United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
EPA-600/8-84-019F
August 1984
Final Report
xvEPA
Research and Development
Mercury Health
Effects Update
Health Issue
Assessment
Final
Report
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EPA-600/8-84-019F
August 1984
Final Report
Mercury Health Effects
Update
Health Issue Assessment
U.S. Environmental Protection Agency
Region 5, Library (PL-12J)
77 West Jackson Boulevard, 12th float
Chicajo, ft 60604-3590
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Research Triangle Park, NC 27711
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NOTICE
This document has been reviewed in accordance with the U.S. Environmental
Protection Agency's peer and administrative review policies and approved for
presentation and publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
U,S. Environmental Protection Agency
11
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PREFACE
The Office of Health and Environmental Assessment, in consultation with
other Agency and non-Agency scientists, has prepared this mercury health effects
update at the request of the Office of Air Quality Planning and Standards.
In the development of this report, the scientific literature has been
inventoried, key studies have been evaluated, and summary/conclusions have
been prepared such that the toxicity of mercury is qualitatively and, where
possible, quantitatively identified. Observed effect levels and dose-response
relationships are discussed where appropriate in order to place significant
health responses in perspective with observed environmental levels.
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ABSTRACT
Mercury is unique amongst the metals as being the only metal in a liquid
form at room temperature. It exists in thr^e oxidative states—metal! ic
(Hg°), mercurous (Hg- ), and mercuric (Hg ) mercury—and a wide variety of
chemical forms, the most important being compounds of methyl mercury, mercuric
mercury, and the vapor of metallic mercury. The global cycle of mercury
involves the emission of Hg° from land and water surfaces to the atmosphere,
transport of Hg° in the atmosphere on a widespread basis, possible conversion
to unidentified soluble species and return to land and water of various deposi-
tional processes. The major source of human exposure to mercury (methyl
mercury) is via the diet, through the consumption of fish and fish products.
Uptake of mercury vapor is through inhalation, whereas uptake of inorganic
and methyl mercury compounds is primarily through oral ingestion. Once ab-
sorbed, mercury in all forms is distributed via the bloodstream to all tissues
in the body; however, in the case of methyl mercury, tissue distribution is
more uniform. Mercury vapor and methyl mercury readily cross the blood-brain
and placenta! barriers.
Chronic exposures to mercury compounds primarily affect the central
nervous system and kidneys. Depending upon the form of mercury and level of
intake, effects on the adult nervous system can range from reversible pares-
thesias and malaise to irreversible destruction of neurons in the cerebellar
and visual cortices, leading to permanent signs of ataxia and constriction of
the visual field. Prenatal life is the most sensitive stage of the life cycle
to methyl mercury poisoning, with effects in infants ranging from psychomotor
retardation to a severe form of cerebral palsy. All prenatal effects to date
have been found to be irreversible.
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TABLE OF CONTENTS
Llbl
LIST
1.
2.
3.
4.
Uh 1 ABLhb
OF FIGURES
INTRODUCTION
SUMMARY AND CONCLUSIONS
2.1 THE NATIONAL EMISSION STANDARD OF 1973
2.1.1 Di rect Exposure Effects
2.1.2 Indirect Exposure Effects
2. 2 FINDINGS OF CURRENT REPORT
2.2.1 Mercury Background Information
2.2.1.1 The Global Cycle
2.2.1.2 Biomethylation of Inorganic Mercury
2.2.1.3 Levels of Mercury in Air, Water, and Food ...
2.2.2 Pharmacokinetics and Biotransformation of Mercury
in Man and Animals
2.2.2.1 Vapor of Metallic Mercury
2.2.2.2 Compounds of Inorganic Mercury
2.2.2.3 Methyl Mercury Compounds
2.2.3 Toxic Effects of Mercury in Man and Animals
2.2.3.1 Vapor of Metal 1 ic Mercury ,
2.2.3.2 Inorganic Compounds of Mercury
2.2.3.3 Compounds of Methyl Mercury ,
2.2.4 Human Health Risk Assessment of Mercury in Air
2.2.4.1 Direct Exposure Effects
2.2.4.2 Indirect Exposure Effects
MERCURY BACKGROUND INFORMATION
3. 1 PHYSIOCHEMICAL PROPERTIES OF MERCURY
3.1.1 Sampling and Analysis
3. 2 ENVIRONMENTAL CYCLING OF MERCURY
3. 2. 1 Global Cycles
3.2.2 Chemical and Biochemical Cycles of Mercury
3. 3 LEVELS OF MERCURY IN VARIOUS MEDIA
3.3.1 Mercury in Ambient Air
3.3.2 Mercury in Ocean and Coastal Waters
3.3.3 Mercury in Drinking Water
3.3.4 Mercury in Food
3.3.5 Relative Contributions of Various Media to Human
Exposure
3.4 SUMMARY
PHARMACOKINETICS AND BIOTRANSFORMATION IN MAN AND ANIMALS
4. 1 VAPOR OF METALLIC MERCURY
4. 1. 1 Routes of Absorption
4. 1. 1. 1 Lung
4.1.1.2 Skin
VI 1 1
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2-2
2-2
2-2
2-2
2-3
2-4
2-4
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2-5
2-5
2-6
2-7
2-7
2-8
2-8
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3-1
3-1
3-1
3-5
3-5
3-7
3-11
3-12
3-13
3-13
3-14
3-18
3-19
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4-1
4-1
4-2
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TABLE OF CONTENTS (continued)
4.1.2 Deposition and Retention 4-2
4.1.2.1 Blood 4-5
4.1.2.2 Brain 4-7
4.1.2.3 Fetus 4-9
4.1.2.4 Kidney 4-9
4.1.3 Excretion 4-10
4.1.4 Biotransformation, Speciation and Transport 4-13
4.1.4.1 Biotransformation 4-13
4.1.4.2 Speciation 4-17
4.1.4.3 Transport 4-20
4.2 COMPOUNDS OF INORGANIC MERCURY 4-24
4.2.1 Compounds of Mercurous Mercury 4-24
4.2.2 Compounds of Mercuric Mercury 4-24
4.3 METHYL MERCURY COMPOUNDS 4-26
4.4 PHENYLMERCURY AND RELATED COMPOUNDS 4-30
4.5 SUMMARY 4-32
5. TOXIC EFFECTS OF MERCURY IN MAN AND ANIMALS 5-1
5.1 VAPOR OF METALLIC MERCURY 5-1
5.1.1 Local Effects 5-1
5.1.2 Systemic Effects 5-1
5.1.2.1 Central Nervous System Effects and
Neurological Effects 5-2
5.1.2.2 Oral Effects 5-6
5.1.2.3 Renal Effects 5-6
5.1.2.4 Reproductive and Developmental Effects 5-9
5.1.2.5 Mutagenic and Carcinogenic Effects 5-11
5.1.2.6 Other Effects 5-11
5.2 OTHER FORMS OF MERCURY 5-12
5.2.1 Inorganic Mercury Compounds 5-12
5.2.2 Methyl Mercury Compounds 5-14
5.2.3 Phenylmercury and Related Compounds 5-15
5.3 INTERACTIVE RELATIONSHIPS 5-17
5.3.1 Inhaled Mercury Vapor Versus Other Forms of Mercury ... 5-17
5.3.2 Other Factors Affecting the Toxicity of Inhaled
Vapor 5-18
5.4 SUMMARY 5-19
6. HUMAN HEALTH RISK ASSESSMENT OF MERCURY IN AIR 6-1
6.1 AGGREGATE HUMAN INTAKE 6-1
6.1.1 Inhaled Mercury Vapor 6-1
6.1.2 Other Forms of Mercury 6-2
6.2 SIGNIFICANT HEALTH EFFECTS 6-4
6.2.1 Inhaled Mercury Vapor 6-4
6.2.2 Compounds of Inorganic Mercury 6-5
6.2.3 Methyl Mercury Compounds 6-5
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TABLE OF CONTENTS (continued)
6.3 DOSE-RESPONSE AND DOSE-EFFECT RELATIONSHIPS 6-5
6.3.1 Inhaled Mercury Vapor 6-5
6.3.1.1 Indices of Exposure 6-5
6.3.1.2 Effect and Dose-response Relationships 6-11
6.3.1.2.1 Effects on the Nervous System 6-12
6.3.1.2.2 Effects on Kidney Function 6-17
6.3.1.2.3 Other Effects 6-18
6.3.1.2.4 Critique and Summary 6-21
6.3.1.3 Factors Affecting the Dose-response
Relationship 6-22
6.3.2 Compounds of Inorganic Mercury 6-23
6.3.3 Methyl Mercury Compounds 6-24
6.3.3.1 Indices of Exposure 6-24
6.3.3.2 Effects and Dose-response Relationships 6-25
6.3.4 Other Mercury Compounds 6-26
6.4 POPULATIONS AT RISK 6-27
6.5 SUMMARY 6-28
7. REFERENCES 7-1
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LIST OF TABLES
Table Page
3-1 Sources of Mercury in the Environment (1971) 3-6
3-2 Fish and Shellfish Consumption in the United States 3-16
4-1 Summary of Half-times of Mercury in Human Tissues 4-4
4-2 The Relative Amount of Mercury Excreted in Urine, Feces, and
Expired Air After Exposure to Mercury Vapor 4-11
6-1 Estimated Average Daily Intake (Retention) of Mercury
Compounds in the U.S. Population Not Occupationally Exposed
to Mercury 6-1
6-2 Medical Findings Related to Mercury Exposure 6-14
6-3 Medical Findings Not Related to Mercury Exposure 6-15
6-4 A Summary of the Relationship Between Observed Effects and
the Concentration of Mercury in Air and Urine 6-22
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LIST OF FIGURES
Page
4-1 Decay-corrected Rates for Four Positions of Crystal Detector
Plotted as a Function of Days After Exposure 4-3
4-2 The Fall in Mercury Concentrations in Blood in Two Adult
Females Following a Brief Exposure to Mercury Vapor 4-6
4-3 A Schematic Representation of the Fate of Inhaled Mercury
Vapor 4-12
4-4 The Deposition and Retention of Mercury in Red Blood Cells in
Volunteers Inhaling a Tracer Dose of Mercury Vapor 4-14
4-5 The Rate of Exhalation of Mercury From a Volunteer Who Received
a Brief (20 min) Exposure to Mercury Vapor Labelled With the
203Hg Isotope 4-16
4-6 Group Averages of Total Mercury Versus Stannous Chloride-
reducible Mercury Plus Elemental Mercury in Urine 4-23
5-1 Tremor Tracings From a Woman Exposed to Mercury Vapor in
a Plant Using Metallic Mercury to Calibrate Pipets 5-4
6-1 Relation of Concentration of Mercury in Blood to the
Corresponding Time-weighted Average Exposure Levels 6-7
6-2 Concentrations of Mercury in Urine (Uncorrected for Specific
Gravity) in Relation to Time-weighted Average Exposure
Level s 6-8
6-3 Concentrations of Mercury in Urine (Corrected to Specific
Gravity of 1.024) in Relation to Time-weighted Average
Exposure Levels 6-8
6-4 The Normalized Concentration of Urinary Mercury Concentration
Versus the 24-hour Mercury Excretion 6-10
6-5 Percentage Incidence of Certain Signs and Symptoms Related to
Exposure of Workers to Mercury 6-13
6-6 Relationship Between the Percentage of Abnormally High Urinary
Concentrations of (0) p2 Microglobulin and (A) Albumin and
Average Urinary Excretion of Mercury in 63 Workers in Two
Chlor-alkali Plants and in 88 "Control" Workers 6-19
6-7 Relationship Between Mercury Concentration in Urine and the
Prevalence of Signs of Renal Dysfunction 6-20
IX
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AUTHORS AND REVIEWERS
The principal author of this document is:
Dr. Thomas Clarkson
University of Rochester
Rochester, New York
Contributing authors:
Dr. Joan Cranmer
University of Arkansas for Medical Sciences
Little Rock, Arkansas
Ms. Donna J. Sivulka
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
Dr. Ralph Smith
University of Michigan
Ann Arbor, Michigan
Project Manager:
Ms. Donna J. Sivulka
Environmental Criteria and Assessment Office
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina
The following individuals reviewed earlier drafts of this document and submitted
valuable comments:
Dr. Joan Cranmer
University of Arkansas for Medical Sciences
Little Rock, Arkansas
Dr. Frank D'ltri
Michigan State University
East Lansing, Michigan
Dr. Rolf Hartung
University of Michigan
Ann Arbor, Michigan
Dr. Richard Henderson
Health Sciences Consultants
Osterville, Massachusetts
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Dr. Leonard Kurland
Mayo Clinic
Rochester, Minnesota
Dr. Steven Lindberg
Oak Ridge National Laboratory
Oak Ridge, Tennessee
Dr. Magnus Piscator
The Karolinska Institute
Stockholm, Sweden
Dr. Ellen Silbergeld
Environmental Defense Fund
Washington, DC
Dr. Ralph Smith
University of Michigan
Ann Arbor, Michigan
Dr. J. Jaroslav Vostal
General Motors Research Laboratory
Warren, Michigan
Dr. Bernard Weiss
University of Rochester
Rochester, New York
Dr. John Wood
University of Minnesota
Navarre, Minnesota
In addition, there are several scientists who contributed valuable information
and/or constructive criticism to interim drafts of this report. Of specific note
are the contributions of: Tracy Barber, Dianne Byrne, Jim Crowder, Rob Ellas,
Naum Georgeiff, Bob Kellam, Si Duk Lee, Ray Morrison, Chuck Nauman, Dave Patrick,
William Pepelko, and G11 Wood.
TECHNICAL ASSISTANCE
Project management, editing, production, word processing and workshop from
Northrop Services, Inc., under contract to the Environmental Criteria and Assess-
ment Office:
Ms. Tami Allen
Ms. Barbara Best-Nichols
Ms. Linda Cooper
Dr. Susan Dakin
Ms. Anita Flintall
Ms. Kathryn Flynn
Ms. Miriam Gattis
Ms. Varetta Powell
Ms. Patricia Tierney
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Word Processing and other technical assistance at the Office of Health
and Environmental Assessment:
Ms. Frances P. Bradow
Ms. Diane Chappell
Mr. Doug Fennel!
Mr. Allen Hoyt
Ms. Barbara Kearney
Ms. Emily Lee
Ms. Marie Pfaff
Ms. Donna Wicker
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1. INTRODUCTION
The purpose of this report is to review and evaluate the scientific infor-
mation on the potential health effects from mercury exposure, with particular
emphasis placed on those effects associated with human chronic inhalation expo-
sures. The findings of this report are based mainly on a review of the scien-
tific literature published since the promulgation of the 1973 National Emission
Standard for Mercury. However, literature published prior to 1973 has also been
evaluated if deemed relevant to the assessment of human health risks from air-
borne mercury.
This report is organized into chapters which provide a cohesive discussion
of all aspects of mercury exposure and delineate a logical linking of this infor-
mation to human health risks. The chapters include: an executive summary
(Chapter 2), which compares and contrasts the information of the past ten years
with information that served as the health basis in 1973; background information
on the chemical and environmental aspects of mercury, including the global cycling
of mercury and the levels of mercury in media with which U.S. population groups
come into contact (Chapter 3); mercury pharmacokinetics and metabolism, where
factors of absorption, biotransformation, tissue distribution, and excretion of
mercury are discussed with reference to the toxicity of the element (Chapter 4);
mercury toxicology, discussing the various acute, subacute, and chronic health
effects of mercury in man and animals (Chapter 5); and a human health risk assess-
ment for mercury, where key information from the preceding chapters is presented
in an interpretive and quantitative perspective highlighting those health effects
of most concern for U.S. populations (Chapter 6).
This report is not intended to be an exhaustive review of all the mercury
literature, but is focused upon those data thought to be most useful and relevant
for human health risk assessment purposes. Particular emphasis is placed on
delineation of health effects and risks associated with exposures to airborne
mercury in view of the most immediate use intended for this present report, i.e.,
to serve as a basis for decision making regarding the possible reconsideration
and revision of the 1973 emission standard. Health effects associated with the
ingestion of mercury or with exposure via other routes are also presented; how-
ever, a comprehensive discussion of these effects is not within the purview of
this report. The background information provided at the outset on sources,
emissions, and ambient concentrations of mercury in various media is presented
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in order to provide a general perspective against which to view the health
effects evaluations contained in later chapters of the report.
The Agency recognizes that the regulatory decision-making process is a con-
tinuous one; therefore, should new information become available in the future
that would warrant a reevaluation of the information contained herein, the Agency
will undertake such an evaluation as part of its mandate to protect the health
of the general U.S. population.
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2. SUMMARY AND CONCLUSIONS
This Chapter mainly summarizes the information contained within the text
of this report. However, for comparative purposes, a brief synopsis is pre-
sented of the scientific information that served as the health basis in the
promulgation of the 1973 National Emission Standard for Mercury.
2.1 THE NATIONAL EMISSION STANDARD OF 1973
On April 6, 1973, the U.S. Environmental Protection Agency promulgated a
National Emission Standard for Mercury as a Hazardous Air Pollutant under
Section 112 of the Clean Air Act (38 FR 8820). The scientific information
which served as the health basis for the standard is presented below.
2.1.1 Direct Exposure Effects
By 1973, the fact that exposure to metallic mercury vapor caused central
nervous system injury and renal damage was well established. Prolonged expo-
3
sure to about 100 ug Hg/m of mercury vapor involved a definite risk of mercury
intoxication. To determine the ambient air level of mercury that did not
impair health, the impact of airborne burden was considered in conjunction
with water and food burdens. Methyl mercury compounds were considered to be
the most hazardous form of mercury and the overall human body burden was
believed to be mainly derived from the ingestion of methyl mercury in the
diet, particularly via fish which concentrate this form of mercury through the
food chain. At the time that the first standard was set, it was considered
prudent to assume that exposures to methyl mercury (diet) and mercury vapor
(air) were equivalent and additive.
Also known by 1973 was the fact that methyl mercury compounds, when
ingested in sufficient amounts, could produce severe and irreversible damage
to the central nervous system both in the adult and in the human fetus. The
effects occurring at the lowest body burden were non-specific symptoms such as
paresthesia. These first symptoms of intoxication had been observed in adults
after prolonged intake of approximately 300 ug Hg as methyl mercury per 70 kg
body weight. It was assumed that a safety factor of ten would provide satis-
factory protection against genetic lesions and poisoning of the fetus and of
children. Thus, it was determined that the total intake of methyl mercury
should not exceed 30 jjg Hg/day/70 kg body weight. Because the burdens of
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mercury vapor and methyl mercury were assumed to be equivalent and additive,
it followed that the daily absorption of both forms of mercury should not
exceed 30 (jg Hg/70 kg body weight.
It was also determined from estimates of average diets that, over a
considerable period of time, mercury intakes of 10 p.g Hg/day/70 kg body weight
might be expected. Thus, in order to restrict total intake to 30 pg Hg/day/70
kg body weight, the average mercury intake from air would have to be limited
to 20 MQ Hg/70 kg body weight. To maintain this level, the air would have to
contain an average concentration of no more than 1 pg Hg/m , assuming inhalation
of 20 m /day by the 70-kg adult.
2.1.2 Indirect Exposure Effects
Prior to promulgation of the standard, data on the environmental transport
of mercury did not permit a clear assessment of the impact of atmospheric
mercury emissions on aquatic and terrestrial environments. Consequently, the
standard promulgated in 1973 was "intended to protect the public health from
the effects of inhaled mercury," taking into consideration dietary contributions
to total body burden, but it did not account for the effects of atmospheric
mercury on other environments that, in turn, contribute to indirect exposures
to mercury.
2.2 FINDINGS OF CURRENT REPORT
The findings of this report are based mainly on a review of the scientific
literature published since the promulgation of the standard in 1973. However,
literature published prior to 1973 has also been evaluated if it is still
relevant to assessment of human health risks from airborne mercury. The
following summary follows the format of the ensuing chapters.
2.2.1 Mercury Background Information
2.2.1.1 The Global Cycle—Despite intensive research in recent years, many
details, both quantitative and qualitative, on the global cycling of mercury
remain obscure. Elemental mercury vapor, Hg°, emitted from land and water
surfaces, is the principal species in the atmosphere and responsible for long
distance (100 to 1,000 kilometers) transport of mercury. The residence time
of this form of mercury is on the order of months, possibly years. A "soluble"
form of mercury, of unknown chemical species, is also present in the atmosphere,
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but to a lesser extent. Soluble mercury is returned by precipitation to the
earth's surface. Its residence time in the atmosphere is believed to be only
on the order of days.
Widely varying estimates (from 10 to 80 percent) have been made for the
anthropogenic contribution of mercury to the atmosphere. The figure arrived
at in this report is approximately 25 percent. Anthropogenic input of mercury
into bodies of fresh water is believed to have increased mercury levels in
waters and sediments by factors two to four as compared to pre-man eras. Oceanic
sediments are believed to be the ultimate depository of mercury in the form of
insoluble mercuric sulfide. The amount of mercury in oceanic water is believed
to be so large (on the order of tens of millions of tons) that man's impact has
been negligible. However, anthropogenic mercury sources have had substantial
impact on the levels of mercury in aquatic organisms in marine coastal waters
near urban centers.
2.2.1.2 Biomethylation of Inorganic Mercury—Within the context of the global
cycle, microbially-mediated methylation and demethylation reactions of mercury
take place in the sediments of fresh and ocean waters. These processes also
can take place within, and on, organic particulate microenvironments within the
water column, especially in eutrophic and hypereutrophic aquatic systems.
These reactions play a key role in the entry of methyl mercury into the human
diet. Microorganisms are capable of methylating inorganic mercury via a
non-enzymic reaction with methyl cobalamines. Many types of microorganisms
are capable of methylating inorganic mercury. The most efficient and effective
are certain aerobes and facultative anaerobes; less efficient are strict anaerobes
such as methanogenic bacteria. Both mono- and dimethyl mercury compounds are
formed, depending on pH and other conditions. Monomethyl mercury compounds
rapidly diffuse from the microorganisms and rapidly accumulate in aquatic food
chains. The highest concentrations are found in large predatory fish at the
top of the aquatic food chain, e.g., trout, pike, and bass in fresh water;
tuna, swordfish, and red snapper in oceanic water.
Many factors influence the extent of accumulation of methyl mercury in
fish, including not only the species of fish, but also the age of the fish,
the levels of mercury in sediment, the presence of zooplankton, organic content
of sediments and particulates in the water column, water temperature, redox
potential, and dissolved oxygen content. Current studies suggest that long-
distance atmospheric transport and acidification of rain water are correlated
with elevated levels of methyl mercury in fresh water fish.
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Methyl mercury compounds are demethylated by microorganisms present in
the environment. The accumulation of methyl mercury in the food chain
ultimately depends upon an ecological balance between methylation and demeth-
ylation reactions as well as trapping within organisms and chemical complexes.
2.2.1.3 Levels of Mercury in Air, Water and Food—Concentrations of mercury
in the atmosphere have been estimated to be in the vicinity of 20 ng Hg/m .
Most recent observations, as yet unconfirmed, indicate that a more accurate
3
estimate of average atmospheric levels is in the range of 2-10 ng Hg/m .
Concentrations of mercury in fresh water are around 25 ng Hg/1, most of which
++
is probably in the mercuric (Hg ) form. Concentrations of mercury in fish
and fish products (the dominant food source of mercury in the human diet)
average from 100 to 220 ng Hg/g fish, almost all (70 to 90 percent) of which
is methyl mercury. Tuna is eaten by approximately two thirds of all fish
consumers in the U.S. However, on an individual consumer basis, freshwater
fish, e.g., pike, bass, and trout, have the highest consumption rate.
In terms of total mercury, the diet greatly exceeds other media, including
air and water, as a source of human exposure and absorption of mercury.
2.2.2 Pharmacokinetics and Biotransformation of Mercury in Man and Animals
2.2.2.1 Vapor of Metallic Mercury—Since 1973, new information has become
available on the pharmacokinetics of inhaled vapor in man and on the biotrans-
formation of elemental mercury in animal tissues. Although a complete pharma-
cokinetic model is not yet established, some principal features have been
identified.
Uptake of mercury vapor is through inhalation and, probably, skin absorp-
tion, although the extent of uptake through the latter route is still unknown.
Approximately 80 percent of the amount inhaled is retained and rapidly trans-
ferred to the bloodstream, where it is distributed to all tissues in the body.
Mercury readily crosses the blood-brain and placenta! barriers, but accumulates
to the greatest extent in the kidney. It is mainly excreted in urine and
feces; however, it is also excreted in sweat, saliva, and, to a small extent,
expired air. Due to the rapid oxidation of absorbed mercury vapor to divalent
mercury in mammalian tissues, it is likely that most of the mercury accumulated
in the kidney and other tissues and excreted is in the divalent form.
The whole body half-time of mercury in man is approximately 50 to 70
days. A rapid component in blood has a half-time of about three days, and a
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slower component has a half-time of about 30 days. A rapid component in the
brain has a half-time of about 21 days. There is evidence of a much slower
component in brain with a half-time on the order of several years.
Dissolved elemental mercury, Hg , is believed to be the most important
++
mobile species in mammalian tissues. It is oxidized to Hg by the hydrogen-
peroxide-catalase complex in red blood cells, liver, kidney and, probably,
many other tissues. Ethanol, at low non-intoxicating doses, can inhibit this
oxidation process and, thereby, lead to a decreased retention of inhaled
mercury. Inorganic divalent mercury, Hg , is reduced to Hg in liver and
kidney tissues and, probably, in other tissues as well. The biochemical
mechanism for this reduction has not yet been identified in mammalian cells
but is well established in bacteria to the extent that even the genetics,
sequence of the enzymes, and active site have been determined through DNA-
sequence analysis.
There is evidence that inhaled mercury vapor can induce the metal-binding
protein metallothionein in kidney tissue and that mercury-selenium complexes
may be formed after chronic exposure.
2.2.2.2 Compounds of Inorganic Mercury—Since 1973, new information has been
published on the kinetics of tracer doses of inorganic mercury in man. However,
a complete pharmacokinetic model for either mercurous or mercuric forms of
mercury has not yet been established.
Although it is known that mercurous chloride is slowly and incompletely
absorbed after oral dosing, amounts sufficient to lead to symptoms of mercurial-
ism can be absorbed on a chronic basis. Once absorbed, mercurous mercury is
probably converted to the mercuric form. Mercuric mercury, ingested as such,
has a less than 15 percent rate of absorption following oral dosing. However,
inferences from animal studies suggest that absorption of mercuric mercury may
be as high as 50 percent in children and infants.
Mercuric mercury is distributed via the bloodstream to all tissues in the
body but penetrates the blood-brain and placenta! barriers to a much lesser
extent (approximately ten times less) than mercury vapor. As is the case with
mercury vapor, the kidney concentrates inorganic mercury to a much greater
extent than other tissues, and excretion is mainly via urine and feces.
The average biological half-time of a tracer dose of divalent inorganic
mercury compounds in man is 42 days for the whole body and 26 days for blood.
2.2.2.3 Methyl Mercury Compounds—New information on the kinetics of methyl
mercury in man and on the mechanisms of biotransformation and excretion does
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not change the picture that existed when the 1973 standard was promulgated.
The pharmacokinetic model of methyl mercury in man is much further advanced
than models for other forms of mercury.
Oral doses of methyl mercury are almost completely absorbed (approximately
95 percent). Methyl mercury is distributed in blood to all tissues of the
body within a few days. Like other forms of mercury, methyl mercury readily
crosses the blood-brain and placenta! barriers; however, unlike other forms,
tissue concentrations of methyl mercury are much more uniform, with the kidney
having somewhat higher concentrations than other tissues. The red blood
cell-to-plasma concentration ratio is typically 20:1, the blood-to-brain ratio
is approximately 1:5, and the blood-to-hair (newly formed) ratio is 1:250.
Approximately 80 percent of total methyl mercury excretion is via the
feces. Methyl mercury is also secreted in bile and reabsorbed back into the
bloodstream to form an enterohepatic cycle. The remainder undergoes demethyla-
tion by flora in the intestine and is excreted as inorganic mercury. Experi-
mental studies indicate that a functioning enterohepatic cycle and active gut
flora are essential to the excretion of mercury after doses of methyl mercury.
It is known that suckling animals cannot excrete methyl mercury in bile and,
therefore, are unable to excrete significant amounts of methyl mercury from
the body. The implication of these animal data to humans is unknown and no
information is available on human infants.
The average biological half-time of methyl mercury in human adults is
approximately 70 days in the whole body and 50 days in the blood compartment.
The biological half-time in brain is probably similar to that of the whole
body or slightly longer. A wide range of biological half-times (up to 120
days in the whole body) has been reported in adults substantially exposed to
methyl mercury. The reason for this wide range is unknown, but in experimental
studies, the type of diet was shown to affect half-times in the experimental
animals.
2.2.3 Toxic Effects of Mercury in Man and Animals
The following section summarizes the toxic effects of mercury in man and
animals, with emphasis placed on effects arising from long-term low-level
exposures. Where possible, greater attention has been focused on direct
observations on human subjects.
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2.2.3.1 Vapor of Metallic Mercury—Since 1973, a number of clinical and
epidemiological studies have been published on workers occupationally exposed
to mercury vapor. In general, the findings of these studies support the
earlier findings that existed when the mercury standard was promulgated.
Occupational studies have shown that chronic exposure to mercury vapor
affects primarily the central nervous system and the kidneys. Effects associ-
ated with the lowest exposure levels—below 100 M9 Hg/m —produce non-specific
symptoms such as introversion, insomnia, and anxiety. Biochemical alterations
have been observed in enzymes of plasma and red blood eel Is, and increases in
urinary excretion of specific proteins and enzymes are known to occur. Higher
chronic exposures produce more pronounced effects in cognitive function, such
as short-term memory loss and changes in personality traits (e.g., increased
anxiety and introversion). An overall body tremor, typical to mercurialism
cases, signals the motor disfunctioning of the central nervous system. No
threshold for these and other effects has been clearly established, although
3
effects have not been seen at air concentrations around 10 |jg Hg/m
Renal effects may be mediated through an autoimmune mechanism and may
exhibit wide individual ranges of sensitivity. Experimental studies on this
sensitivity indicate the possibility of a genetic component related to the
major histocompatibility complex.
Effects on both the nervous system and kidney are usually reversible,
particularly if the effects are mild. Studies have shown that motor effects
reverse more readily than cognitive and neurotic effects.
Information is generally lacking on reproductive and developmental effects
of inhaled mercury vapor.
2.2.3.2 Inorganic Compounds of Mercury--Virtually no new information on the
effects of inorganic compounds of mercury on humans has become available since
1973. In case studies on two adults, it was shown that many years of chronic
oral intake of mercurous chloride (250 mg/day) resulted in typical signs of
mercurialism and chronic renal failure. Chronic oral exposure to mercurous
chloride has also caused acrodynia or Pink's disease in children. Great
differences in individual sensitivity have been reported for such effects,
although, generally, acrodynia associated with urinary levels of 50 [jg Hg/1 is
reversible in children. Based upon comparison studies to mercury vapor and
mercurous salts, it is assumed that chronic exposure to compounds of mercuric
mercury would mainly affect kidney function. Experimental studies supporting
the above evidence are lacking.
2-7
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2.2.3.3 Compounds of Methyl Mercury—Since 1973, new information has become
available on a population exposed to dietary methyl mercury. Findings from
the study population generally support the evidence that existed in 1973 and
confirm the special sensitivity of prenatal life to methyl mercury exposure.
Milder effects at dose levels lower than those observed in 1973 have been
reported for the first time in prenatally exposed infants. The possibility
has been raised of delayed effects appearing in adults several years after the
cessation of exposure.
Methyl mercury primarily damages the central nervous system in both
adults and prenatal infants. Prenatal exposures at the lowest recorded levels
produce signs of psychomotor retardation in infants. Recent studies indicate
that male infants may be more sensitive than females at these low levels of
maternal dietary intake. Substantially higher prenatal exposures, some only
occurring in the last trimester of pregnancy, produce a severe form of cerebral
palsy. Although detailed mechanisms of methyl mercury poisoning are not
known, prenatal effects appear to be due to a derangement of the normal proces-
ses of growth and development of the central nervous system. Ongoing studies
indicate (based on estimated blood levels in the mother during pregnancy) that
the fetus is about three times more sensitive than the adult to methyl mercury
exposures.
Effects on the adult central nervous system result from focal damage to
specific areas of the brain, principally the cortex of the cerebellum and the
visual cortex. The first symptoms of methyl mercury poisoning in adults are
non-specific, e.g., paresthesias and malaise. These effects are believed to
have a low frequency of occurrence (approximately 5 percent) in the general
population and are seen at blood levels ranging from 200 to 500 ng Hg/ml,
which correspond to chronic oral daily intakes of approximately 3 to 7 ug
Hg/kg body weight. Evidence is conflicting on the degree of reversibility of
these first symptoms of poisoning. Dietary intake levels of methyl mercury
that produce irreversible destruction of neurons in the cerebellar and visual
cortices leading to permanent signs of ataxia and constriction of the visual
field are probably at least twice as high as those levels causing mild symptoms.
2.2.4 Human Health Risk Assessment of Mercury in Air
2.2.4.1 Direct Exposure Effects—Because the 1973 standard was based on the
direct exposure effects from airborne mercury, taking into consideration the
2-8
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contribution of dietary mercury intake to total body burden, a similar approach
has been taken here to determine to what extent new information has changed
the perspective on direct risks from mercury in air.
A new evaluation confirms that, while mercury vapor still accounts for
the major fraction of airborne mercury, particulate forms of mercury do exist
in the atmosphere. The diet is by far the dominant, if not the sole source of
human exposure to methyl mercury compounds. In addition, a current evaluation
indicates that the diet is also the dominant source of compounds of inorganic
mercury. In comparing different routes of exposure, contribution of airborne
mercury is between one-tenth and one-twentieth of the total daily amount of
mercury absorbed into the body.
An analysis of dose-response and dose-effect relationships indicates that
current levels of mercury in the atmosphere, irrespective of chemical species,
would present a negligible risk of adverse health effects from direct airborne
exposures. Current atmospheric levels are believed to be 20 ng Hg/m or less.
o
Effects of mercury vapor on human health have not been detected below 1 pg Hg/m ,
and serious debilitating effects have not been observed in occupational settings
where workers have been exposed for periods of months to years to air concen-
trations below 100 ug Hg/m . Even assuming that all the mercury in the atmos-
phere were in the form of methyl mercury compounds, it would require an atmos-
pheric concentration of 10 ug/m to produce an inhalation intake equivalent to
an oral intake of 200 yg/day (believed to be the approximate lowest observed
effect level for adults). Even taking into account the greater sensitivity of
the fetus, there has not been an appreciable change in the health basis upon
which the 1973 standard was based.
2.2.4.2 Indirect Exposure Effects—Mercury in the atmosphere has the potential
to produce indirect exposure effects through increasing levels of methyl
mercury in edible tissues of freshwater fish. As previously noted (see
Section 2.1.2), the effect of atmospheric mercury on indirect exposures was
not considered in the 1973 promulgation because of insufficient information on
the environmental fate of airborne mercury.
While current knowledge of the fate of airborne mercury is still incomplete,
studies in the last ten years strongly suggest the possibility of long-distance
transport of mercury from sources of pollution to deposition of soluble mercury
on land and water. Runoff from land further transfers mercury to bodies of
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fresh water. While it was known in the past that local pollution of lakes and
rivers could give rise to unacceptably high concentrations of methyl mercury
in fish that exceed Federal guidelines, an important recent finding is that
high levels of methyl mercury are also found in certain lakes remote from
anthropogenic sources. In addition, the problem of long-distance transport is
exacerbated by the acidification of rainwater in certain areas of the United
States. A statistical correlation has been found between the acidity of lakes
and elevated levels of methyl mercury in fish.
Many possible mechanisms for this elevation may exist, but the overall
effect is that methyl mercury levels in fish are, to some extent, indirectly
affected by airborne mercury and acid deposition. The question, therefore,
arises as to what extent changes in current atmospheric levels would affect
levels of methyl mercury in edible freshwater fish, and what would be the
predicted impact on human health.
Although the answer to the first question cannot be definitively quanti-
fied at this time, it could be conjectured that if airborne mercury levels
3 3
increased from current levels of 5 to 20 ng Hg/m to the 1,000 ng Hg/m level
that was used as a guideline in setting emission limits for source categories
regulated by the current standard, the environmental consequences could be
severe. At some point in this sharp rise in atmospheric air concentrations,
levels in fish would increase to unacceptably high values.
The health impact on the U.S. is also difficult to express in quantitative
terms. Both action guidelines by the Food and Drug Administration and state
regulations already exist that effectively stop consumption of fish if methyl
mercury levels exceed 1 pg Hg/g wet weight. The outcome, therefore, would
probably be the same as in Scandinavian countries, where elevated mercury
concentrations in edible tissue of fish have resulted in the banning of fish
for consumption purposes from a large number of freshwater lakes. Local
communities, such as reservations of native American populations dependent on
freshwater fish as a main food item, may suffer health consequences if federal
and local regulations do not prevent the consumption of contaminated fish in
these communities.
In conclusion, a more comprehensive reevaluation of existing information
would be required if the potential for indirect exposure effects were considered.
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3. MERCURY BACKGROUND INFORMATION
3.1 PHYSIOCHEMICAL PROPERTIES OF MERCURY
Mercury is unique amongst the metals as being the only metal in a liquid
form at room temperature. The metal has a melting point of -38.9°C and a
boiling point of approximately 356°C. The atomic weight is 200.59. At 20°C
the specific gravity of the metal is 13.546 and the vapor pressure is 0.0012 mm
of mercury. This high vapor pressure of the liquid metal is of significance
with regard to human exposures to the vapor. A saturated atmosphere at room
3
temperature contains mercury vapor at a concentration of approximately 20 mg/m .
This concentration of the metal is over two orders of magnitude greater than the
currently accepted maximum allowable concentration for occupational exposure.
Mercury exists in a wide variety of physical and chemical forms. It has
three oxidation states: Hg° (metallic), Hg? (mercurous) and Hg (mercuric
mercury). It forms stable organometallie compounds with alkyl, e.g. CH-Hg and
+ ^
CHgHgCH- (monomethyl and dimethyl mercury) and aryl, e.g. C-.Hj.Hg (phenyl mercury)
groups. This review chapter will discuss only those chemical and physical forms
of mercury that are involved in the biogeochemical cycle and the forms to which
humans are principally exposed in the environment.
3.1.1 Sampling and Analysis
Mercury and its compounds in the environment have always presented sampling
and analytical challenges not encountered with most environmental pollutants.
Unlike most metals, mercury in the atmosphere is usually found as elemental
mercury vapor. However, mercury compounds can also be present as part of the
particulate matter; thus, making certain vapor-sensing analytical methods un-
satisfactory. In addition, there is reason to be concerned with the valence
state of inorganic mercury compounds and the presence, in some instances, of
both aryl and alkyl organic compounds. The analytical problems related to the
estimation of mercury in air are further compounded when mercury determinations
must be made in biota or biospecimens such as blood, urine, and tissue. In such
samples, elemental mercury is rarely determined as such, but it may become
necessary to differentiate between inorganic and organic forms. Henderson et
al. (1974) have shown that there are at least 3 different forms of mercury which
are identifiable in urine specimens from workers exposed to mercury.
3-1
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Historically, all of these problems have been compounded by the considerable
analytical challenge of determining sub-microgram quantities of mercury in the
presence of other air contaminants or the large amount of organic matter and
other substances accompanying mercury in all biological specimens. For many
years, levels of mercury vapor present in the workplace have been determinable
by sensitive and almost mercury-specific devices, notably the ultraviolet
mercury vapor meters, which are in fact portable atomic absorption units. Their
use in general was limited to the determination of workplace levels of mercury
vapor, and in all probability even early studies of mercury vapor exposure levels
were of relatively good quality insofar as the accuracy and specificity of the
measurements were concerned. Most such studies, of course, did not attempt to
define the non-vapor exposures, and some could have been influenced by certain
organic vapors which interfere with the performance of mercury vapor detectors.
Until the 1960's, most biospecimen analyses were difficult to perform and
required lengthy acid digestions under reflux conditions in order to convert the
mercury to mercuric ions making it amenable to a dithizone colorimetric pro-
cedure. The difficulties and uncertainties inherent in these procedures were
of such magnitude that they tended to discourage analyses, particularly in the
case of blood samples where very small quantities of mercury had to be released
from large amounts of blood constituents. It is probable that for this reason,
until the advent of other methods, urinary mercury analyses, though tedious,
were performed in preference to blood mercury analyses. It is also noteworthy
that analytical studies performed prior to the development of modern techniques
should be considered with an awareness that the analytical results may have
been subject to errors of which the investigators were unaware. A comprehen-
sive review (up to 1972) of all of the sampling and analytical methods for
mercury in air and biospecimens was published by Smith (1972).
The introduction of the "cold vapor" methods of analysis in the 1960's
marked the beginning of a new era in mercury analysis, and in general, this
method and its many subsequent modifications as well as several other methods
have completely revolutionized the analysis of any kind of sample for mercury
content. When applied to biological specimens of any kind, the basic approach
of all such cold vapor methods is to convert the mercury in a small sample to
mercuric ion, then reduce it to elemental mercury with a reductant such as
stannous chloride and measure the mercury vapor in a modified atomic absorption
3-2
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spectrophotometer. A number of recent publications have utilized this general
technique for air, biological and environmental samples (Hatch and Ott, 1968;
Gage and Warren, 1970; Smith, 1972; Henderson et al., 1974; Rathje and Marcero,
1976; Bourcier et al. , 1982). A popular alternative to the cold vapor technique
utilizing conventional flame atomic absorption is the flameless method which
ordinarily utilizes a graphite furnace. Methods based on this approach are
widely used for all types of samples and generally achieve very much lower
detection limits (Lindstedt, 1970; Kubasik et al., 1972; Trujillo and Campbell,
1975; McCullen and Michaud, 1978; Menke and Wall is, 1980; Diggs and Ledbetter,
1983). Once any method has succeeded in releasing mercury vapor, certain
other detection techniques become feasible, and one such method in current use
relies upon the amalgamation of a thin gold layer deposited on a quartz crystal
with measurement based on the piezoelectric effect (Scheide and Taylor, 1974;
1975).
With respect to the measurement of levels of mercury vapor in air, it is
presently possible to make measurements in the workplace using improved direct-
reading mercury vapor meters, direct-reading col orimetric indicator tubes, or
passive badge monitors (McCammon and Woodfin, 1977); or samples may be collected
on an adsorbent material such as charcoal (Yrjanheikki, 1978), Hopcalite
(McCullen and Michaud, 1978; Menke and Wallis, 1980), or silver wool (Bell
et al., 1973a; Long et al., 1973). Whenever particulate mercury compounds must
be collected, such methods must be preceded by conventional particulate matter
collection procedures which ordinarily rely on filtration using high efficiency
filters (Trujillo and Campbell, 1975; Menke and Wallis, 1980).
In workplace environments, mercury may be present at concentrations ranging
from several micrograms to more than 100 micrograms per cubic meter, whereas in
the uncontaminated general atmosphere, background levels are measured in nano-
grams per cubic meter, and even contaminated atmospheres will be found to contain
but a few micrograms per cubic meter. Direct reading devices and certain other
methods of sampling and analysis suitable for workplace measurements, therefore,
are generally not sufficiently sensitive to detect background environmental levels.
Hence, methods must be selected which either remove the mercury from a relatively
large volume of air, or which are specifically designed to be extremely sensitive
(Bell et al., 1973a; Long et al., 1973; Scheide and Taylor, 1974; USEPA 40 CFR 61,
1981).
3-3
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A number of sampling and analytical techniques are satisfactory for work-
place air samples (Krause et al., 1971; Moffitt and Kupel, 1971; Rathje et al. ,
1974; Trujillo and Campbell, 1975; McCammon and Woodfin, 1977; McCullen and
Michaud, 1978; Yrjanheikki, 1978; Diggs and Ledbetter, 1983), and although some
of these may be applied to analyses of the general environment, they frequently
lack required sensitivity.
Most methods for the analysis of blood, urine, and other biological speci-
mens rely on the same analytical methods applicable to air samples, but require
some sort of pretreatment to liberate the bound mercury. Several published
methods may be used for virtually any type of biological samples (Gage and Warren,
1970; Moffitt and Kupel, 1971; Henderson et al., 1974), urine specimens (Rathje,
1969; Krause et al. , 1971; Kubasik et al. , 1972; Henderson et al., 1974;
Stopford et al., 1978; Bourcier et al., 1982), or blood (Krause et al., 1971;
Kubasik et al., 1972; Stopford et al., 1978; Bourcier et al., 1982).
Organic forms of mercury, which are less frequently analyzed, generally
require more sophisticated analytical approaches based on gas-liquid chromato-
graphy, GC-mass spectroscopy, or methods which preferentially separate organic
compounds from ionic species and which thereafter may be analyzed for mercury
content by conventional means (Gage and Warren, 1970; Hoover et al., 1973;
Henderson et al., 1974; Trujillo and Campbell, 1975).
The collection and analysis of workplace samples is believed to be influ-
enced in a somewhat unusual manner by the microenvironment which may be created
by workers' clothing or contaminated skin (Bell et al., 1973a; Stopford et al.,
1978). It has been argued that by using typical personal sampling devices,
an environment enriched in mercury vis-a-vis mercury-contaminated clothing is
actually measured. Although this measurement may in fact more accurately re-
flect a worker's exposure, there is concern that past studies on which current
standards were based were made using area measurements which were not in-
fluenced by this microenvironment; hence, false conclusions concerning the
effects of the measured values could be inferred. Obviously the air-urine
mercury level relationships established in the past could likewise be affected
by this phenomenon. Other problems which have been identified in the unique
environment of a mercury cell room in which chlorine is manufactured arise
from the simultaneous presence of elemental chlorine and mercury which may
combine to produce chlorides not detected by vapor-sensing devices (Menke and
Wall is, 1980).
3-4
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In summary, sampling and analytical methods are presently available which
make it possible to perform estimations of mercury and its compounds at
extremely low levels in air, or virtually any matrix of interest with respect
to contamination of the environment. Such analyses may be performed rapidly
on very small samples and with a high degree of accuracy or precision. Many
important studies of the past (prior to the 1960's) were hampered by the ab-
sence of such methodologies, and findings of these studies should always be
judged with an awareness of the shortcomings inherent in the mercury analyses.
3.2 ENVIRONMENTAL CYCLING OF MERCURY
3.2.1 Global Cycles
The global cycle of mercury has recently been reviewed by Nriagu (1979),
the National Academy of Sciences (1978), and Jernelov et al. (1983). The glo-
bal cycle of mercury involves degassing of the element from the earth's crust
and evaporation from natural bodies of water, atmospheric transport believed to
be mainly in the form of mercury vapor, and deposition of mercury back onto land
and water. Mercury ultimately finds its way to sediments in water, where, par-
ticularly in oceanic sediments, the turnover is very slow.
Andren and Nriagu (1979) have indicated that the residence time of mercury
in the atmosphere may vary from approximately 6 to 90 days. A more recent
estimate of total mercury in the atmosphere indicates a turnover time of 0.3 - 2
years. An as yet unidentified soluble form of mercury, accounting for a small
fraction of total mercury, is estimated to have a turnover time of about a few
weeks (Jernelov et al., 1983). Residence times of mercury are on the order of
1000 years for soils, 2000 years for oceans, and are measured in millions of
years for sediments.
The measurement of mercury in extremely low environmental concentrations
is frequently close to the limit of detection of many current methods. With
this in mind, estimates of quantities of mercury entering the environment from
both natural and anthropogenic sources are presented in Table 3-1.
The predominant reservoir for mercury is ocean water, containing on the
order of 40 million metric tons (Nriagu, 1979). Estimates of the yearly
amounts of mercury finding its way to the ocean indicate that atmospheric
deposition accounts for the major amount, approximately 11,000 metric tons per
year, with land runoff accounting for about 5,000 metric tons per year.
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TABLE 3-1. SOURCES OF MERCURY IN THE ENVIRONMENT (1971)
Amount
Source Metric tons/year
Natural
degassing of earth's crust ~30,000
Anthropogenic
worldwide mining 10,000
combustion of coal 3,000
combustion of oil 400-1,500
smelting of metal sulfide ores 1,500
steel cement phosphates 500
Source: Nriagu, 1979; World Health Organization, 1976.
Little is known about localized high concentrations of mercury in oceanic
waters. Undersea volcanos and mercury-rich ores on the ocean bed may be
responsible for high local or regional levels (for review, see Dahlem Confer-
ence, 1983). The elevation of mercury concentrations in ocean surface waters
from anthropogenic sources is a possibility since surface waters mix very
slowly with the deep waters of the ocean.
In comparison to ocean water, the reservoir for mercury in fresh water is
considerably less, averaging a few thousand metric tons with an additional
several hundred tons contained in freshwater biota (National Academy of
Sciences, 1978).
Recently, the pattern of mercury emissions to bodies of fresh water has been
changing. Due to the imposition of mandatory controls, industrial release of
mercury from point sources, such as chlor-alkali plants, has diminished
considerably, thus, resulting in reductions of mercury emissions to such fresh-
water bodies. However, in the case of chlor-alkali plants, the release of mer-
cury to the environment is small in comparison with, for example, fossil-fueled
power plants; hence, the elimination of mercury discharge from chlor-alkali
plants has had more of a local effect than an overall global effect (Wallin, 1976).
On a global scale, it has recently become apparent that long-distance
atmospheric transport of mercury and acidification of rainwater have become
increasingly important factors in the dissipation of mercury to freshwater
bodies.
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The atmosphere serves as the smallest reservoir for mercury in the environ-
ment, containing only about a thousand metric tons of mercury (National Academy
of Sciences, 1978). Mercury entering the atmosphere from degassing of the
surface of the earth varies widely, but a commonly quoted figure is 30,000
metric tons per year. Wide estimates have been made of the proportion of
mercury in the atmosphere due to anthropogenic sources, with figures varying
from 10 to 80 percent. In comparisons to pre-man emissions of mercury to the
atmosphere, Jernelov and co-workers (1983) believe that the present atmospheric
emissions represent at least 20 percent of the total emissions.
As noted above, because the atmosphere and fresh water contain much less
mercury, the impact of man-made release of mercury would be expected to be
much greater on these smaller reservoirs, especially in instances where the
release is direct. For example, it is estimated that the mercury content of
lakes and rivers may be increased by a factor of 2 to 4 due to man-made release
(National Academy of Sciences, 1978). In contrast, it is estimated that oceanic
concentrations have not appreciably changed in recent history.
3.2.2 Chemical and Biochemical Cycles of Mercury
This overall global cycle of mercury is the result of extremely complex
physical, chemical, and biochemical processes occurring in the main reservoirs
and interfaces between these reservoirs. Most of these processes are poorly
understood but, nevertheless, certain very important fundamental discoveries
have been made in recent years and these are summarized below. It should be
recognized that this is an incomplete picture and that this area is undergoing
very active research at the present time.
The most important single discovery in understanding the chemical and
biochemical cycles of mercury in the environment was made by Swedish investiga-
tors in the 1960s (for a review, see National Academy of Sciences, 1978). An
intensive investigation into the source of methyl mercury compounds in fresh-
water fish led to the finding that microbial activity in aquatic sediments can
result in the methylation of inorganic mercury in the environment (Jensen and
Jernelov, 1967).
The methylation of ionic mercury in the environment appears to occur
under a variety of conditions: in both aerobic and anaerobic waters, in
sediments, in the presence of various types of microbial populations (both
anaerobes and aerobes), and in different types of freshwater bodies such as
eutrophic and oligotrophic lakes.
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The presence of methyl mercury in many species of ocean fish, including
wide-ranging species such as tuna and shark, strongly suggests that the methy-
lation process can occur in oceans as well as in bodies of fresh water.
The mechanism of synthesis of methyl mercury compounds from inorganic
precursors is now well understood in both the terrestrial environment and in
the sea (Wood and Wang, 1983). The most probable mechanism for methylation of
inorganic mercury involves the non-enzymic methylation of mercuric mercury
ions by methyl cobalamine compounds (Vitamin B,?) that are produced as a
result of bacterial synthesis. However, other pathways both enzymic and
non-enzymic may play a role (Beijer and Jernelov, 1979).
To date, two different mechanisms have been determined for methyl-transfer
from methyl-B _ to heavy metals: (1) electrophilic attack by the attacking
metals on the Co-C bond of methyl-B,2 and (2) methyl-radical transfer to an
ion-pair between the attacking metal ion and the corrin-macrocycle.
The ecological significance of B12-dependent biomethylation is best
illustrated by B,0-dependent and B-. _-independent strains of Clostridium
II
cochlearium. The 6,,,-dependent strain is capable of methylating Hg salts to
II
CH,Hg , whereas the B,,-independent strain is incapable of catalyzing this
II
reaction. Both strains transport Hg into cells at the same rate, but the
B,9-independent strain is inhibited by at least a 40-fold lower concentration
T T
of Hg than the B,2-dependent strain. The result demonstrates that Clostridium
cochlearium uses biomethylation as a mechanism for detoxification, giving the
organism a clear advantage in mercury-contaminated systems. This biomethylation
capability has been shown to be plasmid-mediated (Pan Hou and Imura, 1982).
Once methyl mercury is released from the microbial system, it enters food
chains as a consequence of its rapid diffusion rate. In the estuarine environ-
ment, the reduction of sulfate by Desulfovibrio species to produce hydrogen
sulfide is quite important in reducing CH3Hg concentrations by S -catalyzed
disproportionate to volatile (CH^Hg and insoluble HgS. There is evidence
to support the notion that membrane transport of methyl mercury is diffusion
controlled. Fluorescence techniques and high resolution nuclear magnetic
resonance (NMR) show that diffusion is the key to CH3Hg+ uptake (Wood et al.,
1978; Lakowicz and Anderson, 1980). Also, a field study of the uptake of
CH,Hg by tuna fish in the Mediterranean fits the diffusion model for biota in
»3
tuna food chains (Buffoni and Bernhard, 1982).
3-8
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Microorganisms have been isolated which catalyze the reactions described
o +
above for both the forward reaction to Hg and the back reaction to CH,Hg as
presented below:
CH3Hg+ j Hg2+ + Hg°
The enzymes which carry out the forward reactions are coded by DMA on
bacterial plasmids and transposons and not by normal chromosomal genes (Silver,
1984). Therefore it is not too surprising that mercuric and organomercurial
strains of bacteria have been isolated from a variety of ecosystems such as
soil, water, and marine sediments (Friello and Chakrabarty, 1980; Olson et
al., 1979, 1981; Timoney et al. , 1978; Vonk and Sijpesteijn, 1973). The
enzymology of methyl mercury hydrolysis and mercuric ion reduction is now
understood in some detail (Silver, 1984). In fact, the sequence of the active
site of mercuric ion reductase is now determined and has been found to be
identical to that of glutathione reductase (Williams et al. 1982; Friello and
Chakrabarty, 1980). Clearly, the reduction of Hg to Hg , which is volatile,
represents a very effective detoxification mechanism. Much less is known
about the reverse reaction, that is, the oxidation of Hg to Hg . However,
an enzyme which is critical to the oxygen cycle (catalase) will carry out this
reaction. Microbial methylation of mercuric ion is also widespread (Vonk and
Sijpesteijn, 1973; Hamdy and Noyes, 1975). Biomethylation has been shown to
occur in sediments and in human feces. The important role played by sulfide
in the biological cycle for mercury is presented in the equation below:
2 CH3Hg+ + H2S -> (CH^Hg + HgS
Hydrogen sulfide is very effective at volatilization and precipitation of
mercury through disproportionation chemistry in the aqueous environment. Such
reactions occur only in polluted lakes, rivers, coastal zones, estuaries, and
salt marshes where Desulfovibrio species have access to sulfate in anaerobic
ecosystems.
Once in the atmosphere, volatile organometals, such as dimethylmercury,
are unstable since metal-carbon bonds are susceptible to homolytic cleavage by
light.
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Brosset (1981a) has studied the circulation of mercury in air and natural
waters with an emphasis on understanding the mechanisms of the long-distance
transport and deposition of this element. Mercury is present in the atmosphere,
not only as the water-insoluble mercury vapor, but also in water-soluble forms
as well. The origin and chemical nature of these water-soluble forms is not
well understood, but it is known that they are present in particulate matter in
the atmosphere and do not occur as vapors.
The water-soluble forms of mercury may enter droplets of precipitation
and be carried down to bodies of both fresh and marine water. On entering the
water phase, the soluble forms of mercury are subject to reduction processes
either chemical, depending on the local redox potential, or microbiological.
The end product is metallic elemental mercury which, being highly diffusible,
tends to diffuse back into the atmosphere. The remaining soluble mercury
persists in the water phase for a sufficient period of time to attach to
sediments and eventually forms the highly insoluble mercuric sulfide.
There also exists the possibility that atmospheric mercury in the parti-
culate form may be deposited by dry deposition processes from the atmosphere
into the water system following essentially the same chemical reaction as that
for the wet deposition of these compounds. Mercury vapor may also be adsorbed
to the terrestrial surface or absorbed into water.
The extent to which mercury may be taken up and reemitted from water or
land surfaces to the atmosphere is still not understood in quantitative terms.
Nevertheless, the general picture that emerges is one in which long-distance
transport of mercury in the vapor phase is possible. Its uptake into water
and reemission probably occur extensively, and the chemical conversion of
mercury from the elemental to the ionic and to the organic forms is much more
extensive than was originally believed.
Once methyl mercury enters the water phase as a soluble compound, it is
rapidly accumulated by most aquatic biota and attains highest concentrations
in the tissues of such large carnivorous fish as the pike in fresh water and
the shark, swordfish, and tuna in marine water (Buffoni and Bernhard, 1982).
Indeed, it is generally believed that the major amount of methyl mercury
compounds in bodies of water are contained in the biomass of the system. The
biconcentration factors --the ratio of the concentration of methyl mercury in
fish tissue to concentrations in water -- can be extremely large, usually on
the order of 10,000 to 100,000 (U.S. Environmental Protection Agency, 1980).
3-10
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The concentration of methyl mercury in fish tissue is of special interest
in terms of human exposure to this form of mercury. The aquatic food chain is
the main, if not the sole source of human exposure to methyl mercury, barring
episodes of accidental discharge or misuse of man-made methyl mercury compounds.
Thus, factors that affect concentrations of methyl mercury in edible fish
tissue are of considerable importance in assessing potential human health
risks from this form of mercury.
The uptake of mercury by plants has not been extensively studied. Uptake
of mercury through apple tree roots to foliage was not detected for trees ex-
posed to phenylmercury acetate (Ross and Stewart, 1962). Turf grass exposed to
a HgCl»-Hg_Cl2 mixture added in the root zone did not accumulate mercury (Gilmour
and Miller, 1973). However, Browne and Fang (1978) observed direct uptake of
mercury vapor by wheat leaves. Previously, Ratsek (1933) had noted direct up-
take of mercury vapor by rose leaves. In the proximity of the Almaden mercury
mines in Spain, Lindberg et al. (1979) noted that alfalfa plants accumulated
mercury by a dual mechanism. The roots accumulated mercury according to the
soil levels while the aerial plant material absorbed mercury directly from the
atmosphere. It seems unlikely, however, that accumulation of mercury into
plants is an important source of human exposure except possibly under special
circumstances of local contamination and local consumption of the contaminated
plants.
3.3 LEVELS OF MERCURY IN VARIOUS MEDIA
The industrial use of mercury and the release of mercury to the environ-
ment by the non-mercury industries (fossil fuel) has resulted in a general
increase of mercury in the environment throughout the industrial revolution.
This increase is well illustrated in a Swedish study conducted in the late
1960's (for details, see Swedish Expert Group, 1971).
The levels of mercury in air, water, and food have recently been summarized
and reviewed by the World Health Organization (1976) and by the United States
Environmental Protection Agency (1980). Most of the material presented in
this section will be drawn from these two reviews with some additional, more
recent information from specific papers as deemed appropriate.
3-11
-------
3.3.1 Mercury in Ambient Air
Earlier reviews on mercury in the ambient- air (World Health Organization,
1976; U.S. Environmental Protection Agency, 1980) suggested that the average
concentration in the ambient atmosphere throughout the world appeared to be
about 20 ng Hg/m . However, Jernelov et al. (1983), reviewing papers pub-
3
lished since 1979, have concluded that background levels of about 2 ng Hg/m
as gaseous mercury exist in the lower troposphere of the Northern Hemisphere
3
and 1 ng Hg/m exists in the Southern Hemisphere. In regionally polluted
areas, such as rural parts of Southern Sweden and Italy, concentrations more
3
often lie between 3 to 4 ng Hg/m . In urban air, the average concentrations
may be as high as 10 ng Hg/m . Industrialized areas may be even higher. In
the plume of a coal-fired power plant, Lindberg (1980) reported concentrations
3
of gaseous mercury in excess of 1000 ng Hg/m within a few kilometers of the
source. Isolated "hot spots" may have unusually high concentrations of mercury.
3
For example, air levels up to 10,000 ng/m have been found near rice fields
where mercury fungicides have been used and mercury concentrations in the
vicinity of mercury mines have been reported to be as high as 15,000 ng/m
(World Health Organization, 1976).
It is generally accepted that the predominant form of mercury in the
atmosphere is mercury vapor present as a monatomic gas (World Health Organiza-
tion, 1976). However, as indicated previously, other forms of mercury are
also present. Johnson and Braman (1974), in a suburban site in Florida, found
that approximately 60 percent of the mercury in the atmosphere was in the form
of the vapor, but they also noted that 19 percent was present as inorganic
ionic mercury and approximately 17 percent was present as methyl mercury com-
pounds. There is general agreement that mercury in the particulate form
accounts for only a very small fraction, on the order of about 4 percent, of
the total mercury in the atmosphere. It should be noted at this point that
the data of Johnson and Braman are specific to the Tampa Bay area and should
only be applied to other circumstances with caution until corroborating data
are obtained.
Brosset, referred to previously, has also found the presence of "soluble"
forms of mercury in the atmosphere which may be both ionic and monomethyl
mercury compounds (Brosset, 1981b).
The average daily absorption of atmospheric mercury in man has been
quoted by the U.S. Environmental Protection Agency (1980) to be approximately
3-12
-------
320 ng/70 kg body weight. This is based on assumptions that the average
3
atmospheric concentration is 20 ng/m , that the adult male has a ventilation
rate of 20 m , and that 80 percent of the inhaled rate is absorbed. Clearly,
these figures require revision if the conclusions of Jernelov et al. (1983)
are valid. Individuals living in nonpolluted rural areas would absorb
approximately 16 ng Hg/70 kg body weight based on an air concentration of
3
1 ng Hg/m and individuals in urban areas would absorb about 10 times this
amount. It seems unlikely that atmospheric concentrations would exceed
3
average values of 50 ng Hg/m which would correspond to a daily intake of
800 ng Hg.
3.3.2 Mercury in Ocean and Coastal Waters
Levels of mercury in ocean water are generally well below 100 ng/1.
Fitzgerald (1979) noted that the median value for oceanic water was approximately
59 ng/1. Recent estimates made by Matsunaga et al. (1979) indicate that the
"reliable value for baseline mercury in nonpolluted waters is approximately 5-6
ng/1." The most recent review of the literature (Jernelov et al., 1983) con-
cluded that average concentrations in the open ocean are about 3 ng Hg/1. Con-
centrations in coastal waters are somewhat higher, usually within the range of
5 - 10 ng Hg/1. The high concentration of chloride ion would suggest that at
least the inorganic ionic form of mercury would form a complex with chloride.
Measurements have been made on mercury speciation in seawater by Si 11 en and
Martell (1971) that confirm that the principal species in seawater are chloride
complexes of inorganic mercury.
3.3.3 Mercury in Drinking Water
A World Health Organization group (1976) concluded that levels of mercury
in noncontaminated fresh water were usually less than 200 ng/1. Rainwater
also appears to have concentrations generally below 200 ng/1, with most values
ranging between 5 and 100 ng Hg/1. More recent reviews have indicated that
noncontaminated mercury freshwater levels are much lower than 200 ng/1. Thus,
in a review by Fitzgerald (1979), an average level of 25 ng/1 was reported, and
Jernelov et al. (1983) concluded that background concentrations are usually
between 10 to 50 ng Hg/1.
The chemical form of mercury in fresh water and drinking water has not
yet been well established, mainly because of difficulties of analysis. On
3-13
-------
theoretical grounds, one would expect mercury present mainly as Hg compounds
in oxygenated water. Generally speaking, methyl mercury has not been detected
in samples of fresh water. A review by McLean (1980) indicated that methyl
mercury is present at concentrations close to the detection limit of currently
used methods. More recently, Kudo et al. (1982) have reported that methyl
mercury compounds account for an average of 30 percent of the total mercury in
samples of natural waters from the Ottawa River in Canada and from river and
sewage effluent samples in Japan, This is the only publication to date indica-
ting the presence of a substantial fraction of methyl mercury in ambient
water. Further work is necessary before general conclusions can be drawn.
Implications of these findings are not clear with regard to the composition
of mercury in drinking water. Presently, the average daily human absorption
of mercury from noncontaminated drinking water is estimated to be somewhat
lower than 5 ng Hg/day. This is based on assumptions that the concentration
of mercury in most drinking water is less than 25 ng Hg/1, two liters of water
are consumed daily by the standard 70-kg adult, most mercury in noncontaminated
drinking water is probably in the form of complexes of Hg , and gastrointes-
tinal absorption of this form of mercury (Hg ) is around 10 percent. Even if
30 percent of the total mercury is present as methyl mercury compounds, intake
of the latter via drinking water would be negligible compared to intake from
ingestion of fish and shellfish. At the present, the effect of water treatment,
including chlorination, on various forms of mercury, is unknown.
The chemical form and concentration of mercury in fruit juices, soft drinks,
alcoholic beverages, coffee, tea, and other drinks is not well described. It is
unlikely that mercury concentrations will differ greatly from those in ordinary
drinking water as mercury compounds are not known to be involved in the pre-
paration or storage of these beverages.
3.3.4 Mercury in Food
The results of a number of extensive surveys (Swedish Expert Group, 1971;
United Kingdom Department of the Environment, 1976; National Academy of Sciences,
1978) indicate that a major distinction should be drawn between fish, particu-
larly the large carnivorous fish, and also shellfish and marine mammals on the
one hand, and other flora and fauna on the other hand. In general, mercury
concentrations in most vegetable and meat samples that have been tested are
usually so low as to be near or below the limit of detection of mercury by
3-14
-------
most analytical methods. Thus, figures from surveys conducted by the U.S.
Food and Drug Administration (Gartrell, 1984) indicate that most foodstuffs
have total mercury levels of below 20 ng/Hg/g wet weight, although occasionally
poultry and meat have been reported to contain levels of up to 200 ng/g wet
weight. In view of the uncertainty of these generally reported low numbers,
any calculations of average daily intakes from non-fish food merely represent
crude estimates of mercury intake from such sources. Indeed, a low intake of
mercury from non-fish sources is consistent with the finding that non-fish
eaters have the lowest blood concentrations of mercury.
Analysis of fish tissue indicates that on the order of 70 to 90 percent
of the total mercury is present as monomethyl mercury compounds (World Health
Organization, 1976). Levels of methyl mercury in the larger predatory oceanic
fish such as tuna and shark may reach values up to 5 ppm devoid of any direct
contamination of the fish or the water by human activities (International
Register of Potentially Toxic Chemicals, 1980). For example, over 50 percent
of swordfish tested to date have values in excess of 1 ppm. Observations on
canned tuna indicate average total mercury concentrations on the order of
0.24 ppm (Table 3-2).
In fresh water, the average concentration in most fish is below 0.2 ug/g;
however, levels of mercury in pike may frequently exceed 1 ug/g, and values as
high as 28 ug/g have been reported in heavily polluted areas (Fimreite and
Reynolds, 1973). More details are available in a review by the United Nations
Environmental Protection Program (International Register of Potentially Toxic
Chemicals, 1980), in a large survey conducted in the United States on commercial
species of fish (U.S. Department of Commerce, 1978), and in an extensive
survey in England (United Kingdom Department of the Environment, 1976).
Some of the factors influencing the levels of methyl mercury in fish have
been discussed briefly in the previous section. In addition to these factors,
it should be noted that the concentration of methyl mercury in the aquatic
system itself is a major contributing factor to levels of methyl mercury in
fish. Two other controlling factors are the age and species of the fish.
Marine mammals can also accumulate mercury. For example, the livers of
seals may, in some cases, contain very high concentrations of total mercury on
the order of 340 ug/g, but over 90 percent of this is in the form of inorganic
mercury which is probably combined in an inert form with selenium (Koeman et
al., 1973). Nevertheless, sufficient amounts of methyl mercury are found in
3-15
-------
TABLE 3-2. FISH AND SHELLFISH CONSUMPTION IN THE UNITED STATES
(September 1973-August 1974)
Total
Tuna (mainly canned)
Unclassified
(mainly breaded,
including fish
sticks)
Shrimp
Ocean Perch3
Flounder
Clams
Crabs/lobsters
Salmon
Oysters/scallops
Troutb
Coda
Bassb
Catfishb
Haddock3
Pollock3
Herring/smelt
Sardines
Pikeb
Halibut3
Snapper
Whiting
All other
classified
Rank
1
2
3
4
5
6
7
8
9
9
11
12
12
12
15
16
17
18
18
20
Amount,
106
Ib/yr
2957
634
542
301
149
144
113
110
101
88
88
78
73
73
73
60
54
35
32
32
25
152
Percent of
total by
weight
100.0
21.4
18.4
10.2
5.0
4.9
3.6
3.7
3.4
3.0
3.0
2.7
2.5
2.5
2.5
2.0
1.8
1.2
1.1
1.1
0.9
5.1
Number of
actual users
(mil 1 ions)
197
130
68
45
19
31
18
13
19
14
9
12
7.6
7.5
11
11
10
2.5
5.0
4.3
3.2
Mean amount
per user
g/day
18.7
6.1
10.0
8.3
9.7
8.6
7.6
10.6
6.7
7.8
12.3
8.1
12.0
12.1
8.6
6.8
6.7
17.4
8.0
9.3
9.7
Aver.c
mercury
cone.
ppm
0.24
j
0.21d
0.46
0.13
0.10
0.05
0.25
0.05
0.04
0.42
0.13
0.21e
0.15
0.11
1.41
0.06
0.61
0.33
0.45
0.05
0.21
Mainly imports.
Fresh water.
The geometric means.
The value was assumed to be equal to the mean mercury concentration in all species
reported by the U.S. Department of Commerce (1978), excluding the species reported in
this table.
P
Measurement values not available. Same assumptions made as in d.
Source: U.S. Department of Commerce (1978).
3-16
-------
seal tissue, including liver, such that individuals consuming seal meat, like
the Eskimo, have been shown to have high blood concentrations of methyl mercury
(Galster, 1976).
The U.S. Department of Commerce (1978) conducted a survey of over 25,000
individuals, representative of the United States population, in order to
determine the intake of methyl mercury from fish. On a per weight basis, it
was found that consumption of tuna exceeds that of other species of fish
in the United States (Table 3-2). However, since the actual number of users
or consumers of tuna is also very high, the amount of tuna consumed per user
is not dramatically different than the consumption per user of other species
of fish. It is of interest to note that the highest consumption per user is
of Northern pike, giving a value of 17.4 g/day, and that other species of
freshwater fish — bass, catfish, and trout — are next highest per user
consumption at about 12 g/day. Tuna falls more or less in the midrange,
between 6 and 10 g/day. In fact, the range in per user consumption of dif-
ferent species is quite small, being no more than a factor of two, despite
the huge range in total consumption of each species.
The data in Table 3-2 from the U.S. Department of Commerce (1978) do not
allow for an accurate calculation of the average daily intake of fish, nor even
for an accurate calculation of the range of daily intake. However, a rough
estimate can be derived by dividing the total amount of fish consumed in the
United States (top of column 3) by the total number of people consuming fish
(top of column 5), resulting in a value of 18.7 g (top of column 6). This
calculation is only a rough approximation of the average intake of fish since
the distribution of individual consumption is not known. Similarly, a rough
calculation of average mercury consumption may be made in the same way. Using
the figures for amount consumed of each species of fish (column 3) and the
average concentration in each species (column 7), total intake of mercury from
all species of fish for the entire population may be calculated. By dividing
the total mercury intake by the total number of consumers (197 million, top of
column 5), a value of 4.7 ug Hg/day is obtained. It should be emphasized that
this calculation is very speculative and it assumes all factors affecting fish
consumption and mercury levels in fish are randomly distributed.
Fouassin and Fondu (1978) have calculated that, in Belgium, the intake of
mercury due to fish consumption is 2900 ng Hg/day. Bernhard and Andreae (1984)
estimated an average adult human intake worldwide of 2 pg Hg/day from seafoods.
3-17
-------
Previously, Clarkson and Shapiro (1971) had presented calculations indicating
an intake of methyl mercury for U.S. adults of 3 (jg Hg/day based on blood
levels.
The average consumption of fish given in Table 3-2 as 18.7 g fresh weight
per day compares with a reported value of 16 g/day from the Food and Agriculture
Organization (FAO, 1980) of the United Nations. However, it should be noted
that considerable national and individual differences must exist. Populations
largely dependent on fish as a source of protein have average daily intakes of
up to 193 g fresh weight (FAO, 1980). Canadian Indians have been reported to
take in as much as 1300 g/day during the fishing season (Piotrowski and Inskip,
1981). These native populations live in villages close to large freshwater
fishing areas and have very high intakes of freshwater fish that tend to be
high in the food chain, such as pike, walleye, and bass. Intake of methyl
mercury in the special population groups having unusually high intake of fish,
may be 10 to 100 times greater than that in the general population.
3.3.5 Relative Contributions of Various Media to Human Exposure
The three major media contributing to human intake of mercury are air,
drinking water, and food. In considering human intake, it is most important
to treat each major chemical species of mercury separately. Of greatest
concern are metallic mercury vapor (Hg°), compounds of inorganic mercury
(Hg ) and compounds of methyl mercury (CH-Hg ). The relative contribution of
these species to mercury intake is presented in detail in Table 6-1 (Chapter
6).
Air is the only source of human exposure to Hg°. People living in non-
polluted rural areas would absorb about 16 ng Hg/day/adult as compared to
about 160 ng Hg/day/adult absorbed by individuals living in cities. It is
highly unlikely that average daily intakes over the long term would exceed 800
ng Hg/day/adult. Drinking water only contributes marginally to human daily
intake, resulting in probably no more than 5 ng Hg/day. While the chemical
form of mercury in drinking water is not totally established, most is thought
to be in the form of Hg++ If all were in the form of Hg++ compounds, probably
not more than 10 percent would be absorbed into the bloodstream (See Chapter
4). It is possible, however, that up to 30 percent may be present as methyl
mercury compounds, in which case the percentage absorbed would be considerably
higher. However, by far the predominant source of human exposure to methyl
mercury compounds is fish and fish products. In Section 3.3.4, based on data
3-18
-------
in Table 3-2, it was calculated that the average intake for an adult in the
United States is 4700 ng Hg/day. This is a speculative number in view of the
assumptions that had to be made in the calculation of the number, but this value
compares reasonably well with other estimates for worldwide intake (2000 ng
Hg/day) and for intake measured in an industrialized European country (2900 ng
Hg/day) and a previous estimate for the U.S. population (3000 ng Hg/day).
3.4 SUMMARY
Mercury exists in three oxidation states -- Hg° (metallic), Hg_ (mercurous)
++
and Hg (mercuric) mercury — and a wide variety of chemical forms, the most
important being compounds of methyl mercury, mercuric mercury, and the vapor of
metallic mercury. Mercury forms stable organometallic compounds in which the
mercury atom is covalently bound to one or more carbon atoms.
The global cycle of mercury involves the emission of Hg° from land and
water surfaces to the atmosphere, transport of Hg° in the atmosphere on a global
scale, possible conversion of unidentified soluble species, and return to land
and water by various depositional processes. The ultimate deposition of mer-
cury, probably as HgS, is believed to be in ocean sediments.
Inorganic mercury undergoes methylation by microorganisms that are wide-
spread in bodies of both fresh and ocean water and probably in soils. Methyl
mercury is avidly accumulated by fish and attains highest concentrations in
large predatory fish at the top of the aquatic food chain. By this means, it
enters the human diet. Certain microorganisms can demethylate CH^Hg ; others
«• »
can reduce Hg to Hg°. Thus, microorganisms are believed to play an important
role in the fate of mercury in the environment and in affecting human exposure.
Man's contribution of Hg° to the atmosphere is believed to range from 10
to 80 percent of total input with estimates presented within this chapter of at
least 20 percent. The burning of fossil fuels is an important anthropogenic
source. Background levels in the troposphere of the Northern Hemisphere are
now estimated at 2 ng Hg/m . In regionally polluted areas, values lie between
3 3
3 to 4 ng Hg/m . Urban air may have average concentrations up to 10 ng Hg/m .
Most of the mercury in the atmosphere is probably in the form of Hg°.
Mercury in drinking water is usually in the range of 5 to 100 ng Hg/1 with
an average value of about 25 ng Hg/1. The forms of mercury in drinking water
A^.
are not well studied, but Hg is probably the predominant species present as
complexes and chelates with ligands in water.
3-19
-------
Concentrations of mercury in most foodstuffs are often below the detection
limit (usually 20 ng Hg/g fresh weight). Fish and fish products are the domi-
nant source of mercury in food, mainly in the form of methyl mercury compounds
(70-90 percent of the total). The average concentrations in edible tissues
of various species of fish cover a wide range, from 50 to 1400 ng Hg/g fresh
weight. Large predatory freshwater fish, such as Northern pike (610 ng Hg/g
fresh weight) and trout (450 ng Hg/g fresh weight), have some of the highest
average concentrations.
The atmosphere is the only source of human exposure to Hg°. The daily
amount absorbed into the bloodstream by adults is about 16 ng Hg in rural
areas and about 160 ng Hg in urban areas. Drinking water supplies somewhat
under 25 ng Hg/day, only a small fraction of which is absorbed into the blood-
stream. Intake of fish and fish products results in the average daily absorp-
tion of amounts of methyl mercury variously estimated to be between 2000 to
4700 ng Hg. The absorption of inorganic mercury from foodstuffs is difficult
to estimate because levels of total mercury are close to the limit of detection
in many food items and the chemical species of mercury have not usually been
identified.
The intake of total dietary mercury has been measured by the United
States Food and Drug Administration (Gartrell, 1984) over a number of years for
various age groups. The average daily intake over the period 1973 to 1982 has
been in the range of 2000 to 7000 ng Hg for adults and up to 1000 ng Hg for
toddlers and infants. The most recent figures (fiscal year 1981-82) were 3000
ng Hg for adults, 1000 ng Hg for toddlers, and less than 1000 ng Hg for infants.
These figures support the conclusion that fish and fish products are the major
source of total mercury in the diet.
3-20
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4. PHARMACOKINETICS AND BIOTRANSFORMATION IN MAN AND ANIMALS
4.1 VAPOR OF METALLIC MERCURY
In 1973, a Task Group on Metal Accumulation made the following recommenda-
tions:
"Indices of metal accumulation and exposure are urgently needed.
It has been shown that metal levels in available biological material
(blood, urine, hair, etc.) might give an approximate indication on
recent exposure but with few exceptions cannot be used to calculate
metal concentration in critical organs or in whole body. Consequent-
ly, in many cases, it is impossible to tell on the basis of sample
analysis whether accumulation in the critical organ is progressing
and how far metal concentration in the critical organ is from the
critical level. The reason for this lack of knowledge is two-fold.
One is the lack of proper numerical values which could be set up in
an equation; the other is the lack of a proper mathematical model
which is adequate to describe with approximate accuracy the complex-
ity of metal accumulation in the body."
A World Health Organization environmental criteria document (1976) made special
note that this information was lacking in the case of inhaled mercury vapor.
Although the literature does not contain sufficient information from
which to construct a satisfactory compartmental model, a review of the field
reveals important findings that should be incorporated into a complete scheme.
These findings are summarized and discussed below.
4.1.1 Routes of Absorption
4.1.1.1 Lung—About 80 percent of the inhaled mercury vapor is retained in
body tissues as evidenced by observations on both animals and man (Teisinger
and Fiserova, 1965; Nielson-Kudsk, 1965b). Teisinger and Fiserova (1965)
originally proposed that the vapor was absorbed across the walls of the bron-
chioles and larger airways of the lung, but subsequent evidence points strongly
to the alveolar region as the predominant site of absorption into the blood-
stream (Berlin et al., 1969a). During the absorption process, mercury becomes
deposited in lung tissue, as evidenced by animal experiments and by observations
4-1
-------
in volunteers inhaling a tracer dose of mercury (Berlin and Johansson, 1964;
Hursh et al., 1976).
4.1.1.2 Skin—Studies in the early part of the century indicate that absorption
of mercury can take place across the skin of man (Juliusberg, 1901) and animals
(Schamberg et al., 1918) when exposed to metallic mercury. It is surprising
that no further studies have been reported since droplets of metallic mercury
in footwear and clothing probably come into contact with skin during occupa-
tional exposure. Most reports on air concentrations of mercury vapor and
corresponding concentrations in samples of blood and urine have not taken into
account possible absorption across the skin from contact with droplets of
metallic vapor and from high concentrations of vapor trapped in the footwear.
While it has been proposed that, on an individual basis, such contact may
contribute to overall mercury absorption (see section 6.3.1.1 for a discussion
of the importance of microenvironmental exposure), it is presently not known
whether mercury would be directly absorbed from the droplets, or whether
mercury vapor, formed from the droplets, would be absorbed.
4.1.2 Deposition and Retention
Mercury distributes to all parts of the body following inhalation of
mercury vapor. A general picture of distribution, deposition and elimination
from tissues is indicated in Figure 4-1. The data are based on regional and
whole-body counting of volunteers who inhaled, over a period of 20 minutes,
3
air containing 0.1 mg Hg/m labelled with a radioactive isotope. As can be
seen from the figure, the kidney accumulated the highest concentration of
mercury. Distribution of mercury appeared to be complete within 24 hours for
most regions of the body except for the head, where peak radioactivity was not
attained until two to three days later. Elimination from the whole body and
kidney region took place at about the same rate. Clearance from the head
region was more rapid than from most other areas of the body with an elimina-
tion half-time of about 20 days (Table 4-1). Decline in radioactivity in the
chest region was biphasic. A rapid component, attributed by Hursh et al.
(1976) to mercury deposited in lung, had an elimination half-time of about 2
days. A slower component, half-time similar to kidney and whole body, was
attributed to radioactivity in other tissue in the chest region. Experiments
in non-human primates confirm the finding that mercury clearance from lung is
more rapid than from other tissues (Berlin et al., 1969a).
4-2
-------
10s
LU
I-
D
O.
CO
z
o 10*
O
Q
LLI
O
LU
cc
cc
o
o
<
o
LU
o
103
SUBJECT P.K.
A CHAIR
o KIDNEY
D CHEST
• LUNG
# HEAD
10 20 30
DAYS POST EXPOSURE
40
Figure 4-1. Decay-corrected rates for four posi-
tions of crystal detector plotted as a function of
days after exposure. Points for the lung (dotted
line) are generated by extrapolating the straight
line for the chair position to zero time and plot-
ting the difference between values on this line
and the measured data points. The chair postion
is the position assumed by the subject such
that the recorded radiographic counts most
closely correspond to the total body burden of
the subject.
Source: Hursh et al. (1976).
-------
TABLE 4-1. SUMMARY OF HALF-TIMES OF MERCURY IN HUMAN TISSUES
Tissue
Blood3
Blood0
Blood0
d
•£=• Lung
Kidney
Headd
Whole Bodyd
Exposure
Cone.
(mg/m3)
0.1
»0.1
-0.05
0.1
0.1
0.1
0.1
Duration
20 min
few hours
months
20 min
20 min
20 min
20 min
First Component
T 1/2
% deposited (days)
>60
-90
?
-100
-100
-100
-100
3.3
-2.0
?
1.7
64.0
21.0
58.0
Second Component
T 1/2
% deposited (days)
not detected
-10
-100
not detected
not detected
not detected
not detected
20
30
*Cherian et al., 1978.
Other components having longer half-times cannot be excluded but would account for small fraction of the total
Tlarkson, 1978.
dHursh et al., 1976.
-------
Autoradiographic studies (Berlin and Ullberg, 1963b; Berlin and Johansson,
1964; Berlin et al., 1966) indicate that after inhalation of mercury vapor,
mercury distributes preferentially to certain types of cells. Mercury, whether
++ ++
administered as Hg or converted in the body to Hg from inhaled Hg , has a
special affinity for ectodermal and endodermal epithelial and glandular cells.
Thus, mercury is seen to be accumulated in the mucosa of the intestines, in
epithelial cell layers of the skin and in glandular tissue such as salivary,
pancreas and sweat glands, in the kidneys, and in epithelial-type organs such
as testes and prostate.
Deposition and clearance in blood, brain, kidney, and fetal tissue are
discussed in more detail below in view of their importance in the metabolism
and toxicity of inhaled mercury.
4.1.2.1 Blood--Cherian et al. (1978), in studies on volunteers exposed for
20 minutes to a tracer dose of radioactive mercury vapor, reported that approx-
imately 2 percent of the absorbed dose was deposited in one liter of whole
blood after initial distribution was completed. Uptake in the red cell com-
partment was complete within a few hours, but plasma uptake reached a maxi-
mum in about one day. The concentration of mercury in the red cells was about
twice that in plasma, a relationship that persisted for at least six days after
exposure. Cherian et al. (1978) also reported a mean half-time in blood of
3.3 days in volunteers exposed for 20 minutes to a tracer dose of radioactive
mercury vapor (Table 4-1). This half-time accounted for the loss of at least
50 percent of the radioactive mercury from blood. Red blood cells and plasma
had similar half-times. -However, blood and excreta were only followed for
about 5-7 days due to counting problems encountered in working with a short-
lived isotope. As a result, blood mercury levels and excretion rates were
still changing at the end of the 7-day period due to distributional phenomena.
This observation was supported by the fact that whole body counts, measured in
the chair position (a measure of whole-body radioactivity ) did not go into a
terminal decay phase until after approximately 9 days and may even have been
developing a slower component after 30 days.
An accidental mercury vapor exposure of a family in Boston (Figure 4-2)
has supplied some additional information concerning blood half-times (Clarkson,
1978). The major portion of the exposure probably occurred within a half-hour
period, with a smaller, protracted exposure over the duration of an evening.
It appears that there was an early, rapid decline over the first few days post-
exposure, and, by about days 5-7, the mercury in blood was decreasing with an
4-5
-------
160
i i i I i r
120
80
D)
x
O)
d
o
o
40
I
o
O
O
oc
o
•2.
I 1 I
1 I
200
100
50
20
10
L I I I I I
i I \l i I i
25 30 4
OCT.
9 14 19
NOVEMBER
24
Figure 4-2. The fall in mercury
concentrations in blood in two adult
females following a brief exposure (less
than 3 hr) to mercury vapor. Upper graph
has a linear scale on the ordinate. The
lower graph has a logarithmic scale and
curve stripping procedures were used to
estimate a component with the different
half-time (slow component, 14.9 days;
fast component, 2.4 days).
Source: Clarkson (1978).
4-6
-------
approximately 15-day half-time, which was maintained for the remainder of the
first month post-exposure. A 7-month period lapsed before the next samples
were collected, and by that time the blood levels were down to the 6-11 ng/ml
range, which is in the vicinity of a high normal background level.
Another family exposure to mercury vapors involved a husband and daughter
who were exposed for 6 to 8 months in the home; the wife had experienced a
prior exposure of about 18 months in her workplace (Clarkson, 1978). Samples
of blood were collected starting about 1 month after cessation of exposure.
Therefore, an early rapid fall in concentration due to short half-time compo-
nents was missed. The blood concentration of mercury in the wife declined
with a half-time of 30 days. The other two family members had longer half-
times, but their blood levels were sufficiently low that dietary mercury might
have influenced the results.
If the mercury in the body is all in exchangeable pools, one would antici-
pate a protracted half-time in the blood to agree with the protracted whole-body
retention half-times of 40-60 days (Hursh et al., 1976; Rahola et al., 1973).
The observation of a 30-day half-time is consistent with the findings of
Rahola et al. (1973), who reported slow components for red cells of 13-42 days
following the oral administration of an inorganic mercury salt, but it is less
than the whole-body half-times reported by Hursh et al. (1976). However, if
there is sequestration, such a protracted blood half-time will not be observed
if the sequestered mercury is cleared into the excreta directly.
4.1.2.2 Brain.--As shall be discussed later, inhaled mercury vapor is rapid-
ly oxidized in blood and other tissues to the divalent form (Hg ). This is
consistent with the finding that the general pattern of deposition in organs
and tissues after exposure to mercury vapor is essentially similar to that
pattern seen when divalent salts of mercury, such as mercuric chloride, are
given to animals parenterally (Rothstein and Hayes, 1960; Hayes and Rothstein,
1962). However, the amount deposited in the brain is about ten times greater
in the case of exposure to mercury vapor as compared to similar doses of ionic
mercury (Berlin and Johansson, 1964). Although these observations are from
animal experiments, the fact that similar results are seen in several different
species strongly suggests that the same situation might apply to man (Berlin
et al., 1969b). Volunteers inhaling radioactive mercury accumulate about
7 percent of the dose in the head region, consistent with diffusion into the
brain (Hursh et al., 1976).
4-7
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Experiments in mice given a 4-hour exposure indicated a longer retention
time in brain than in other tissues (Berlin et al. , 1966). The amount deposited
in the brain has been reported for a variety of species and is approximately
similar when expressed on a per gram tissue basis. The amount deposited is
usually between 0.2 and 1 percent of the dose per gram tissue. A notable
exception to this observation is in a report by Magos (1967), where it was
noted that as much as 6 percent was deposited in the brains of mice used in
his study. The results suggest an important strain difference in the mice
used by Magos, although the lower body weight of his mice might account for
some of the difference. It is noteworthy that it was in this same strain of
mice that Magos reported a long biological half-time of mercury in the brain
versus other tissues.
Autoradiographic studies of central nervous system tissue in mice and
rats exposed to radioactive mercury, 6 hours daily, for 10 days, and killed at
intervals of up to 60 days after exposure, indicate that more mercury is
accumulated in gray matter than white matter (Cassano et al. 1966, 1969). The
highest concentrations of radioactivity were found in the cerebellum and brain
tissue stem nucleii. In the cerebellum, the greatest accumulation was in the
cytoplasma of the purkinje cells. High concentrations were seen in periventri-
cular structures and other tissues in close contact with cerebrospinal fluid.
Berlin and Ullburg (1963a) suggested that cerebrospinal fluid may be an impor-
tant route of entry into the brain. However, the data are also consistent
with the premise that blood is the major entry portal of mercury into the
brain and that cerebrospinal fluid is the major exit pathway.
Hursh et al. (1976) observed a 21-day clearance half-time (Table 4-1)
from the head, following a brief vapor exposure to humans. This half-time was
observed over a 40-50 day post-exposure period and is in the range of observed
half-times for blood. The peak value of the head counts came near the peak
time for the plasma, raising the question of whether or not the brain levels
were following the plasma. However, for the subject cited, the change between
the last two counting days was not as great as expected, which raises the
possibility that some material was either being sequestered in the brain or at
least was being cleared at a considerably slower rate. Indeed, Takahata et
al. (1970) and Watanabe (1971) reported that mercury persists in brain for
many years following the cessation of occupational exposure to mercury vapor,
and Berlin (1976) noted that mercury concentrations in brains of squirrel
monkeys continued to increase after two months of exposure.
4-8
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In the above considerations regarding the relationship between dose and
brain mercury content, Henderson et al. (1974) have noted the potential impor-
tance of rate of dosage of mercury vapor in view of the conversion of Hg to
++
Hg by the red blood cells. They suggest that higher rates of mercury vapor
intake might lead to a greater fraction of inhaled vapor reaching the blood-
brain barrier as Hg than would lower rates of intake (see Section 4.1.4.3).
4.1.2.3 Fetus--No quantitative data are available on the rate of transfer
of inhaled vapor to the fetus in humans. When pregnant rats received a 15
minute exposure to radioactive vapor on day 17 of gestation, the amount of
mercury was 4 times greater in the fetuses from these dams as compared to
fetuses from mothers given an equivalent dose of HgCl? (Clarkson et al.,
1972). In this study, the fetuses were examined immediately after exposure.
Dencker et al. (1983) reported that, after 60-minute exposures of mice to
mercury vapor, more mercury was accumulated by the fetus at later stages of
gestation. Pretreatment of the mother with a large dose of ethanol (2 g/kg)
increased the total mercury accumulation in the fetus by about fourfold (Khayet
and Dencker, 1982). No information is available on long-term exposures.
In two cases of exposure of pregnant human females to mercury vapor, it
was found that the concentration of mercury in infant's blood was similar to
that in the mother's blood at the time of delivery (Clarkson, 1978).
4.1.2.4 Kidney—The overall pattern of deposition in the body is dominated
by accumulation in kidney tissue. Concentrations in kidney are several orders
of magnitude higher than in other tissues following both single and repeated
exposures (Hayes and Rothstein, 1962; Rothstein and Hayes, 1964). In the
experiments of Hayes and Rothstein, the amount of mercury accumulated in
kidney accounted for as much as 90 percent of the total body burden. The
retention of this large amount of mercury in the kidney may be of considerable
significance in assessing potential toxic hazard, as will be discussed below.
Some agents that tend to reduce mercury levels in kidney tissue increase
mercury concentrations in all other tissues. This has been discussed in detail
by Magos (1973), who cited examples of a number of chemicals that would reduce
kidney concentrations and elevate mercury throughout the rest of the body.
Thus, important factors affecting the toxicity of inhaled mercury vapor might
be those processes or conditions which lead to diminished renal uptake of mer-
cury.
4-9
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Sexual dimorphism may also affect metabolism. Shaikh (1981, 1983) has
reported that concentrations of mercury are greater in male mice and rats
exposed to mercury vapor than in females similarly exposed.
Observations in humans (Cherian et al., 1978) and in rats (Gage, 1961)
are consistent with the observed pooling and probable sequestration of mercury
in the kidney. It therefore seems plausible to assume that the urinary excre-
tion rate of mercury should not be simply proportional to the plasma level but
should also include a term proportional to the kidney level. It is also
entirely possible, as suggested by Gage's data, that the kidney consists of
more than one compartment, which would further add to the complexity of the
system.
4.1.3 Excretion
Urine and feces are the main pathways of excretion after exposure to
mercury vapor, although exhalation of vapor and excretion in saliva and sweat
may contribute to overall excretion (Lovejoy et al., 1974; Joselow et al. ,
1968). Animal data indicate that, shortly after exposure, the gastrointestinal
tract is the predominant pathway of excretion, but, as the kidney becomes more
and more the predominant site of storage of mercury, urinary excretion takes
over (Rothstein and Hayes, 1964). In humans, following a brief exposure,
urine accounted for 13 percent of the total urine and fecal excretion, but,
after long-term occupational exposure, urine accounted for 58 percent (Table
4-2). In tracer experiments in volunteers it was noted that the specific
activity of mercury in urine was unrelated to and significantly lower than the
specific activity in plasma (Cherian et al., 1978). This observation suggests
that urinary mercury originates from a large pool of mercury in kidney as
opposed to glomerular filtration of plasma mercury. However, this conclusion
is valid only if the plasma activity reflects the filterable fraction.
In volunteers exposed to mercury vapor, it was found that approximately
7 percent of the inhaled dose would eventually be excreted via exhalation in
the expired air. Most of the exhalation was completed within one week and
constituted approximately 37 percent of total mercury excretion during the
same period (Table 4-2). If the reduction reactions in the body (see below)
are sufficiently rapid to maintain equilibrium between mercury vapor and the
oxidized form in the blood and tissues, both the exhalation of vapor over a
longer period than that observed by Hursh et al. (1976) and, consequently, a
4-10
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TABLE 4-2. THE RELATIVE AMOUNT OF MERCURY EXCRETED IN URINE, FECES, AND
EXPIRED AIR AFTER EXPOSURE TO MERCURY VAPOR
Excretion Type of Percent of
medium exposure total excretion
Expired air Short-term* 37
Urine Short-term 13
Feces Short-term 50
Urine Long-term. 58
Feces Long-term 42
aAverage excretion in the first week following exposure to 0.1 mg Hg/tn3 for a
20 minute period (Hursh et al., 1976; Cherian et al., 1978).
The daily excretion in urine and feces was measured in individuals exposed
for several years to 0.05 to 0.2 mg Hg/m3 (Tejning and Ohman, 1966). Infor-
mation on excretion by other routes was not available.
greater than 7-percent excretion by that pathway would be expected. However,
the increment may not have any overall significance.
From the work of Gay et al. (1979), it has been shown that mercury from
tooth fillings can increase the amount of mercury expired in air. After
15 minutes of chewing, people with no fillings expired from 1 to 6 ng Hg/10
breaths, whereas people who had their teeth filled one to two years prior to
testing, expired from 17 to 76 ng Hg/10 breaths. People with teeth filled
within one to two weeks prior to testing expired between 172 to 244 ng Hg/10
breaths. Prior to chewing, expiration of mercury did not exceed 22 ng Hg/10
breaths irrespective of the time after an individual's teeth were filled. The
significance of these findings to potential human health effects is wholly
unknown.
Quantitative information on excretion via sweat and saliva is not avail-
able. In workers experiencing profuse perspiration, amounts of mercury excreted
in the sweat may exceed those in the urine (Lovejoy et al. , 1974).
A highly schematic and simplified version of processes that might be
operative in the transport of mercury from inspired air to various tissues is
given in Figure 4-3. The roles of three of the major processes instrumental
in this transport are discussed below. Each has been dealt with separately
for convenience of presentation, but it must be recognized that considerable
interaction must occur between them.
4-11
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TARGET ORGANS
ft
OTHER TISSUES
AIR
Hg°
•i.e.
EXCRETORY
ORGANS
/NHg°5^Hgd+TT
1 V\ // 1
V v> //„,. ,7
\ '"tfd* /
EXCRETA
Figure 4-3. A schematic representation of the fate of inhaled mercury vapor. The symbols have
the following significance:
Hg°
HgV
i.e.
- mercury vapor
- divalent mercury present as diffusible complexes and chelates
- divalent mercury in a non-diffusible form and in equilibrium with Hg
- inert complexes of mercury
The blood compartment should be represented as two subcompartments — plasma and cells. As
discussed in the text, the distribution of mercury favors the cell compartment after exposure to
mercury vapor, whereas after doses of inorganic mercury salts, the distribution is more or less
equal.
-------
4.1.4 Biotransformation, Speciation and Transport
4.1.4.1 Biotransformation—Studies on human blood exposed i_n vitro to mercury
vapor have indicated that the vapor becomes oxidized to the divalent form
++
(Hg ). The reaction takes place principally, if not solely, in the blood
cells. The process occurs via the hydrogen peroxide catalase pathway where
monatomic mercury is oxidized by catalase complex I in a peroxidative reaction
believed to be similar to other peroxidative reactions by catalase (Halbach
and Clarkson, 1978). The process of oxidation by red cells can be greatly
accelerated by the infusion of hydrogen peroxide into the red cell suspension
or by the use of such agents as methylene blue that enhance endogenous hydrogen
peroxide production. The process can be inhibited by low concentrations of
ethanol, which presumably act as a competitive substrate. Other alcohols that
are substrates for the peroxide reaction inhibit the uptake of mercury vapor
by red cells (Nielsen-Kudsk, 1973). The importance of the oxidation step in
the retention of inhaled vapor and its deposition in the bloodstream is demon-
strated by observations on the effects of alcohol. For example, Nielsen-Kudsk
(1965a) showed that workers who had ingested a moderate dose of alcohol retained
about 50 percent less vapor than workers not ingesting alcohol. The deposition
in blood was dramatically reduced when volunteers took alcohol before being
exposed to mercury vapor. This evidence is presented in Figure 4-4 where it
may be seen that the deposition of mercury in the red cells was reduced almost
by a factor of ten in individuals having alcohol blood levels less than 8 mg
percent. However, all the observations to date on both animals and man have
been concerned with single or brief exposures to vapor and alcohol. No infor-
mation is available on the role of repetitive dosing with alcohol in animals
or man continually exposed to mercury vapor.
That oxidation of mercury occurs in the lung tissue is suggested by the
fact that treatment of animals with ethanol dramatically reduces the amounts of
mercury deposited in lung tissue after brief exposures to vapor (Magos et al.,
1973). Lung deposition was also reduced by ethanol in humans exposed to tracer
doses of mercury vapor (Hursh et al., 1980).
Oxidation of mercury vapor in liver tissue is suggested by the fact that
treatment of animals with alcohol can drastically change the uptake by the
liver. Observations on homogenates of rat liver indicate that mercury is
readily oxidized and that the hydrogen peroxide catalase pathway is the pre-
dominant pathway of oxidation (Magos et al., 1978). The oxidational capacity
4-13
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100
O
Z
o
Z
o
o
10
i—i—i—i—r
i i—i—r
RBC
EtOH O*
I
I M I I 1 I I I
I I
-2
4
DAYS
10
Figure 4-4. The deposition and retention of mercury in red blood cells in
volunteers inhaling a tracer dose of mercury vapor. Ethanol (EtOH) was
consumed 20 minutes prior to exposure to mercury vapor. The maximum
blood concentrations were about 80 mg%. The shaded area covers the range
of mercury concentrations in five subjects not taking ethanol. Two other
subjects ( a and • ) did not take ethanol and were observed for a longer
period (10 days) than the other control group. Exposure to vapor (0.1 mg
Hg/m3) was for approximately 20 minutes.
Source: Adapted from Hursh et al. (1980).
4-14
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is so great that, under i_n vitro conditions, the rate of delivery of mercury
vapor to the homogenate appears to be rate-determining in the uptake process.
This may also be true in the intact animal. Thus, treatment of animals with
alcohol actually produces a large increase in deposition of mercury in the
liver following brief exposure to mercury vapor (Magos et al., 1973). Alcohol,
by inhibiting oxidation in blood, allows more vapor to be carried to the liver
where the large reserve of catalase complex I is able to readily oxidize this
increased supply of vapor. Autoradiographic studies by Dencker et al. (1983)
support this interpretation.
The extent to which oxidation and reduction processes are occurring
either in the placenta or in the fetus has not yet been thoroughly studied.
The autoradiographic findings of Dencker et al. (1983) suggest that oxidation
is taking place in fetal liver tissues.
Recently, evidence has come to light that the divalent (oxidized) form of
mercury is subject to reduction in mammalian tissues. This is evidenced by
the finding that exhalation of vapor occurs in mice and rats treated parenter-
ally with mercuric chloride (Clarkson and Rothstein, 1964; Dunn et al., 1978,
1981b; Sugata and Clarkson, 1979). Ethanol is able to elicit a tenfold increase
in the exhalation of vapor in volunteers exposed briefly to mercury vapor (as
shown in Figure 4-5). More recently, ethanol has been shown to elicit exhala-
tion of vapor in volunteers given tracer doses of mercuric chloride (Clarkson,
1978) and to increase exhalation of vapor in mice dosed parenterally with
mercuric chloride (Dunn et al., 1981b). It is not known to what extent this
reduction process applies to all tissues in the body; however, it is known
that mercury will volatilize from liver and kidney homogenates of animals
given divalent mercury and that the volatilization rate is increased by adding
ethanol to the homogenate (Dunn et al., 1981a).
The effect of alcohol in increasing volatilization of mercury ijn vitro
and jui vivo is probably due to its inhibitory action on the oxidation step,
thus, preventing the reoxidation of the vapor. This proposed mechanism is
supported by the finding that other inhibitors of catalase also increase
volatilization of mercury (Sugata and Clarkson, 1979; Dunn et al., 1981a).
The enzyme responsible for reduction of mercury has not yet been identi-
fied. Glutathione reductase is a distinct possibility in view of the finding
by Williams et al. (1982) that this enzyme is similar in structure to mercuric
ion reductase in microorganisms. If this proves to be the case, ethanol may
4-15
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.01
.005
UJ
V)
o
o
.001 —
.0005 —
.0001
DAYS
Figure 4-5. The rate of exhalation of mercury from a
volunteer who received a brief (20 min) exposure to mercury
vapor labeled with the 203Hg isotope. Alcohol was consumed
at 48 hours after the exposure to vapor in an amount that in-
creased blood alcohol concentration to about 80 mg%.
Source: Hursh et al. (1980).
4-16
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directly enhance the reduction process. The reduction of Hg by bacterial
reductase requires NADPH as follows:
Hg++ + NADPH + H+ —»• Hg° + NADP+ + 2H+
The metabolism of ethanol to acetaldehyde could provide NADPH for this con-
version. However, oxidation of alcohol occurs almost entirely in liver tissue
and, therefore, would not provide NADPH for volatilization observed in kidney
slices.
In summary, an oxidation-reduction cycle for mercury exists in mammalian
cells. Mercury in the zero oxidation state, Hg , is probably the more mobile
species, whereas divalent mercury, Hg , is the more reactive species inas-
much as it will more avidly bind to tissue ligands. The recently discovered
cycle, mediated by at least two enzyme systems, is probably of profound impor-
tance in the toxicology of inorganic mercury.
The oxidation-reduction cycle may also play a role in the metabolism of
alkylmercury compounds. It has been shown that mice dosed with methyl mercury
exhale mercury vapor and that ethanol increases the rate of this exhalation
(Dunn and Clarkson, 1980). The rate of vaporization of mercury from homogenates
of liver or kidneys of animals treated with methyl mercury has been demonstra-
ted to be proportional to the amount of inorganic mercury in these tissues.
In short, it appears that inorganic mercury released into mammalian tissues by
the demethylation of methyl mercury enters the oxidation-reduction cycle for
inorganic mercury.
4.1.4.2 Speciation—Several different chemical and physical species of
mercury are known to exist in blood following exposure to mercury vapor.
These species are indicated in a general form in Figure 4-3. Hg . is taken to
represent the divalent species that is in the form of diffusible complexes.
Hgncj represents those species which are protein-bound or of high molecular
weight and are in equilibrium with the diffusible form. It is also possible
that there exist sites of strong binding whereby mercury is trapped. Evidence
for these species of mercury varies considerably from one tissue to another.
Magos (1967) identified dissolved elemental mercury vapor both in blood
from mice exposed to vapor and in samples of human blood exposed i_n vitro to
vapor. Recently, Satoh et al. (1981) have confirmed Magos1 in vitro findings.
A non-diffusible protein-bound or high-molecular-weight species has also been
4-17
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identified. Mercury in plasma is predominantly in a non-diffusible form
(Berlin and Gibson, 1963). The specific protein complex may depend upon the
dose of mercury and, in one case, has been reported to be an albumin complex
(Clarkson et al., 1961). However, other complexes with globulins have also
been reported (Cember et al., 1968).
When salts of divalent mercury are given parenterally along with doses of
sodium selenite, a complex is formed associated with protein in which mercury
and selenium are present in a one-to-one atomic ratio (Burk et al., 1974).
Such complexes might represent one form of trapped mercury in the blood (Burk et
al., 1977).
Little is known about the chemical forms of mercury in the brain. Ashe
et al. (1953), in their studies of rabbits exposed to mercury vapor, were able
to distinguish between "water-soluble and -insoluble" forms of mercury in
brain homogenates. These two forms of mercury probably correspond to the
non-protein- and protein-bound forms of mercury reported by Cassano et al.
(1966) in brain tissue from mice and rats repeatedly exposed to mercury vapor.
The ratio of the protein- and non-protein-bound forms tended to remain constant
in different parts of the brain at different times after exposure to mercury
vapor, suggesting an equilibrium between the two forms. These investigators
were unable to detect any mercury associated with lipid material in the brain.
Examination of autopsy tissue in miners exposed to mercury vapor in
Yugoslavia indicated a remarkable correlation between mercury and selenium
being present in a one-to-one atomic ratio over a wide range of concentrations
(Kostial et al., 1975). Observations on Japanese workers who died ten years
after their last exposure indicated high residual concentrations of mercury in
the brain (Takahata et al. , 1970). Thus, it appears that some "trapping" of
mercury may occur. Smal1-molecular-weight complexes have not been identified
in the case of mercury vapor as has been reported with methyl mercury in
brain, where a glutathione complex is believed to account for about 30 percent
of the total mercury (Thomas and Smith, 1979).
Little is known about the species of mercury in fetal tissues. Sapota et
al. (1974) reported higher concentrations of metallothionein in fetal liver of
rats than in maternal liver. They also reported that exposure of the mother
to mercury vapor leads to binding of mercury to metal!othionein in the fetal
liver. However, no increase in metallothionein concentration was observed in
maternal or fetal liver. Webb (1983) recently reviewed the role of metallo-
4-18
-------
thionein in mercury metabolism in pre- and postnatal development. Livers of
prenatal and suckling animals contained high concentrations of metallothionein.
The hepatic metal!othionein of the newborn provided immediately available
binding sites for mercury, binding mercury in replacement for zinc.
Studies on adult rats exposed to mercury vapor gave no evidence of in-
creased biosynthesis of metallothionein in the liver (Cherian and Clarkson,
1976). After doses of mercuric chloride, mercury was shown to be excreted in
bile, mainly in a protein-bound form and with only trace amounts of small-
molecular-weight complexes (Norseth and Clarkson, 1971), suggesting that
protein-bound and diffusible forms of mercury exist in liver tissue.
The kidney has an enormous capacity to accumulate divalent forms of
mercury. Exposure of rats to high concentrations of mercury vapor induced
metallothionein in kidney tissue that resulted in the binding of divalent
mercury (Sapota et al., 1974; Cherian and Clarkson, 1976). Clarkson and Magos
(1966) identified three classes of sulfhydryl groups in kidney differing in
terms of their affinity for ionic mercury. The highest-affinity site corre-
sponded to the amount of metallothionein in kidney tissue. The ability of
kidney tissue to accumulate large amounts of mercury may well be related to
the induction of metallothionein in this tissue.
Although small-molecular-weight forms of mercury have not been identified
in renal tissue, evidence from examination of urine samples suggests that they
exist. Mudge and Weiner (1958), in their study on the mechanism of action of
mercurial diuretics, identified mercuric cysteine complex in urine of dogs.
Other workers using sephadex column chromatography have identified a variety
of molecular weight species of mercury in the urine (Piotrowski et al., 1973).
These data must be considered as indirect evidence at best. Cysteine complexes
in urine could originate from tissues other than kidney and might ultimately
derive from the breakdown of protein complexes.
The different forms of mercury in urine are consistent with the observa-
tions of Henderson et al. (1974) on occupationally exposed workers. The
authors were able to identify three distinct forms of mercury. One was elemen-
tal mercury, which could be removed by "degassing" the urine sample. A second
form was released from urine by reduction with stannous chloride, and a third
form could be liberated from the urine sample only after complete organic
destruction. The form reducible by stannous chloride was probably the mercuric
cysteine complex identified by Mudge and Weiner (1958), as this complex is
4-19
-------
known to be readily reducible by stannous chloride (Clarkson and Greenwood,
1970).
3
Stopford et al. (1978), studying workers exposed to 0.016-0.68 mg Hg/m
of mercury vapor, found that Hg° could be detected in urine at levels less
than 2 pg Hg/1. Yoshida and Yamamura (1982) confirmed these findings in
thermometer workers who were exposed to air concentrations as high as 0.67 mg
3
Hg/m . Elemental mercury in urine never accounted for more than one percent
of total mercury in these workers. The authors suggested that Hg° in blood is
filtered at the glomerulus, thereby, explaining its rapid appearance in urine.
++
Inorganic divalent mercury, Hg , on the other hand, is first taken up by
++
kidney tissue before being excreted in urine. The authors concluded that Hg
in urine reflects kidney levels of mercury, whereas Hg° in urine reflects
blood levels of Hg° and, therefore, very recent exposure to the metal.
Other factors may also contribute to the variability in urinary excretion
of mercury. Highly variable and fluctuating concentrations of mercury vapor
may exist in the microenvironments of the workers (Henderson, 1973).
The kidney appears to play a double role with regard to mercury vapor
toxicity (for review, see Magos, 1973). On the one hand, it is a target for
the action of mercury (see Chapter 5). In accumulating high amounts of mercury,
however, the kidney also serves as a sink, maintaining lower concentrations in
other tissues and so playing a protective role in regard to these tissues.
The fact that metallothionein is induced in kidney tissue (Cherian and Clarkson,
1976) further adds to the possibility of a protective role played by this
organ.
4.1.4.3 Transport--Mercury vapor is a monatomic gas, highly diffusible and
soluble in lipids (the heptane-to-water partition coefficient is approximately
20). These properties are believed to account for its rapid and virtually
complete diffusion across the alveolar membranes in the lung (Friberg and
Vostal, 1972).
The back diffusion of mercury vapor dissolved in plasma into expired air
has been shown to occur in animals receiving an intravenous (i.v.) injection
of a saline solution containing dissolved Hg (Magos et al., 1973). Seventeen
percent of the injected dose was exhaled. The observation of mercury in
expired air in humans who have been exposed to mercury vapor is further evidence
that the diffusion can occur from blood to expired air (Hursh et al. , 1976).
4-20
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The transfer of mercury from the blood to brain is believed to occur
primarily by diffusion of the dissolved vapor from the plasma across the
blood-brain barrier. This conclusion is based on the observation that brain
concentrations of mercury are approximately ten times greater in animals
exposed to mercury vapor versus those exposed to equivalent doses of ionic
mercury (Berlin and Johansson, 1964). A diffusible form of mercury in plasma,
other than the dissolved vapor, has not yet been identified, in part, probably
because of difficulties of analysis since at least 99 percent of mercury in
plasma is in a non-diffusible form.
The processes involved in the transport of mercury from mother to fetus
are probably similar to those involved in the uptake into brain. However, one
important difference might be that the placenta plays an active role in the
regulation of transport from mother to fetus. In Figure 4-3 it is postulated
that dissolved mercury vapor is a predominant species involved in the transport
from maternal blood. The evidence is that the amount of mercury found in the
fetus is greater in animals exposed to mercury vapor than in those given an
equivalent dose of injected mercuric salts (Clarkson et al., 1972). Also, the
amount retained by the placenta! tissues is much less in the case of exposure
to mercury vapor than in animals dosed with mercuric salts. Dencker et al.
(1983) have reported that treatment of the mother with ethanol will increase
the amount of mercury transferred to the fetus during maternal inhalation of
mercury vapor. This finding also lends support to the idea that dissolved
mercury vapor is involved in maternal-fetal transport of mercury .
The placenta may -interrupt the transport of divalent mercury by the
presence of high-affinity binding sites. Exposure of pregnant rats to in-
organic mercury results in an increase of metal!othionein concentrations in
the placenta. No information is available on exposure to mercury vapor.
On the assumption that mercury vapor dissolved in plasma is the primary
transport species into the brain and into the fetus, Henderson et al. (1975)
have proposed that the oxidation process in the red cells represents a protec-
tive mechanism. The more rapidly mercury vapor is oxidized to the divalent
forms, the less it is available for transport to the brain. Henderson has
proposed that as the concentration of inhaled vapor is increased, at some
point, the oxidation capacity of the red blood cells will be exceeded. At
this point, the dissolved mercury levels will rise rapidly in plasma with a
consequent rapid transport to the brain. The "saturation" of the oxidation
4-21
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process might be regarded as a threshold above which effects would be expected
in the central nervous system.
In support of this theory, Henderson et al. (1974) noted that workers
exhibiting signs and symptoms of mercury poisoning were those that had detec-
table levels of elemental mercury in their urine samples. These occurred at
air concentrations in excess of 0.5 mg/m . Below this air concentration, the
authors reported no adverse effects on workers, and no detectable dissolved
elemental mercury was found in the urine samples. As the concentration of
total mercury increased (Figure 4-6), there was, at first, a gradual increase
in elemental and reducible mercury in the urine samples, but at higher concen-
trations of total mercury, the concentration of these forms of mercury increased
much more sharply.
To experimentally test their ideas, Henderson et al. (1975) gave the same
total exposure to three groups of rats. The concentration of mercury vapor
3
was 0.1, 0.2, and 0.6 mg Hg/m and the corresponding exposure times each day
were 90, 45, and 15 minutes, respectively. The mercury levels in the brain
after 10 days and 19 days of exposure were 0.9 mg/m for the highest vapor
3 3
level, 0.5 to 0.3 mg/m for the intermediate level, and 0.3 to 0.35 mg/m for
the lowest level. This increase in brain concentration with increased intensity
of exposure for the same total exposure supports the concept that a rapid rate
of entry of vapor into the bloodstream tends to overwhelm the oxidative capacity
of the red cells.
Loss of mercury from the brain has been observed in humans and animals
after exposure to mercury vapor (as discussed above). Hg° would be one possi-
ble transport species in view of its high diffusibility and lipid solubility.
Shortly after exposure, vapor already deposited in the brain may diffuse
outward as the blood concentration of Hg falls. At later times, the mobiliza-
tion from brain tissue to blood might be, in part, mediated by a reduction
process occurring in the central nervous system. To what extent this reduction
process plays a role in the movement of diffusible complexes of divalent
mercury is not known. Thus, critical information is lacking as to the pathways
by which mercury is removed from the brain after exposure to mercury vapor.
This reduction process raises the possibility that the mobility of in-
organic mercury in the body might be mediated by the atomic species. It is
also possible that diffusible forms of divalent mercury play a role in transport.
4-22
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o>
o>
o*
0>
.11
.09
i i i \ i i i r
S -07
3
O
ui
Of
111
0 .05
cc
3
O
S .03
O
z
<
w .01
I I I I I I I I
.3
.7 1.1 1.5
TOTAL MERCURY, mg/l
1.9
Figure 4-6. Group averages of total mercury
versus stannous chloride-reducible mercury
plus elemental mercury in urine.
Source: Henderson et al. (1974).
4-23
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For example, Doherty (1977) noted a rapid transport of mercury into the fetus
immediately after exposure to the vapor. Animals given the equivalent dose of
the ionic salt exhibited a slower movement of mercury to the fetus; however,
after 24 hours, the fetal levels were similar in both groups. Thus, it is
important to look into the question of repetitive exposures to mercury vapor.
The possibility exists that, as the burden of the oxidized form of mercury
accumulates, a diffusible species of divalent mercury might play an increasing
part in transport to the fetus.
4.2 COMPOUNDS OF INORGANIC MERCURY
4.2.1 Compounds of Mercurous Mercury
Very few quantitative data are available on the pharmacokinetics of
compounds of mercurous mercury. Calomel was widely used in teething powders
for children and as a vermifuge until about 1951, when it was discovered to be
the cause of the childhood disease of "Acrodynia" (Warkany and Hubbard, 1948).
Calomel is highly insoluble in water; thus, it was assumed to be poorly ab-
sorbed from the gastrointestinal tract. Some absorption must occur, however,
as very high tissue levels have been reported (527 ug Hg/g in the kidney) in
at least one individual who took calomel as a laxative over a long period
(Weiss et al., 1973).
The intravenous administration of mercurous mercury (Hg? ), as calomel,
to laboratory animals (rats, rabbits, and guinea pigs) resulted in the deposi-
tion of mercuric ions in kidney and red blood cells, as evidenced by histochem-
ical methods (Hand et al., 1944). An autopsy report of an individual who had
chronically ingested calomel indicated the presence of mercuric sulfide crystals
in cells in kidney, liver, and intestinal tissues (Weiss et al., 1973). The
mechanism of conversion of mercurous to mercuric mercury in mammalian tissues
is unknown. It may result from the disproporti onati on of the mercurous ion
known to occur in vitro in the presence of -SH groups, i.e.:
4.2.2 Compounds of Mercuric Mercury
Quantitative data on pulmonary retention of compounds of mercuric mercury
are lacking in humans. Mercuric oxide aerosol (mean diameter, 0.16 (jm) was
retained in the dog (Morrow et al. , 1964). Approximately 45 percent of the
aerosol was cleared in 24 hours; the remainder had a half-time of 33 days.
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Approximately 15 percent of a tracer dose of mercuric nitrate (6 ug Hg/
adult) given orally as an aqueous solution or attached to liver protein was
absorbed from the gastrointestinal tracts of adult volunteers. Animal data
confirm that gastrointestinal absorption is 15 percent or less (for review,
see Clarkson, 1972). Gastrointestinal absorption in suckling animals is much
higher, on the order of 50 percent of an oral dose (Kostial et al., 1978).
Inorganic mercury is absorbed across the skin, but quantitative data are
lacking in humans. Friberg et al. (1961) found that 8 percent of mercuric
chloride applied to the skin of experimental animals was absorbed within five
hours.
Mercuric mercury is transported in the bloodstream, being present in
roughly equal concentrations in plasma and red blood cells (for a recent
review, see Berlin, 1983). In plasma, it is protein bound, the distribution
between different proteins depending upon dose, time, and method of administra-
tion.
Mercuric mercury penetrates, to a small degree, the blood-brain and the
placenta! barriers. Deposition in various tissues and organs shows great
differences and is dependent on time, dose, and route of administration. Data
on steady-state tissue levels are lacking for both man and animals. After a
single dose, the kidney is the main site of deposition; according to studies
in several animal species, approximately 30 percent of the dose is initially
deposited in the kidney. Approximately two weeks after a single dose to rats,
as much as 90 percent of the remaining body burden is located in the kidneys
(Rothstein and Hayes, 1960). Concentrations of inorganic mercury in other
tissues are much lower, as already described for inhaled mercury vapor.
Autoradiographic observations on mice, given a single non-toxic dose of Hg ,
indicate that localized accumulation also occurs in the cells of mucous mem-
branes in the intestines, the epithelial layers of the skin, the spleen, the
interstitial cells of the testicles, and the choroid plexus in the brain
(Berlin and Ullberg, 1963a).
The urinary and gastrointestinal tracts are the principal pathways of
excretion. In a study by Rahola et al. (1973), it was noted that fifty days
after a single oral dose of mercuric mercury, urinary and fecal excretion were
of approximately equal magnitude in ten adult volunteers. The pathways involved
in fecal excretion are not known in detail, but inorganic mercury is known to
be secreted in saliva and bile, and by cells of the large intestine. Urinary
4-25
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excretion probably occurs via the uptake of mercury from plasma to renal
tubular cells and subsequent release into the tubular fluid (for review, see
Berlin, 1983). Excretion probably also occurs in sweat, and a small amount
may be excreted in expired air as noted in observations on people exposed to
mercury vapor (see Section 4.1).
The biological half-time in the whole body was found to be 42 days (SE =
3 days) in ten volunteers receiving a single oral tracer dose of inorganic
mercury compounds (Rahola et al. , 1973). Five females in the group had an
average half-time of 37 ± 3 days and five males had an average half-time of
48 ± 5 days. The biological half-time in the red blood cells for the whole
group was 28 ± 6 days, significantly lower than the whole body. The biological
half-time in plasma of a 17-year old girl who had received a toxic dose of
inorganic mercury was also in the range reported by Rahola and co-workers for
red blood cells (Newton et al., 1983).
4.3 METHYL MERCURY COMPOUNDS
Observations on volunteers have indicated that approximately 95 percent
of an oral dose of methyl mercury is absorbed in the gastrointestinal tract
regardless of whether the methyl mercury is given as a simple salt (methyl
mercury nitrate) (Aberg et al., 1969), is attached to liver protein, (Miettinen,
1973), or is naturally present in oceanic fish, such as tuna (Turner et al.,
1975). Observations on individuals who accidentally consumed toxic amounts of
methyl mercury fungicide in homemade bread suggest that absorption is virtually
complete (Al-Shahristani et al., 1976).
Methyl mercury distributes much more uniformly throughout all the tissues of
the body as compared to inorganic mercury. Observations on volunteers given a
single radioactive dose of methyl mercury have indicated that most of the tissue
distribution is complete within a few days (Aberg et al. , 1969; Miettinen,
1973). When distribution was completed in these volunteers, approximately 10 per-
cent of the radioactivity was found in the head region, presumably in the brain,
and approximately 7 percent was found in the blood compartment. The figure for
the blood compartment was confirmed by observations on volunteers ingesting a
measured dose of methyl mercury in fish (Kershaw et al., 1980).
As a consequence of the mobility of methyl mercury in the body, tissue
concentration ratios tend to be constant. For example, the plasma-to-red
4-26
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blood cell concentration ratio in man is approximately 10:1 according to
observations on volunteers (Miettinen, 1973; Kershaw et al. , 1980) and on
individuals who ingested toxic doses of methyl mercury (Bakir et al., 1973).
The blood-to-brain ratio has been shown to be approximately constant within
species, and, therefore, blood may be used as an index of average concentrations
in the brain (the target tissue) (Nordberg, 1976). Observations on volunteers
taking radioactive methyl mercury (Aberg et al., 1969) and on non-human primates
(Berlin et al., 1975; Evans et al., 1977; Willes et al. , 1978) indicate that
the blood-to-brain ratio is approximately 5.
Methyl mercury readily crosses the placenta. Observations on fish eaters
in Sweden have indicated that fetal blood is about 20 percent higher than
maternal blood (Swedish Expert Group, 1971), but, in an Iraqi outbreak, ratios
much higher than this were reported in mothers receiving toxic doses of methyl
mercury in bread (Amin-Zaki et al., 1974; 1976).
Methyl mercury accumulates in hair at the time hair is formed in the
follicle. Once incorporated into hair, the mercury concentration does not
change. Since hair grows approximately one centimeter a month, each centimeter
segment of hair represents one month's average blood concentration for that
month during which the hair was formed.
Hair-to-blood concentration ratios have been measured both in volunteers
ingesting a measured dose of methyl mercury, as well as in individuals exposed
to methyl mercury from fish in their diet and in people who accidentally
received toxic doses of methyl mercury as occurred in Japan and Iraq. Since
there is individual variation in the hair-to-blood concentration ratios
(Phelps et al. , 1980), it is preferable, when collecting hair samples, to
obtain at least one blood sample to determine the ratio for that particular
individual.
Methyl mercury is slowly broken down to inorganic mercury in mammals.
The fraction of total mercury present in tissues as inorganic mercury depends
on the duration of exposure to methyl mercury and the time after cessation of
exposure. The kidneys usually contain the highest fraction of inorganic
mercury; values as high as 70 percent were reported approximately two months
after a single dose of methyl mercury was administered to rats (Norseth and
Clarkson, 1970). In this same study, the percentage of inorganic mercury in
the central nervous system of rats was low, never exceeding 4 percent.
The percentage of inorganic mercury in human tissues in samples collected
about two months after the end of exposure in the above mentioned Iraqi outbreak
4-27
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has been reported by Bakir et al. (1973), Magos et al. (1976), and Amin-Zaki
et al. (1976). The following fractions (expressed as percentage total mercury)
were found in human tissues and fluids: whole blood, 7 percent; plasma,
22 percent; milk, 39 percent; liver, 16 to 40 percent; and urine, 73 percent.
Inorganic mercury accounted for about 5 percent of total mercury in whole
blood and about 20 percent in samples of head hair taken from a population
consuming methyl mercury in fish (Phelps et al. , 1980).
The fecal pathway accounts for most of the excretion of total mercury in
animals (Norseth and Clarkson, 1970), and inorganic mercury accounts for
virtually all the mercury in human feces (Turner et al., 1975). Urinary
mercury accounts for less than one-third of total excretion, and hair and milk
do not contribute significantly to total excretion. Thus, the elimination of
mercury from the body of humans after exposure to methyl mercury depends
almost entirely on conversion to inorganic mercury.
The site of conversion of methyl to inorganic mercury in the body has not
yet been identified, but there is evidence that the intestinal flora may be
involved in the breakdown of methyl mercury (Rowland et al., 1980; Nakamura et
al. , 1977). Methyl mercury is secreted in bile of rats (Norseth and Clarkson,
1971) and non-human primates (Berlin et al., 1975), but it is reabsorbed back
into the bloodstream. Only conversion to inorganic mercury prevents this
reabsorption. Evidence for secretion of methyl mercury in bile in human
subjects is mainly indirect. A thiolated resin known to trap methyl mercury
secreted in bile in animals and to prevent its reabsorption has been shown to
be effective in increasing fecal excretion in human subjects (Clarkson et al.,
1979).
Observations on volunteers taking a tracer dose of radioactive methyl
mercury indicate that the body burden of radioactivity declines according to
first order kinetics and, therefore, can be characterized by a single biological
half-time (Aberg et al. , 1969; Miettinen, 1973). The biological half-time in
adult males is 79 days and in adult females is 71 days. The half-time in
blood in the same series of studies was found to be, on the average, 50
days, with a standard deviation of 7 days. The biological half-time was found
to be 52 days in five volunteers ingesting a measured amount of methyl mercury
in fish (Kershaw et al. , 1980). A half-time of 65 days was reported for 16
patients who were heavily exposed in Iraq (Bakir et al., 1973). Al-Shahristani
and Shibab (1974) used hair samples to calculate biological half-times of
4-28
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methyl mercury in the victims of the Iraqi outbreak. These authors calculated
the biological half-time in the blood compartment from the rate of decline in
concentration along the length of a hair sample after exposure had stopped.
The length along the hair was converted to time from the measured growth of the
hair strands. They found an average biological half-time in hair of 72 days,
but half-times had a very wide range (35 days to 189 days). This wide range of
biological half-times may have been due, in part, to errors in hair analysis and
to uncertainties in hair growth (Giovanoli-Jakubczak and Berg, 1974). Never-
theless, the mean value of 72 days was close to the 65-day value observed by
direct blood analysis in the Iraqi victims. A wide range of biological half-
times in blood or in red blood cells has also been observed in a few individuals
who have consumed methyl mercury in fish (Birke et al., 1972).
Biological half-times have been reported for radioactivity in the head
region in three volunteers who ingested a single tracer dose of radioactive
methyl mercury (Aberg et al., 1969). The reported biological half-times for
the head region did not differ significantly from those reported for the whole
body. However, Japanese investigators, analyzing samples of brain tissue
several years after what was believed to be cessation of exposure to methyl
mercury, estimated that half-time in the brain could be more than 200 days
(Takeuchi and Eto, 1975). Unfortunately, it is not clear whether or not
ingestion of methyl mercury had, indeed, ceased in the study individuals.
Observations on a deceased individual in Northwestern Quebec, who had blood
levels as high as 600 ng/ml two years prior to death, indicated that brain
levels at the time of death were virtually normal. If correct, this finding
would dispute a biological half-time of 200 days in brain tissue (Wheatley
et al., 1979).
The biological half-time of methyl mercury in suckling infants is not
known, but observations in rodents indicate that mercury is not eliminated
from the body when methyl mercury is given during the suckling period (Doherty,
1977).
From the above information, it can be surmised that the accumulation and
excretion of methyl mercury in man can be represented by a simple one compart-
ment model. Roughly 95 percent of an oral dose is absorbed into the body,
and, on the average, about 1 percent of this amount (equivalent to a biological
half-time of 69 days) is eliminated per day. Equations describing the accumula-
tion of methyl mercury in the whole body, in the blood compartment, and in
4-29
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hair have been presented elsewhere (World Health Organization, 1976; Environ-
mental Protection Agency, 1980, 1984). These equations have been used to
characterize the accumulation of mercury, assuming an individual receives a
constant average daily intake until a steady state is reached, followed by an
elimination phase where intake is stopped. In general, it takes approximately
5 biological half-times to attain steady state, i.e., where intake balances
excretion. With a biological half-time in the whole body of approximately 70
days and a biological half-time in blood (and, therefore, hair) of approximately
50 days, it would take roughly one year to attain a state of balance. Likewise,
upon cessation of exposure, it would take another year for the amount in the
tissue compartments to fall to pre-exposure levels.
4.4 PHENYLMERCURY AND RELATED COMPOUNDS
In the last decade, a number of general reviews on mercury have included
the pharmacokinetics and metabolism of phenylmercury compounds (World Health
Organization, 1976; Nordberg, 1976; Environmental Protection Agency, 1980).
Phenylmercury compounds are usually assumed to be toxicologically representa-
tive of other aryl and alkoxyaryl mercurials (Goldwater, 1973). This assump-
tion is somewhat tenuous as most of the available data are restricted to
phenylmercury compounds. Furthermore, most of what is known about phenylmercury
compounds comes from experimental animal studies despite the fact that human
exposure to such compounds is not uncommon.
Phenylmercury is rapidly metabolized to inorganic mercury. Following a
single dose of phenylmercury, the absorption, transport, and initial tissue
distribution of mercury is similar in some respects to that of other organic
mercurials such as methyl mercury. Within one week, tissue distribution and
excretion approximates that seen after doses of inorganic mercury compounds.
Studies on exposed populations suggest, but do not prove, that phenyl-
mercury compounds can be absorbed across the skin (Goldwater, 1973). Several
thousand infants exposed to a phenylmercury fungicide in their diapers had
urine levels substantially higher than non-exposed infants (Gotelli, 1982).
Laug and Kunze (1949) demonstrated that, in rats, phenylmercury compounds
were well absorbed from the vaginal tract -- approximately 75 percent of the
administered amount in about 8 hours. In addition, women using phenylmercury
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spermicidal preparations were reported to have small elevations in urinary
mercury concentrations (Eastman and Scott, 1944).
The efficiency of absorption of oral doses is not known in humans.
Experiments on mice indicate that gastrointestinal absorption is greater than
80 percent of the dietary intake (Clarkson, 1971). Experiments on a variety
of animal species indicate that gastrointestinal absorption of phenylmercury
compounds is much greater than compounds of inorganic mercury (Ellis and Fang,
1967; Fitzhugh et al., 1950; Miller et al., 1967; Roberts et al. , 1979).
Phenylmercury appears to be reabsorbed intact into the blood stream,
where it tends to distribute to a greater extent into the red cells than into
plasma (Miller et al., 1960; Gage, 1964; Berlin, 1963). Phenylmercury distri-
butes rapidly from the bloodstream to soft tissue, the highest concentration
of the intact mercurial being found in the liver. Transport across the blood-
brain and placental barriers appears to be minimal, much less than methyl
mercury and similar to inorganic mercury (Yamaguchi and Nunotani, 1974; Berlin
and Ullberg, 1963b).
The intact mercurial disappears from body tissues within a few days due,
in part, to excretion, but mainly due to metabolic transformation to inorganic
mercury (Miller et al., 1960; Gage, 1964; Ellis and Fang, 1967). The metabolic
conversion is believed to involve hydroxylation of the benzene ring, resulting
in an unstable metabolite that spontaneously releases inorganic mercury (Gage,
1973). The released inorganic mercury then rapidly accumulates in the kidney.
Generally, within one or two weeks after cessation of exposure, the pattern of
distribution approximates that of inorganic mercury.
Fecal excretion is the dominant pathway of excretion in the first few
days after dosing. This may be related to biliary excretion and to the pro-
nounced accumulation in epithelial cells of the gastrointestinal tract (Berlin
and Ullberg, 1963b). In the first day or two, urinary mercury is mainly in the
form of the intact mercurial. This condition is followed by a delayed excre-
tion of inorganic mercury which, in rats, has been shown to reach a maximum in
approximately four days (Gage, 1964). Urine samples taken from infants chroni-
cally exposed to phenylmercury acetate in their diapers contained mainly, if
not entirely, inorganic mercury (Gotelli, 1982).
Some accumulation of mercury in rat fur has been found after repeated
dosing of phenylmercury; however, the reported concentrations were about ten
times lower than those observed after similar dosing with methyl mercury
(Gage, 1964).
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4.5 SUMMARY
The pharmacokinetics and biotransformation of mercury depends upon its
chemical and physical form.
In the case of mercury vapor, approximately 80 percent of inhaled vapor is
absorbed across the lung and retained in the body. Mercury distributes via the
bloodstream to all tissues in the body, the initial distribution process being
complete in about three days. Within the blood, concentrations in red cells
tend to be higher than in plasma shortly after exposure to mercury vapor.
Mercury readily penetrates the blood-brain and placenta! barriers after expo-
sure; however, the kidney is the major site of accumulation. Mercury is pre-
dominantly excreted in urine and feces at approximately equal rates.
The half-times of mercury vary within the body. The whole body half-time
is approximately 50 days whereas the half-time in the brain is about 20 days.
The blood contains two compartments having half-times of about 3 and 30 days
each. Blood levels can serve as indicators of recent mercury vapor exposure.
Conversely, urine levels correlate with long-term exposure, however, only on a
group basis. Individual variability of urine levels can be considerable.
Inhaled mercury vapor is oxidized to divalent ionic mercury in body tis-
sues by the hydrogen-peroxide catalase pathway. This oxidation step is
inhibited by non-intoxicating doses of ethanol. Pretreatment with ethanol can
lead to decreased retention and increased exhalation in the lung. Dissolved
mercury vapor in plasma is believed to be the species transported to the brain
and the fetus and may be important in transport and distribution to all tissues
in the body. Inhalation of mercury vapor can lead to the induction and binding
of mercury to metallothionein in the kidneys. After long-term (lifetime)
exposures, mercury has been reported to exist in tissue bound, at least in part,
to selenium in a 1 to 1 atomic ratio.
In the case of inorganic divalent mercury, approximately 15 percent of an
oral, non-toxic dose is absorbed from the gastrointestinal tract in adults and
retained in body tissues. In children, the gastrointestinal absorption is
probably greater. The kidney is the predominant site of inorganic mercury
accumulation, but accumulation also occurs in the cells of the mucous membranes
of the gastrointestinal tract. This form of mercury penetrates the blood-
brain and placenta! barriers only to a small extent. Excretion is mainly via
urine and feces at roughly equal rates by each pathway. The whole body half-
time in adults is about 40 days. Inorganic divalent mercury can induce and
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bind to metallothionein in the kidney and probably forms complexes with selenium
in tissues after chronic exposure.
Methyl mercury compounds are absorbed almost completely in the gastro-
intestinal tract and retained in the body. Certain methyl mercury compounds
are probably well absorbed across the skin. Distribution takes place via the
bloodstream to all tissues in the body, the initial phase being complete in
about three days. The pattern of tissue distribution is .much more uniform than
after inorganic mercury exposure except in red cells where the concentration
is ten to twenty times greater than the concentration in plasma. Methyl
mercury readily crosses the blood-brain and placenta! barriers, and as with
other forms, the kidneys retain the highest tissue concentration.
At the end of the initial phase of distribution, approximately one percent
of methyl mercury is found in one liter of blood in the 70-kg human adult. The
brain-to-blood concentration ratio is about 5:1. Methyl mercury accumulates
in hair in the process of formation of hair strands. The hair-to-blood con-
centration ratio is approximately 250:1 in humans. Once incorporated into the
hair, this concentration remains unchanged. Excretion is predominantly via the
feces. Methyl mercury is slowly broken down to inorganic mercury and most,
if not all, of the excreted mercury is in the inorganic form. Animal experi-
ments indicate that fecal excretion originates, at least in part, from biliary
secretion.
The whole body half-time of methyl mercury is usually between 70 to 80 days,
but substantial individual differences occur. The brain half-time is roughly
the same as the whole body, whereas the half-time in the blood compartment is
about 50 days. Blood concentration is a useful indicator of body burden, and
hair concentration, when measured along the length of a hair strand, is a use-
ful indicator of past blood levels.
Phenylmercury compounds are well absorbed across the intestinal tract and
retained by the body. They are probably absorbed across the skin as well. They
are carried in the bloodstream and deposited in most tissues, but penetration
to the brain and to the fetus is much less than is the case with methyl mer-
cury compounds. In this regard, phenylmercury compounds are much more similar
to inorganic mercury compounds. The kidney is, again, the predominant site of
accumulation, and excretion is via urine and feces. Most of the distribution
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and excretion patterns can be understood by the fact that phenylmercury compounds
are rapidly broken down to inorganic mercury. The intact mercurial is usually
not detectable in animal tissue one week after exposure has stopped.
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5. TOXIC EFFECTS OF MERCURY IN MAN AND ANIMALS
5.1 VAPOR OF METALLIC MERCURY
5.1.1 Local Effects
Acute exposure to high concentrations of mercury vapor may lead to metal
fume fever and pneumonitis. Garnier et al. (1981) reported on two cases of
acute mercury vapor exposure and reviewed the literature on twenty other cases
(also, see Milne et al., 1970). Ten percent of the fatalities which occurred
in the cases were due to lung damage. In most cases, an acute gingio-stomatis
was generally observed, but encephalopathy and renal damage were uncommon.
In a recent review of the literature, Jaffe et al. (1983) noted that in-
fants 4 to 30 months of age appear to be more susceptible than older children
and adults to the direct effects of mercury vapor. In case reports, acute
exposure to mercury vapor was shown to cause exudative alveolar and intestinal
edema and erosion, necrosis and desquamation of the bronchiolar epithelium.
Actual vapor concentrations were not measured, but the nature of these acute
exposures suggests that the vapor concentrations were very high. The reason
for the increased susceptibility of infants is not known, but it may be due
to the increased exposures experienced by the infants as they crawl on the
floor where mercury vapor concentrations would be highest.
Contact dermatitis may result from exposure to liquid metallic mercury
when prolonged skin contact occurs (Hunter, 1969). This manifests itself as a
papular erythema with slight hyperkeratosis. It should be noted, however, that
this particular effect of metallic mercury has not been widely reported in the
literature.
5.1.2. Systemic Effects
The major systemic effects of inhaled mercury have been described since
antiquity (for reviews, see Ramazzini, 1713; Hunter, 1969; Goldwater, 1972).
These major effects classically present as erethism, tremor and gingivitis.
More recently, Trachtenberg (1969) and Smith et al. (1970) have described a
milder form of poisoning involving a number of non-specific neurological and
psychological symptoms. The signs and symptoms of systemic mercury vapor
poisoning are described in more detail below, classified according to the
function or tissue that is affected.
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5.1.2.1 Behavioral and Neurological Effects—The major behavioral effects in man
are usually described by the term erethism. This syndrome includes a number of
psychological effects: excessive introversion, emotional lability, irritability
and anxiety. Hallucinations, delusions, and mania have been noted in the severe
forms of erethism. In previous centuries, mercury was used in the manufacture of
mirrors, and erethism was a common effect in the mirror makers of Venice
(Ramazzini, 1713) and Furth and Nurnberg (Kussmaul, 1861). Hunter (1969) has
noted that erethism is now rare. Milder, less obvious and less specific beha-
vioral changes have been reported in occupational exposures to levels of mercury
that are lower than those thought to lead to fully developed erethism. For ex-
ample, Smith et al. (1970) found that an increase in complaints of insomnia,
loss of appetite, weight loss and shyness were the earliest changes associated
with occupational exposure to mercury vapor. Williamson et al. (1982) reported
deficits in short-term memory in a group of twelve workers. All twelve were
probably exposed to mercury vapor, but eight may have had additional exposure
to mercuric chloride and methoxyethy1-mercury compounds. The mercury-exposed
group also exhibited poor psychomotor coordination and premature fatigue as
compared to a matched control group. The range of urinary mercury concentra-
tions in the exposed group at the time of the study was from < 10 to 670 (jg Hg/1
with a mean value of approximately 132 ug Hg/1. Urinary mercury values measured
over the five previous years were in the same range. However, it should be noted
that some workers that had current low values had much higher urine levels at
earlier examinations. The work of Langolf et al. (1978) indicates that exposures
which induce short-term memory deficits occur at levels lower than those that
cause damage in psychomotor function.
The association between mercury vapor exposure and emotional disturbances
has been the subject of some controversy. Chaffin et al. (1973) consider
emotional disturbances to be a consequence of psychomotor disturbances, whereas
Vroom and Greer (1972) consider them as secondary to memory deficits.
Forzi and co-workers (as cited by Hanninen, 1982) conducted two studies
on mercury workers. The first study found that neurotic and introvert personal-
ity traits were associated with exposure to mercury vapor, but the second
follow-up study found only neuroticism associated with such exposure. Angotzf
et al. (1980), using the personality inventory of Cattell, noted a tendency
towards anxiety and introversion in mercury-exposed workers.
Shapiro et al. (1982) have reported that disturbances in neurophysiological
and neuropsychological function occur at low tissue levels common in the dental
5-2
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profession. In a group of dentists exposed to high levels of mercury (as
determined by analysis of dentine in teeth; N = 24), 30 percent had poly-
neuropathies as compared to zero percent in the controls (P <0.01). Mild
neuropsychological effects were indicated by higher distress values, as recorded
on a self-reporting check list (P <0.05), and lower scores on the Bender-Gestalt
test (P <0.01).
Neurological effects mainly present in the form of an intention tremor.
Hunter (1969) noted that mercurial tremor, though seldom the first sign to
appear, is the most characteristic sign of neurological disorder. It is not
as fine or as regular as tremor due to hyperthyroidism, and it is interrupted
every few minutes by coarse, jerky movements. In a more recent study, Wood et
al. (1973) presented tracings that were recorded from a patient suffering from
occupational mercury vapor poisoning and compared them to tracings recorded
after the patient had recovered (Figure 5-1). Chaffin et al. (1973) and
Langolf et al. (1978) also measured tremor in chlor-alkali workers exposed to
mercury vapor. Chaffin et al. (1973) reported a statistically significant
correlation between mean tremor frequency and current urinary mercury concen-
trations. The scatter of the individual data points was so great it was not
possible to identify a lower effect level. Both Chaffin1s and Langolf's
groups noted that shifts in the power spectrum were correlated with elevated
urinary mercury concentrations.
In summary, recent studies have added information to that found in the
landmark papers of Neal et al. (1941) and Smith et al. (1970), indicating that
motor system disturbances may be more reversible than decrements in cognitive
functions (mainly memory deficits). It can be surmised from these studies that
introversion appears to be the most prominent personality trait. The fact that
motor changes are more easily detected and more likely to be reversed upon expo-
sure cessation suggests, as stated by Hanninen (1982), that "the more insidiously
developing cognitive decrements and emotional alterations may be the most harmful
health hazard for mercury workers today."
A number of case reports and studies of occupationally exposed groups indi-
cate that the peripheral nervous system is also affected by mercury vapor.
Shapiro et al. (1982) found a high prevalence of polyneuropathies in dentists
exposed to mercury vapor. Case reports by Iyer et al. (1976), Goldstein et
al. (1975) and Hryhorczuk et al. (1982) provide evidence of sensory polyneuro-
pathies. Vroom and Greer (1972), in detailed neurological studies of patients
5-3
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Figure 5-1. (A) Tremor tracings from a woman exposed to mer-
cury vapor in a plant using metallic mercury to calibrate pipets.
The upper tracing was recorded when the victim first was
seen at the hospital. The lower tracing was recorded 9 months
later, with no intervening exposure. Recordings were made by
having the patient rest the index finger in a Lucite slot
attached to a strain gauge while attempting to maintain a
force between 10 and 40 g. (B) Tremor spectra corresponding
to the tracings in (A). Strain gauge output was amplified and
fed to the analogdigital convecter of a PDP-12 computer. The
power spectrum was calculated by a Fast Fourier Transform.
Note the multiple peaks in the spectrum corresponding to the
more severe tremor.
Source: Wood et al. (1973).
5-4
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suffering from mercurial ism, found that one patient had limb weakness, another
had distal paresthesias, and two had fasciculations and cramps. The authors
suggested that damage to the anterior horn cells and axonal degeneration would
explain most of these abnormalities. This suggestion was supported by electro-
myographic observations indicating involvement of the motor nerves reminiscent
of the syndrome of amyotrophic lateral sclerosis. More recently, Levine et al.
(1982) performed nerve conduction tests on eighteen workers exposed to mercury
vapor in a chlor-alkali plant. Average urinary mercury concentrations ranged
from 20 to 450 |jg/l with a group mean (spot samples) of 290 pg/1 over a three-
year observation period. The authors found that prolonged motor and sensory
distal latencies correlated with increasing urine mercury concentrations as
integrated over the time of the study.
In a case report on a 54-year old man who experienced a two-day exposure
to high levels of mercury vapor, (the air concentration must have been very
high as it resulted in a urine concentration of 100 pg Hg/1), Adams et al.
(1983) noted that the man developed a syndrome resembling amyotrophic lateral
sclerosis. The syndrome disappeared when urinary mercury returned to normal.
The authors speculated that mercury toxicity must be considered "not only in
individuals with recent anterior horn-cell dysfunction, but also with otherwise
unexplained peripheral neuropathy, tremor, ataxia, and a gamut of psychiatric
symptoms, including confusion and depression".
Animal studies have attempted to reproduce the neurological and behavioral
effects of inhaled mercury vapor. Armstrong et al. (1963) were the first to
report behavioral effects in animals. At very high mercury concentrations
(17 mg Hg/m , i.e., a virtually saturated atmosphere), a decrement in perfor-
mance was noted in pigeons trained to certain pecking routines. Subsequently,
Beliles et al. (1968) also found decrements in the conditioned behavior of
3
rats exposed for 15 days to the same mercury concentration (17 mg Hg/m ).
Fukuda (1971) was able to elicit a "fine" tremor in the fore and hind limbs of
two of six rabbits exposed intermittently to mercury vapor (average concentra-
3
tion of 4.0 mg Hg/m for 6 hr/day, 4 days/week, for 13 weeks). The brain
concentrations ranged from 0.8 to 3.7 pg Hg/g wet tissue. Kishi et al. (1978)
found a decline in conditioned avoidance response in rats after exposure to
3 mg Hg/m for 3 hr/day, 5 days/ week. The time to onset of effects varied
from 12 to 39 weeks. All rats recovered to pre-exposure baseline levels of
performance within 12 weeks after the termination of exposure. Significantly
5-5
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poor performance was noted at brain concentrations of 20 pg Hg/g wet weight
and recovery to normal behavior was observed when the brain levels fell to
10 ug Hg/g wet weight. No pathological changes in brain tissue were observed.
Unfortunately, animal experiments have so far failed to find an appropriate
animal model for man. The signs observed in animals are not obviously related
to effects in humans, and very high concentrations are needed to produce
behavioral and neurological effects.
5.1.2.2 Oral Effects—Sal i vation and tenderness of the gums and mouth are
usually early symptoms of mercury vapor poisoning (Hunter, 1969). The gums
become swollen and readily bleed. Occasionally, a mercurial line is visible
on the gums. It usually resembles the blue line caused by lead exposure.
Early loss of teeth may result from occupational exposure to mercury vapor.
In historical accounts of mercury poisonings, Kussmaul (1861) noted that in
the towns of Furth and Niirnberg, well known for their mirror-making industries,
almost every adult male was without a single tooth. Such severe effects may
be a legacy of the past, however, as Smith et al. (1970) did not report oral
effects in their more recent study of occupationally exposed workers.
5.1.2.3 Renal Effects—Friberg et al. (1953) reported two cases of nephrosis
in workers exposed to mercury vapor in the chlor-alkali industry. This illness,
characterized by fatigue, irritability, edema of the face and ankles and the
presence of protein (albumin) and hyaline casts in the urine, abated in the
two reported cases within a few months upon termination of exposure. Kazantzis
et al. (1962) also reported albuminuria in four workers exposed to mercury
vapor and other forms of mercury. The authors noted that urine levels were in
excess of 1000 ug/1, but that many workers had levels in excess of this value
without exhibiting albuminuria. In one factory, two cases of albuminuria were
observed, but 50 other workers similarly exposed did not develop albuminuria
even though 13 of these workers had urine values in excess of 1000 ug/1.
Kazantzis et al. (1962) therefore suggested that the nephrosis in these cases
might have been an idiosyncratic reaction.
Smith and Wells (1960) carried out electrophoretic separation of urinary
protein in workers with proteinuria due to exposure to mercury vapor. Analysis
by ultracentrifugation on amino acid composition suggested the proteins origi-
nated from the serum.
Stewart et al. (1977) reported a mild proteinuria (median value: 117 mg/24 hr)
in 21 laboratory technicians exposed to mercury vapor (median urinary mercury
5-6
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excretion: 53 ug/24 hr) as compared to a non-exposed control group (urinary
proteins; 48 mg/24 hr, urinary mercury; 15 |jg/24 hr). The maximum air con-
centration of mercury ranged up to 0.1 mg Hg/m .
Buchet et al. (1980) measured the urinary excretion of a number of specific
proteins in a group of 63 workers from two chlor-alkali plants and in 88
control workers without occupational exposure to mercury. Values of urinary
proteins were considered abnormal if they exceeded the arithmetic mean plus
two standard deviations as calculated in the control group. The prevalence of
abnormal values did not seem to be well correlated with mercury concentrations
in blood, but the prevalence of abnormal values for high-molecular-weight
proteins (albumin, transferrin) increased with increasing urinary excretion of
mercury. Urinary excretion of low-molecular-weight proteins (e.g., (3?-micro-
globulin) was not affected.
In a subsequent study, Roels et al. (1982) were able to confirm an in-
creased prevalence of albuminuria in 51 male workers exposed to mercury vapor
when compared to a control group (51) matched for age, sex, socioeconomic
status and job characteristics. The median (range) mercury levels in urine
for controls were 1.3 (0.6-4.7) and for exposed were 71 (9.9-286) ug Hg/g
creatinine.* Observations on psychomotor performance indicated that decrement
in performance was found in mercury-exposed workers but occurred independently
from the presence of proteinuria.
*The urinary excretion of mercury is frequently expressed in this way when
"spot" urine samples have been analyzed. The rate of urinary excretion of
creatinine is proportional to the lean body mass, and therefore does not
change greatly for a given individual or for groups of workers having roughly
similar body weights. Conversely, urine volume flow rates vary greatly,
depending upon the degree of hydration of the individual. The concentration
of mercury in spot urine samples may be greatly affected by the degree of
hydration of the subject and, therefore, not accurately indicative of the
true excretion rate. Human adults excrete approximately 1 to 2 grams of
creatinine per day. Therefore, expressing the mercury excretion per gram
creatinine gives a rough indication of daily excretion rate and avoids errors
due to fluctuations in dilution of the spot urine sample. Since normally
hydrated individuals excrete between 1 and 2 liters of urine per day, the
mercury excretion in ug Hg/g creatinine is approximately equal to 1 ug Hg/1
urine. Expressing mercury excretion by this "creatinine correction" also
has another advantage. Since creatinine excretion is proportional to lean
body mass, urinary creatinine excretion is a "sizing factor." Thus, urinary
mercury expressed as ug Hg/g creatinine amounts to a (lean) body weight
corrected excretion rate.
5-7
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Stonard et al. (1983) studied the excretion of specific proteins and
enzymes in urine samples of 87 control workers (mean urinary mercury in the
range of 3.3 to 4.6 ug Hg/g creatinine, based upon three separate visits) and
in 105 exposed workers (mean urinary mercury in the range of 63 to 71 ug Hg/g
creatinine, based upon three separate visits). The range of individual values
was 0.4 to 275 ug Hg/g creatinine. The corresponding mean blood mercury
values were 5 and 17.5 ug Hg/1, respectively. Highly significant correlations
were found between blood and urinary mercury concentrations. Urinary gamma
glutamyl transferase correlated with urinary mercury levels in the exposed
group. The prevalence of greater than normal activities of the enzymes,
N-acetyl-p-glucosaminidase and gamma glutamyl transferase, appeared to increase
when the mercury concentration in urine exceeded 100 ug Hg/g creatinine, but
there was no evidence of a dose-response relationship over the full range of
mercury concentrations. These authors were not able to confirm the findings
of Buchet et al. (1980) of an increased prevalence of elevated urinary albumin
despite the fact that mercury values were comparable in the two studies. (The
mean value in Buchet et al's. (1980) group of workers was 59 ug Hg/g creatinine,
and the range of individual values was 5 to 206 ug Hg/g creatinine.)
A recent case-report study of two workers exposed to inorganic mercury
(probably in the form of mercury vapor) indicates that the proteinuria consis-
ting of large-molecular-weight proteins is due to a glomerular nephritis
resulting from immunopathologic action (Weening et al., 1978). Immunohisto-
chemical studies demonstrated confluent, finely granular epimembranous deposits
of IgG and C3 antibodies in the glomerulus.
Lauwerys et al. (1983) recently found further evidence that mercury vapor
may lead to immune dysfunction with the possibility of immune glomerular
nephritis. In 62 workers exposed to mercury for an average of 5.5 years, cir-
culating anti-laminin antibodies were found in the sera of eight workers
whereas none were found in the sera from 60 matched controls (laminin is a
non-coilagenous protein isolated from basement membranes). The urinary
mercury excretion in ug/g creatinine was 1.0 ± 1.1 (SE) in the controls,
53 ± 7 in the workers without anti-laminin, and 77 ± 25 in the eight workers
with anti-laminin. It should be noted that several parameters of renal func-
tion did not differ between the exposed and the control groups or between the
groups with and without anti-laminin.
5-8
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Experiments in animals given inorganic salts of mercury confirm an immuno-
pathological mechanism underlying the glomerular damage (Bariety et a!., 1971;
Druet et al., 1978, 1982; Weening et al., 1978). The nature of the antigen is
not known, but a recent report by Druet et al. (1982) suggests that mercury
may act directly in the immunoregulatory mechanism. Earlier studies by the
same group suggested a genetic control of susceptibility of the disease in an
inbred strain of rats, thus, explaining the original suggestion of Kazantzis
et al. (1962).
Exposures in mercury cell chlor-alkali plants are to mixed mercury vapor
and chlorides of mercury. If an ultraviolet mercury vapor instrument is used
to measure exposure, that portion of the total exposure due to chlorides will
be missed. Some of the studies reviewed above used ultraviolet instruments,
e.g., Buchet et al. (1980). However, it should be noted that the overwhelming
percentage of mercury in the working environment of chlor-alkali plants is
present as vapor. Kazantzis et al. (1962) reported that exposure was to both
the vapor and to compounds of mercury. Thus, it is possible that exposure to
the inorganic salts of mercury may have played a role in the development of
the nephrotic syndrome in some, but probably not all, of the reports reviewed
above. Animal experiments, reviewed above, indicate that the nephrotic syndrome
can be elicited by dosing animals with inorganic salts of mercury.
5.1.2.4. Reproductive and Developmental Effects—Little information is avail-
able on biological effects in humans due to prenatal exposure to mercury
vapor. Unfortunately, in the few human studies in the literature, details on
methodology and on dose and duration of exposure are not provided. Early
studies suggested that women chronically exposed to mercury vapor experienced
increased frequencies of menstrual disturbances and spontaneous abortions;
also, a high mortality rate was observed among infants born to women who
displayed symptoms of mercury poisoning (Laraview, 1956; cited in Baranski and
Szymczyk, 1973). It should be noted, however, while the degree of exposure of
these women was unknown, it must have been fairly high in order for symptoms
of mercury poisoning to be manifested. (Laraview, 1956; cited in Baranski and
Szymczyk, 1973). In 1967, an epidemiological survey in Lithuania called
attention to an increased incidence of abortion and mastopathy related to
duration of time on the job among women working in dental offices where mercury
vapor concentrations ranged up to 0.08 mg/m (Wiksztrajtis, 1967; cited in
Baranski and Szymczyk, 1973). Another report described the case of a woman
5-9
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chronically intoxicated by mercury vapor in whom two pregnancies ended unfavor-
ably. After recovery from overt mercury poisoning, this woman gave birth to a
healthy child (Derobert and Tara, 1950). The most recent citation available
(Mishonova et al., 1980) reports a study on the course of pregnancy and parturi-
tion in 349 women exposed via inhalation to metallic mercury vapors in the
workplace as compared to 215 non-exposed women. The investigators concluded
that the rates of complications of pregnancy and labor were higher among
exposed women and depended on "the length of service and concentration of
mercury vapors." Insufficient detail was available to evaluate dose-response
relationships.
Baranski and Szymczyk (1973), reported that female rats, after being
3
exposed for 21 days to an average of 2.5 mg Hg/m (6 hr/day, 5 day/week), had
longer estrus cycles than non-exposed animals. In addition, their mercury-
induced cycles were longer than their original cycles prior to exposure. The
initial phase of the cycle was protracted, but complete inhibition of the
cycle did not occur. These animals, in the second and third weeks of exposure,
developed signs of mercury poisoning which included restlessness, attacks of
chronic seizures, and trembling of the entire body. The authors speculated
that the effects on the estrus cycle were due to the action of mercury on the
central nervous system.
Rats exposed prenatally to mercury vapor were reported to have died
within six days after birth (Baranski and Szymczyk, 1973). In one experiment
where exposures were continued throughout gestation, all of the pups died.
Some of the deaths could be attributed to a failure of lactation of the dams.
However, in the second part of the experiment which exposed the dams only
prior to the time of impregnation, lactation and nursing of viable pups appeared
normal yet, 25 percent of the pups died before day 6. No teratologic effects
were observed, birth weights were reportedly within the normal range, and
histopathologic findings were negative although the concentrations of vapor
were high (2.5 mg Hg/m , the LC?t. for the adult females) (Baranski and Szymczyk,
1973).
In a study by Khayet and Dencker (1982), the placental transport of
mercury in pregnant mice and its localization in the embryo and fetus from
early organogenesis through the whole fetal period was studied by whole-body
203
autoradiography and gamma counting. Metallic mercury ( Hg°) after inhala-
203
tion was compared to inorganic mercury ( HgCl-) after intravenous injection.
2+
The authors reported that the Hg° appeared to be oxidized to Hg in the fetal
5-10
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tissues and that Hg° inhalation resulted in about 4-fold higher fetal mercury
2+
concentration than Hg injection (9.9 versus 2.4 percent gram dose per gram
tissue).
5.1.2.5. Mutagenic and Carcinogenic Effects—Carcinogenesis in humans has not
been associated with occupational exposure to mercury vapor (Leonard et al.,
1983). However, it should be noted that group sizes in health effect studies
of mercury vapor-exposed workers have been small; the largest epidemiological
study reported to date (Smith et al., 1970) involved 600 workers.
Aneuploidy and other chromosomal aberrations have been observed in lympho-
cytes from whole blood cultures of workers occupationally exposed to mercury,
including people working with mercury amalgams (Verschaeve et al., 1976;
Popescii et al., 1979).
Mutagenic effects in experimental test systems have not been reported for
mercury vapor; whether such tests have been conducted is unknown. Cancer or
tumors in animals exposed to mercury vapor have not been reported.
5.1.2.6. Other Effects—A wide variety of adverse health effects have been
reported in historical accounts of cases where mercury vapor concentrations
must have been very high (Ramazzini, 1713). In one such account, mercury miners
were noted to be "the subjects of asthma" (Ramazzini, 1713).
In 1943, Atkinson found a new physical sign of exposure to mercury vapor
which he termed "mercurialentis." He described mercurialentis as being a
change in the lens of the eye consisting of a discoloration of the anterior
capsule which exhibits a light reflex varying in intensity from light brown to
coffee brown. He noted that the change was bilateral and symmetrical and was
usually accompanied by fine punctate opacities in each lens, especially in
the anterior capsule. Visual acuity was reported to be unaffected. In mercuri-
alentis, the discoloration of the lens capsule appears a long time before the
onset of signs of mercury poisoning and is therefore of value in early detec-
tion of exposure to atmospheric mercury. Mercurialentis has also been described
in other groups exposed to mercury vapor (Locket and Nazroo, 1952; Rosen,
1950; Smith et al., 1970).
Biochemical changes due to exposure to mercury vapor have rarely been
reported. Lauwerys and Buchet (1973) reported that, in workers exposed to
mercury vapor concentrations of less than 0.05 mg Hg/m , plasma galactosidase,
catalase, and erythrocyte cholinesterase activities were affected. Buchet et
5-11
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al. (1980) reported that the prevalence of increased levels of serum p-galac-
tosidase activity in plasma increased with increasing mercury concentrations
in urine. Studies on mercury-exposed workers indicate no change in red blood
cell glutathione levels due to mercury (Wada et al., 1969; Rentes and Seligman,
1968).
5.2 OTHER FORMS OF MERCURY
5.2.1 Inorganic Mercury Compounds
Salts of mercuric mercury can produce acute renal failure when ingested
as a single dose; the lethal dose of HgCl- in human adults has been estimated
to be approximately 1 to 4 g (Gleason et al. , 1957). (For a more detailed
description of the effects of inorganic mercury compounds in humans and animals,
see United States Environmental Protection Agency, 1984.) The inducement of
effects in rats given acute doses of HgCl? were found to be temperature sensi-
tive (Burgat-Sacaze et al., 1982). Information is lacking on chronic human
exposures and on animals repeatedly dosed with compounds of inorganic mercury.
It is assumed that mercuric mercury (Hg ) is the proximate toxic species in
mercury vapor poisoning and that differences in effects represent differences
in initial tissue deposition of the two forms of mercury. Given the small
amount of translocation of Hg across the blood-brain and placenta! barriers,
inorganic salts are less likely to affect the central nervous system and the
fetus than are mercury vapor exposures. The work of Druet and co-workers
(1978; 1982) (see Section 6.1) indicates that, in experimental animals, the
main effect of chronic exposure is damage to the kidney, produced by an immuno-
logical mechanism.
Barber (1978) reported that two workers in a mercuric oxide manufacturing
plant developed neurological changes suggestive of the syndrome of amyotrophic
lateral sclerosis (ALS). The sural nerves of these workers showed markedly
distal latencies and slow conduction velocities. Three months after removal
from work, the neurological examinations and el ectromyelograms of the workers
were completely normal. An additional nineteen workers developed signs and
symptoms that were considered to be an early phase of the neurotoxic effects
of ALS and might have progressed to the full ALS syndrome. The neurological
effects in these workers also proved to be reversible. The workers were
exposed to mercuric oxide particles and to mercury vapor. Air levels, checked
5-12
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3
at a later date, were in the range of 0.5 to 5 mg Hg/m with peaks to 10 mg
3
Hg/m as total mercury. It was stated that exposures were predominantly to
mercuric oxide and were for periods of 60 to 80 hours per week.
In case reports on two adult females who had chronically ingested mercurous
chloride for many years as a laxative (two tablets of 125 ng Hg^CK/day) Davis
et al. (1974) and Wands et al. (1974) noted that the women developed classic
symptoms of mercurialism. Both patients suffered from chronic renal failure.
Death in one case was due to pneumonia; the other patient died following
surgical operation for intestinal bleeding. The brains of both patients were
small and showed loss of cerebellar granular cells. The cerebrums of occipital
cortex were normal as scanned by light microscopy. Timm's silver stain revealed
many punctate granules thought to be deposits of mercury in the cytoplasm of
neurons. Deposits of mercury observed in the colon and renal cortex were
identified as crystals of mercuric sulfide.
Children exposed to salts of inorganic mercury may develop acrodynia or
Pink's disease (Cheek, 1980). The signs and symptoms include bluish-pink
hands and feet, crimson cheeks, profuse sweating, painful joints, photophobia,
glove and stocking paresthesias, irritability and other nervous disturbances.
Although only a small fraction of children exposed to inorganic mercury develop
the full syndrome of acrodynia, it is possible that large numbers may suffer
the incomplete and clinically unrecognized syndrome.
Parenteral administration of salts of inorganic mercury produce teratolog-
ical abnormalities in experimental animals. Gale (1981) reported a variety of
abnormalities including edema, retardation, ventral wall defects, pericardia!
cavity distension, cleft palate, hydrocephalus, and heart defects in hamster
fetuses given a single subcutaneous dose of mercury acetate (15 mg/kg) on the
8th day of gestation and killed on the 12th to 15th day. These findings
confirm previous reports of experimental teratogenesis in hamsters given
inorganic (mercuric acetate) or organic (phenylmercury acetate) compounds of
mercury. The human relevance of these experimental findings, in which highly
toxic doses were delivered to animals via parenteral administration, is wholly
unknown.
Grin et al. (1981) studied pregnant rats following 24-hour inhalation
exposure to varying concentrations of a mixture of mercury-containing salts.
No methods of any procedures were included in this report; thus, interpretation
of results is not possible. In a similar manner, Govorunova et al. (1981)
5-13
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studied pregnant rats following 24-hour inhalation exposure to mercuric diiodide.
Again, lack of any reported methodology precludes interpretation of results.
Mercuric salts ijn vitro enhance viral transformations of hamster cells
and reduce the molecular weight of DNA in Chinese Hamster Ovary cells, but do
not produce mutagenesis in non-mammalian cells. Mutagenic responses in mamma-
lian cell cultures have been equivocal (for recent reviews, see Heck and
Costa, 1982 a and b; Christie and Costa, 1983). As is the case with the
teratogenic effects, the relevance of these findings to effects on human
health is unknown.
5.2.2 Methyl Mercury Compounds
Methyl mercury and other short-chain alkylmercurials primarily damage the
central nervous system in man. (For a more detailed description of the effects
of methyl mercury on the adult and on developing humans, see World Health Organi-
zation, 1976; Nordberg, 1976; United States Environmental Protection Agency,
1980, 1984; Rodier, 1983). The mildest cases of poisoning are manifested by
non-specific symptoms such as paresthesia, malaise and blurred vision. These
symptoms usually appear after a latent period of weeks to months during chronic
low-level exposures or following acute high-level exposures. The more severe
cases present signs of bilateral constriction of the visual fields, deafness,
dysarthria and ataxia. The most severe cases suffer from mental derangement and
coma, and the outcome is often death. Methyl mercury destroys neuronal cells in
areas of the central nervous system concerned with sensory and coordination
functions.
Prenatal life is the most sensitive stage of the life cycle to methyl
mercury. In the 1955 mercury poisoning outbreak in Minamata, Japan, severe
brain damage was described in infants whose mothers, during pregnancy, had
ingested fish contaminated with methyl mercury (Harada, 1968). Similar cases
of severe brain damage were reported in the 1971-72 outbreak of methyl mercury
poisoning in Iraq (Amin-Zaki et a!., 1974). In such poisonings, damage is
widespread to the developing central nervous system and probably involves
derangement of basic developmental processes such as neuronal migration (Choi
et al., 1978; Matsumoto et al., 1965) and neuronal cell division (Sager et al.,
1982).
In more recent follow-up studies of the Iraq outbreak, Marsh et al. (1979,
1980) reported milder effects at lower maternal exposures than those reported
5-14
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by Amin-Zaki et al. (1974). These effects manifested as delayed achievement
of developmental milestones and mild neurological abnormalities. In a Canadian
study, Eyssen et al. (1983) also noted developmental delays and mild or ques-
tionable psychomotor retardation in prenatally exposed children at methyl mer-
cury concentrations in maternal hair lower than those reported by Marsh et al.
(1980). In the Canadian study, effects were not seen in prenatally exposed
female children.
Mechanisms of action of methyl mercury on both the adult and developing
nervous system have been recently discussed in review articles (Clarkson, 1983;
Mottet and Perm, 1983; Rodier, 1983). The reason for the long latency prior
to the manifestation of clinical effects and for the selective action in cer-
tain areas of the adult brain is still not understood. Experimental work
indicates that protein synthesis is disrupted in neuronal cells before overt
signs of intoxication appear. The selective damage to granular cells as con-
trasted to the purkinje cells of the cerebellum has been attributed to the
experimental findings that protein synthesis recovers in the latter, but not
in the former, class of cells. It is reasonable to purpose that the greater
sensitivity of the developing nervous system to methyl mercury arises from
action on processes unique to the developing brain, e.g. cell division and
cell migration. Methyl mercury is known to be a mitotic inhibitor that damages
microtubules and is known to bind to tubulin, a protein component of micro-
tubules. Cell division and cell migration both require intact microtubules
for normal functioning and, therefore, have been suggested as primary targets
for methyl mercury disruption in the developing nervous system.
Other less noted toxic effects of methyl mercury compounds include kidney
and teratogenic and reproductive effects (see review by the United States
Environmental Protection Agency, 1984).
5.2.3 Phenylmercury and Related Compounds
A wide variety of other organic mercury compounds have been manufactured
for various purposes (fungicides, diuretics, antiseptics, contraceptives). In
general, these organo-mercury compounds undergo cleavage of the carbon-mercury
bond in mammalian tissues, resulting in the release of inorganic mercury.
Gage (1973) has published evidence that phenylmercury is first hydroxylated by
liver microsomal enzymes and that this hydroxylation is followed by a non-
enzymic breakdown to phenol and inorganic mercury.
5-15
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In a recent exposure of an estimated 6000 infants to a phenylmercury
compound, Astolfi and Gotelli (1981) reported that several infants developed
acrodynia. In contrast, Goldwater (1973) found no evidence of toxicity in 13
workers employed for 11-23 years in the manufacture of phenylmercury. Exposure
levels were not reported but urinary concentrations of mercury varied from
85-100 ug/1. Cotter (1947) found liver damage in ten subjects exposed to
phenylmercury salts, but other substances may have been involved in the expo-
sure. Renal damage and intestinal complaints have been reported (see review
by Skerfving and Vostal, 1972). In general, there seems to be no difference
in the toxicity of various phenylmercurials which have been studied. The
symptoms, where noted, resemble those of inorganic mercury. According to
clinical evidence (Biskind, 1933), phenylmercury compounds, when applied
topically to the skin, can produce signs of toxicity. Delayed-type
hypersensitivity has been reported from skin contact with phenylmercury com-
pounds (Mathews, 1968).
Phenylmercury acetate was widely used as a spermicidal contraceptive
administered vaginally in a gel. Enhanced urinary excretion of mercury is
believed to result from the vaginal absorption of phenylmercury, but no adverse
health effects have been reported from use of the contraceptive (for review,
see Goldwater, 1973).
In an animal study by Fitzhugh et al. (1950), rats were fed phenylmercury
acetate as well as mercury acetate for 2 years. Daily intakes for the phenyl
compounds were estimated to equal approximately 0.005, 0.025, 0.125, 0.50,
2.0, and 8.0 mg/kg/day. Growth was retarded at 2 mg/kg in both sexes, while
0.5 mg/kg retarded growth in males. As little as 0.025 mg/kg resulted in
detectable kidney damage in the form of coagulative necrosis of the convoluted
tubules in females. In males, effects were detected at 0.125 mg/kg. By
contrast, the smallest dose of mercuric acetate causing detectable effects was
2 mg/kg/day. Tryphonas and Nielsen (1970) fed weanling piglets phenylmercuric
chloride at daily doses equivalent to 0.19, 0.38, 0.76, 2.28, and 4.56 mg/kg
body weight. Decreased weight gain, but no pathological lesions, were detected
in the 0.76 mg/kg group. Weight loss, diarrhea, necrosis of intestinal walls
and kidney pathology were the primary effects detected at the two highest doses.
Very little information is available concerning the effects of phenyl-
mercury compounds upon the nervous system. In the study by Fitzhugh et al.
(1950), no neurological effects were reported in rats even after they were fed
5-16
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phenylmercury acetate for 2 years at daily doses as great as 8 mg/kg/day. In
a similar study with pigs, doses of phenylmercury chloride up to 4.56 mg/kg/day,
which produced definite kidney injury, were not reported to affect the nervous
system (Tryphonas and Nielsen, 1970).
The only teratogenic information on phenylmercury compounds was reported
by Gale and Perm (1971), in which Syrian golden hamsters were intravenously
dosed with 5, 7.5, 8 and 10 mg/kg phenylmercuric acetate on the eighth day of
gestation. With the exception of the lowest dose, all other doses induced
increased resorption rates and edema along with a few miscellaneous abnormali-
ties, including exencephaly, cleft lip and palate, and rib fusions.
5.3 INTERACTIVE RELATIONSHIPS
Goldwater (1964) emphasized the importance of "host factors" in deter-
mining human exposure to mercury vapor. He warned that "undue preoccupation
with an agent (i.e., inhaled mercury vapor) or the environment to the exclusion
of interest in the host may retard progress in unravelling some of the mysteries
about the effects of mercury vapor on man." He noted that, in any individual
case, there was not likely to be a correlation between mercury content (of
blood and urine) and clinical evidence of poisoning. He noted Zbinden's list
of seven unrelated factors which could affect the outcome of animal toxicity
experiments, namely: diet, sex, age, spontaneous diseases, environment, heredity
and endocrine status. Of these, genetic factors have already been discussed in
determining nephrotoxicity of mercury vapor. In general, these host factors
have not been explored either epidemiologically or experimentally.
However, it should be noted that the potential of these seven "unrelated
factors" in affecting an individual's response to mercury must be viewed in
regard to the fact that dose-response relationships in humans have been
demonstrated for mercury vapor and methyl mercury compounds. These unrelated
factors are not so confounding as to completely undermine estimates of risks
from known exposures or levels of mercury in indicator media, at least on the
group basis, nor is there evidence to indicate that mercury toxicity is more
influenced by these "host factors" than other toxicants.
5.3.1 Inhaled Mercury Vapor Versus Other Forms of Mercury
The central nervous system is the principal target tissue for both inhaled
mercury vapor and ingested methyl mercury compounds. These are the two forms
5-17
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of mercury to which human populations are principally exposed. Unfortunately,
no studies have been reported on the effects of exposure to both forms of
mercury. From a biochemical viewpoint, additive interaction between these two
forms of mercury is, at least, a theoretical possibility as evidenced by the
intensive neurophysiological and neuropsychological studies conducted by Vroom
and Greer (1972) on nine thermometer workers. These workers showed typical
signs and symptoms of mercurial ism that led the authors to conclude that
"severe inorganic mercury poisoning may produce many of the abnormalities
associated with organic mercury poisoning". Vroom and Greer noted that memory
loss, tremor, rigidity, and truncal unsteadiness were common to both forms of
poisoning, suggesting that the same areas of the brain (the cerebellum and
temporal lobes) may be affected when exposed to the different forms of mercury.
However, it should also be noted that in the early stages of poisoning, the
effects of mercury vapor and of methyl mercury are not similar.
Both inhaled mercury vapor and methyl mercury are transformed to divalent
inorganic mercury (Hg ) in mammalian tissues. It is possible, but not proven,
++
that Hg may be the proximate toxic species to the central nervous system for
both forms of mercury (for discussion, see Clarkson, 1983; Shamoo, 1982).
5.3.2 Other Factors Affecting the Toxicity of Inhaled Vapor
The previous section has described the effects of moderate doses of
ethanol on the metabolism of inhaled mercury vapor. One effect is that indivi-
duals who have ingested ethanol retain substantially less inhaled mercury
vapor. On the other hand, ethanol allows dissolved mercury vapor to persist
in plasma for longer periods of time and, therefore, the potential of mercury
vapor to penetrate the central nervous system increases. Indeed, Hamilton
(1925) noted that alcoholism greatly favored the development of tremor and
that no total abstainer ever suffered from tremor in the severe form.
The interaction of inhaled mercury vapor with selenium compounds in the
body may also possibly affect the toxicity of mercury vapor. In autopsy
tissue from mercury miners in Idria (Yugoslavia), it was noted that the atomic
ratio of mercury to selenium was constant at a value of 1:1 (Kostial et al.,
1975). Tubbs et al. (1982) noted an association between mercury and selenium
in tubular epithelial phagolysosomes in nephrotic kidneys of individuals
exposed to mercury vapor.
5'18
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5.4 SUMMARY
The toxic effects of mercury and its compounds depend upon the chemical
form of mercury. The four major forms of mercury to which humans are exposed
are mercury vapor, compounds of methyl mercury, inorganic divalent mercury,
and phenylmercury. Each of these four major chemical classes of mercury
elicits characteristic toxic effects.
Mercury vapor primarily damages the nervous system, but effects are seen,
depending on the doses, on the oral mucosa and on the kidneys. Effects on the
nervous system are manifested as tremor and erethism. Some of the earliest
effects seen are deficits in short-term memory and introversion. The peripheral
nervous system may also be involved, as evidenced by electromyographic changes.
The effects on the nervous system are usually reversible, especially those on
motor functions. The more insidiously developing cognitive decrements and
emotional alterations may be the most harmful in light of current exposures
in the workplace.
Mercury vapor can elicit the nephrotic syndrome characterized by excess
loss of protein (mainly albumin) in the urine and edema. Differences in indi-
vidual susceptibility appear to be great. Lower levels of exposure to mercury
vapor are associated with mild proteinuria and enzymeuria which are reversible.
Limited information is available on the effects of mercury vapor on the
early stages of the human life cycle. One report in the foreign literature
(Mishonova et al., 1980) reported effects on pregnancy and parturition in women
occupationally exposed to mercury vapor; insufficient detail was available to
evaluate dose-response-relationships.
Inorganic divalent mercury compounds are corrosive poisons; acute single
doses can cause death by kidney failure and systemic shock. Little information
is available on the chronic effects of inorganic mercury compounds in humans.
Occupational exposure to mercuric oxide has been shown to damage the peripheral
nervous system and to produce effects somewhat similar to amyotrophic lateral
sclerosis; however, these effects are reversible. Exposure to inorganic diva-
lent mercury compounds has been noted to produce acrodynia (Pink's disease) in
children.
Methyl mercury compounds mainly damage the nervous system. In human
adults, the damage is selective to certain areas of the brain concerned with
sensory and coordination functions, particularly neurons in the visual cortex
and granular cells of the cerebellum. Effects such as constricted visual
5-19
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fields and ataxia appear to have a latent period of weeks to months. Such
effects are usually irreversible. The first effect usually noted is a subjec-
tive complaint of paresthesia in the extremities and in the circum-oral region.
Paresthesias may or may not be irreversible. The peripheral nervous system
may also be affected, especially at high doses, but usually after effects have
already appeared in the central nervous system.
The prenatal stage is the most susceptible stage of the human life cycle
to methyl mercury exposure. Severe effects, such as cerebral palsy, may be
seen in the offspring from mothers whose effects have been minimal or absent.
The milder effects seen at lower exposures are psychomotor retardation. All
prenatal effects that have been followed to date are irreversible.
Despite widespread use of phenylmercury compounds, little is known about
their human toxicology. Liver damage has been reported after occupational
exposure. These compounds are rapidly metabolized to inorganic mercury in the
body. This may explain why they produce similar effects such as acrodynia in
children and mild kidney damage in experimental animals. It is not known
whether phenylmercury compounds produce prenatal effects in humans.
Generally speaking, mercury and its compounds are not mutagenic. Despite
widespread and long-term human exposures, no carcinogenic actions have been
reported.
5-20
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6. HUMAN HEALTH RISK ASSESSMENT OF MERCURY IN AIR
6.1 AGGREGATE HUMAN INTAKE
The estimates of human intake and retention of mercury and its compounds
presented in this chapter are based on levels of mercury in air, water, and
food discussed in Chapter 3 and on the efficiencies of pulmonary or gastro-
intestinal absorption presented in Chapter 4. These estimates are summarized
in Table 6-1 and are discussed in more detail below.
TABLE 6-1. ESTIMATED AVERAGE DAILY INTAKE (RETENTION) OF MERCURY COMPOUNDS
IN THE U.S. POPULATION NOT OCCUPATIONALLY EXPOSED TO MERCURY
Exposure Estimated mean daily intake, ng Hg/day (retention)
Compounds of Mercury
Mercury vapor Inorganic Methyl
Atmosphere
Food
Fish
Non-fish
Drinking water
120(96)
38(30)
940(94)
20,000(2000)
50(5)
34(27)
3760(3572)
Total
120(96)
20,978(2124)
3794(3599)
For assumptions underlying the calculations of average daily intake and
retention, see text. The numbers in parentheses represent the estimated
amount retained in the body of an adult.
6.1.1 Inhaled Mercury Vapor
Evidence was presented in Section 3.3.1 that background levels of total
3
mercury in the Northern Hemisphere are 2 ng Hg/m . Regionally polluted rural
3
areas often lie between 3 and 4 ng Hg/m and urban areas may have average concen-
trations as high as 10 ng Hg/m . Rarely will mercury concentrations exceed
3
average values of 50 ng Hg/m . For purposes of calculation, the average
atmospheric level of total mercury to which humans are exposed is assumed to
3
be 10 ng Hg/m . Unfortunately, there is considerable uncertainty with regard to
qualitative speciation of mercury in the atmosphere, although it is generally
accepted that the major fraction is in the form of mercury vapor. While
recognizing the possible limitations of the Johnson and Braman (1974) data
6-1
-------
(see Section 3.3.1), it is, nevertheless, possible to calculate daily air
intakes from these data. Assuming that 60 percent of mercury in the atmosphere
is in the form of vapor, 19 percent is inorganic ionic mercury, and 17 percent
3
is methyl mercury compounds, and assuming a daily ventilation rate of 20 m
for the average adult and 80 percent retention of all forms of mercury, various
air intakes can be derived for different mercury species (Table 6-1). Because
particulate matter accounts for such a small percentage of total atmospheric
mercury (4 percent), intake calculations for this form of mercury have not
been included in Table 6-1.
6.1.2 Other Forms of Mercury
In Section 3.3.3 average human intake of total mercury from drinking
water was calculated to be approximately 50 ng/day. This figure was based on
the review by Fitzgerald (1979) that reported average concentrations of 25 ng
Hg/£ in drinking water. Assuming that the average consumption in adults is
2 £/day and assuming that gastrointestinal absorption is around 10 percent
(see Section 3.3.3), the estimated daily retention of mercury from drinking
water is approximately 5 ng (Table 6-1). This value may be overestimated,
however, in light of the most recent review by Jernelov et al. (1983), which
states that data from freshwater studies in Sweden suggest that the true
average of mercury in water is less than 25 ng/£ and may be as low as 3 ng/£.
Most reports indicate that the proportion of methyl mercury in samples
from bodies of natural water is very small, frequently beyond the limit of
detection (Brouzes et al., 1977). It is not known to what extent the findings
of a recent report (Kudo et al., 1982), that 30 percent of mercury in water is
methyl mercury, apply to mercury in drinking water. The figures reported in
Table 6-1 are based on the assumption that all mercury in drinking water is in
the form of Hg (for further discussion, see Section 3.3.3).
In Section 3.3.4 average human intake of mercury from various food
sources is discussed in greater detail. The food figures reported in Table
6-1 are based on data presented in Table 3-2 in Chapter 3. An estimate was
made of the total mercury intake from fish and seafood and this number was
divided by the total number of fish consumers to yield an average daily intake
of 4.7 \jg Hg for an adult fish consumer living in the United States. The esti-
mates presented in Table 6-1 are based on the assumption that 80 percent of the
total mercury in edible fish and seafood tissues is in the form of methyl mercury
compounds and that the remainder is as inorganic mercury compounds. Of these
6-2
-------
compounds, 95 percent of the methyl mercury and 10 percent of the inorganic mer-
cury is absorbed and retained.
Non-fish food items are assumed to contain an average mercury concentra-
tion of 10 ng Hg/g fresh weight, all in the form of inorganic mercury compounds
(see Section 3.3.4). The retention of inorganic mercury is assumed to be 10 per-
cent of the amount ingested in food. Assuming that a standard 70-kg adult con-
sumes 2 kg of food per day, total daily intake of inorganic mercury is estimated
as 20,000 ng Hg and total retention as 2000 ng Hg (Table 6-1). It should be noted
that this calculation is subject to large error as the "background" level of
mercury in non-fish food items (here assumed to be 10 ng/g) is frequently below
the limit of detection.
The total average daily intake of all forms of mercury (methyl mercury and
inorganic) from food, given in Table 6-1, may be estimated to be 24.7 (jg
(20,000 + 940 ng Hg as inorganic mercury and 3760 ng Hg as methyl mercury).
This may be compared with a figure of 13 ug Hg calculated as the average daily
intake of total mercury in food for the population of Belgium (Fouassin and
Fondu, 1978). Fouassin and Fondu based their measurement of total mercury on
2500 samples of various food items and on food production figures and import and
export statistics for Belgium. Buchet and co-workers (1983) made direct measure-
ments of mercury intake from food and beverages by analyzing mercury in one
hundred and twenty four daily meals collected in three areas of Belgium. The
median total mercury intake from food was 6.5 |jg. The distribution was not
normally distributed since the arithmetic average was 13 (jg/day. Two diets
exceeded the FAO/WHO (1972) tolerable provisional weekly intake of 5 pg/kg body
weight (i.e., 50 ng Hg/day for a 70-kg adult) with values of 80 and 497 pg kg/day.
As presented in Table 6-1, the average daily intake of total mercury from
fish and seafood is 4.7 (jg Hg (940 ng Hg as inorganic mercury and 3760 ng Hg as
methyl mercury). Fouassin and Fondu (1978) estimated the average daily intake of
total mercury from fish in the Belgian population to be 2.9 ug Hg, Bernhard and
Andreae (1984) estimated the average worldwide intake from seafood to be 2 ug
Hg/day, and Clarkson and Shapiro (1971) presented calculations indicating the
intake of methyl mercury by U.S. adults to be 3 pg Hg/day.
A number of conclusions about atmospheric mercury may be drawn from Table
6-1: (1) atmospheric mercury accounts for approximately 6 percent of the
total amount of mercury retained each day, (2) it accounts for all the mercury
6-3
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vapor retained each day, and (3) it accounts for approximately 2 percent of
the methyl mercury retained each day. From these conclusions, it is reasonable
to assume that direct inhalation of normal levels of mercury in air should not
make a significant contribution to overall human body burden. The biological
half-time of inorganic mercury in man is, if anything, somewhat shorter than
that of methyl mercury (for details, see Chapter 4). Even assuming that all
mercury in air were in the form of methyl mercury, the contribution of intake
from food (fish) would still be the determining factor in accumulated body
burden.
6.2 SIGNIFICANT HEALTH EFFECTS
6.2.1 Inhaled Mercury Vapor
Evidence reviewed in Chapter 5 indicates that most of the significant
health effects of inhaled mercury vapor arise mainly from the action of the
vapor on the nervous system. These effects may be classified according to
their severity. The mild effects, which are non-specific, consist of emotional
alterations, such as introversion and anxiety, and cognitive changes, such as
short-term memory loss. Neurological signs, such as slight tremors, may also
be present. Moderate effects, which may be partly debilitating, include
pronounced tremors which begin at peripheral parts of the body, such as fingers,
eyelids, and lips. Psychological disturbances, such as anxiety and memory
loss, also become more pronounced, and gums may become sore. As effects
become more severe, the peripheral nerves may be affected. In severe cases,
delusion and hallucinations occur accompanied by excessive secretion of saliva,
which may amount to 1 liter per day. A general tremor develops throughout the
whole body with violent chronic spasms occurring in the extremities.
Effects on kidney function are important to individuals who are suscepti-
ble to this form of damage. The nephrotic syndrome is a serious but usually
reversible health effect (see Section 5.1.2). Preclinical effects such as
urinary excretion of abnormal amounts of large molecular protein, but without
a fully developed nephrotic syndrome, may serve as an early warning sign.
More studies are needed on this topic.
Some degree of recovery usually takes place after poisoning from mercury
vapor. Motor effects, such as tremor, disappear more rapidly than the psycho-
logical effects. Very severe cases result in long-term damage to the nervous
system. Baldi et al. (1953) monitored 135 cases of mercury poisoning for
6-4
-------
several years and found that only 69 improved, whereas 33 were unchanged, 28
deteriorated, and 5 died of other illnesses.
Most cases of nephrotic syndrome due to mercury poisoning gradually
recover after cessation of exposure.
6.2.2 Compounds of Inorganic Mercury
Data on effects of chronic exposure to inorganic mercurial compounds are
scarce. Case reports of oral intake of mercurous compounds indicate effects
are the same as those reported for inhalation of mercury, with damage occurring
primarily to the nervous system and the kidneys.
Acrodynia is a serious but reversible effect seen in children exposed to
inorganic mercury and those organic compounds of mercury that rapidly break
down to inorganic mercury in mammalian tissues, e.g., phenylmercury compounds
(for details, see Section 5.2).
6.2.3 Methyl Mercury Compounds
Methyl mercury and other short-chain alkyl mercurials primarily damage
the central nervous system. A range of significant health effects are produced.
Mild effects are paresthesias of the extremities and circumoral areas, malaise,
and blurred vision. Moderate effects include bilateral constriction of the
visual fields, dysarthria, ataxia and diminished hearing. Severe cases suffer
from mental derangement, coma, and complete loss of vision and hearing. The
earliest effects may be reversible, although the literature evidence is conflic-
ting on this point. The moderate and severe effects are essentially irreversi-
ble, as they result from destruction of neuronal cells in the brain. The
prenatal developing central nervous system is more sensitive to methyl mercury
than the mature system. Mild but significant health effects include delayed
achievement of developmental milestones, seizures, and mild neurological
signs. More serious effects resemble cerebral palsy and are irreversible.
6.3 DOSE-RESPONSE AND DOSE-EFFECT RELATIONSHIPS
6.3.1 Inhaled Mercury Vapor
6.3.1.1 Indices of Exposure—Urine is the most frequently used indicator medium
for exposures to mercury vapor, as well as to inorganic mercury compounds, phenyl-
mercury, and other organic mercury compounds that rapidly break down in the body
to inorganic mercury. In a study sponsored by the World Health Organization and
6-5
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summarized by Goldwater (1972), some 1107 urine samples from fifteen countries
were analyzed for mercury by the method of Jacobs et al. (1961). These samples,
collected from individuals with no known exposures (either occupational or
other deliberate exposures to mercury), were found to contain mercury below
the limit of detection (0.5 ug Hg/1) in 78 percent, below 5 ug Hg/1 in 86
percent, below 10 ug Hg/1 in 89 percent and below 20 (jg Hg/1 in 95 percent of
all samples tested. More recent reports on "control groups" in occupational
and epidemiological studies confirm these findings.
The health effects of mercury vapor are almost certainly due to inhalation,
although some skin absorption may occur. Under steady-state conditions, one
would expect to see linear relationships between mercury levels in air and
concentrations in indicator media such as blood and, particularly, urine.
Indeed, Smith et al. (1970) have published graphs (Figures 6-1, 6-2, and 6-3)
indicating that blood and urine concentrations of workers exposed for many
years are linearly proportional to time-weighted average air concentrations of
mercury vapor. The data on blood-versus-air concentrations (Figure 6-1)
indicate that steady-state blood levels will increase by about 49 ng Hg/ml for
3
each 100 ug/m increase in the air concentration. The data on urinary mercury
concentrations indicate that they are also linearly related to time-weighted
average air concentrations; however, the slope of the line relating urine to
air concentrations depends upon how the urinary mercury concentrations are
expressed. Thus, uncorrected urine concentrations have the flattest slopes
indicating that for every 100 ug/m increase in mercury air concentrations,
the urine concentration would increase about 200 pg/1 (Figure 6-2). If urinary
concentrations are corrected to a specific gravity of 1.024, the proportional
3
increase in urinary concentration would be about 300 ug/1 for every 100 ug/m
increase in mercury air concentration (Figure 6-3). The latter value is
similar to other values reported in the literature.
Lundgren et al. (1967) and Hernberg and Hassanon (1971) also reported
relationships between mercury in blood and mercury in urine. These relation-
ships may be combined with the blood level versus air concentrations reported
by Smith et al. (1970) to predict that the urinary concentration of mercury
3
will increase approximately 300 ug/1 for every 100 ug/m increase in time-
weighted average air concentration.
The above relationships were based upon the measurement of air concentra-
tions using static samplers. Henderson (1973) was the first to report quanti-
tative differences in mercury concentrations in the general working environment
6-6
-------
20
_ 15
E
§
a>
3.
di
I
Q
O
00
10
I
I
0.05 0.10 0.15 0.20 0.25 0.30
Hg AIR LEVELS (mg/m3), time-weighted averages
0.35
Figure 6-1. Relation of concentration of mercury in blood to the
corresponding time-weighted average exposure levels.
Source: Smith et al. (1970).
6-7
-------
1.00
q
C/3
-2 .75
T3
9)
o
u
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.E
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x
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to
o
+*
•o
£
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o
u
~5>
X
.50
.25
I
0.05 0.10 0.15 0.20 0.25 0.30
Hg AIR LEVELS (mg/m3), time-weighted averages
0.35
Figure 6-2. Concentrations of mercury in urine (uncorrected for
specific gravity) in relation to time-weighted average exposure
levels.
Source: Smith et al. (1970).
1.00
.75
.50
.25
I
0.05 0.10 0.15 0.20 0.25
Hg AIR LEVELS (mg/m3), time-weighted averages
0.30
Figure 6-3. Concentrations of mercury in urine (corrected to
specific gravity of 1.024) in relation to time-weighted average
exposure levels.
Source: Smith et al. (1970).
6-8
-------
compared to the "microenvironment" in the breathing zone of the individual
worker. This was confirmed by Stopford et al. (1978), who noted that breathing
zone samples may average several-fold higher in concentration than concurrent
area samples, reflecting a "microenvironmental" contribution of exposure to
mercury vapor, presumably from contaminated clothing and hands. Thus, several
3
reports have found that when personal samplers are used, a 100 pg/m increase
in air concentration is associated with an increase in urinary concentration
of 100 ug/1 (Bell et al., 1973b), 130 pg/1 (Berode et al., 1980), or 160 ug/1
(Lindstedt et al., 1979), all of which are considerably lower than the increase
of 300 ug Hg/1 urine based on area (static sampling) levels of mercury.
Recently, a report by Schuckmann (1981) has indicated that, by intensify-
ing compliance with personal hygiene and safety regulations and by improving
technology of production in the factory, static samplers can approach the
ratio of air-to-urine concentrations as observed by use of personal samplers.
These presumed steady-state relationships noted above have been based on
observations on groups of workers. However, high individual variation and
great fluctuations from day to day have been reported in individual workers
under similar conditions of exposure (Ladd et al., 1963; Jacobs et al. 1964).
Indeed, Copplestone and McArthur (1967) found no correlation between urinary
concentrations and air concentrations. Their own findings and their reviews
of previous publications (Jacobs et al., 1964; Neal et al., 1941) led them to
propose that "mercurialism might be due to an inability to excrete absorbed
mercury rather than simply due to exposure." However, subsequent studies
reviewed above have not generally supported this viewpoint.
Wallis and Barber (1982) reported on the individual variability of mercury
concentrations in 146 spot urine samples collected from a total of 10 men and
10 women who were occupationally exposed to mercury vapor (Figure 6-4). In
this figure, the normalized values (concentration in spot urine sample divided
by the 24-hour excretion) are plotted according to the 24-hour excretion rate for
each individual worker. It may be seen that a wide range of normalized concen-
trations is found in spot samples collected on the same day for each individual
and that there is no relationship between these normalized concentrations and
the 24-hour excretion rate. Wall is and Barber (1982) also reported that correct-
ing the concentration for specific gravity significantly reduced the variance in
daily spot urine samples. The first sample collected after a night's rest was
more representative of the composites of all spot samples collected on one day
6-9
-------
O)
E
0
o>
- NO CORRECTION
N
A
o
B
S
RH
I 6 I
I
0.100
0.200
0.300
0.400
O. mg
Figure 6-4. The normalized concentration of urinary
mercury concentration versus the 24-hour mercury
excretion.
Source: Wallis and Barber (1982).
6-10
-------
than spot samples collected at other times. This can probably be attributed
to the fact that the first spot sample of the morning typically represents a
collection of from si* to eight hours as compared to only two to four hours
from other spot samples. Similar observations have been made by Piotrowski
et al. (1975). In a follow-up publication, Barber and Wall is (1984) noted
that correction of concentrations of mercury in spot urine samples for specific
gravity or osmolality reduced the variability to about the same extent and
that correction for creatinine was the most effective in reducing this varia-
bility.
Short-term (non-steady-state) exposures may not show consistent relation-
ships to indices of exposure. Mercury clearance from blood is described by
several exponentials. After a single dose, over 50 percent of the mercury is
cleared with*a half-time of a few days. A component with a half-time of about
20-30 days accounts for about 10 percent of total mercury in blood (for details,
see Chapter 4). Thus, under non-steady-state conditions, blood levels of
mercury may represent recent exposure.
Similarly, the relationship between urinary concentrations and air levels
will be difficult to predict under circumstances of non-steady-state conditions.
Piotrowski et al. (1975) reported that urinary concentrations fell according
to a two-exponential equation corresponding to half-times of 2 and 70 days in
workers whose exposures to mercury vapor had ceased. According to studies
carried out on volunteers receiving a tracer dose of mercury vapor, mercury in
urine is not directly related to blood concentrations but probably reflects
the kidney burden of mercury (Cherian et al., 1978).
Indeed, many factors other than non-steady-state conditions may contribute
to observed variability in urinary excretion of mercury. Roels et al. (1982)
have noted that workers who smoke have higher urinary mercury levels than
non-smoking workers under similar conditions of exposure. Other factors
contributing to the variability could be daily changes in urinary specific
gravity, problems with analytical methodology and volatilization of mercury
from urine (Magos et al., 1964), and the nature of the container (Greenwood and
Clarkson, 1970).
6.3.1.2. Effect and Dose-response Re1ationships-~Dose-effect and dose-response
relationships for human exposure to mercury vapor have been reviewed by a
number of expert groups (World Health Organization, 1976, 1980; Nordberg,
1976; U. S. Environmental Protection Agency, 1980, 1984). Some of these rela-
tionships are presented below.
6-11
-------
6.3.1.2 1 Effects on the nervous system. The largest study on human exposure
was published by Smith et at. (1970). This involved 642 workers from 21
chlor-alkali plants in the United States and Canada. Worker exposure to
mercury vapor, measured on a time-weighted average concentration in the working
environment, was compared to individual medical findings and to concentrations
of mercury in individual samples of blood and urine. The control group consis-
ted of 382 workers not occupationally exposed to mercury. Both control and
exposed groups had similar age distributions, smoking habits and alcohol
consumption patterns. The exposure-response relationship found in this study
is illustrated in Figure 6-5. A number of medical findings related to effects
on the nervous system and exhibited a statistically significant relationship
to exposure (Table 6-2), whereas many other medical findings (Table 6-3) did
not correlate with exposure to mercury. Most strongly related to excessive
exposure were the symptoms of loss of appetite and weight, insomnia, and other
indicators of early effects on the nervous system, such as tremors. The
authors stated there was no evidence of kidney or other organic injury.
Interestingly, no statistical correlation was found between exposure and
effects on the gums and teeth.
A dramatic increase in frequency of some symptoms and signs, such as loss
of appetite, weight loss, insomnia, and objective tremors, took place at the
3
highest time-weighted air concentrations (0.24 to 0.27 mg Hg/m ). It seems
unlikely that the prevalence of objective tremors was increased over the
control prevalence at air concentrations below 0.1 mg Hg/m , but such non-
specific symptoms as weight loss and loss of appetite, insomnia, and shyness
may have increased at the lowest levels. The dose-response relationship
depicted in Figure 6-5 does not exhibit any clear threshold.
Chaff in et al. (1973) conducted a study on 142 workers of which 75 had
currently been exposed to mercury vapor and 65 had previously been exposed.
Workers' urinary mercury levels were reported to range from less than 10 M9
Hg/1 to just above 1000 ug Hg/1. Workers were questioned about symptoms,
particularly those of irritability, sleep disturbance, anorexia and weight
loss. In addition, all workers' medical records were reviewed over previous
work periods (3 to 10 years) in order to detect significant changes in body
weight.
The authors reported that no significant weight changes occurred in any
of the workers during the study period under review and that the responses of
6-12
-------
en
t—*
OJ
70
60
50
40
30
20
10
85.2
92.6
TWA mg/m3
1 CONTROL
2-< .01-.05
3 .06-.10
4- .11-.14
5 .15-.27
Iff
123451234512345123451234512345123451234512345
INSOMNIA SHYNESS DIASTOLIC FREQ. OF HISTORY DIARRHEA
LOSS OF
APPETITE
WEIGHT
LOSS
OBJ.
TREMOR
DIASTOLIC
BLOOD
PRESS.
FREQ. OF
COLDS
HISTORY
NERV.
Figure 6-5. Percentage incidence of certain signs and symptoms related to exposure
of workers to mercury.
Source: Smith et al. (1970).
-------
TABLE 6-2. MEDICAL FINDINGS RELATED TO MERCURY EXPOSURE
(Based on dose-response relationship)
Findings
Loss of appetite
Weight loss
Objective tremors
Insomnia
Shyness
Diastol , blood pres.
Frequent colds
Nervousness
Diarrhea
Alcohol consump.
Dizziness
Basis
Symptom
Symptom
Sign
Symptom
Symptom
Sign
Symptom
Symptom
Symptom
Symptom
Symptom
t-Value of
correlation
coefficient
19.55
16.51
7.06
6.98
4.54
-3.38
3.09
2.79
2.41
2.33
2.08
Significant
at
P-Level
0.001
0.001
0.001
0.001
0.001
0.001
0.001
0.005
0.020
0.020
0.040
Symptoms - subjective findings, reported by patient.
Signs - objective findings, measured by physician or laboratory.
Source: Smith et al. (1970).
6-14
-------
TABLE 6-3. MEDICAL FINDINGS NOT RELATED TO MERCURY EXPOSURE
(Based on dose-response relationship)
Findings
Palpitation
Oropharyngeal
W.B.C. count
Cardiopulm. illness
Subj. tremors
Neurological illness
Cough
Hematocrit
Abn. teeth-gums
Tooth decay
Heart trouble
Chest pain
Systol. blood pres.
Fatigue
Abn. EKG
Short breath
Sputum
Headache
Constipation
Anxiety
Abn. chest x-ray
Basis
Symptom
Symptom
Sign
Symptom
Symptom
Symptom
Symptom
Sign
Sign
Symptom
Symptom
Symptom
Sign
Symptom
Sign
Symptom
Symptom
Symptom
Symptom
Symptom
Sign
t-Value of
correlation
coefficient
1.96
1.83
-1.78
1.76
1.50
1.23
1.20
1.16
1.07
-0.92
-0.64
-0.53
-0.45
0.41
0.35
0.27
0.19
0.17
-0.17
0.16
--
Significant
at
P-Level
0.050
0.070
0.075
0.075
0.150
0.200
0.300
0.300
0.300
0.300
--
--
--
--
--
—
--
--
—
--
--
Source: Smith et al. (1970).
6-15
-------
the workers to questions about symptoms failed to confirm the findings of
Smith and co-workers (1970). It should be noted, however, that there were no
identifiable controls in this study. Also, "current" blood and urine mercury
concentrations were used as independent variables in the exposure analysis and
those variables were noted to vary "a great deal from month to month."
Trachtenberg (1969) reported an increased prevalence of a syndrome defined
as a combination of insomnia, sweating, and emotional lability in workers
exposed to air concentrations in the range of 0.01 to 0.05 mg Hg/m as compared
to a control group with exposures less than 0.01 mg Hg/m . However, ambient
temperatures in the working areas of exposed versus control groups were not
identical and no details were given as to the selection and evaluation of
these workers. In support of Trachtenberg1s findings, Bidstrup et al. (1951)
and Turrian et al. (1956) reported that certain psychological disturbances may
occur at air concentrations below 0.1 mg Hg/m .
It should be noted that there is no evidence that either Trachtenberg
(1969), Bidstrup et al. (1951), or Turrian et al. (1956) measured the concen-
trations of mercury vapor in the microenvironment of the workers; nor did they
measure the possible continuing exposure beyond work hours from contaminated
skin, hair, clothing, and smoking materials.
Electromyographic, neuromuscular, and psychomotor tests have been conduc-
ted on workers exposed to mercury in the chlor-alkali industry (Chaffin et
al., 1973; Miller et al., 1975; Langolf et al. , 1977; 1978; and Schuckmann,
1979). Miller et al. (1975) found a relationship between the mean frequency
of tremor and urinary mercury concentrations, indicating effects at urinary
mercury concentrations as low as 100 ug/1. Conversely, Langolf et al. (1977;
1978), using power spectral analysis, were unable to detect tremor effects at
urinary concentrations below 500 ug/1. Schuckmann (1979) was unable to find
psychomotor activity changes in a group of 39 workers exposed to mercury vapor
in a chlor-alkali plant. The mean urinary mercury concentration of the workers
was 108 ug/1 in 1977, but in the period 1974-1976 it was 116 ug/1, with 8 percent
of the workers between 350 and 525 ug/1 and another 8 percent over 525 ug/1.
More recently, Roels et al. (1982) reported on the results of psychomotor
tests on 43 workers exposed to mercury and on 47 control workers matched for
age, socioeconomic status and job characteristics. The groups had similar
smoking and alcohol consumption characteristics. Two psychomotor tests were
used: one for testing eye-hand coordination (the orthokinesimeter test) and
6-16
-------
the other for testing arm-hand steadiness (the hole tremormeter test). No
clear-cut dose-response relationship could be established between abnormal
responses on these tests and concentrations of mercury in samples of blood and
urine. However, although statistically not significant, there was a tendency
for an increase of preclinical alterations for eye-hand coordination and arm
steadiness at blood levels between 10 to 20 ng Hg/ml and urinary excretion
rates greater than 50 ug Hg/g creatinine.
Thus, the studies using specific psychomotor tests are in agreement that
effects are clearly evident at urine concentrations of 500 ug/1, and some of
these studies suggest effects down to urine values of 100 ug/1 (Miller et al.,
1975; Reels et al. , 1982). Using the conversion factor discussed in Section
6.3.1.1, urine values of 500 and 100 ug/1 would correspond to time-weighted
average air concentrations, as measured by static sampler, of 0.05 to
3
0.20 mg Hg/m , respectively. These studies taken as a whole do not identify a
threshold urine value below which there are no effects on psychomotor function.
Short-term measurements of total mercury in spot urine samples may not be
adequate to identify a threshold for effects on psychomotor function. More
studies are needed where time-weighted air and urinary concentrations are used
as these indicators may give a better estimate of mercury exposure and, therefore,
a better estimate of levels of mercury in the nervous system.
6.3.1.2.2 Effects on kidney function. Buchet et al. (1980) have described
dose-response relationships for preclinical effects of mercury on kidney
function. Their study group consisted of 63 workers from two chlor-alkali
plants. The control group (88 workers) was judged by the plant physician to
have no occupational exposure to mercury and to have urinary excretion of
mercury and other toxic metals (Cd and Pb) in the normal range of a non-exposed
population (mercury in urine less than 5 ug Hg/g creatinine). A broad range
of clinical chemistry tests were performed on whole blood, plasma and urine to
assure similarity between the exposed and control groups. The groups were
similar with regard to age distribution and smoking habits. Alcohol consumption
was not mentioned. The effects of mercury on kidney function were followed by
measurement of a number of specific proteins in urine—total protein, albumin,
transferrin, IgG, p2-microglobulin and p-galactosidase. Abnormal excretion
was defined as that exceeding the upper 95-percent limit calculated from the
control group. The prevalence of abnormal urinary excretion rates did not
relate well with the blood concentrations of mercury, but the excretion of
6-17
-------
high molecular proteins did correlate with urinary mercury levels. This
relationship is depicted in Figure 6-6. The figure indicates that the fre-
quency of abnormal values of the high-molecular-weight protein (albumin)
increased with urine mercury concentrations above the background frequency
when urinary mercury excretion rose above 10-50 ug Hg/g creatinine. In con-
trast, no effects were seen in the excretion of the low-molecular-weight
protein, p2-microglobulin. Considering all the proteins that were measured,
the results of Buchet et al. (Figure 6-7) suggest that a detectable mercury
effect can be seen at urinary excretion rates exceeding 50 ug Hg/g creatinine.
However, it should be noted that Stonard et al. (1983) were unable to confirm
effects on albumin.
Roels et al. (1982) performed a similar study on 102 workers divided
equally into control and mercury vapor-exposed subjects. Again, the authors
found no effect on the excretion of low-molecular-weight proteins O2-micro-
globulin). No statistically significant effect was seen on urinary excretion
of albumin, but excretion of total protein was significantly affected. The
median urinary concentration for the mercury-exposed group was 71 ug Hg/g
creatinine and the upper 95 percentile level was 245 ug Hg/g creatinine. The
authors concluded that these findings were "in satisfactory agreement with
those previously reported" by Buchet et al. (1980). However, if anything, the
second study casts some doubt on the conclusion that effects were occurring at
urinary excretion rates as low as 50 ug Hg/g creatinine.
6.3.1.2.3 Other effects. Preclinical biochemical changes have been reported
in a study of 81 subjects exposed to mercury vapor in a chlor-alkali plant
(Foa et al. , 1976). The airborne mercury concentrations were in the range of
0.06 to 0.3 mg Hg/m . A number of lysosomal enzymes -- p-galactosidase,
p-glucosamidase, acetyl glucosamidase and p-glucosidase--were determined in
plasma. Workers in the highest exposed group (N=5, mean urinary mercury 158
ug/1) had significant elevations of three of these lysosomal enzymes. Only
p-glucosidase activity was unaffected. The same group of workers was subdivided
into four groups based on an index of integrated exposure (duration and inten-
sity). Highly statistically significant correlations were seen in these four
subgroups with regard to elevation of plasma lysosomal enzyme activity and the
integrated exposure index.
In a more recent study, Stonard et al. (1983) noted that abnormally high
urinary levels of two enzymes, N-acetyl-glucosaminidase and gama-glutamyl
6-18
-------
C on
o •*" i i I
§• O J32 MICROGLOBULIN
a A ALBUMIN
Z
O
0.
W
UJ
2 10
I
O —
0.5 1.0 5 10 50 100
URINARY MERCURY, Mg Hg/g CREATININE
Figure 6-6. Relationship between the percentage of abnormally
high urinary concentrations of (O)/32 microglobulin and (A)
albumin and average urinary excretion of mercury in 63
workers in two chloralkali plants and in 88 "control" workers.
The "controls" were judged not to have occupational exposure
to mercury vapor and the urinary excretion of mercury was less
than 5 ^g Hg/g creatinine. The straight lines were drawn accor-
ding to hockey stick analysis.
Source: Buchet et al. (1980).
6-19
-------
MERCURY IN URINE (M/g CREATININE)
NUMBER OF WORKERS
Hg-U (X, f^g/g creat)
Cd-U (X, /ug/g creat)
Pb-U (X, uglg creat)
Hg-B (X, Mg/100 ml)
Cd-B (X, M9/100 ml)
Pb-B (X, M9/100 ml)
<5
88
1.4
0.9
13.3
1.7
0.23
16.4
5-49.9
37
19.8
0.9
9.5
2.2
0.14
14.7
50-99.9
11
73.2
0.9
8.4
3.3
0.17
16.7
MOO
15
145.5
1.1
7.4
4.2
0.16
14.9
4U
30
0 20
H
U
Z
£ 10
Q
-* 0
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— -^ 3 3
?D rf A3
O ^
LU
CC „
Q. 20
10
0
'
^
=> a. D
(j O eT m m
^- ^^ ^^ ^v »v
55 • CD (o
^ ^ E 13 13
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6789 10 6789 10 6
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345 12345
40%
j
i n
La
f^ ^^
n
^ \
^
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—
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8 9 10 6 7 8 9 10
Figure 6-7. Relationship between mercury concentra-
tion in urine and the prevalence of signs of renal
dysfunction. The parameters are as follows; (1) total
proteinuria (Prot-U), (2) albumin-U (Alb-U), (3)
transferrin-U (Trans-U), (4) orosomucoid-U (Oroso-U), (5)
IgG-U, (6) /Vmicroglobulin-U (/?2-microglobulin
(/32-mic-U), (7) plasma 2-microglobulin (/32-mic-P), (8)
plasma creatinine (Creat-P), (9) alkaline phosphatase-U
(AP-U), (10) /?-galactosidaso-U (/3-galact-U).
Source: Buchet et al. (1980).
6-20
-------
transferase, become evident when urinary mercury exceeded 100 ug Hg/g creati-
nine.
6.3.1.2.4 Critique and summary. The studies reviewed above have attempted to
relate medical and preclinical findings to various measures of exposure and
dose, e.g., time-weighted average air concentrations or concentrations of
mercury in samples of blood or urine. As mentioned in Section 6.3.1.1, average
mercury concentrations in the working area may not represent true exposure
because the actual concentration inhaled may be affected by the workers'
"microenvironment," such as contaminated clothing and cigarette smoking,
transient exposures, or high concentrations of vapor in some phases of the
working activities. Intake of mercury vapor will be affected by changes in
lung ventilation rates.
Concentrations of mercury in samples of blood and urine may be of value
on a group basis for workers having long-term exposures. However, the relative
contributions of recent exposures to blood and urine concentrations compared
to the release of stored mercury in tissues resulting from earlier exposures
is not well understood.
Table 6-4 summarizes the information presented in Section 6.3.1.1 giving
a rough indication of the relationship between mercury exposure and health
effects. Objective tremors and probably other effects of mercury vapor are
3
likely to occur at air concentrations in excess of 250 ug/m , equivalent to
steady-state urinary values in the range of 750-1500 ug Hg/g creatinine.
Tremors, perhaps of less intensity and at lower prevalence, have occurred in
groups of workers exposed to air concentrations in the range of 100 to
3 3
250 |jg/m . Below 100 ug/m , the medical effects and their prevalence are less
well established. Probably non-specific symptoms are elevated above background
prevalence. No threshold air concentration and concentration in urine or
blood have been identified. A number of studies have raised the possibility
3
of preclinical effects at air concentrations below 50 ug/m . The clinical
significance of the findings of these studies is not fully evident. They do
raise the question as to which organ is first affected by mercury; the evidence
of high-molecular-weight proteins in urine suggest that glomerular function
may be first to be affected. Also, it is of interest that the finding of
elevated lysosomal enzyme activity in plasma is consistent with several experi-
mental studies on a variety of mercury compounds (Verity and Reith, 1967;
Norseth, 1967, 1969; Coonrod and Peterson, 1969; Norseth and Brendeford, 1971;
6-21
-------
Fowler, 1972; Lauwerys and Buchet, 1972). The tissue origin of these enzymes
is not known.
6.3.1.3 Factors Affecting the Dose-response Re1ationship--The dose-effect
relationships summarized in Table 6-4 are believed to apply to the general
population. However, the occurrence of nephrotic syndrome in a small fraction
of similarly exposed workers and experimental evidence indicating an immunolog-
ical mechanism operative in certain strains of rats suggest a genetic suscepti-
bility in certain individuals. Experiments on rats suggest that susceptible
individuals may be identified by examination of characteristics of the histo-
compatibility complex.
TABLE 6-4. A SUMMARY OF THE RELATIONSHIP BETWEEN OBSERVED EFFECTS AND
THE CONCENTRATION OF MERCURY IN AIR AND URINE
Mercury levels
Observed effects
Objective tremor
Objective tremor
and psychomotor tests
Non-specific symptoms
Frequency of
effect
High
Low
Low
Aira
pg/m3
250-500
100
50
Urine
|jg/g creatjinine
or |jg/l
750-1500
300b
150b
Preclinical plasma
lysosomal enzymes
Urinary proteins Low
50c
15-30C
150
50-100
The air concentrations measured by static air samplers are assumed to be a
time-weighted average assuming 40 hrs/week exposure.
""Calculated from the air concentrations as described in Section 6.3.1.1.
"Calculated from the urine value as described in Section 6.3.1.1. These air
concentrations would be time-weighted average values over sufficient periods
of time to allow urinary excretion rates to attain 50 to 100 (jg/gm
creatinine.
^Information on frequency is not available but the statistical significance
of the effect was high (Foa et al. , 1976).
6-22
-------
The relative sensitivity of different stages of the life cycle to mercury
vapor is not known. The developing mammal is not protected from exposure to
mercury vapor jm utero. Studies reviewed in Section 4.1 indicate that mercury
vapor readily crosses the placenta to be deposited in fetal tissues. Inhaled
mercury vapor may also lead to secretion of inorganic mercury in milk. Health
effect studies are incomplete with regard to prenatal exposure and exposure
through suckling milk (for discussion see Chapter 5).
Ethanol is known to affect the metabolism of inhaled mercury vapor (for
review, see Section 4.1.4.1). No reports are available on studies in animals
or humans which demonstrate the influence of ethanol on the toxicity of inhaled
mercury vapor. Based on the clinical evidence, Hamilton (1925) stated that
alcoholism greatly favors the development of mercurial tremor and that no real
abstainer has ever suffered from tremor in a severe form.
Many experimental studies have indicated a protective action of selenium
on the toxicity of various forms of mercury including inorganic mercury.
Unfortunately, no studies have been reported on interactions between selenium
and inhaled mercury vapor. Autopsy observations on mercury miners in Idria,
Yugoslavia, have found a correlation between mercury and selenium in tissues,
including the brain (Kostial et al., 1975).
Mercury is excreted in the sweat of workers exposed to mercury vapor
(Lovejoy et al., 1974). Anecdotal reports in the early literature claim that
profuse sweating may alleviate the symptoms of mercury vapor exposure. It is,
therefore, at least theoretically possible that temperature, humidity, physical
exertion and other factors that influence perspiration may also affect dose-
response relationships.
Even though there has been little work done on the relation of diet to
mercury exposure effects, dietary factors may be important. Theoretically, a
deficiency in sulfur-containing ami no acids would interfere with synthesis of
thioneine, one of the proteins to which mercury is bound. Drinking milk (a
good source of sulfur-containing ami no acids) during the work shift was believed
to reduce the effects of exposure to mercury by some chlor-alkali workers
(Henderson, personal communication).
6.3.2. Compounds of Inorganic Mercury
The effects of inorganic compounds of mercury arise mainly through oral
intake, especially in cases of acrodynia due to mercurous salts. The acute
6-23
-------
lethal dose of mercuric compounds is believed to be 1 to 4 grams in adult
subjects (Gleason et al., 1957). Long-term dose-effect relationships for this
class of mercury compounds are not known. Chronic oral ingestion of 250 mg
Hg.Cl_ results in adverse effects on the functions of both the nervous system
and kidneys.
Acrodynia appears to be an idiosyncratic response to inorganic mercury.
In children who are sensitive to contracting the syndrome, effects have been
seen at urinary concentrations as low as 50 ug Hg/1 (Warkany and Hubbard,
1948). According to Cheek (1980), roughly one in one thousand infants develops
acrodynia if exposed to inorganic mercury.
6.3.3 Methyl Mercury Compounds
6.3.3.1 Indices of Exposure—Blood and strands of head hair are indicator media
of choice for individuals suspected of exposure to methyl mercury compounds. In
the study sponsored by the World Health Organization, Goldwater (1972) summarized
the results of analysis of 812 blood samples obtained from non-exposed indivi-
duals in the same 15 countries used for the study of normal urine values (see
Section 6.3.1.1). The concentration of total mercury in samples of whole blood
were less than the detectable limit (0.5 ug Hg/1) in 77 percent, less than 1 ug
Hg/1 in 85 percent, and less than 3 ug Hg/1 in 95 percent of all the samples.
However, it should be noted that the concentration of total mercury in blood is
usually influenced by an individual's fish intake as fish and fish products are
a dominant source of methyl mercury in the diet. For example, in a study of
41 dieters eating tuna and swordfish, it was reported that 25 percent of the
group had average blood levels of 17 ug Hg/1 and the highest blood level was
in excess of 50 ug Hg/1 (McDuffie, 1973). Individuals living in areas almost
totally dependent on large carnivorous fish as the major source of protein may
have blood levels in excess of 200 ug Hg/1 (Turner et al., 1980).
As discussed in Chapter 4, methyl mercury is incorporated into human hair
and its concentration in hair is proportional to the concentration of methyl
mercury in blood at the time of formation of the hair. Concentrations of
mercury along the length of a hair strand reflect past blood levels of methyl
mercury -- one centimeter of hair corresponds to one month's growth and, there-
fore, the mercury concentration in one centimeter indicates the average blood
concentration for that month.
6-24
-------
This aspect of mercury accumulation in hair must be taken into account
when evaluating the numerous reports of mercury concentration in hair (U.S.
Environmental Protection Agency, 1979). Some authors report mercury concen-
tration for a specified length of hair, others for the entire length of the
hair strand. The situation is further complicated, as is the case of other
metals, by the possibility of external contamination and by the vagaries of
different washing procedures. A World Health Organization study reported a
mean level of total mercury in hair of 1 pg Hg/g (standard error = 0.4) in
963 individuals in rural Iraq who had no known exposure to mercury and had low
or no fish consumption (Kazantzis et a!., 1976). These findings agree with a
study on "normal" individuals in Canada having low fish consumptions (Perkons
and Jervis, 1966) and with a study of 119 males in the U.S. Navy (Gordus et
al., 1974). In both these studies, the average mercury concentrations in
hair were 1.5 pg Hg/g (range, 1.0 to 3.0 pg Hg/g) and 1.9 pg Hg/g (range not
given), respectively. Hair levels in normal subjects in Japan appear to be
generally higher than those in the United States with mean values of approxi-
mately 4 pg Hg/g (Yamaguchi and Matsumoto, 1968). As in the case of blood
concentrations, fish intake has an important influence on hair concentrations
of mercury. Individuals having unusually high dietary intakes of fish or
marine mammals may exceed values of 50 pg Hg/g in hair (Wheatley, 1979).
6.3.3.2 Effects and Dose-response Relationships—The effects of methyl mercury
compounds arise primarily through oral ingestion of contaminated fish or bread,
although a few cases of methyl mercury industrial poisoning have probably been
due to inhalation and skin absorption. Skin absorption, as a possible route of
methyl mercury exposure, has been noted in cases where methyl mercury was used
to treat fungal infections of the skin (WHO, 1976). Signs and symptoms of methyl
mercury poisoning are not affected by the route of intake, but characterizations
of dose-effect and dose-response relationships are available only for oral expo-
sures to adults and transplacental passage to the fetus.
Dose-effect and dose-response relationships for methyl mercury compounds
in man have been presented and evaluated previously (Bakir et al., 1973; World
Health Organization, 1976, 1980; Nordberg, 1976; U.S. Environmental Protection
Agency, 1980). The WHO Expert Group (World Health Organization, 1976, 1980)
concluded that a low prevalence (about 5 percent) of the population could pre-
sent with the earliest symptom of methyl mercury poisoning (paresthesia) at
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blood concentrations of methyl mercury in the range of 0.2 to 0.5 pg/1, corres-
ponding to hair concentrations in the range of 50 to 125 ug/g or to long-term
daily intakes of methyl mercury between 3 to 7 ug/kg body weight. Nordberg
and Strangert (1978), in a more recent analysis, calculated the expected
prevalence (risk) of paresthesia based on both data relating blood levels to
frequency of paresthesia (Bakir et al. , 1973) and data relating daily intake
to blood levels (Al-Shahristani and Shihab, 1974). For human adults, it was
calculated that a long-term daily intake of 200 jjg Hg as methyl mercury
(approximately 3-4 ug/kg body weight) would give rise to a risk of about
8 percent for symptoms of paresthesia. It was also calculated that a daily
intake of 50 ug/Hg as methyl mercury would give rise to a risk of about
0.3 percent, assuming that the threshold, if it exists, lies below this daily
intake.
Both epidemiological and experimental observations indicate that prenatal
life is the most sensitive stage of the life cycle to methyl mercury exposure.
Dose-response and dose-effect relationships have been published for the earli-
est (mildest) effects arising from prenatal exposure (Marsh et al. , 1980,
1981; Clarkson et al., 1980; Berlin, 1983). These data are still under evalua-
tion, but preliminary reports indicate that prenatal life is about three to
four times more sensitive than are adults.
6.3.4 Other Mercury Compounds
Phenylmercury compounds belong to a broad chemical class of aryl and
alkoxyaryl mercurials which have worldwide use as fungicides, contraceptive
spermicides, and disinfectants. Despite the fact that human exposure has been
extensive in the agricultural, paint, and pharmaceutical industries, quantita-
tive information on dose-effect relationships such as reported for mercury
vapor (Smith et al. , 1970; Buchet et al., 1980) and methyl mercury (Bakir et
al., 1973) has not been reported for this important class of organic compounds.
Goldwater (1973) found no evidence of toxicity in 13 workers employed for
11 to 23 years in the manufacture of phenylmercury. Exposure levels were not
reported, but urinary concentrations of mercury varied from 85 to 100 ug/1.
Cotter (1947) found liver damage in ten subjects exposed to phenylmercury
salts, but other substances may have been involved in the exposure. Renal
damage and intestinal complaints have been reported (Skerfving and Vostal,
1972). In general, there seems to be no difference in the toxicity of various
6-26
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phenylmercurials which have been studied. The symptoms, where noted, have
resembled those of inorganic mercury. According to clinical evidence (Biskind,
1933), phenylmercury compounds, when applied topographically to the skin, can
produce signs of toxicity. Delayed-type hypersensitivity has been reported
from skin contact with phenylmercury compounds (Mathews, 1968).
Phenylmercury acetate was widely used as a spermicidal contraceptive
administered vaginally in a gel. Enhanced urinary excretion of mercury was
believed to result from the vaginal absorption of phenylmercury, but no adverse
health effects have been reported from use of the contraceptive (Goldwater,
1973).
6.4 POPULATIONS AT RISK
With regard to the direct health effects of inhaled mercury vapor, the
special groups at risk are those occupationally exposed. Exposure, therefore,
to the adult human is in the workplace. Some of the people exposed are women
of childbearing age. The effect of prenatal exposures and exposure during the
suckling period has not been adequately investigated. Of special interest is
the group of female dental assistants exposed to mercury vapor through the use
of dental amalgams containing metallic mercury in dental fillings. An unknown
number of women of childbearing age are also exposed to mercury vapor in such
industries as thermometer manufacturing and industries where the calibration
of pipettes and the manufacture of other scientific instruments involves the
use of liquid metallic mercury. One report in the foreign literature (Mishonova
et al., 1980) reported effects on pregnancy and parturition in women occupa-
tional^ exposed to mercury vapor; insufficient detail was available to evaluate
dose-response relationships.
Homes of people occupationally exposed to mercury vapor may be liable to
contamination. This aspect of occupational exposure in industries using
liquid metallic mercury has not been well explored, but at least one report in
the literature (Danzinger and Possick, 1973) indicates that contamination of
the home can occur.
Specific segments of the general public may be at risk from methyl mercury
compounds especially pregnant ^omen, small children, and those who commonly
consume two or more times the national average of 15 pounds of fish per year.
As discussed in Chapter 5, it is at least theoretically possible that
exposures to both methyl mercury compounds and to mercury vapor may have
additive effects on the central nervous system. Epidemiological surveys have
6-27
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not yet been made to assess the probability of combined exposures to methyl
mercury in fish and seafood and the occupational exposure to mercury in women
of childbearing age. It would be highly desirable for the U.S. Environmental
Protection Agency and the Food and Drug Administration to coordinate their
efforts to determine the population(s) and relative degree of risk.
6.5 SUMMARY
Atmospheric mercury accounts for all the mercury vapor and approximately
2 percent of the methyl mercury retained each day. The diet, mainly fish and
fish products, accounts for most, 98 percent, of the daily retention of methyl
mercury. The diet also accounts for virtually all of the intake of inorganic
mercury compounds.
Time-weighted air concentrations are the usual means of assessing human
exposure to mercury vapor. Urine is the most frequently used indicator medium
to assess body burden after chronic exposure to mercury vapor. Long-term
2
exposure to 100 ug Hg/m , when measured by static samplers, is roughly equi-
valent to a urine concentration of 300 ug Hg/1. However, when measured by
o
personal samplers, 100 ug Hg/m is equivalent to about 100 ug Hg/1 of urine.
Approximately 95 percent of all urine samples are below 20 ug Hg/1 in people
who have had no known exposure to mercury. Mild proteinuria may occur in the
most sensitive adults at urine values between 50 and 100 ug Hg/1 following
chronic occupational exposures. Objective tremor and psychomotor disturbances
appear in sensitive individuals usually at urine values above 300 ug/1, but no
clear threshold has been established. The effects of mercury vapor usually
disappear within a few months after cessation of exposure. Despite the fact
that inhaled mercury vapor crosses the placenta, little information has been
published on the consequences of prenatal and perinatal exposures.
Blood and head hair are the most commonly used indicator media for body
burden of mercury after exposure to methyl mercury compounds. Levels of
methyl mercury in these media are influenced by fish consumption. For average
persons with low level fish consumption, approximately 95 percent have blood
levels below 3 ug Hg/1 and average hair values usually less than 2 ug Hg/g.
In individuals having unusually high fish intake, such as "weight watchers"
eating tuna and swordfish, blood levels may exceed 50 ug Hg/1. In the most
sensitive adults, the mild effects of methyl mercury, such as paresthesia, may
appear at blood levels of 200 ug Hg/1, which is equivalent to hair levels of
50 ug Hg/gm. More severe effects, such as constricted visual field and ataxia,
6-28
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appear at blood levels above 500 to 1000 ug Hg/1, equivalent to hair levels of
125 to 250 (jg Hg/g. The severe effects are irreversible; paresthesia may or
may not be irreversible.
Prenatal life is the most sensitive stage of the life cycle to methyl
mercury with the milder effects, such as psychomotor retardation, being asso-
ciated with maternal hair levels during pregnancy in the vicinity of 10-20 ug
Hg/gm. The most severe effects associated with maternal blood levels in excess
of 100 ug Hg/1 are cerebral palsy and microcephaly. All prenatal effects to
date have been found to be irreversible.
Possible effects due to chronic exposure to compounds of inorganic mercury
have been rarely reported. Occupational exposure to aerosols of mercuric oxide
may lead to signs and symptoms similar to the syndrome of amyotrophic lateral
sclerosis. These manifestations of mercuric oxide exposure are reversible upon
cessation. Dose-effect relationships have not been reported, but air concen-
trations associated with these effects are probably higher than those associated
with the earliest effects of mercury vapor.
Dose-effect relationships for phenylmercury compounds have not been
reported in humans. Occupational experience suggests that the human inhalation
toxicity of this class of organomercurials is less than that of mercury vapor.
Dietary intake studies in rodents yields evidence that these compounds are better
absorbed than inorganic mercury compounds and that the kidney is the target organ
as in the case of inorganic mercury. There is need for quantitative dose-response
data in humans on this class of organomercurials.
6-29
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