a larger
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selection of studies as the basis for the panel's recommendation of 0.010 mg/L as the DWEL
for inorganic mercury (U.S. Environmental Protection Agency, 1988a).
8.3 MAXIMUM CONTAMINANT LEVEL GOAL
The EPA promulgated a maximum contaminant level goal (MCLG) of 0.002 mg/L
(Federal Register, 1991) based upon this DWEL and an assumed drinking water contribution
of 20% (i.e., the MCLG assumes that drinking water exposure accounts for just 20% of an
individual's total exposure to inorganic mercury).
8.4 MAXIMUM CONTAMINANT LEVEL
The maximum contaminant level (MCL) is equal to the MCLG of 0.002 mg/L. Ground
water systems must be monitored every 3 years and surface water systems must be monitored
annually to ensure compliance with the MCL.
8.5 ORAL REFERENCE DOSE
An oral Reference Dose for chronic oral exposure (RfD) of 3 E-4 mg/kg/day has been
determined by the EPA, based on autoimmune glomerulonephritis observed in rats. The RfD
was back-calculated from the 0.01 mg/L DWEL discussed previously.
8.6 INHALATION REFERENCE CONCENTRATION
Only two studies on the health effects of inhaled mercuric chloride are available, one
investigating autoimmune disease in rats (Bernaudin et al., 1981) and the other genotoxicity
and developmental effects in mice (Selypes et al., 1984).
Bernaudin et al. (1981) exposed Brown Norway rats (male and female, number per
gender not specified) to aerosols of mercuric chloride for 4 h/week for 2 mo. The exposure
was not well characterized (i.e., no mass median aerodynamic diameter or sigma g provided,
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and the particle generation system was not adequately described). The authors calculated a
retained amount of 5 to 6 jwg HgCl2/h/100 g of body weight based on radiolabeled mercury.
During immunomorphological studies of the pattern of fixation of fluoresceinated sheep
anti-rat IgG conjugates to kidney biopsies during the exposure period (Day 15) and to kidney,
lung, and spleen tissue from sacrificed animals at the conclusion of the exposure period
(Day 60), the following were observed: linear pattern of fixation in kidney glomeruli for
five of five rats at Day 15 and granular pattern of fixation in kidney glomeruli and arteries,
lung, and spleen for three of three rats at Day 60. The difference in the number of animals
for which observations were made at the conclusion of the exposure period (i.e., three rather
than five) was not explained. In two of three rats exposed to aerosols and examined when
sacrificed, weak proteinurea (1, 28, and 47 mg/day) was detected. Data for 22 control rats
(10 administered acidic water, 10 injected subcutaneously, 7 exposed to aerosol, and 5 force-
fed) were presented together with no report on statistical analysis. No fixation of IgG
conjugate was observed in any of the control animals.
Selypes et al. (1984) exposed an unspecified number of female CFLP mice to an
uncharacterized aerosol of 2.1 or 0.23 mg/m3 for 4 h on 4 days during pregnancy (Days 9 to
12). A "significant" increase in dead embryos and postimplantation dominant lethals at both
concentrations was reported. Values are provided for controls, but no statistical analysis is
mentioned. A "significant" increase in the number of embryos with bone aberrations
(retardation symptoms described as similar to those caused by lead) was also reported at both
concentrations, but no changes indicating teratogenic effects were found based on
"investigation of the inner organs." Significantly increased numbers of embryonic cells with
chromosomal aberrations (most frequently deletions) were reported.
No information is available on the health effects of inhaled mercuric chloride in
humans. Information on health effects from oral exposures is principally from accidental or
intentional acute oral exposures. These ingestions can be fatal and often involve corrosive
effects on the gastrointestinal tract and occasionally renal failure (Troen et al., 1951).
Due to the limitations of the available inhalation studies and the inadequacy of the
toxicologic and pharmacokinetic data bases, the EPA RfD/RfC Work Group determined that
derivation of an RfC is not possible. The posting of this determination on the EPA IRIS
database is proceeding concurrent with the finalization of this document.
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